Bonnie K. Black

Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.

BACKGROUND Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the probands family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

The Neuropathic Postural Tachycardia Syndrome

BACKGROUND The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs. METHODS We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects. RESULTS At base line, the mean (+/-SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135+/-30 vs. 215+/-55 pg per milliliter [0.80+/-0.18 vs. 1.27+/-0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001+/-0.09 vs. 0.12+/-0.12 ng per minute per deciliter of tissue [0.006+/-0.53 vs. 0.71+/-0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02+/-0.07 vs. 0.23+/-0.17 ng per minute per deciliter [0.12+/-0.41 vs. 1.36+/-1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008+/-0.09 vs. 0.19+/-0.25 ng per minute per deciliter [0.05+/-0.53 vs. 1.12+/-1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04). CONCLUSIONS The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs.

The pressor response to water drinking in humans : a sympathetic reflex?

BACKGROUND Water drinking increases blood pressure profoundly in patients with autonomic failure and substantially in older control subjects. The mechanism that mediates this response is not known. METHODS AND RESULTS We studied the effect of drinking tap water on seated blood pressure in 47 patients with severe autonomic failure (28 multiple system atrophy [MSA], 19 pure autonomic failure patients [PAF]). Eleven older controls and 8 young controls served as control group. We also studied the mechanisms that could increase blood pressure with water drinking. Systolic blood pressure increased profoundly with water drinking, reaching a maximum of 33+/-5 mm Hg in MSA and 37+/-7 in PAF mm Hg after 30 to 35 minutes. The pressor response was greater in patients with more retained sympathetic function and was almost completely abolished by trimethaphan infusion. Systolic blood pressure increased by 11+/-2.4 mm Hg in elderly but not in young controls. Plasma norepinephrine increased in both groups. Plasma renin activity, vasopressin, and blood volume did not change in any group. CONCLUSIONS Water drinking significantly and rapidly raises sympathetic activity. Indeed, it raises plasma norepinephrine as much as such classic sympathetic stimuli as caffeine and nicotine. This effect profoundly increases blood pressure in autonomic failure patients, and this effect can be exploited to improve symptoms due to orthostatic hypotension. Water drinking also acutely raises blood pressure in older normal subjects. The pressor effect of oral water is an important yet unrecognized confounding factor in clinical studies of pressor agents and antihypertensive medications.

Effects of Volume Loading and Pressor Agents in Idiopathic Orthostatic Tachycardia

BACKGROUND Idiopathic orthostatic tachycardia (IOT) is characterized by an increase in heart rate (HR) with standing of > or = 30 bpm that is associated with elevated catecholamine levels and orthostatic symptoms. A dynamic orthostatic hypovolemia and alpha1-adrenoreceptor hypersensitivity have been demonstrated in IOT patients. There is evidence of an autonomic neuropathy affecting the lower-extremity blood vessels. METHODS AND RESULTS We studied the effects of placebo, the alpha1-adrenoreceptor agonist midodrine (5 to 10 mg), the alpha2-adrenoreceptor agonist clonidine (0.1 mg), and I.V. saline (1 L) in 13 patients with IOT. Supine and upright blood pressure (BP) and HR were measured before and at 1 and 2 hours after intervention. Midodrine decreased both supine and upright HR (all HR values are given as bpm) at 2 hours (from 78+/-2 supine to 108+/-5 upright before treatment and from 69+/-2 supine to 95+/-5 upright after treatment, P<.005 for supine and P<.01 for upright). Saline decreased both supine and upright HR (from 80+/-3 supine to 112+/-5 upright before infusion and from 77+/-3 supine to 91+/-3 upright 1 hour after infusion, P<.005 for supine and P<.001 for upright). Clonidine decreased supine HR (from 78+/-2 to 74+/-2, P<.03) but did not affect the HR increase with standing. Clonidine very significantly decreased supine systolic BP (from 109+/-3 at baseline to 99+/-2 mm Hg at 2 hours, P<.001), and midodrine decreased supine systolic BP mildly. CONCLUSIONS IOT responds best acutely to saline infusion to correct the underlying hypovolemia. Chronically, this can be accomplished with increased salt and water intake in conjunction with fludrocortisone. The response of patients to the alpha1-agonist midodrine supports the hypothesis of partial dysautonomia and indicates that the use of alpha1-agonists to pharmacologically replace lower-extremity postganglionic sympathetics is an appropriate overall goal of therapy. These findings are consistent with our hypothesis that the tachycardia and elevated catecholamine levels associated with IOT are principally due to hypovolemia and loss of adequate lower-extremity vascular tone.

Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome

Background—Patients with postural tachycardia syndrome (POTS) experience considerable disability, but in most, the pathophysiology remains obscure. Plasma volume disturbances have been implicated in some patients. We prospectively tested the hypothesis that patients with POTS are hypovolemic compared with healthy controls and explored the role of plasma renin activity and aldosterone in the regulation of plasma volume. Methods and Results—Patients with POTS (n=15) and healthy controls (n=14) underwent investigation. Heart rate (HR), blood pressure (BP), plasma renin activity, and aldosterone were measured with patients both supine and upright. Blood volumes were measured with 131I-labeled albumin and hematocrit. Patients with POTS had a higher orthostatic increase in HR than controls (51±18 versus 16±10 bpm, P<0.001). Patients with POTS had a greater deficit in plasma volume (334±187 versus 10±250 mL, P<0.001), red blood cell volume (356±128 versus 218±140 mL, P=0.010), and total blood volume (689±270 versus 228±353 mL, P<0.001) than controls. Despite the lower plasma volume in patients with POTS, there was not a compensatory increase in plasma renin activity (0.79±0.58 versus 0.79±0.74 ng · mL−1 · h−1, P=0.996). There was a paradoxically low level of aldosterone in the patients with POTS (190±140 pmol/L versus 380±230 pmol/L; P=0.017). Conclusions—Patients with POTS have paradoxically unchanged plasma renin activity and low aldosterone given their marked reduction in plasma volume. These patients also have a significant red blood cell volume deficit, which is regulated by the renal hormone erythropoietin. These abnormalities suggest that the kidney may play a key role in the pathophysiology of POTS.

Sympathetically Mediated Hypertension in Autonomic Failure

BACKGROUND Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity. METHODS AND RESULTS In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of alpha(1)-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248+/-543 versus 467+/-209 mm Hg. min; P=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874+/-809 versus 785+/-189 mm Hg. min; P=0. 0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67+/-8 and 12+/-6 mm Hg in MSA and PAF patients, respectively (P<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4+/-5.8% and 40.7+/-9.5%, respectively (P=0. 0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (r=0.98; P=0.001). CONCLUSIONS Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.

Interaction of Carbon Dioxide and Sympathetic Nervous System Activity in the Regulation of Cerebral Perfusion in Humans

Recent studies suggest that activation of the sympathetic nervous system either directly or indirectly influences cerebrovascular tone in humans even within the autoregulatory range. In 6 healthy subjects (aged 29±4 years), we used transcranial Doppler sonography to determine cerebral blood flow velocity during sympathetic activation elicited through head-up tilt (HUT) and sympathetic deactivation through ganglionic blockade. Paco2 was manipulated through hyperventilation and CO2 breathing (5%). With subjects in the supine position and during HUT, mean arterial pressure was not influenced by Paco2. During ganglionic blockade, mean arterial pressure decreased markedly with hyperventilation (−13±1.9 mm Hg). Manipulation of sympathetic tone elicited only mild changes in cerebral blood flow (64±5.8 cm/s supine, 58±4.9 cm/s upright, and 66±6.2 cm/s during ganglionic blockade;P =0.07 by ANOVA). The slope of the regression between Paco2 and mean velocity was 1.6±0.18 cm/(s · mm Hg) supine, 1.3±0.14 cm/(s · mm Hg) during HUT, and 2.3±0.36 cm/(s · mm Hg) during ganglionic blockade (P <0.05). Spontaneous Paco2 and ventilatory response to hypercapnia were also modulated by the level of sympathetic activity. Changes in sympathetic tone have a limited effect on cerebral blood flow at normal Paco2 levels. However, the sympathetic nervous system seems to attenuate the CO2-induced increase in cerebral blood flow. This phenomenon may indicate a moderate direct effect of the sympathetic nervous system on the cerebral vasculature. Furthermore, sympathetic activation tends to increase ventilation and thus can indirectly increase cerebrovascular tone.

Contrasting actions of pressor agents in severe autonomic failure

BACKGROUND Orthostatic hypotension is the most disabling symptom of autonomic failure. The choice of a pressor agent is largely empiric, and it would be of great value to define predictors of a response. PATIENTS AND METHODS In 35 patients with severe orthostatic hypotension due to multiple system atrophy or pure autonomic failure, we determined the effect on seated systolic blood pressure (SBP) of placebo, phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin (50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg). In a subgroup of patients, we compared the pressor effect of midodrine (5 mg) with the effect of phenylpropanolamine (12.5 mg). RESULTS There were no significant differences in the pressor responses between patients with multiple system atrophy or pure autonomic failure. When compared with placebo, the pressor response was significant for phenylpropanolamine, yohimbine, and indomethacin. In a subgroup of patients, we confirmed that this pressor effect of phenylpropanolamine, yohimbine, and indomethacin corresponded to a significant increase in standing SBP. The pressor responses to ibuprofen, caffeine, and methylphenidate were not significantly different from placebo. Phenylpropanolamine and midodrine elicited similar pressor responses. There were no significant associations between drug response and autonomic function testing, postprandial hypotension, or plasma catecholamine levels. CONCLUSIONS We conclude that significant increases in systolic blood pressure can be obtained in patients with orthostatic hypotension due to primary autonomic failure with phenylpropanolamine in low doses or yohimbine or indomethacin in moderate doses. The response to a pressor agent cannot be predicted by autonomic function testing or plasma catecholamines. Therefore, empiric testing with a sequence of medications, based on the risk of side effects in the individual patient and the probability of a response, is a useful approach.

Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome Less Is More

Background— Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate on standing. β-Blockade is an appealing treatment approach, but conflicting preliminary reports are conflicting. We tested the hypothesis that propranolol will attenuate the tachycardia and improve symptom burden in patients with POTS. In protocol 1, a low dose (20 mg) was compared with placebo, and the dose response was assessed in protocol 2. Methods and Results— In protocol 1, patients with POTS (n=54) underwent acute drug trials of propranolol 20 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, heart rate, and symptoms were assessed while the patients were seated and after standing for up to 10 minutes before and hourly after the study drug. Supine (P<0.001) and standing (P<0.001) heart rates were significantly lower after propranolol compared with placebo. The symptom burden improvement from baseline to 2 hours was greater with propranolol than placebo (median, −4.5 versus 0 arbitrary units; P=0.044). In protocol 2, 18 patients with POTS underwent similar trials of high-dose (80 mg) versus low-dose (20 mg) propranolol. Although the high dose elicited a greater decrease than the low dose in standing heart rate (P<0.001) and orthostatic tachycardia (P<0.001), the improvement in symptoms at 2 hours was greater with low-dose propranolol (−6 versus −2 arbitrary units; P=0.041). Conclusions— Low-dose oral propranolol significantly attenuated tachycardia and improved symptoms in POTS. Higher-dose propranolol did not further improve, and may worsen, symptoms.

Acetylcholinesterase Inhibition Improves Tachycardia in Postural Tachycardia Syndrome

Background—Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance notable for an excessive increase in heart rate that occurs on standing. Many current therapeutic strategies focus on sympatholysis, but the alternative strategy of enhancing cardiovagal tone has not been studied. The objective of this study was to test the hypothesis that acetylcholinesterase inhibitors will attenuate the tachycardia and improve symptom burden in patients with POTS. Methods and Results—Seventeen patients with POTS underwent acute drug trials of pyridostigmine 30 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressures, heart rate, and symptoms were assessed while patients were seated and after they had been standing for up to 10 minutes both before the study drug was given and at 2 and 4 hours after study drug. The heart rate was significantly lower at 2 hours after pyridostigmine than after placebo (100±16 versus 111±14 bpm, P=0.001). Pyridostigmine significantly decreased the standing heart rate from baseline (119±16 bpm) at 2 hours (104±16 bpm, P<0.001) and 4 hours (100±16 bpm, P<0.001) after administration. There was no significant change in blood pressure. The decrease in symptom burden within 4 hours after study drug was significantly greater with pyridostigmine than placebo (−10.4±14.0 AU versus 0.6±7.5 AU, P<0.025). Conclusions—Acute acetylcholinesterase inhibition significantly attenuated tachycardia in POTS. There was also an improvement in symptom burden with this promising therapy.