Baroreflex sensitivity and power spectral analysis in different extrapyramidal syndromes
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- Friedrich, C., Rüdiger, H., Schmidt, C. et al. J Neural Transm (2008) 115: 1527. doi:10.1007/s00702-008-0127-3
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Cardiac autonomic abnormalities have been described in Parkinson’s disease and other extrapyramidal syndromes. To investigate baroreflex sensitivity as an important risk marker of cardiovascular mortality in patients with Parkinson’s disease and other extrapyramidal syndromes. We recorded continuously blood pressure, ECG and respiration in 35 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 46 patients with idiopathic Parkinson’s disease (PD) and in 27 corresponding healthy subjects (Con). Recordings of 2 min at rest were used to calculate baroreflex and spectral analysis of heart rate and systolic blood pressure. Resting baroreflex sensitivity (BRS) was significantly lower in the MSA and the PSP group but not in the PD group in comparison to the Con group. With increasing Hoehn & Yahr stage, BRS significantly decreased in all patient groups. In spectral analysis, all patient groups had a significantly lower relative low frequency (LF)-band power than the healthy controls. Patients with extrapyramidal disorders frequently demonstrate pathologically decreased BRS values and abnormalities of spectral analysis. This may have fundamental impact on the cardiovascular prognosis of patients with extrapyramidal disease.
KeywordsAutonomic dysfunctionBaroreflex sensitivityExtrapyramidal diseaseSpectral analysis
The response of heart rate to a given change of systolic blood pressure is a fundamental characteristic of the short-term regulation of the cardiovascular system. It is mediated by the baroreflex arc, which includes peripheral afferent (aortic and carotid baroreceptors) and efferent (vagal and sympathetic tone) as well as central mechanisms (brainstem and higher cerebral centers). This arterial baroreflex regulating blood pressure and heart rate is of essential importance for cardiovascular homeostasis (Karemaker and Wesseling 2008). An increase of blood pressure will be responded by a decrease of heart rate, and vice versa. To assess function of the baroreflex arc, baroreflex gain or sensitivity (BRS) is calculated by measuring the changes of heart rate related to blood pressure changes (Parati et al. 2000).
The impairment of baroreflex function plays an adverse role in a wide range of diseases. Recently, several studies including prospective, randomized, multicenter studies like the ATRAMI study in patients after myocardial infarction have shown that depressed BRS is an independent predictor for sudden cardiac death and life threatening arrhythmias (Schwartz 1998; La Rovere 2000). As for patients with diabetes or after myocardial infarction, increased cardiovascular mortality has been reported in patients with different extrapyramidal disorders (Ben-Shlomo and Marmot 1995; Bennett et al. 1996). Although it is known that there are cardiavascular autonomic abnormalities (Goldstein 2003; Goldstein et al. 2007; Ziemssen and Reichmann 2007), only few studies have assessed baroreflex function in PD patients (Appenzeller and Goss 1971; Szili-Torok et al. 2001; Oka et al. 2003; Goldstein 2007). Up to now, no study has compared BRS in typical versus atypical Parkinsonian syndromes like progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) so far.
This maybe the case because of methodological problems as BRS is typically assessed by specific stimulatory tests like Valsalva manoeuvre, metronomic breathing or even as gold standard by drug application (e.g. Modified Oxford method) (Hilz and Dutsch 2006). Such procedures cannot be performed by all patients with extrapyramidal disease and needs special settings (Oka et al. 2003). In contrast to traditional techniques of BRS estimation, trigonometric regressive spectral analysis (TRS) combines statistical elements to cope with the stochastic nature of time-varying clinical signals with the ability to use short data segments for analysis, even in patients with decreased variability of biosignals (Ziemssen et al. 2008). Therefore, using TRS, only 2 min recording intervals of resting heart rate and blood pressure are sufficient for analysis, without the need of an additional provocative manoeuvre to induce blood pressure changes. As BRS is calculated by our TRS method using spectral analysis, we performed additionally power spectral analysis of heart rate and systolic blood pressure (SBP) in this study. Power spectral analysis has the advantage of being a simple, non-invasive measurement capable of assessing dynamic changes in the autonomic control of heart rate and blood pressure (Malliani and Montano 2002).
The aim of the present planned cross-sectional study was (1) to assess the BRS and the mentioned spectral parameters in patients with different extrapyramidal disorders. (2) Correlations of BRS with other clinical characteristics (e.g. Hoehn & Yahr stage) and other autonomic function tests (e.g. Valsalva manoeuvre, metronomic breathing or tilt testing) which are used in common practice were analysed.
Patients and methods
Clinical data of patients and controls clinical characteristics of the patients with multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and with Parkinson′s disease (PD) as well as healthy controls (Con) (mean ± SD)
Number of patients
Age at investigation
62 ± 8
66 ± 7
66 ± 8
60 ± 6
Age at onset of disease
58 ± 8
61 ± 7
57 ± 10
Duration of disease (years)
4.0 (3.0; 6.0)
3.5 (3.0; 6.5)
8.0 (3.5; 13.0)
Hoehn & Yahr staging
4.0 (3.0; 4.0)
4.0 (3.0; 4.0)
2.5 (2.0; 3.0)
Patients with medication
Mean daily dose in mg
550 ± 246
482 ± 210
517 ± 209
Pramipexole (mean daily dose in mg)
7(1.9 ± 0.6)
2(1.4 ± 1.0)
12(2.3 ± 1.4)
MAO inhibitor (Selegeline)
Mean daily dose in mg
357 ± 131
325 ± 129
229 ± 108
Recordings were performed in a specialized autonomic laboratory, in a quiet environment with controlled temperature and humidity during the morning after usual drug application in the most cases. Besides PD medication, no other medication was allowed. Continuous cardiovascular monitoring of heart rate and blood pressure was performed using the SUEMPATHY device (Suess Medizin-Technik, Aue, Germany) including the non-invasive blood pressure monitoring CBM3000 device (Nihon Colin Co., Komaki, Japan). The subjects rested in a supine position of a tilt table for 20 min until a cardiovascular steady state was reached. First, 2 min of resting supine subjects were recorded for BRS and spectral analysis. Thereafter, deep metronomic breathing with 6 cycles/min for 3 min was performed to calculate expiration/inspiration (E/I) ratio as parameter of cardiovagal function. After having reached a cardiovascular steady state again, at least three recordings of Valsalva manoeuvre were done by having the supine subjects exhale into a mouthpiece at an expiratory pressure of 40 mmHg for 15 s. After staying at least for 20 min in resting supine position, patients were tilted up to a 60° upright position within 15 s for 10 min during head-up tilt-table (HUT) testing (Schmidt et al. 2008a). Patients with orthostatic hypotension were defined according (Kaufmann 1996), for further details see (Schmidt et al. 2008a, b).
Trigonometric spectral analysis with baroreflex analysis
The algorithm of the Trigonometric Regressive Spectral (TRS) analysis provides a pure physiological spectrum using only statistical methods (trigonometric regression) and not Fast Fourier Transformation (Rudiger et al. 1999; Ziemssen et al. 2008). So short data segments up to 20 s can be analysed. In this study, stationary global data segments of 2 min were analysed by TRS using single time windows of 30 s which were shifted beat by beat which allows determination of spectral parameters (frequency, amplitude) over time. A summary of the algorithm can be found on the website of the European Working Group on Blood Pressure and Heart rate Variability (http://www.cbi.polimi.it/esh-wg/).
The EuroBavar Study by Laude et al. (2004), which compared different methods of non invasive calculation of baroreflex sensitivity, demonstrated a good agreement of TRS with many techniques, and it clearly detected impaired baroreflex sensitivity in subjects with autonomic failure.
In addition to BRS estimation, spectral analysis can be performed by TRS as well. Spectral analysis of heart rate may identify autonomic inputs to the heart. Two major spectral bands are usually identified: High-frequency (HF) power of heart rate (RR-HF) relates to respiratory sinus arrhythmia and therefore to parasympathetic cardiovagal tone. In contrast, low frequency (LF) power of heart rate (RR–LF) reflects baroreflexive modulation of autonomic outflows. Regarding systolic blood pressure, the LF component of systolic blood pressure (SBP–LF) spectra, referred to as Mayer’s wave, is mediated by the sympathetic nervous system, especially vasomotor function, while the HF component (SBP–HF) depends on mechanical respiratory movements and is unaffected by autonomic activity.
Data are presented as mean ± SD. For statistical analysis, Mann–Whitney rank sum test was used to compare the individual groups. Differences were considered as significant when P < 0.05. Spearman’s rank test was used to assess correlations.
Performance of autonomic and BRS testing
In this study, 113 patients with extrapyramidal disorders and 27 healthy controls were included. In addition to continuous recording of blood pressure, ECG and respiration in the resting patients and healthy patients, a standard autonomic test battery including metronomic breathing, Valsalva manoeuvre and tilt testing was performed. For BRS analysis using the TRS algorithm, 2 min of continuous recording during rest were analysed. By this method, BRS could be calculated in all 113 patients and 27 healthy controls who were included in this trial. In contrast, Valsalva manoeuvre and metronomic breathing, which were used for BRS determination by others (Goldstein 2003; Oka et al. 2003), could be only performed by 69% respectively 71% of all patients and 93% respectively 100% of healthy controls because of oral muscle weakness or limited respiratory movements.
BRS and spectral analysis in extrapyramidal syndromes
Correlation of BRS/spectral analysis with clinical characteristics
Correlation of BRS/spectral analysis with other autonomic tests
In our study, we could demonstrate significant pathological parameters of the autonomic cardiovascular system (BRS, spectral analysis) in patients with extrapyramidal disorders in only 2 min undisturbed recordings. Especially for patients with atypical Parkinsonian disorders like PSP and MSA, there were significant lower, pathological BRS values. It is interesting that even in the PSP group, BRS is pathologically decreased which is in line with our previous studies on autonomic dysfunction in PSP (Schmidt et al. 2007, 2008b). We could not find significant differences between the PD and healthy control group due to the variability of the BRS values in both the PD and control group. This is in line with fact that autonomic dysfunction is quantitatively and qualitatively different between individual PD patients in contrast to the atypical Parkinsonian syndromes (Mathias 1998). So only 30% of PD patients demonstrate with significant clinical autonomic dysfunction. Comparing MSA with PD patients, BRS values were significantly lower in the MSA group.
Only few studies have demonstrated pathological BRS values in PD, but not yet in atypical Parkinsonian syndromes as PSP and MSA (Appenzeller and Goss 1971; Szili-Torok et al. 2001; Goldstein 2003, 2007; Oka et al. 2003). When we investigated the correlation between Hoehn & Yahr stage of disease and BRS, our study including more than 100 patients is in line with a previous pilot study by Oka et al. (2006a, b) to demonstrate a decrease of BRS with increase Hoehn & Yahr stage of disease. Interestingly, nearly all patients with a disease onset of more than 10 years ago presented with a pathologically low BRS (data not shown). So, disease stage and duration seem to have an important impact on BRS, as it is already described for other autonomic parameters (Oka et al. 2006a, b).
Histopathological studies of Braak and others could recently demonstrate that already early in the disease process of extrapyramidal disorders important autonomic centers are damaged (Braak et al. 2004). However, the exact site or sites of the CNS lesions responsible for produce baroreflex failure are largely unknown (Goldstein 2003). Potential candidates in the CNS with cell loss and the occurence of Lewy bodies are the locus coeruleus, the C1 cells of the rostral ventrolateral medulla, the dorsal motor nucleus of the vagus nerve and the nucleus of the solitary tract which is the main site of termination of baroreceptor afferents (Halliday et al. 1990; Rub et al. 2002; Wakabayashi and Takahashi 2006). Damage to any of these centers may influence the measured value of BRS.
If established autonomic function tests were compared with BRS and spectral analysis, Goldstein et al. (2003) have shown that cardiovagal gain as BRS parameter derived from analysis of the Valsalva manoeuvre was significantly decreased in PD patients with PD stratified by the presence of orthostatic hypotension. We were not able to find a correlation between orthostatic hypotension in our more than 100 patients with extrapyramidal syndromes. In contrast, our subanalysis demonstrated that lower BRS values correlated with pathological cardiovagal function as assessed by a decreased E/I ratio during metronomic breathing. This has been already reported by Szili-Török et al. (2001).
In addition to the baroreflex analysis, we performed spectral analysis of heart rate and systolic blood pressure using our TRS technique in this study. In all patient groups, we were able to describe pathologically low relative LF-band power of RR interval and SBP spectrum without pathological HF-band values. So the ratio (LF/HF) of both RR–LF to RR–HF and SBP–LF to SBP–HF were significantly lower than the respective control values, despite no significant difference in RR–HF. This has been described for PD patients by Oka et al. (2006a, b). Up to now, the pathologically increased relative UHF-band power of RR interval spectrum in patients with extrapyramidal disease has not been described so far. This cannot be clinically interpreted so far.
While Rodriguez et al. (1996) described a decrease of all spectral bands of the HR power spectrum, our results are in line with the results of Oka et al. (2006a, b) in PD patients. As Moak et al. (2007) have demonstrated, we could show that relative LF-band power represents baroreflex function, as BRS correlated with relative LF-band power.
The relative LF-band power seems to be a sensitive marker to detect autonomic cardiovascular abnormalities, as decreased relative LF-band power is present in patients with orthostatic hypotension and with parasympathetic dysfunction. In addition, relative LF-band power is correlated with the BRS itself. Spectral analysis with the measurement of relative LF-band power may be helpful in extrapyramidal syndromes. However, the clinical correlate of pathologies with sympathetic or parasympathetic dysfunction has still to be clarified.
Because of practical reasons—autonomic testing could not be performed in OFF state of a patient—most of our patients were on medication during testing. But in a subanalysis, we were not able to describe significant differences between patients with and without drugs. Although the percentage of L-dopa treated patients was similar, more PD patients were treated with dopamine agonists. We regard this effect only minor from the literature and our unpublished data (Mesec et al. 1993; Goldstein 2003; Bouhaddi et al. 2004).
Assessment of baroreflex sensitivity plays an important role in the evaluation of the cardiovascular autonomic function. Regarding methodology, BRS has conventionally been assessed by bolus injection of vasoactive drugs, such as phenylephrine in the Oxford manoeuvre. However, the procedure is invasive and has several limitations like altering afferent discharge and BRS itself to pressure. As an alternative, BRS can be assessed using the cardiovascular response to the Valsalva manoeuvre (Goldstein 2003; Oka et al. 2003). However, 31% of our patients with extrapyramidal disorders could not perform the Valsalva manoeuvre because of oral muscle weakness or limited respiratory movements. Another non-invasive method, the sequence method in the resting patient, is difficult to perform because of the only very small and rare fluctuations of the biosignals at rest. Using this approach, Oka et al. (2003) obtained BRS values only in 54% of the investigated PD patients. Szili-Török et al. (2001) had to use 60 min continuous recordings of cardiovascular signals to get enough sequences for analysis. The necessity for these long recording intervals implies the risk of unstationary signals and impractibility for clinical practice in comparison to our used 2 min intervals. If sequence method would have been combined with metronomic breathing, as Oka proposed to increase the overall fluctuations (Oka et al. 2003), again 29% could not be analysed in our study. In addition, Valsalva manoeuvre and metronomic breathing may modulate BRS itself, as our preliminary data indicate (Friedrich et al., in preparation).
In contrast to these methodological problems, our TRS method which needs cardiovascular recordings of only 2 min duration allowed the calculation of BRS in 100% of patients and healthy controls, even in patients with advanced disease who were not able any more to perform the autonomic function tests.
What are the clinical implications of the decreased BRS and pathological spectral analysis? In patients with heart failure and after myocardial infarction, a decreased BRS can serve as a predictor of adverse outcome (De Ferrari et al. 2007). In cerebral stroke, impaired BRS is associated with increased long-term mortality after acute ischemic stroke, irrespective of age, sex, stroke type, and BP (Robinson et al. 2003). Psychiatric, non cerebro-cardiovascular diseases like depression have been demonstrated that autonomic dysregulation can cause increased cardiovascular mortality (Carney et al. 2005). In neurodegenerative diseases, the significance of the abnormal BRS is still unclear. Here, we would like to mention the hypothesis that cardiovascular autonomic dysfunction which can be quantified by BRS analysis can be at least partly responsible for the increased mortality in patients with extrapyramidal disease. The mortality of PD patients is almost doubled compared with age and sex-matched healthy controls (Bennett et al. 1996). Ben-Shlomo and Marmot (1995) demonstrated in a 20-year follow-up study an increase in heart ischemia related deaths which may account for the increased mortality.
So larger prospective studies using our innovative TRS approach which is easy and quick (2 min) to perform are needed to investigate a possible predictive value of BRS and other spectral parameters for individual patients in extrapyramidal syndromes. In our clinical practice, every patient with extrapyramidal syndrome is analysed by this method, non-invasively and without assistance of the patient. As there are PD patients with and without significant autonomic dysfunction and with and without pathological BRS values (Szili-Torok et al. 2001; Oka et al. 2003; Goldstein 2007), the clinical correlate and prognostic value has to be described in this patient group.