Luis E. Okamoto

Autoimmune Basis for Postural Tachycardia Syndrome

Background Patients with postural tachycardia syndrome (POTS) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS. We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors (AR). Methods and Results Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P<0.001) when coexisting β2AR dilative activity was blocked; and this was suppressed by α1AR blockade with prazosin. POTS sera acted as a partial α1AR antagonist significantly shifting phenylephrine contractility curves to the right. All POTS sera increased β1AR activation (130±3% of baseline, P<0.01) and a subset had increased β2AR activity versus healthy subjects. POTS sera shifted isoproterenol cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells. Conclusions POTS patients have elevated α1AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1AR for vasoconstriction and concurrent βAR‐mediated tachycardia. Coexisting β1AR and β2AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.

Nocturnal Blood Pressure Dipping in the Hypertension of Autonomic Failure

Blood pressure (BP) normally decreases during the night. Absence of this phenomenon (nondipping) is associated with increased cardiovascular risk. Altered autonomic and endocrine circadian rhythms are suspected to play a role. Patients with peripheral autonomic failure offer a unique opportunity to study this phenomenon, because ≈50% develop supine hypertension despite very low autonomic function. The purpose of this study was to define the prevalence of dipping in these patients and to determine whether dipping is associated with less severe autonomic impairment or exaggerated nocturnal sodium excretion. We collected BP and urine from 8:00 pm to 8:00 am in 41 peripheral autonomic failure patients with supine hypertension. Dipping (systolic BP fall ≥10% during 12 am to 6 am from baseline [8 pm to 10 pm]) occurred in 34% of patients, with an average decrease of −44±4 mm Hg at 4 am. Systolic BP, averaged from 12 am to 6 am, decreased to normotensive levels in 50% (n=7) of dippers and 15% (n=7) of nondippers. There were no significant differences in the severity of autonomic failure, nocturnal diuresis, or natriuresis (0.18±0.01 in dippers versus 0.18±0.01 mEq/mg of creatinine in nondippers; P=0.522) between groups. At 8:00 am, orthostatic hypotension was similar between groups (−84/−35±9/4 mm Hg in dippers versus −93/−39±6/3 mm Hg in nondippers; P=0.356 for systolic BP). In conclusion, dipping was observed in one third of patients with peripheral autonomic failure, so that a significant percentage of patients would not require treatment for supine hypertension. Dipping was not associated with increased nocturnal urinary sodium or volume excretion or less severe autonomic failure. Thus, mechanisms independent of autonomic pathways contribute to BP dipping in these patients.

Comparative Efficacy of Yohimbine Against Pyridostigmine for the Treatment of Orthostatic Hypotension in Autonomic Failure

Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the &agr;-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11±3 mm Hg [95% CI: 6 to 16 mm Hg]; P<0.001). On the contrary, pyridostigmine did not increase the standing diastolic BP (0.6±3 mm Hg [95% CI: −5 to 5 mm Hg]; P=0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension.

Renal Impairment of Pure Autonomic Failure

Supine hypertension is difficult to manage in patients with pure autonomic failure (PAF), because treatment can worsen orthostatic hypotension. Supine hypertension in PAF has been associated with left ventricular hypertrophy, but end organ damage in the kidney has not been assessed. We reviewed hemodynamic and laboratory data of 64 male patients with PAF who were 69±11 (mean±SD) years old. Systolic blood pressure fell by 67±40 mm Hg within 10 minutes of standing, with an inappropriately low 13±11-bpm increase in heart rate. Plasma norepinephrine levels were below normal (0.62±0.32 nmol/L supine and 1.28±1.25 nmol/L standing). A control data set of 75 men (67±12 years) was obtained from a deidentified version of the Vanderbilt University Medical Center electronic medical chart database. Compared with controls, PAF patients had lower hemoglobin (8.3±0.9 versus 9.3±0.8 mmol/L; P<0.001), packed cell volume (0.40±0.04 versus 0.45±0.04; P<0.001), and red blood cell count (4.4±0.5×1012 versus 5.0±0.5×1012 cells/L; P<0.001). Serum creatinine and blood urea nitrogen levels were elevated in patients. Forty-eight percent of patients with PAF had supine hypertension (supine systolic blood pressure: ≥150 mm Hg). Serum creatinine was higher in patients with supine hypertension (133±44 versus 106±27 &mgr;mol/L; P=0.021) and estimated glomerular filtration rate was lower (57±22 versus 70±20 mL/min per 1.73 m2; P=0.022) compared with patients who did not have supine hypertension. These findings may indicate that renal function is diminished in PAF in association with supine hypertension.

Angiotensin II, Independent of Plasma Renin Activity, Contributes to the Hypertension of Autonomic Failure

At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Although the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable, suggesting renin–angiotensin (Ang) pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that Ang II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating Ang II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/mL, n=11) compared with matched healthy controls (27±4 pg/mL, n=10; P=0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/mL per hour, respectively; P=0.449). To determine the contribution of Ang II to supine hypertension in these patients, we administered the AT1 receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mm Hg at 6 hours after administration (P<0.05), decreased nocturnal urinary sodium excretion (P=0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of captopril on supine blood pressure in a subset of these patients. These findings suggest that Ang II formation in autonomic failure is independent of plasma renin activity, and perhaps Ang-converting enzyme. Furthermore, these studies suggest that elevations in Ang II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT1 receptor blockers for treatment of these patients.

Efficacy of Atomoxetine Versus Midodrine for the Treatment of Orthostatic Hypotension in Autonomic Failure

The clinical presentation of autonomic failure is orthostatic hypotension. Severely affected patients require pharmacological treatment to prevent presyncopal symptoms or frank syncope. We previously reported in a proof of concept study that pediatric doses of the norepinephrine transporter blockade, atomoxetine, increases blood pressure in autonomic failure patients with residual sympathetic activity compared with placebo. Given that the sympathetic nervous system is maximally activated in the upright position, we hypothesized that atomoxetine would be superior to midodrine, a direct vasoconstrictor, in improving upright blood pressure and orthostatic hypotension–related symptoms. To test this hypothesis, we compared the effect of acute atomoxetine versus midodrine on upright systolic blood pressure and orthostatic symptom scores in 65 patients with severe autonomic failure. There were no differences in seated systolic blood pressure (means difference=0.3 mm Hg; 95% confidence [CI], −7.3 to 7.9; P=0.94). In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P=0.03) compared with midodrine. Furthermore, atomoxetine (means difference=0.4; 95% CI, 0.1 to 0.8; P=0.02), but not midodrine (means difference=0.5; 95% CI, −0.1 to 1.0; P=0.08), improved orthostatic hypotension–related symptoms as compared with placebo. The results of our study suggest that atomoxetine could be a superior therapeutic option than midodrine for the treatment of orthostatic hypotension in autonomic failure.

Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes

Several studies recognized an overlap between CFS (chronic fatigue syndrome) and POTS (postural tachycardia syndrome). We compared the autonomic and neurohormonal phenotype of POTS patients with CFS (CFS–POTS) to those without CFS (non-CFS–POTS), to determine whether CFS–POTS represents a unique clinical entity with a distinct pathophysiology. We recruited 58 patients with POTS, of which 47 were eligible to participate. A total of 93% of them reported severe fatigue [CIS (Checklist of Individual Strength), fatigue subscale >36], and 64% (n=30) fulfilled criteria for CFS (CFS–POTS). The prevalence of CFS symptoms (Centers for Disease Control and Prevention criteria) was greater in the CFS–POTS group, but the pattern of symptoms was similar in both groups. Physical functioning was low in both groups (RAND-36 Health Survey, 40±4 compared with 33±3; P=0.153), despite more severe fatigue in CFS–POTS patients (CIS fatigue subscale 51±1 compared with 43±3; P=0.016). CFS–POTS patients had greater orthostatic tachycardia than the non-CFS–POTS group (51±3 compared with 40±4 beats/min; P=0.030), greater low-frequency variability of BP (blood pressure; 6.3±0.7 compared with 4.8±1.0 mmHg2; P=0.019), greater BP recovery from early to late phase II of the Valsalva manoeuvre (18±3 compared with 11±2 mmHg; P=0.041) and a higher supine (1.5±0.2 compared with 1.0±0.3 ng/ml per·h; P=0.033) and upright (5.4±0.6 compared with 3.5±0.8 ng/ml per h; P=0.032) PRA (plasma renin activity). In conclusion, fatigue and CFS-defining symptoms are common in POTS patients. The majority of them met criteria for CFS. CFS–POTS patients have higher markers of sympathetic activation, but are part of the spectrum of POTS. Targeting this sympathetic activation should be considered in the treatment of these patients.

Pharmacotherapy of autonomic failure.

The clinical picture of autonomic failure is characterized by severe and disabling orthostatic hypotension. These disorders can develop as a result of damage of central neural pathways or peripheral autonomic nerves, caused either by a primary autonomic neurodegenerative disorder or secondary to systemic illness. Treatment should be focused on decreasing pre-syncopal symptoms instead of achieving blood pressure goals. Non-pharmacologic strategies such as physical counter-maneuvers, dietary changes (i.e. high salt diet, rapid water drinking or compression garments) are the first line therapy. Affected patients should be screened for co-morbid conditions such as post-prandial hypotension and supine hypertension that can worsen orthostatic hypotension if not treated. If symptoms are not controlled with these conservative measures the next step is to start pharmacological agents; these interventions should be aimed at increasing intravascular volume either by promoting water and salt retention (fludrocortisone) or by increasing red blood cell mass when anemia is present (recombinant erythropoietin). When pressor agents are needed, direct pressor agents (midodrine) or agents that potentiate sympathetic activity (atomoxetine, yohimbine, pyridostigmine) can be used. It is preferable to use short-acting pressor agents that can be taken on as needed basis in preparation for upright activities.

Low-dose propranolol and exercise capacity in postural tachycardia syndrome A randomized study

Objective: To determine the effect of low-dose propranolol on maximal exercise capacity in patients with postural tachycardia syndrome (POTS). Methods: We compared the effect of placebo vs a single low dose of propranolol (20 mg) on peak oxygen consumption (VO2max), an established measure of exercise capacity, in 11 patients with POTS and 7 healthy subjects in a randomized, double-blind study. Subjects exercised on a semirecumbent bicycle, with increasing intervals of resistance to maximal effort. Results: Maximal exercise capacity was similar between groups following placebo. Low-dose propranolol improved VO2max in patients with POTS (24.5 ± 0.7 placebo vs 27.6 ± 1.0 mL/min/kg propranolol; p = 0.024), but not healthy subjects. The increase in VO2max in POTS was associated with attenuated peak heart rate responses (142 ± 8 propranolol vs 165 ± 4 bpm placebo; p = 0.005) and improved stroke volume (81 ± 4 propranolol vs 67 ± 3 mL placebo; p = 0.013). In a separate cohort of POTS patients, neither high-dose propranolol (80 mg) nor metoprolol (100 mg) improved VO2max, despite similar lowering of heart rate. Conclusions: These findings suggest that nonselective β-blockade with propranolol, when used at the low doses frequently used for treatment of POTS, may provide a modest beneficial effect to improve heart rate control and exercise capacity. Classification of evidence: This study provides Class II evidence that a single low dose of propranolol (20 mg) as compared with placebo is useful in increasing maximum exercise capacity measured 1 hour after medication.

Synergistic Effect of Norepinephrine Transporter Blockade and α-2 Antagonism on Blood Pressure in Autonomic Failure

Patients with autonomic failure have disabling orthostatic hypotension because of impaired sympathetic activity. Norepinephrine transporter blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the &agr;-2 antagonist yohimbine would potentiate the pressor effect of norepinephrine transporter blockade with atomoxetine and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg or atomoxetine 18.0 mg, and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for ⩽10 minutes before and 1 hour postdrug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated systolic blood pressure and orthostatic tolerance (P<0.001 and P=0.016, respectively) in a synergistic manner. The maximal increase in seated systolic blood pressure seen with the combination was 31±33 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination of yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of norepinephrine in peripheral sympathetic neurons by &agr;-2 antagonism combined with a reduced norepinephrine clearance by norepinephrine transporter blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.