Dobutamine stress test unmasks cardiac sympathetic denervation in Parkinson's disease

OBJECTIVE: Cardiac uptake of [(123)I]metaiodobenzyl guanidine (MIBG) is reduced in patients with Parkinson's disease (PD). However, the cardiac sympathetic abnormality associated with this reduction is unclear. To unmask this abnormality in PD patients we examined the functional consequences of cardiac beta-receptor activation. METHODS: Cardiovascular responses to stepwise administration of the beta1-receptor agonist, dobutamine (DOB), were assessed in 25 PD patients and 12 age-matched controls. Changes in blood pressure were compared to determine the optimal dose at which to detect denervation supersensitivity, and cardiac contractility was measured by DOB echocardiography, based on peak aortic flow velocity. The relations of these cardiovascular responses to the ratio of MIBG uptake into the heart vs. that into the mediastinum (H/M ratio) were analyzed. RESULTS: At 4 microg/kg/min DOB, systolic blood pressure increased more in PD patients than in controls (PD, 17.5+/-12.3 mm Hg; control, 7.2+/-6.2 mm Hg, p<0.01), suggesting the presence of denervation supersensitivity. At this DOB dose cardiac contractility also increased more in PD than in controls (PD, 39.0+/-15.7%; control, 23.5+/-5.2%, p<0.005) and this hyperdynamic response was significantly correlated with reduced H/M ratios (early: r=-0.63, p<0.01, delayed: r=-0.66, p<0.01). CONCLUSION: Low-dose DOB unmasks cardiac sympathetic denervation in PD patients, and decreased MIBG uptake indicates the presence of denervation supersensitivity within the heart, resulting in hyperdynamic cardiac contractility in response to a beta 1-stress condition.     

Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension

BackgroundDiseases 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-[¹⁸F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function.MethodsCardiac 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).ResultsThe 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.ConclusionsAmong 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.     

Role of cardiac sympathetic nerves in preventing orthostatic hypotension in Parkinson's disease

PurposeCardiac sympathetic denervation is associated with orthostatic hypotension (OH) in Parkinson's disease (PD); however, the physiological role of cardiac sympathetic nerves has yet to be elucidated. To clarify the role of the heart in orthostatic stress, we evaluated whether cardiac sympathetic nerves can alter cardiac activity and systolic blood pressure (BP) in association with elevations or depressions of total peripheral resistance during the head-up tilt test.MethodsNinety-five PD patients and 17 normal controls were enrolled. Using impedance cardiography, we measured total peripheral resistance, stroke volume, heart rate, and systolic BP during the head-up tilt test. Cardiac denervation was defined as a heart-to-mediastinum ratio <1.7 for cardiac ¹²³I-metaiodobenzylguanidine uptake on delayed images.ResultsAt 60° tilt, total peripheral resistance decreased from the initial value in 49 PD patients. Among these, 36 patients exhibited cardiac denervation with severe reductions in systolic BP but little change in stroke volume; among these patients 22 had OH. The remaining 13 patients without cardiac denervation exhibited significant increases in stroke volume and well-preserved systolic BP with no OH. On the other hand, 46 patients had elevations in total peripheral resistance and reduced stroke volume, but little change in systolic BP, regardless of the presence or absence of cardiac denervation. Only one of these patients experienced OH.ConclusionUnder orthostatic stress, cardiac sympathetic denervation with failure to increase total peripheral resistance leads to large reductions in systolic BP. However, patients without cardiac denervation exhibited a positive inotropic response against vasodilatation, which may prevent OH.     

Norepinephrine and cardiovascular responses to maximal exercise in Parkinson's disease on and off medication

The aim of this experiment is to understand how Parkinson's disease (PD) medication affects the autonomic responses of individuals during an acute exercise stress test. Fourteen people with PD and fifteen healthy individuals age‐matched between 50 and 80 years performed a modified Bruce protocol. Subjects with PD performed the test once off medication (PD‐off) and then 1 week later on medication (PD‐on). Heart rate (HR), blood pressure (BP), VO₂, and norepinephrine (NE) levels were taken at rest and at peak exercise. At peak exercise HR, BP, and NE values for the PD‐on and PD‐off group were all significantly lower than healthy controls, regardless of whether subjects were on their medication. Autonomic abnormalities during exercise in this population appear to be disease manifested and not impactedby medications used to treat PD. We can assume, both on and off medication, this population will show markedly lower BP, HR, and NE responses. © 2009 Movement Disorder Society     

Degeneration of cardiac sympathetic nerve can occur in multiple system atrophy

Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) on [¹²³I] MIBG myocardial scintigraphy, a sensitive biological marker for Parkinson’s disease (PD), is related to cardiac sympathetic denervation in patients with PD. A slight decrease in cardiac uptake of MIBG has also been reported in some patients with multiple system atrophy (MSA). However, the pathophysiological mechanism accounting for the slight decrease in MIBG uptake in MSA remains to be elucidated. For confirmation, we examined cardiac tissue and sympathetic ganglia from patients with MSA. We immunohistochemically examined each specimen of 15 patients with MSA together with 10 control subjects using antibodies against tyrosine hydroxylase (TH) and neurofilament (NF). The number of TH-immunoreactive nerve fibers in the epicardium was preserved in 8 of 15 patients with MSA as well as in 10 control subjects. The number of TH-immunoreactive, but not of NF-immunoreactive nerve fibers in the epicardium was mildly or moderately decreased in six patients with MSA, of whom four showed a decrease of TH immunoreactivity in the neuronal somata in the sympathetic ganglia. Moreover, TH- and NF-immunoreactive nerve fibers almost entirely disappeared in the heart of one patient with MSA, in whom Lewy body pathology was present in the sympathetic ganglia. These findings suggest that mild degeneration of the cardiac sympathetic nerve can occur in MSA which is closely related to the pathological change of neurons in the sympathetic ganglia, accounting for the slight decrease in cardiac uptake of MIBG. Moreover, concurrent Lewy body pathology in the sympathetic ganglia might accelerate cardiac sympathetic denervation even in MSA.     

Cardiac stress test is normal in pre‐motor Parkinson's disease

Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n = 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age‐ and sex‐matched subjects (ratio 1:2) who did not. We identified 28 subjects (24 males) who developed PD at follow‐up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 ± 8.82 vs. 48.91 ± 10.60 years, P < 0.001). The time between the first ergometric test and motor symptoms onset was 4.64 ± 2.86 years. Patients who later developed PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age‐ and sex‐matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD. © 2014 International Parkinson and Movement Disorder Society     

Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease

Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) on [¹²³I]MIBG myocardial scintigraphy has been reported in Parkinsons disease (PD) and dementia with Lewy bodies (DLB). We hypothesized that cardiac sympathetic denervation might account for the pathomechanism. To elucidate the extent, frequency and pattern of cardiac sympathetic nerve involvement in Lewy body disease and related neurodegenerative disorders, we immunohistochemically examined heart tissues from patients with PD (n=11), DLB (n=7), DLB with Alzheimers disease (DLB/AD; n=4), multiple system atrophy (MSA; n=8), progressive supranuclear palsy (PSP; n=5), pure AD (n=10) and control subjects (n=5) together with sympathetic ganglia from patients with PD (n=5) and control subjects (n=4), using an antibody against tyrosine hydroxylase (TH). TH-immunoreactive nerve fibers in the hearts had almost entirely disappeared in nearly all the patients with PD, DLB and DLB/AD, whereas they were well preserved in all the patients with PSP and pure AD as well as in all except for one patient with MSA. In PD, neurons in the sympathetic ganglia were preserved in all except for one patient. Decreased cardiac uptake of MIBG in Lewy body disease reflects actual cardiac sympathetic denervation, which precedes the neuronal loss in the sympathetic ganglia.     

Effects of levodopa and bromocriptine on blood pressure and plasma catecholamines in parkinsonians

Blood pressure (BP), heart rate (HR), plasma noradrenaline (NA), and adrenaline (A) levels in the lying and standing position were compared in patients with Parkinson's disease (PD) and control subjects. Three groups of PD patients (stage 2 and 3) were investigated: six patients deprived of antiparkinsonian drugs from 48 h, seven levodopa + benserazide-treated patients, and seven bromocriptine-treated patients. BP, HR, NA, and A were similar at rest and in the standing position in controls and in PD patients deprived of antiparkinsonian drugs from 48 h. Chronic treatment with levodopa (+ benserazide) failed to modify BP, HR, NA, and A. Bromocriptine decreased BP, HR, and NA (but not A) at rest. In PD patients treated with levodopa (+ benserazide) or bromocriptine alone, the rise in NA (but not A) elicited by standing up was reduced. These results indicate that (a) stages 2 to 3 of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and (b) dopaminergic drugs blunted the sympathetic response to standing up.     

Spectrum of abnormalities of sympathetic tyrosine hydroxylase and alpha-synuclein in chronic autonomic failure

Objective

Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson’s disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients.

Methods

Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA).

Results

MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSP patient had AS co-localized with tau but not TH.

Conclusions

Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.

     

Linear and nonlinear measures of blood pressure variability: increased chaos of blood pressure time series in patients with panic disorder

Arterial blood pressure (BP) variability increases progressively with the development of hypertension and an increase in BP variability is associated with end organ damage and cardiovascular morbidity. On the other hand, a decrease in heart rate (HR) variability is associated with significant cardiovascular mortality. There is a strong association between cardiovascular mortality and anxiety. Several previous studies have shown decreased HR variability in patients with anxiety. In this study, we investigated beat-to-beat variability of systolic and diastolic BP (SBP and DBP) in normal controls and patients with panic disorder during normal breathing and controlled breathing at 12, and 20 breaths per minute using linear as well as nonlinear techniques. Finger BP signal was obtained noninvasively using Finapres. Standing SBPvi and DBP BPvi (log value of BP variance corrected for mean BP divided by HR variance corrected for mean HR) were significantly higher in patients compared to controls. Largest Lyapunov exponent (LLE) of SBP and DBP, a measure of chaos, was significantly higher in patients in supine as well as standing postures. The ratios of LLE (SBP/HR) and LLE (DBP/HR) were also significantly higher (P<.001) in patients compared to controls. These findings further suggest dissociation between HR and BP variability and a possible relative increase in sympathetic function in anxiety. This increase in BP variability may partly explain the increase in cardiovascular mortality in this group of patients.     

Dysfunctional baroreflex regulation of sympathetic nerve activity in remitted patients with panic disorder

Background Many researchers have studied the abnormalities of autonomic nervous system (ANS) such as decreased heart rate variability, which is a risk factor for sudden cardiac death, in patients with panic disorder (PD). However, no consistent abnormality has been uncovered to date. One of the reasons for this controversy may be due to the fact that most of these conventional studies have analyzed each physiological variable independent of other indices. We examined the ANS in PD patients using a new method which can more directly investigate the function of the baroreflex by examining the relation between the blood pressure (BP) and heart rate (HR). Methods During rest and audiovisual stimulation (AS) as mental stress such as being exposed to video imaginary of experiences such as driving motor vehicles, cardiovascular parameters, HR and BP were consecutively measured in 13 remitted PD patients and twenty aged and gender–matched normal controls (NC). In this study, to assess the cardiovascular ANS function (baroreflex) in PD we used the power spectrum analysis as usual and the mean of lag time (τ) between the Mayer wave components, which was closely related to sympathetic nerve activity of vasomotor, of HR and BP variability as a new trial. Results The PD patients and NC did not differ with regard to the power spectrum analysis of the heart rate. We found that τ in the PD group was significantly shorter than that in the NC both before and after AS, especially before. Conclusions These findings suggest that remitted PD patients may have a dysfunctional baroreflex regulation of sympathetic nerve activity.     

Impaired myocardial 123I-metaiodobenzylguanidine uptake in Lewy body disease: comparison between dementia with Lewy bodies and Parkinson's disease

BACKGROUND: Iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy has been used to evaluate cardiac sympathetic denervation in Lewy body disease (LBD) including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Patients with LBD had marked reductions in cardiac MIBG accumulation, indicative of severe impairment of the cardiac sympathetic nervous systems. However, the differences in scintigraphy between DLB and PD have not been determined. OBJECTIVE: To compare cardiac sympathetic function in early disease stage measured with 123I-MIBG scintigraphy between DLB and PD. METHODS: 123I-MIBG myocardial scintigraphy was performed in 22 patients with early-stage DLB, 41 patients with early idiopathic PD and 15 normal control subjects who were matched for age and disease duration. The heart-to-mediastinum (H/M) ratio was calculated. RESULTS: 123I-MIBG uptake of the myocardium was significantly lower in patients with early DLB than in controls. The mean value of H/M ratio in patients with DLB was significantly lower than those in patients with PD, independent of the Hoehn and Yahr stage. CONCLUSIONS: Our findings suggest that cardiac sympathetic function in DLB is severely impaired even in the early disease stage.     

Influence of left versus right hemibody onset Parkinson's disease on cardiovascular control

Whereas the left hemisphere is involved in regulating the parasympathetic nervous system, the right hemisphere regulates the sympathetic. Given the asymmetrical onset of motor symptoms and neuropathology in PD, differences in cardiovascular functions might be expected between PD patients with left hemibody onset (LHO) versus right hemibody onset (RHO). A total of 66 PD patients served as participants, including 31 LHO patients and 35 RHO PD patients. All participants had their resting heart rate (HR) and blood pressure (BP) recorded. Although the LHO group had lower systolic BP, it had higher resting HR than did the RHO group. The reason for this dissociation is not known but might be related to asymmetrical vagus nerve control of the heart (SA node). Future researchers might want to use additional indices of cardiovascular functioning that are more precise measures of parasympathetic and sympathetic functioning, as well as learn the influence of dopaminergic medications.     

The effect of parasympathetic postganglionic denervation on parotid salivary protein secretion in anaesthetized sheep

Effects of unilateral parasympathetic denervation of ovine parotid glands were examined in anaesthetized sheep 21-28 days after nerve section. Parasympathetic denervation reduced the mass of the ipsilateral gland while increasing that of the contralateral gland to the extent that total gland mass was greater than in sheep with normally innervated glands. The spontaneous secretion (8.8 +/- 1.1 microl min(-1) g gland(-1)) was significantly less from denervated than from innervated glands of normal control animals (26.0 +/- 2.7 microl min(-1) g gland(-1); P< 0.01) and contained more protein. Rates of flow, and the outputs of sodium and potassium, in response to sympathetic stimulation, were similar from normally innervated and chronically denervated glands, when allowance was made for the discrepancy in weights, whereas the output of protein was significantly enhanced following parasympathetic denervation (innervated--31.4 +/- 7.3 microg g gland(-1), denervated--83.4 +/- 26.6 microg g gland(-1); P< 0.05). Intra-arterial infusions of acetylcholine (130 pmol min(-1) kg(-1)) elicited a flow of parotid saliva, the protein content of which was significantly enhanced by prior parasympathetic denervation. Intra-arterial infusions of vasoactive intestinal peptide (VIP; 2.5 pmol min(-1) kg(-1)) produced a small but statistically significant (P< 0.05) increase in the flow of parotid saliva from the contralateral, innervated but not from denervated glands. It also caused a small increase in protein output, which was significantly enhanced by prior denervation. VIP had no synergistic effect on the parotid responses to acetylcholine. The results show that the parasympathetic innervation to the parotid gland of the sheep exerts important trophic effects on the gland. Interaction of adrenergic and cholinergic receptors makes an important contribution to stimulation of the secretion of protein and prior denervation potentiates the protein responses to both acetylcholine and VIP.     

Cardiac MIBG scintigraphy in Primary Progressive Freezing Gait

Freezing of gait (FOG) generally occurs as a late manifestation of Parkinson's Disease (PD). FOG, however, can present in isolation, constituting the so-called "Primary Progressive Freezing Gait"(PPFG). Myocardial (123)Metaiodiobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac nerve terminals. MIBG uptake reflects sympathetic system integrity, and reduced myocardial uptake of the tracer has been observed in nearly all patients with PD. We investigated MIBG uptake in 7 patients with PPFG, 14 patients with mild PD, and 6 patients with advanced PD and FOG (PD-FOG), and 18 control subjects. Our study shows that myocardial MIBG uptake was normal in all patients with PPFG (H/M ratio: mean+/-SD, 1.85+/-0.11 early; 1.71+/-0.15 delayed) and in the controls (H/M ratio: mean+/-SD, 1.94+/-0.18 early; 2.02+/-0.19 delayed) whereas it was markedly decreased in the patients with mild and advanced PD (H/M ratio: mean+/-SD, PD: 1.17+/-0.02 early; 1.16+/-0.02 delayed; PD-FOG: 1.22+/-0.10 early; 1.08+/-0.06 delayed). Our findings demonstrate that cardiac sympathetic denervation did not occur in patients with PPFG, confirming that PPFG and PD are distinct diseases.     

Spectral analysis of blood pressure and heart rate,catecholamine and neuropeptide Y plasma levels in a new model of neurogenic orthostatic hypotension in dog

The aim of the study was to compare changes in blood pressure (BP) and heart rate (HR) variability, catecholamine and neuropeptide Y (NPY) plasma levels induced by passive head-up tilt in normal and sino-aortic denervated (SAD) chloralose-anaesthetized dogs. In controls, 80° head-up tilt test failed to change BP and increased HR. Plasma noradrenaline and NPY levels (but not adrenaline) significantly rose. In SAD dogs, head-up tilt rest induced a marked and reproducible decrease in BP without any change in HR or noradrenaline and NPY plasma levels. In SAD dogs, spectral analysis in supine position was characterizied by reduced variability in the high frequency (HF) band of the HR spectrum without changes in low frequency (LF) bands of both HR and systolic blood pressure (SBP). Head-up tilt test increased the LF component of SBP variability and decreased the HF component of HR variability in controls but failed to modify HR and BP variabilities in SAD dogs. In conclusion, sino-aortic denervation in dogs elicits a reproducible postural fall in BP with impaired adaptation of sympathetic nervous system activity. This model may be of value in evaluating the pharmacological effects of drugs for the management of orthostatic hypotension.     

Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson's disease

We aimed to characterize the relationship between cardiac sympathetic and parasympathetic dysfunction employing cardiac (123)I-meta-iodobenzylguanidine (MIBG) uptake and other autonomic function parameters in Parkinson's disease (PD). 79 PD patients were studied. We performed (123)I-MIBG myocardial scintigraphy to assess the extent of cardiac sympathetic denervation. Electrocardiogram readings at rest and postural change in blood pressure were also examined. Coefficient variation of RR intervals (CVR-R) was used as an index for cardiac parasympathetic activity. Cardiac (123)I-MIBG uptake did not vary significantly among the Hoehn-Yahr (H-Y) stages. There was a significant correlation between cardiac (123)I-MIBG uptake and CVR-R (early, r=0.457, p<0.001; late, r=0.442, p<0.001). While the correlation was present among the patients who had had the disease less than two years (early, r=0.558, p<0.001; late, r=0.530, p<0.001), the patients with the disease duration longer than two years did not have such a significant correlation. Age, disease duration, corrected QT interval, or postural blood pressure change did not correlate with cardiac (123)I-MIBG uptake. Orthostatic hypotension was observed in 13 out of 72 subjects, and reduced CVR-R was a major determinant for the development of orthostatic hypotension. We conclude that cardiac parasympathetic dysfunction occurs concurrent with sympathetic denervation as revealed by (123)I-MIBG myocardial scintigraphy in PD and contributes to the development of orthostatic hypotension.     

Regulation of sympathetic trophic factors in smooth muscle

The level and nature of trophic activity present in the chicken expansor secundariorum muscle has been shown to be altered by denervation. This muscle receives a dense, sympathetic innervation and contains high concentrations of trophic factors, which were found to be immunologically and functionally distinct from mouse Nerve Growth Factor. In young birds, denervation increased the number of neurons which could be supported by muscle extract. This difference was apparent with regard to E8 to E16 sympathetic neurons. Innervated but not denervated extract was additive with NGF in promoting neurite outgrowth. In contrast, when extracts of denervated and innervated muscle from mature birds were examined, no difference was seen in the number of neurons supported by each extract. However when the denervated and innervated extracts from mature birds were combined more neurons were supported than by a saturating dose of either extract alone. Furthermore, muscle from mature birds responded to denervation only between 2 and 9 days, whereas in young birds the effect was apparent for at least 3 weeks. Analysis of intact, control muscles during the first 8 weeks posthatch demonstrated that the number of neurons that could be supported by the individual extracts varied with the age of the bird. It is concluded that denervation does not in all instances lead to an increase in trophic activity, but does produce a change in the nature of the activity present, such that a different neuronal subpopulation may be supported.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired cardiovascular autonomic control in newly and long-term-treated patients with Parkinson's disease: involvement of L-dopa therapy

In idiopathic Parkinson's disease (PD), autonomic dysfunction is frequent, causing orthostatic hypotension. The respective roles of disease progression and dopaminergic treatment remain unclear. In this study, we investigated the autonomic control of cardiovascular functions and its relation to L-dopa therapy in both newly diagnosed (ND) and long-term-treated (LT) patients. Study subjects were: (1) nine ND patients never having undergone treatment with L-dopa; (2) 18 LT patients who had been receiving L-dopa treatment for a long period. ND patients were investigated before L-dopa treatment and after stabilization of their L-dopa dosage. LT patients were investigated once with their regular treatment and once after a 12-h interruption of L-dopa treatment; (3) nine healthy subjects served as controls. At each test session, blood pressure (BP), heart rate (HR), plasma catecholamines, heart rate variability (HRV), and spontaneous baroreflex sensitivity were assessed in the supine and upright positions. Before receiving L-dopa medication, ND patients had reduced E/I ratios (HR response/deep breathing) and lowered HRV when compared to controls; this was evidence of early effects of the disease on autonomic HR control. Introduction of L-dopa treatment reduced BP, HR, and plasma levels of adrenaline and noradrenaline. Similar changes were found in LT patients when contrasting the short-term treatment interruption and the usual L-dopa dosage. The treatment-linked increase in plasma dopamine also correlated with the decrease in noradrenaline. These results showed that mild impairment of autonomic cardiovascular control occurred early in the course of PD. They also provided evidence that the side effects of L-dopa aggravated the impairment of the autonomic control of BP and HR.     

Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis

Signs or symptoms of impaired autonomic regulation of circulation often attend Parkinson disease (PD). This review covers biomarkers and mechanisms of autonomic cardiovascular abnormalities in PD and related alpha-synucleinopathies. The clearest clinical laboratory correlate of dysautonomia in PD is loss of myocardial noradrenergic innervation, detected by cardiac sympathetic neuroimaging. About 30-40% of PD patients have orthostatic hypotension (OH), defined as a persistent, consistent fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of change in position from supine to standing. Neuroimaging evidence of cardiac sympathetic denervation is universal in PD with OH (PD+OH). In PD without OH about half the patients have diffuse left ventricular myocardial sympathetic denervation, a substantial minority have partial denervation confined to the inferolateral or apical walls, and a small number have normal innervation. Among patients with partial denervation the neuronal loss invariably progresses over time, and in those with normal innervation at least some loss eventually becomes evident. Thus, cardiac sympathetic denervation in PD occurs independently of the movement disorder. PD+OH also entails extra-cardiac noradrenergic denervation, but this is not as severe as in pure autonomic failure. PD+OH patients have failure of both the parasympathetic and sympathetic components of the arterial baroreflex. OH in PD therefore seems to reflect a "triple whammy" of cardiac and extra-cardiac noradrenergic denervation and baroreflex failure. In contrast, most patients with multiple system atrophy, which can resemble PD+OH clinically, do not have evidence for cardiac or extra-cardiac noradrenergic denervation. Catecholamines in the neuronal cytoplasm are potentially toxic, via spontaneous and enzyme-catalyzed oxidation. Normally cytoplasmic catecholamines are efficiently taken up into vesicles via the vesicular monoamine transporter. The recent finding of decreased vesicular uptake in Lewy body diseases therefore suggests a pathogenetic mechanism for loss of catecholaminergic neurons in the periphery and brain. Parkinson disease (PD) is one of the most common chronic neurodegenerative diseases of the elderly, and it is likely that as populations age PD will become even more prevalent and more of a public health burden. Severe depletion of dopaminergic neurons of the nigrostriatal system characterizes and likely produces the movement disorder (rest tremor, slowness of movement, rigid muscle tone, and postural instability) in PD. Over the past two decades, compelling evidence has accrued that PD also involves loss of noradrenergic neurons in the heart. This finding supports the view that loss of catecholaminergic neurons, both in the nigrostriatal system and the heart, is fundamental in PD. By the time PD manifests clinically, most of the nigrostriatal dopaminergic neurons are already lost. Identifying laboratory measures-biomarkers-of the disease process is therefore crucial for advances in treatment and prevention. Deposition of the protein, alpha-synuclein, in the form of Lewy bodies in catecholaminergic neurons is a pathologic hallmark of PD. Alpha-synucleinopathy in autonomic neurons may occur early in the pathogenetic process. The timing of cardiac noradrenergic denervation in PD is therefore a key issue. This review updates the field of autonomic cardiovascular abnormalities in PD and related disorders, with emphasis on relationships among striatal dopamine depletion, sympathetic noradrenergic denervation, and alpha-synucleinopathy.