Clinical Autonomic Research

Crouching then standing induces large changes in arterial blood pressure. Ingestion of carbohydrate and water are known to have contrasting effects on cardiovascular control in patients with various forms of autonomic dysfunction. We tested the hypothesis that, in patients with attacks of posturally related (neurogenic or vasovagal) syncope, postural maneuvers would cause greater changes in blood pressure than in normal controls and that they would be affected differently by carbohydrate and water. We studied 7 patients with histories indicating posturally related syncope and who we had shown to have abnormal responses to an orthostatic stress test, and 7 healthy volunteers with normal orthostatic responses. Responses of blood pressure (Portapres® finger photoplethysmography) were determined to crouching and subsequent standing, before and after ingestion of a high carbohydrate ”meal” (2.5MJ) and (on a different day) water (500 ml). Before the “meal” or water there were no differences between groups in baseline blood pressures or in the responses to crouching and standing. In controls, neither carbohydrate nor water had any significant effect on baseline blood pressure or on the responses to the maneuvers. In the patients, the standing pressures were also unaffected by carbohydrate but they did increase after water. In the patients the increases in pressure during the crouch were larger after carbohydrate, but smaller after water. These results show that, in patients with posturally related syncope, unlike in control subjects, carbohydrate ingestion and water result in opposite effects on blood pressure during postural maneuvers. These results raise the possibility that these patients might have a mild form of autonomic dysfunction.

The peptide catestatin is produced from the precursor protein chromogranin A. Apparently, catestatin regulates autonomic nervous system function through blockade of ganglionic nicotinic acetylcholine receptors. A recent study suggests that genetic polymorphisms affecting catestatin may have a bearing on human blood pressure regulation. In a study in autonomic failure patients, inhibition of carbohydrate reabsorption with the alpha glucosidase inhibitor acarbose attenuated postprandial hypotension. The study may be therapeutically relevant. The neuronal norepinephrine transporter affects cardiovascular regulation through combination of central nervous and peripheral mechanisms. In a new study, pharmacological norepinephrine transporter inhibition elicited a profound pressor response in patients with central autonomic failure due to multiple system atrophy. Blood pressure did not respond in patients with peripheral autonomic neuropathies. The investigators suggest that the pressor response results from peripheral norepinephrine transporter inhibition that is unopposed by a central sympatholytic effect. In vitro, human growth hormone has a neuroprotective effect. A small placebo-controlled clinical trial evaluated the safety of human recombinant growth hormone treatment in patients with multiple system atrophy. The intervention was well tolerated. Unfortunately, the study was to small to evaluate efficacy.

At the time of cardiac transplantation all nerves from the donor ventricles are cut. These nerves may regrow, but there is no method of measuring any regrowth. Arginine vasopressin (AVP) release was studied during hypotension induced by head-up tilt and lower body negative pressure (LBNP) in transplant recipients and in normal controls. Subjects were tilted to 60° for up to 60 min or until symptomatic. Lower body negative pressure (40 mmHg) was applied for 10 min after 30 min rest. Seven of 17 transplant recipients and 11 of 12 controls became symptomatic during tilt testing, and 9 of 12 controls and 9 of 17 transplant recipients became symptomatic after 10 min of LBNP. Symptoms during tilt did not predict symptoms during LBNP. Resting AVP levels were similar but osmolality was greater in transplant recipients. Resting haematocrit was reduced, and atrial natriuretic peptide increased in transplant recipients, suggesting increased plasma volume. In symptomatic subjects, changes in humoral concentrations were similar when compared between transplant recipients and normals, except that the rise in AVP at the time of symptoms was reduced in transplant recipients, with a comparable drop in blood pressure consistent with persistent cardiac afferent denervation in a subset of transplant recipients.

Thoracic positron emission tomographic (PET) scanning after injection of 6-[18F]fluorodopamine ([18F]-6F-DA) visualizes cardiac sympathetic innervation. We tested whether changes in curves relating myocardial [18F]-6F-DA-derived radioactivity with time (time-activity curves, TACs) can reflect changes in important aspects of cardiac sympatheticfunction. Thoracic PET scans were obtained after intravenous administration of [18F]-6F-DA or the perfusion imaging agent [13N]ammonia into normal volunteers. Ganglion blockade with trimethaphan (TRI) was used to decrease sympathoneural traffic, desipramine (DMI) to block neuronal uptake of catecholamines, and tyramine (TYR) to displace vesicular amines. After [18F]-6F-DA administration, myocardial concentrations of [18F]-6F-DA-derived radioactivity declined bi-exponentially from the peak value. TRI increased they-intercept (y o) value for the early phase (p=0.01), and DMI decreased they o for the late phase (p=0.01). The TRI effect did not result from increased arterial [18F]-6F-DA concentrations or from increased myocardial perfusion. TYR infusion, begun 90 min after [18F]-6F-DA administration, accelerated the decline of myocardial radioactivity by 2.6-fold (p=0.003). Alterations in post-ganglionic sympathoneural traffic, neuronal catecholamine uptake, and vesicular turnover of monoamines produce distinct changes in myocardial TACs after [18F]-6F-DA injection. [18F]-6F-DA PET scanning may therefore enable assessments of effects of stressors, drugs, and neurocardiological disorders on specific aspects of cardiac sympathoneural function.

The risk related to cardiovascular autonomic neuropathy dys-autonomia should lead to a specific assessment of this complication of diabetes. The aim of this study was to estimate the accuracy of a battery of blood pressure (BP) and heart rate (HR) variability indexes obtained in different subgroups of diabetic subjects classified according to the conventional laboratory autonomic function tests (Ewing scores). Blood pressure was measured continuously at the finger level with a Finapres monitor while subjects were in the supine position and again while they were standing. Pulse intervals were derived from BP recordings and were taken as surrogates for R-R intervals. Subjects with borderline or definite cardiovascular autonomic neuropathy showed a similar degree of alterations of both HR and BP variability (spectral measures) and in the relationship between BP and HR (cross-spectral and sequence analysis). Subjects with no evidence of cardiovascular autonomic neuropathy on the basis of the conventional tests showed an altered relationship between BP and HR. This baroreceptor-HR reflex dysfunction could represent an early stage of cardiovascular autonomic neuropathy undetected by the conventional tests. The areas under the receiver operating characteristic plots indicated that the high-frequency peak of pulse interval was highly discriminant in the supine and standing positions. The cross-spectral analysis showed the best discrimination for the gain in the high-frequency range. For the sequence analysis, the slope was the best discriminant factor for any degree of cardiovascular autonomic neuropathy. In conclusion, these estimates of baroreceptor-HR function may provide a powerful tool for assessing cardiovascular autonomic neuropathy at any stage, including the early stage, which is not detected by the conventional tests.