Correction: Heart rate variability provides prognostic value in multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, and cerebellar impairment. Understanding the physiological correlates of disease severity and survival remains challenging due to heterogeneity in disease progression. Heart rate variability (HRV) is a noninvasive measure of autonomic nervous system function. However, the role of nonlinear HRV in MSA remains incompletely understood. This study investigated the association between HRV features, clinical severity, and survival in MSA (n = 214). Regression models were used to examine relationships between HRV and disease severity assessed by the Unified MSA Rating Scale (UMSARS), as well as time to death. Survival analyses evaluated the contribution of HRV features to risk stratification, and mediation analysis explored the relationships among HRV, UMSARS, and survival. HRV features were negatively associated with disease severity, consistent with progressive autonomic dysfunction. While individual HRV features showed limited associations with UMSARS, their combination demonstrated a stronger relationship. Models incorporating HRV features showed associations with time to death comparable to those based on UMSARS, and the combined inclusion of HRV and UMSARS was associated with improved accuracy. Mediation analyses suggested that HRV captures physiological information related to survival that is not fully reflected by clinical severity scores. HRV features are associated with disease severity and survival in MSA and provide complementary physiological information beyond established clinical scales. These findings support the relevance of HRV as an exploratory modeling tool for autonomic dysfunction in MSA and highlight candidate features for future longitudinal and validation studies, rather than establishing a validated prognostic model.

Introduction Parkinsonian syndromes of different nature feature autonomic nervous system dysfunction (ANSd) which may herald or follow motor symptoms (MS) in Parkinson disease (PD), but anticipate by years and progress more rapidly in multiple system atrophy (MSA). Abnormal Heart Rate Variability (HRV) has been reported in both PD and MSA. Purpose This study aimed to evaluating if HRV analysis (HRVa) could contribute to differentiate PD from MSA and to guide early and more appropriate treatment and prognostic assessment. Methods 66 consecutive parkinsonian patients (pts) (48 males, 18 females) (mean age 63.8±10 y) were enrolled between 2010 and 2020. Initial clinical diagnosis was MSA (19), PD (20), PD with autonomic impairment (PD-AI) (10), Lewy body disease (2), supranuclear palsy (3), undefined Parkinsonism (UP) (12). The severity of MS was quantified with UPDRS and Hoehn/Yahr scales. HRV was analyzed with linear (TD and FD) and non-linear (NL) methods (Kubios Premium 3.4.1), during daily activity and NREM sleep (2-minutes intervals) and during REM sleep (1-minute Interval). 44/66 underwent also ASN functional evaluation with the Ewing protocol. Data of 52 age-matched healthy subjects (HS) were used for comparison. For statistical analysis, SPSS software (version 21) was used. Discriminant Analysis (DA) was applied to identify the more relevant parameters differentiating PD from MSA and classifying “undefined” cases. Prolonged follow-up (f-up) provided clinical diagnostic certainty, as goldstandard for validation of HRVa classification accuracy. Results UPDRS and Hoehn/Yahr scores were higher in MSA than in PD (p<0.0001). Along 10-years of f-up, 16/66 pts died (56,2% MSA), 5/66 had new diagnostic definition, and 15/66 were lost to f-up. Most of HRV parameters of 34 pts with certain diagnosis (17 MSA and 17 PD) whose f-up was completed, were significantly different from those of HS. VLFpower and recurrence plot parameters calculated during active wakefulness were different (p<0.05) between MSA and PD, and correctly classified them with 88,2% predictive accuracy (PA) at DA, according to the formula: F1 = (vlfpw%ar* − 0,087) + (rprec* − 0,319) + (rpshen*10.81) + (−20,53) Comparative classification accuracy of HRVa, Ewing score, UPDRS and Hoehn/Yahr scales is shown in Table 1. Attempting prognostic risk assessment by applying F1 to HRV data of pts with PD-AI and of pts with UP, those classified as MSA according to F1 showed the worst clinical outcome during the f-up. Conclusions This study confirms that a higher degree of prevailing sympathetic ASNd in MSA compared to PD can be identified by a combination of Linear and NL HRV parameters, and correctly differentiate with high (88,2%) predictive accuracy all pts with certain diagnosis verified during prolonged f-up. Moreover, HRVa might be useful for earlier prognostic stratification of pts with parkinsonian symptoms of uncertain nature and to improve clinical and pharmacological management. Funding Acknowledgement Type of funding sources: None.

Because heart rate is controlled mainly by the autonomic nervous system, cardiovascular autonomic dysfunction may contribute to the prognosis of patients with multiple system atrophy (MSA). To clarify cardiovascular autonomic dysfunctions in MSA, the authors investigated the relation between blood pressure (BP) and pulse rate (PR), and assessed a power spectral analysis of heart rate variability (HRV) during the clinical course using ambulatory BP and a heart rate monitor for 24 hours. The authors studied seven patients with MSA (five men and two women, aged 61.0 +/- 5.8 years) and seven healthy volunteers (four men and three women, aged 58.0 +/- 6.6 years) without hypertension, heart disease, or intracranial lesions. The MSA group showed abnormal circadian variations of BP and PR and a significantly decreased correlation coefficient between BP and PR. A significant decrease and altered circadian variation also existed in the number of changes in successive R-R intervals greater than 50 msec (RR50) and in the power of the high- and low-frequency component of HRV. The authors observed a significant negative correlation between the duration of illness and the number of changes in successive R-R intervals greater than 50 msec. The characteristic dysautonomia in MSA was a decrease in sympathetic and parasympathetic activity, with an abnormal circadian rhythm of BP and HRV. The balance between sympathetic and parasympathetic activity was also impaired. The parasympathetic modulation represented by RR50 worsened according to the development of the illness. Those autonomic dysfunctions may have affected the cardiovascular systems, which may indicate a poor prognosis in patients with MSA. An analysis of HRV and the circadian rhythm of BP and HRV are useful in evaluating cardiac autonomic dysfunctions in MSA.

Background The Baevsky Stress Index (BSTRi), calculated from Heart Rate Variability (HRV) data, has been proposed for quantitative assessment of physiological stress, with higher scores indicating higher levels of physical and/or psychological stress [1]. Cardiac autonomic modulation can be synthetically quantified by calculating the parasympathetic (PNSi) and the sympathetic (SNSi) indexes. The values of the BSTRi, SNSi, and PNSi in patients with synucleinopathies of different prognoses have not been reported yet. Purpose To quantify, in patients with Parkinson's disease (PD) and Multisystem Atrophy (MSA), the BSTRi, its correlation with the PNSi and the SNSi indexes, and their potential value for a synthetic assessment of cardiac autonomic modulation and early differential diagnosis between PD and MSA. Methods Holter ECG data of 66 patients with Parkinsonian syndromes were retrospectively analyzed after 10 years of follow-up. Out of them, 34 patients with a certain diagnosis of PD (17) and MSA (17) were selected for this study. HRV was analyzed with the Kubios software (version 4.0), providing automatic calculation of the BSTRi, PNSi, and SNSi [2], as well as of time domain (TD), frequency domain (FD), nonlinear (NL), and time-varying (TV) HRV parameters. HRV was calculated from selected short-term intervals (of 5 minutes), during daily activity (ACT5’), and non-REM sleep (NREM5’), and from 24-hours Holter recordings. Patients’ HRV findings were compared with those of 51 age-matched healthy subjects (HS). Results An example of individual automatic graphic summary is shown in Figure 1. Both short-term and 24-hour BSTRi and SNSi values were significantly (p < 0.05) higher in PD and MSA compared to those of HS, in all investigated conditions. Short-term PNSi was significantly higher in HS than in PD in all conditions, but only during NREM5’ in MSA patients (Table 1). No significant difference was found between the indexes of PD and MSA patients. As in HS (R=92), BSTRi was positively correlated with the SNSi in MSA (average R= 0.83 and 0.89 during ACT5’ and NREM5’, respectively), but less evident in PD (R=0.67). The inverse correlation between PNSi and SNSi (R=0.75 in HS) was lost in both MSA and PD. Conclusions Higher values of BSTRi in PD and MSA compared to HS suggest that patients with synucleinopathies do experience higher levels of psychophysiological stress, which may affect their quality of life negatively. However, since no significant difference was found in this study between BSTRi values of PD and MSA patients, BSTRi seems at present unreliable for early differentiation between the two diseases. Telematic assessment of BSTRi, SNSi, and PNSi could be useful for remote monitoring of PD and MSA patients’ psychophysiological stress, to provide timely intervention and adaptive treatment.Fig.1 Example of graphic summary (ACT5')

Oligodendroglial alpha-synucleinopathy and MSA-like cardiovascular autonomic failure: Experimental evidence

To assess and compare autonomic nervous system (ANS) dysfunction, especially cardiovascular dysautonomia, in Parkinson's Disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls. Assessment of ANS can be useful in differential diagnosis. Dysautonomia affects quality of life and can lead to potentially life-threatening complications. There is very little literature data regarding dysautonomia in PSP in relation to other parkinsonian syndromes. This study expands the knowledge about ANS dysfunction in parkinsonisms, especially PSP. Patients with PD, MSA and PSP were prospectively recruited to our study. Demographic data and information about clinical and neuropsychological assessment, medication and comorbidities was collected. SCOPA-AUT questionnaire, 5-minute tilt test, and 5-minute heart rate variability (HRV) analysis in time and frequency domains were used to assess ANS. Analysis was also performed in patients with PSP-RS and PSP-P phenotypes, and in a subgroup with eliminated confounding factors, including age and disease duration. 76 PD, 25 PSP, and 12 MSA patients, and 20 controls, were included. Symptoms of dysautonomia revealed by a SCOPA-AUT questionnaire were present in all groups of patients. Urinary dysfunction was more pronounced in atypical parkinsonisms, and cardiovascular symptoms in α-synucleinopathies. HRV was disrupted in all groups of patients. However, when PSP-P and PSP-RS phenotypes were considered, HRV was diminished in PSP-RS, but there were no differences in HRV parameters between PSP-P and controls. Neurogenic orthostatic hypotension was present in 25% of PD and 58% of MSA patients, but it was absent in PSP patients and the control group. 13 PD and nine PSP patients and 16 controls were included in subanalysis. This revealed that PSP, but not PD, patients had significantly more symptoms of dysautonomia and lower HRV indices compared to controls, and that orthostatic hypotension was even more common in PD than in controls. Our study suggests that dysautonomia is common in PD, MSA and PSP, even though it has different profiles in the different diseases. NOH is present in PD and MSA, but not in PSP.

The correlates of indices of long-term ambulatory heart rate variability (HRV) of the autonomic nervous system have not been completely understood. In this study, we evaluated conventional HRV indices, obtained from the daytime (12:00–18:00) Holter recording, and a recently proposed non-Gaussianity index (λ; Kiyono et al., 2008) in 12 patients with multiple system atrophy (MSA) and 10 patients with Parkinson disease (PD), known to have varying degrees of cardiac vagal and sympathetic dysfunction. Compared with the age-matched healthy control group, the MSA patients showed significantly decreased HRV, most probably reflecting impaired vagal heart rate control, but the PD patients did not show such reduced variability. In both MSA and PD patients, the low-to-high frequency (LF/HF) ratio and the short-term fractal exponent α1, suggested to reflect the sympathovagal balance, were significantly decreased, as observed in congestive heart failure (CHF) patients with sympathetic overdrive. In contrast, the analysis of the non-Gaussianity index λ showed that a marked increase in intermittent and non-Gaussian HRV observed in the CHF patients was not observed in the MSA and PD patients with sympathetic dysfunction. These findings provide additional evidence for the relation between the non-Gaussian intermittency of HRV and increased sympathetic activity.

It is thought that the autonomic nervous system modulates QT interval, but traditional autonomic blockade combining propranolol and atropine has produced conflicting results. We used the alternative approach of interrupting neurotransmission at the level of autonomic ganglia to determine its effect on the QT interval. We infused trimethaphan at increasing doses (0.5 to 10 mg/min IV) while monitoring heart rate, heart rate variability spectra, QT interval, and blood pressure in 10 normal volunteers, 9 patients with multiple system atrophy (MSA), and 8 patients with pure autonomic failure (PAF). The QT interval was corrected for heart rate using Bazett's formula (QTc). Patients with PAF had very low heart rate variability and a prolonged QTc at baseline (465+/-8 ms) compared with patients with MSA (448+/-6 ms) and normal subjects (432+/-6 ms). In normal subjects, trimethaphan dose-dependently prolonged QTc (to 469+/-7 ms), decreased RR interval (995+/-45 to 670+/-35 ms), and abolished heart rate variability. In MSA patients, trimethaphan also prolonged QTc (to 463+/-7 ms) and reduced heart rate variability but did not significantly change RR interval (from 813+/-38 to 801+/-39). Autonomic blockade prolongs QT interval in normal subjects to a similar duration as in PAF patients. Furthermore, blocking residual autonomic tone in PAF patients is associated with a further increase in QT interval length. Patients with MSA have greater residual sympathetic tone and greater prolongation of the QT interval during ganglionic blockade than PAF patients.

ABSTRACTBackgroundDegenerative parkinsonian syndromes, including the alpha‐synucleinopathies (aSYN) Parkinson's disease (PD), and multiple system atrophy (MSA), and the tauopathy progressive supranuclear palsy (PSP), are characterized by motor and non‐motor symptoms. The later subsume autonomic dysfunction, which may appear early or progress with the disease. Cardiac dysfunction varies by syndrome and can also occur in isolated REM sleep behavior disorder (iRBD), a prodromal stage of aSYN. Overlapping motor features make early differentiation challenging. Heart rate variability (HRV) analysis is a noninvasive tool for evaluating cardiac autonomic function, with deceleration capacity (DC) as a sensitive parasympathetic marker. This study compares HRV and DC across parkinsonian syndromes to assess their potential in early diagnosis and differentiation.MethodsUsing standardized 30‐min resting ECG recordings in the early morning, we analyzed HRV parameters in five groups: iRBD (n = 10), PD (n = 10), MSA (n = 10), PSP (n = 9), and healthy controls (HC, n = 10). Evaluated HRV parameters included HRV index (HRVI), reflecting overall variability, and DC.ResultsAs expected, DC was significantly lower in MSA (3.82 ± 1.38) and unexpectedly even lower in PSP (3.19 ± 2.77), compared to HC (9.66 ± 4.67) and PD (7.55 ± 2.48). These findings are novel for PSP. HRVI was significantly reduced in PSP, while other HRV parameters showed no significant differences.ConclusionsDeceleration capacity (DC) reduction in MSA and PSP suggests pronounced cardiac parasympathetic dysfunction. DC may support differentiation between PD and atypical syndromes, but larger studies are needed for validation. Given the impact of autonomic dysfunction on quality of life and mortality, comprehensive autonomic testing should be included in the diagnostic workup.

Differentiation of Parkinson’s disease and multiple system atrophy in early disease stages by means of I-123-MIBG–SPECT

The differentiation between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) may be difficult but is important for prognostic and therapeutic purposes. Varying degrees of autonomic failure have been described in PD and MSA, whereas its involvement in PSP remains controversial. The aim of this study was to investigate autonomic function in patients fulfilling strict clinical diagnostic criteria for the disorders above, to evaluate the diagnostic capacity of laboratory autonomic tests. The study group was consecutively recruited among patients referred to a movement disorder unit. Thirty-four patients with PD, 15 patients with PSP, and 47 patients with MSA were compared with 18 healthy age-matched controls. Autonomic tests included analysis of heart rate variability (HRV) in temporal domain, at rest and during forced respiration, as well as blood pressure (BP) changes during 75 degrees head-up tilt. HRV did not differ between groups during quiet breathing but was significantly reduced during forced respiration in MSA (P < 0.01), while PD and PSP groups did not differ from controls. Hypotensive responses during orthostatic provocation were seen in PD (P < 0.01) and MSA (P < 0.001), whereas BP remained stable in most PSP patients, not differing from the healthy control group. On an individual basis, decreased HRV and severe hypotensive responses were seen in MSA patients regardless of age and disease duration, whereas PD patients showed this combination only at high age and long duration. In PSP, only a few cases with decreased HRV and limited hypotensive responses were found. We conclude that cardiovascular reflex tests can supplement the clinical differentiation of Parkinsonian syndromes.

To the Editor: We have read the article by Barthel et al1 describing the first prospective trial to determine the predictive value of heart rate turbulence (HRT) in patients after acute myocardial infarction. In previous studies, the ability of HRT to predict risk was only determined retrospectively.2 We would like to critically discuss here the uniqueness of the emerging risk factor, HRT, in comparison with other parameters. Interestingly, Barthel et al1 found that HRT was the strongest ECG-based risk predictor. This conclusion is surprising for 2 reasons, as follows. First, in an editorial comment3 on the original article by Schmidt et al,2 it was noted that the positive predictive value of HRT is only moderately higher than other ECG risk parameters, and it was suggested that …

Parkinson's disease (PD) with autonomic dysfunction is difficult to differentiate from Parkinsonism-predominant multiple system atrophy (MSA-p). This study aimed to analyze the validity of MIBG scintigraphy for PD with autonomic dysfunction and MSA-p. Thirty-nine patients (PD: 27 patients, MSA-p type: 12) and 12 age-matched controls were prospectively enrolled and underwent MIBG scintigraphy and autonomic function test (AFT). We separately calculated early and delayed heart-to-mediastinal (H/M) ratio and washout rates (WRs). AFT was composed of sympathetic skin reflex and parasympathetic tests based on heart rate variability. Abnormal AFT was observed in 17 (63%) of PD and 10 (83%) of MSA-p. On comparing PD with abnormal AFT with MSA-p, either the early or delayed H/M ratio in PD was not different from that in MSA-p (P > 0.05). Only the WR could differentiate PD with abnormal AFT from MSA-p (47.07 +/- 57.48 vs. 31.39 +/- 31.52, respectively) (P = 0.026). According to the results, WR may be more useful than the early and delayed H/M ratio to distinguish MSA-p from PD with abnormal AFT. Furthermore, the MIBG uptake did not reflect the disease duration or severity.

Autonomic dysfunction in multiple system atrophy (MSA) comprises cardinal symptoms of orthostatic hypotension (OH) and urinary incontinence. Additionally, cardiovagal and sudomotor abnormalities can be present. Previous studies compared hand skin temperature and its response to cooling in subjects with probable MSA and Parkinson's disease (PD). Significant differences were found indicating that disturbed thermoregulation belongs to MSA autonomic features and could be helpful in differentiation of MSA from PD. The objective of this study was to improve our knowledge about impaired thermoregulation of distal extremities in MSA with parkinsonian features (MSA-P) and PD and to assess the possible interrelations for the different subtypes of autonomic dysfunction in a large cohort of MSA-P, PD and control patients. The patients underwent a standard cooling-rewarming procedure, termed ice test (IT). Electroneurography, heart rate variability, sympathetic skin response and orthostatic tests were performed for the subdivision of the patients. The prevalence of pathological IT was slightly increased in MSA compared with PD and control groups. The presence of pathological IT was related with older patient's age in PD and control groups significantly (p<0.05). This relation was absent for the MSA patients, who themselves were significantly younger (p=0.001). Significant association between the presence of pathological IT and OH was determined (p<0.001). Defective thermoregulation of distal extremities seems to be more severe in the MSA patients. The dysfunction of preganglionic sympathetic neurons might be involved in impaired response to cooling for MSA. The results suggest pathophysiological affinity of impaired sympathetic neurovascular regulation between pathological IT and OH.

OPINION article Front. Physiol., 12 September 2014Sec. Clinical and Translational Physiology https://doi.org/10.3389/fphys.2014.00347