Sandra Pechnik

Association Between Supine Hypertension and Orthostatic Hypotension in Autonomic Failure

Abstract—Supine hypertension occurs commonly in primary chronic autonomic failure. This study explored whether supine hypertension in this setting is associated with orthostatic hypotension (OH), and if so, what mechanisms might underlie this association. Supine and upright blood pressures, hemodynamic responses to the Valsalva maneuver, baroreflex-cardiovagal gain, and plasma norepinephrine (NE) levels were measured in pure autonomic failure (PAF), multiple-system atrophy (MSA) with or without OH, and Parkinson’s disease (PD) with or without OH. Controls included age-matched, healthy volunteers and patients with essential hypertension or those referred for dysautonomia. Baroreflex-cardiovagal gain was calculated from the relation between the interbeat interval and systolic pressure during the Valsalva maneuver. PAF, MSA with OH, and PD with OH all featured supine hypertension, which was equivalent in severity to that in essential hypertension, regardless of fludrocortisone treatment. Among patients with PD or MSA, those with OH had higher mean arterial pressure during supine rest (109±3 mm Hg) than did those lacking OH (96±3 mm Hg, P =0.002). Baroreflex-cardiovagal gain and orthostatic increments in plasma NE levels were markedly decreased in all 3 groups with OH. Among patients with PD or MSA, those with OH had much lower mean baroreflex-cardiovagal gain (0.74±0.10 ms/mm Hg) than did those lacking OH (3.13±0.72 ms/mm Hg, P =0.0002). In PAF, supine hypertension is linked to both OH and low baroreflex-cardiovagal gain. The finding of lower plasma NE levels in patients with than without supine hypertension suggests involvement of pressor mechanisms independent of the sympathetic nervous system.

Neurocirculatory Abnormalities in Parkinson Disease With Orthostatic Hypotension: Independence From Levodopa Treatment

Patients with Parkinson disease often have orthostatic hypotension. Neurocirculatory abnormalities underlying orthostatic hypotension might reflect levodopa treatment. Sixty-six Parkinson disease patients (36 with orthostatic hypotension, 15 off and 21 on levodopa; 30 without orthostatic hypotension) had tests of reflexive cardiovagal gain (decrease in interbeat interval per unit decrease in systolic pressure during the Valsalva maneuver; orthostatic increase in heart rate per unit decrease in pressure); reflexive sympathoneural function (decrease in pressure during the Valsalva maneuver; orthostatic increment in plasma norepinephrine); and cardiac and extracardiac noradrenergic innervation (septal myocardial 6-[18F]fluorodopamine-derived radioactivity; supine plasma norepinephrine). Severity of orthostatic hypotension did not differ between the levodopa-untreated and levodopa-treated groups with Parkinson disease and orthostatic hypotension (−52±6 [SEM] versus −49±5 mm Hg systolic). The 2 groups had similarly low reflexive cardiovagal gain (0.84±0.23 versus 1.33±0.35 ms/mm Hg during Valsalva; 0.43±0.09 versus 0.27±0.06 bpm/mm Hg during orthostasis); and had similarly attenuated reflexive sympathoneural responses (97±29 versus 71±23 pg/mL during orthostasis; −82±10 versus −73±8 mm Hg during Valsalva). In patients off levodopa, plasma norepinephrine was lower in those with (193±19 pg/mL) than without (348±46 pg/mL) orthostatic hypotension. Low values for reflexive cardiovagal gain, sympathoneural responses, and noradrenergic innervation were strongly related to orthostatic hypotension. Parkinson disease with orthostatic hypotension features reflexive cardiovagal and sympathoneural failure and cardiac and partial extracardiac sympathetic denervation, independent of levodopa treatment.

Generalized and neurotransmitter-selective noradrenergic denervation in Parkinson's disease with orthostatic hypotension.

Patients with Parkinsons disease (PD) often have manifestations of autonomic failure. About 40% have neurogenic orthostatic hypotension (NOH), and among PD+NOH patients virtually all have evidence of cardiac sympathetic denervation; however, whether PD+NOH entails extra‐cardiac noradrenergic denervation has been less clear. Microdialysate concentrations of the main neuronal metabolite of norepinephrine (NE) and dihydroxyphenylglycol (DHPG) were measured in skeletal muscle, and plasma concentrations of NE and DHPG were measured in response to i.v. tyramine, yohimbine, and isoproterenol, in patients with PD+NOH, patients with pure autonomic failure (PAF), which is characterized by generalized catecholaminergic denervation, and control subjects. Microdialysate DHPG concentrations were similarly low in PD+NOH and PAF compared to control subjects (163 ± 25, 153 ± 27, and 304 ± 27 pg/mL, P < 0.01 each vs. control). The two groups also had similarly small plasma DHPG responses to tyramine (71 ± 58 and 82 ± 105 vs. 313 ± 94 pg/mL; P < 0.01 each vs. control) and NE responses to yohimbine (223 ± 37 and 61 ± 15 vs. 672 ± 130 pg/mL, P < 0.01 each vs. control), and virtually absent NE responses to isoproterenol (20 ± 34 and 14 ± 15 vs. 336 ± 78 pg/mL, P < 0.01 each vs. control). Patients with PD+NOH had normal bradycardia responses to edrophonium and normal epinephrine responses to glucagon. The results support the concept of generalized noradrenergic denervation in PD+NOH, with similar severity to that seen in PAF. In contrast, the parasympathetic cholinergic and adrenomedullary hormonal components of the autonomic nervous system seem intact in PD+NOH.

Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension

BACKGROUND Diseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function. METHODS Cardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD+NOH or PAF (PD+NOH/PAF group, N=13). We compared the results to those in patients with multiple system atrophy, which usually entails NOH with normal cardiac sympathetic innervation (MSA, N=15), and in normal control subjects (N=5). RESULTS The innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD+NOH/PAF group. For similar heart rate responses, the PD+NOH/PAF group required less isoproterenol (p<0.01) and had lower plasma isoproterenol levels (p<0.01) than did the MSA group. CONCLUSIONS Among patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors.

Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation.

Background Power spectral analysis of heart rate variability (HRV) has been used to indicate cardiac autonomic function. High-frequency power relates to respiratory sinus arrhythmia and therefore to parasympathetic cardiovagal tone; however, the relationship of low-frequency (LF) power to cardiac sympathetic innervation and function has been controversial. Alternatively, LF power might reflect baro reflexive modulation of autonomic outflows. Objective We studied normal volunteers and chronic autonomic failure syndrome patients with and without loss of cardiac noradrenergic nerves to examine the relationships of LF power with cardiac sympathetic innervation and baroreflex function. Methods We compared LF power of HRV in patients with cardiac sympathetic denervation, as indicated by low myocardial concentrations of 6-[18F]fluorodopamine-derived radioactivity or low rates of norepinephrine entry into coronary sinus plasma (cardiac norepinephrine spillover) to values in patients with intact innervation, at baseline, during infusion of yohimbine, which increases exocytotic norepinephrine release from sympathetic nerves, or during infusion of tyramine, which increases non-exocytotic release. Baroreflex-cardiovagal slope (BRS) was calculated from the cardiac interbeat interval and systolic pressure during the Valsalva maneuver. Results LF power was unrelated to myocardial 6-[18F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover. In contrast, the log of LF power correlated positively with the log of BRS (r = 0.72, P < 0.0001). Patients with a low BRS (⩽ 3 msec/mm Hg) had low LF power, regardless of cardiac innervation. Tyramine and yohimbine increased LF power in subjects with normal BRS but not in those with low BRS. BRS at baseline predicted LF responses to tyramine and yohimbine. Conclusion LF power reflects baroreflex function, not cardiac sympathetic innervation

Sympathoadrenal function in patients with paroxysmal hypertension: pseudopheochromocytoma.

Objectives The causes of paroxysmal hypertension in patients in whom pheochromocytoma has been excluded (‘pseudopheochromocytoma’) usually remain unclear. Blood pressure disturbances and symptoms of catecholamine excess in these patients may reflect activation of the sympathetic nervous and adrenal medullary systems. We therefore examined sympathoadrenal function in patients with pseudopheochromocytoma compared with age-matched control subjects in whom there was no suspicion of pheochromocytoma. Methods Plasma catecholamines and hemodynamics were examined in response to intravenous glucagon, yohimbine, and trimethaphan in 11 patients with pseudopheochromocytoma and a comparison group of nine normotensive and five hypertensive volunteers. Adrenomedullary function was also assessed by abdominal 18F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, the O-methylated metabolite of epinephrine. Results Compared with controls, patients with pseudopheochromocytoma had normal plasma concentrations of norepinephrine, but 120% higher (P < 0.05) baseline plasma concentrations of epinephrine, 80% higher (P < 0.01) baseline plasma concentrations of metanephrine, and sixfold larger (P < 0.05) increases in plasma epinephrine after glucagon. Adrenal 18F-fluorodopamine-derived radioactivity did not differ between groups. Compared with changes in plasma norepinephrine, falls in blood pressure after trimethaphan were 13-fold larger (P < 0.005) and increases in blood pressure after yohimbine were threefold larger (P < 0.01) in pseudopheochromocytoma patients than in controls. Conclusion Patients with pseudopheochromocytoma exhibit a pattern of normal sympathetic noradrenergic outflow, adrenomedullary activation, and augmented blood pressure responses to changes in the sympathoneural release of norepinephrine.

Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes

Background: Neurogenic orthostatic hypotension (OH) characterizes pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson disease (PD) with autonomic failure. We used neuropharmacologic probes that might distinguish these diseases based on loss of sympathetic noradrenergic nerves in PAF and PD + OH but not in MSA, and related the results to neurochemical and neuroimaging findings in the same patients. Methods: Patients with neurogenic OH (PD + OH; N = 35), MSA (N = 41), and PAF (N = 12) received iv trimethaphan (TRI), which inhibits sympathetic nerve traffic, or yohimbine (YOH), which stimulates sympathetic traffic. Dependent measures included blood pressure, plasma norepinephrine (NE) levels, and interventricular septal myocardial radioactivity after iv injection of the sympathoneural imaging agent, 6-[18F]fluorodopamine. Results: The PD + OH and PAF groups had smaller pressor responses to YOH (12 ± 8 and 13 ± 1 mm Hg) and depressor responses to TRI (−14 ± 8 and −17 ± 7 mm Hg) than did the MSA group (43 ± 8 mm Hg, −57 ± 8 mm Hg; P = 0.01, P = 0.03). The PD + OH and MSA groups did not differ in NE responses to YOH and TRI. The depressor response to TRI, the pressor response to YOH, and the blood pressure difference between YOH and TRI all correlated positively with myocardial 6-[18F]fluorodopamine-derived radioactivity. Conclusions: The PD + OH resembles PAF and differs from MSA in hemodynamic responses to drugs that alter NE release from sympathetic nerves. The results fit with sympathetic noradrenergic denervation in PD + OH and PAF but not in MSA.

Neurocirculatory Abnormalities in Chronic Orthostatic Intolerance

Background—Chronic orthostatic intolerance (COI) occurs in postural tachycardia syndrome (POTS) and in some individuals with repeated neurocardiogenic syncope/presyncope (NCS), without POTS. This study addressed whether patients with COI and POTS or NCS have neurocirculatory abnormalities during supine rest. Methods and Results—Adult patients referred for COI who had POTS (n=90, mean±SEM age 40±1 years, 86% women) or NCS (n=36, 41±2 years old, 78% women) underwent measurements of plasma levels of catecholamines and forearm hemodynamics. Comparison data were obtained from 32 age- and gender-matched normal volunteers (39±2 years old, 81% women). The POTS group had a relatively fast mean heart rate (79±2 bpm) during supine rest compared with the NCS group (69±1.6 bpm, P=0.03) and normal volunteers (66±3 bpm, P=0.0004). The POTS group also had higher mean arterial norepinephrine (1.61±0.11 nmol/L, n=37) and epinephrine (0.39±0.03 nmol/L, n=37) concentrations than the NCS group (1.03±0.12 nmol/L, n=20, P=0.0012; 0.21±0.03 nmol/L, n=20, P=0.0005) and normal volunteers (1.13±0.11 nmol/L, n=20, P=0.006; 0.17±0.03 nmol/L, n=15, P=0.0001). The NCS group had higher mean forearm vascular resistance (52±6 U) than the POTS group (36±2 U, P=0.003). Conclusions—Overall, POTS features increased heart rate and sympathetic nervous and adrenomedullary hormonal system outflows during supine rest. Increased sympathetic outflow may contribute to the relative tachycardia in POTS. NCS features forearm vasoconstriction during supine rest but not sympathoneural or adrenomedullary activation.

Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS.

Background: L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinsons disease. Adjunctive anti‐parkinsonian drugs might interact with L‐DOPS. We tested whether L‐aromatic amino‐acid decarboxylase inhibition by carbidopa (CAR) attenuates L‐DOPS conversion to NE and blocks the pressor effect of L‐DOPS, whereas catechol‐O‐methyltransferase inhibition by entacapone (ENT) interferes with L‐DOPS metabolism and augments the pressor effect. Methods: Twelve patients with autonomic failure took 400 mg of L‐DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L‐DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. Results: L‐DOPS+PLA and L‐DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L‐DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15000th that in L‐DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L‐DOPS. Conclusions: After L‐DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L‐DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O‐methylation and evokes vasoconstriction before reaching the systemic circulation.

Failure of propranolol to prevent tilt-evoked systemic vasodilatation, adrenaline release and neurocardiogenic syncope

In patients with neurocardiogenic syncope, head-up tilt often evokes acute loss of consciousness accompanied by vasodilatation, increased plasma adrenaline and systemic hypotension. Since hypotension increases adrenaline levels and adrenaline can produce skeletal muscle vasodilatation by activating beta2 receptors, adrenaline might induce a positive feedback loop precipitating circulatory collapse. We hypothesized that propranolol, a non-selective beta-blocker, would prevent adrenaline-induced vasodilatation and thereby prevent syncope. Eight subjects with recurrent neurocardiogenic syncope and previously documented tilt-induced syncope with elevated plasma adrenaline levels participated in the present study. Subjects underwent tilt table testing after receiving oral propranolol or placebo in a double-blind randomized crossover fashion. Haemodynamic and neurochemical variables were measured using intra-arterial monitoring, impedance cardiography, arterial blood sampling and tracer kinetics of simultaneously infused [3H]noradrenaline and [3H]adrenaline. The occurrence of tilt-induced neurally mediated hypotension and syncope, duration of tilt tolerance, extent of the decrease in SVRI (systemic vascular resistance index) and magnitude of plasma adrenaline increases did not differ between the propranolol and placebo treatment phases. SVRI was inversely associated with fractional increase in plasma adrenaline during both phases. One subject did not faint when on propranolol; this subjects response is discussed in the context of central effects of propranolol. In this small, but tightly controlled, study, propranolol did not prevent tilt-induced vasodilatation, syncope or elevated plasma adrenaline.