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ORIGINAL ARTICLE
Year : 2023 | Volume
: 26
| Issue : 1 | Page : 33-38
Neurogenic supine hypertension and cardiovascular autonomic dysfunction in patients with parkinson's disease
Sunil Kapoor1, Alvee Saluja2, Shubha Laxmi Margekar1, Mayank Agarwal3, Sunita Mondal3, Rajinder K Dhamija2
1 Department of Medicine, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
2 Department of Neurology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
3 Department of Physiology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
Correspondence Address:
Rajinder K Dhamija
Director Professor and Head of Neurology Department, Lady Hardinge Medical College and SSK Hospital New Delhi - 110 001
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aian.aian_476_22
Abstract
Background: Natural history and disease progression in patients with Idiopathic Parkinson's Disease (PD) is quite heterogeneous. Autonomic dysfunction occurs commonly among Idiopathic PD patients. Heart rate variability and ambulatory blood pressure monitoring are used to assess cardiac autonomic dysfunction. The prevalence and magnitude of supine hypertension in Indian PD patients has not been studied to date. The present study aimed to record cardiovascular autonomic functions and supine hypertension in PD patients and to correlate them with the age of onset, duration and severity of the disease, and non-motor symptom burden. Material and Methods: The cross-sectional study involved 60 PD patients. Webster rating scale was used to determine the disease severity. Non-motor symptom burden was assessed using the Non-Motor Symptom Scale (NMSS). Ambulatory blood pressure monitoring and heart rate variability parameters determined cardiac autonomic function. Supine hypertension was defined as Systolic Blood Pressure (SBP) ≥150 mmHg and/or DBP ≥90 mmHg. Less than 10% decrease or even increase in blood pressure during the night were classified as non-dippers. Pearson coefficient was used appropriately to establish correlation. P ≤ 0.05 was considered significant. Results: Age of onset was 61.2 ± 8.7 years and duration of disease was 1.7 ± 1.1 years. Mean Webster and non-motor symptom scores were 12.7 ± 4.4 and 15.5 ± 8.0, respectively. About 50 patients (83%) were non-dipper, while 32 (53%) had supine hypertension. Low Frequency oscillations (LF) (r = 0.28), High Frequency oscillations (HF) (r = 0.29), Standard Deviation NN intervals (SDNN) (0.26), and Root Mean Squared Successive Differences of NN intervals (RMSSD) (r = 0.28) correlated significantly with non-motor symptoms scale. LF (r = −0.39), HF (r = −0.43), SDNN (−0.40), RMSSD (r = −0.41), NN50 (r = −0.38), PNN50 (r = −0.42), mean SBP (r = 0.26), and mean DBP (r = 0.33) correlated significantly with disease duration. PNN50 (r = −0.255), mean SBP (r = −0.29), and mean DBP (r = −0.27) correlated significantly with age at onset. Conclusion: Awareness regarding neurogenic supine hypertension is needed as it occurs commonly among Indian PD patients. Heart rate variability (HRV) parameters and ambulatory blood pressure are of significant help in the detection of early cardiovascular autonomic dysfunction and correlate significantly with disease duration and non-motor symptom burden among PD patients.
Keywords: Ambulatory blood pressure monitoring, autonomic dysfunction, heart rate variability, non-dipper, Parkinson's disease, supine hypertension
Introduction 
Parkinson's disease (PD) is a common neurodegenerative disorder affecting roughly 1% of individuals above the age of 60 years.[1] In India, the age-specific prevalence of PD among individuals above the age of 50 years, has been estimated to vary from 76–148/100,000 individuals across various studies.[2],[3],[4] Thus, the absolute number of individuals suffering from PD in India is huge. Although, the cardinal motor features of PD are bradykinesia/akinesia along with resting tremors, rigidity and postural imbalance, non-motor symptoms such as autonomic disturbances are frequently seen during the course of the disease.[5] Furthermore, studies have shown that the quality of life in one-third to four-fifths of PD patients are significantly impaired by autonomic dysfunction.[6],[7] Autonomic dysfunction starts to occur very early in PD and increases in frequency as the disease progresses.[8] Studies have shown that cardiovascular dysregulation is one of the commonest forms of dysautonomia that occurs in PD.[5],[8],[9]
Cardiovascular autonomic dysfunction in PD manifests as blood pressure variability in the form of Orthostatic hypotension, supine or nocturnal hypertension, and absence of decrease in blood pressure during the night.[9],[10],[11],[12] Since, dysfunction of both sympathetic and parasympathetic arms of the autonomic nervous system occurs in PD, changes in heart rate variability are evident as well.[8],[13],[14],[15]
There is scant literature available from India on the occurrence of cardiovascular autonomic dysfunction and it's correlation with age, disease severity, and duration among PD patients. In fact, there has only been one prior study among 30 Indian PD patients which has attempted to find a correlation between heart rate variability with deep breathing (HRDB) with disease severity and non-motor symptom scale scores (NMSS).[16] However, there have been no prior studies which have assessed the correlation of cardiovascular autonomic disturbances as a whole with age of onset, disease duration and severity among Indian PD patients. Furthermore, there have been no prior studies that have assessed the correlation of ambulatory blood pressure patterns with disease severity, duration, and non-motor symptom burden among Indian Parkinson's disease patients. Prior studies have shown ethnic variations in heart rate variability (HRV) parameters among African Americans compared to the Caucasian population. In a meta-analysis of 17 studies with over 11,162 participants, African Americans exhibited higher HRV compared to their Caucasian counterparts independent of confounders such as age, sex, and health status.[17] Similarly, Indian Asians residing in Europe have been found to have significantly shorter mean RR interval, lower total RR interval power, and lower baroreceptor sensitivity compared to Europeans.[18] Due to the paucity of literature regarding these parameters among Indian PD patients, the present study was designed to record ambulatory blood pressure as well as HRV parameters in idiopathic Parkinson's patient and to correlate these parameters with the age of onset, duration, and severity of the disease.
Methodology The present hospital based cross-sectional observational study was carried out over a period of one and half years. Participants were recruited into the study after taking ethical clearance from the Institutional Ethics Committee (ECHR/2018/125T). A written and informed consent was taken from all the subjects prior to enrolment into the study. Subjects more than 18 years of age, having idiopathic PD [as per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria] were included as cases in the study.[19] Patients having other neurogenerative disorders (such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy body) and those with pre-existing hypertension and diabetes mellitus were excluded from the study. A total of 60 participants (sample of convenience) were included in this study.
A detailed history, general physical, and detailed neurological examination was done for all the subjects using a structured proforma. The Movement Disorder Society Non-Motor Symptoms Scale (NMSS) is used for the assessment of non-motor symptom burden among the PD patients, and the Webster Scale is used for the assessment of disease severity.[20],[21],[22],[23] We use the Webster's Rating Scale (WRS) in our study as it is also a validated clinical rating scale with moderate to good interrater reliability; takes relatively short time to perform in a busy Out Patient Department (OPD) setting and is relatively easy to perform. After clinical assessment of disease severity, ambulatory blood pressure monitoring (ABPM) and HRV were assessed.
A portable blood pressure device (Meditech ABPM-05, Meditech Ltd., Budapest) was used for ABPM. Subjects were made accustomed to the working of the portable ambulatory blood pressure device and were instructed to follow their usual daily routine activities while the device was attached to their non-dominant hand. The device was programmed to measure blood pressure for 24 hours with a recording frequency of every 15 minutes during the day and every 30 minutes during the night. After the removal of the device from the subject's arm, data was transferred to a computer that calculated the awake time, sleep time, and 24-hour mean blood pressure. Based on the data, subjects were classified as dippers and non-dippers. Supine hypertension was defined as systolic blood pressure (SBP) ≥150 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg measured after at least 5 minutes of rest in the supine position.[24] Dippers were defined as subjects with a physiological fall in blood pressure greater than or equal to 10% while supine and asleep at night. Study participants whose blood pressure did not decrease by 10% or even increased during the night with respect to daytime were classified as non-dippers.[25]
HRV was recorded using the autonomic neuropathy analyzer (RMS VAGUS HRV machine, Recorders and Medicare System, Chandigarh, India) following the European Society of Cardiology Task Force guidelines.[26] HRV assessments were carried out in the morning hours to eliminate the effect of the circadian rhythm on readings. Subjects were instructed to avoid coffee, tea, cola drinks, and smoking for 12 hours and alcoholic beverages 24 hours before the procedure. HRV was recorded following slow-paced breathing (6–8 breaths per minute) in the supine position after 5 minutes of rest. Stationary time series of 5 minutes duration and free of artefacts were used for analysis of Heart Rate variability (HRV).
Statistical analysis
Initial data entry was done in Microsoft Excel spreadsheets followed by data analysis using SPSS version 20.0 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp). Shapiro-Wilk and Kolmogorov-Smirnov test was applied to know the normality of distribution. Mean ± Standard deviations or median ± interquartile ranges were used appropriately for descriptive statistics. Natural logarithmic transformation was used for skewed data. Categorical data was expressed in terms of percentages or proportions. Pearson correlation was used to establish a correlation between ABPM/HRV with age of onset, disease duration, disease severity (Webster scores) and NMSS scores. P value ≤ 0.05 was considered to be statistically significant.
Results The mean age of the subjects in the study was 62.3 ± 8.9 years. Out of 60 PD patients in the study, 35 (58%) were males while 25 (42%) were females. Twenty-one (35%) out of 60 subjects were smokers while only eight (13%) patients were alcoholics. The mean disease duration was 1.7 ± 1.1 years, and the mean age of onset was 61.2 ± 8.7 years. The mean Webster score of the subjects in the study was 12.7 ± 4.4 while the mean NMSS score was 15.5 ± 8.0. Majority of the patients (48 out of 60 PD patients) in our study were newly diagnosed and untreated cases. Remaining 12 patients were receiving Levodopa + carbidopa, Trihexyphenidyl, and Rasagiline. The demographic parameters of the study population are shown in [Table 1].
Table 1: Demographic profile of Parkinson's Disease patients enrolled in the studyHRV was assessed by calculating values using spectral analysis (Fast Fourier Transformation) to yield very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations. These oscillations are markers of sympathetic as well as vagal activity (efferent neural discharges) which modulates the sinus node. Additionally, variability in the normal-to-normal intervals (NN) between adjacent electrocardiographic notation (QRS) complexes in Electrocardiogram (ECG) were denoted in the form of NN50 (signifying number of interval differences of >50 ms between successive NN intervals), PNN50 (proportion obtained by dividing NN50 by total number of NN intervals), SDNN (standard deviation of NN intervals), and RMSSD (square root of the mean squared differences of successive NN intervals). ABPM was done among 60 patients, and 50 patients (83%) were classified as non-dipper while ten patients (17%) showed a normal physiological dipping pattern. All dipper patients were normotensive. Among the 50 non-dippers, 32 had supine hypertension, while 28 did not demonstrate supine hypertension. Only five patients (8.3%) demonstrated orthostatic fall of blood pressure in this study. We did not find any correlation among HRV parameters, SBP/DBP ABPM recordings, and smoking. Furthermore, we assessed the association between smoking and the presence of supine hypertension. There was no significant association in the occurrence of supine hypertension with smoking in our study (15 smokers had supine hypertension while 18 non-smokers demonstrated supine hypertension in this study; P value = 0.10). This difference in number of patients with supine hypertension according to the pattern on ABPM was statistically significant (P value = 0.00). HRV and ABPM data are shown in [Table 2] and [Table 3], respectively. The HRV parameters such as LF, HF, SDNN, and RMSSD all showed a statistically significant positive correlation with the non-motor symptom scale (NMSS) scores among PD patients. However, a significant negative correlation was obtained between HRV parameters with the duration of PD. The results of the correlation between various HRV parameters with NMSS scores and disease duration are elaborated in [Table 4] and [Table 5], respectively. Among the HRV parameters, only PNN50 (r = −0.26, P = 0.04) had a mild positive correlation with age of onset of disease. Mean systolic (r = −0.29, P = 0.02) and diastolic blood pressures (r = −0.27, P = 0.03) showed a statistically significant mild negative correlation with age at onset of PD, while a significant mild positive correlation (mean systolic blood pressure r = 0.26, P = 0.04; mean diastolic blood pressure r = 0.33, P = 0.01) was obtained with the duration of Parkinson's disease. However, there was no correlation between HRV parameters and ABPM recording patterns with disease severity assessed by Webster scores.
Table 2: Heart Rate Variability parameters among Parkinson's Disease patients
Table 3: Proportion of patients with supine hypertension and non-dipping ambulatory blood pressure pattern among patients with Parkinson's Disease
Table 4: Correlation of heart rate variability parameters with Non-motor symptom scale
Table 5: Correlation of heart rate variability parameters with duration of Parkinson's disease Discussion The study was done to assess the cardiovascular autonomic dysfunction in patients of idiopathic PD by recording HRV and ABPM parameters and further correlating these with the age of onset, duration, and severity of the disease. HRV parameters are affected by various factors but they serve as a marker of sympathovagal imbalance or in other words autonomic dysfunction.[27],[28] PNN50 is closely correlated to the activity of the parasympathetic nervous system, and is a measure of cardiovagal activity.[29] In our study, PNN50 had a negative correlation with the duration of PD. Our findings could be explained by the relatively short disease duration among PD patients in the study (1.7 ± 1.1 years) which may have resulted in higher chances of parasympathetic nervous system dominance over the sympathetic nervous system as there is greater sympathetic dysfunction early in the disease course among PD patients.[30] Our findings are in line with a prior Indian study which showed that HRV due to deep breathing (which is a measure of cardiovagal activity) is negatively correlated with duration of disease among PD patients.[16] As the disease progresses, even the parasympathetic system becomes involved, thus variability attributable to PNN50 is diminished. Furthermore, a recent metanalysis has proven that sympathetic autonomic dysfunction occurs early in PD.[13]
RMSSD and HF are predominantly influenced by the parasympathetic nervous system as well. LF and SDNN are influenced by both sympathetic and parasympathetic inputs but in short-term heart rate variability measurement with slow-paced breathing, the primary source of variation is vagal (parasympathetic) activity.[29] Degeneration of postganglionic neurons of the cardiac sympathetic nervous system precedes involvement of other structures leading to changes in heart rate variability parameters that indicates early parasympathetic dominance.[31],[32],[33] This may explain the negative correlation observed between RMSSD, HF, LF, and SDNN with disease duration in this study. However, this was a small cross-sectional study that included mild-moderate PD patients having a short disease duration that may have impacted the findings. Thus, recruitment of cases with a longer disease duration and greater disease severity may shed further light on the correlation between various HRV parameters and disease duration among Indian PD patients.
Thus, all HRV parameters had a significant negative correlation with disease duration which is similar to the findings by Harnod et al.[34] and Bidikar et al.[16] However, caution is needed to interpret our study results since no control group was included and the physiological effect of age on HRV parameters cannot be ruled out. Furthermore, few prior studies have shown that changes in heart rate variability parameters among PD patients might be related to age rather than the disease itself.[8],[35] Hence, larger age-matched case-control studies from India would be required before any definite conclusion can be drawn.
Interestingly, HRV parameters showed a mild positive correlation with non-motor symptoms of PD. Changes in HRV and their relation with NMSS scores may be explained by the early involvement of the autonomic nervous system in PD. It is well-known that certain non-motor symptoms such as anosmia, REM behavior disorder (RBD), constipation, and low mood can precede the cardinal motor manifestations of PD by many years. This is essentially due to the Lewy body pathology involving the dorsal motor nucleus of vagus, submucosal gastrointestinal plexus, and post-ganglionic sympathetic neurons early in the disease course. Furthermore, Valkovic et al.[36] found that both early stage and advanced stage PD had correlation with total NMSS score, and that the correlation profile of various NMS domains were not significantly different between early stage and advanced stage PD. Thus, non-motor symptoms can be a significant burden in early PD as well and may lead an overall poorer health related quality of life. However, our finding supposes a positive correlation between total NMSS scores and HRV parameters which is in contrast to the study by Bidikar et al.[16] who demonstrated a negative correlation between HRV and total NMSS scores. The contrasting findings between the two studies may be due to differences in mean disease duration (7 years vs 1.7 years), sample size variations, and methodology (lack of control group in our study). Thus, further case-control studies investigating the correlation of HRV parameters among moderate to severe Indian PD cases with longer disease duration are required before drawing any conclusion.
As PD advances, the parasympathetic dominance also diminishes which may result in lesser HRV. However, none of the HRV parameters correlated with disease severity. Prior studies have reported conflicting results with regard to the correlation between HRV and disease severity. Our findings are similar to the prior study by Harnod et al.,[34] while Bidikar et al.[16] reported a negative correlation between HRV parameters and disease severity. However, our study had a small sample size, lacked a control group, and we included PD patients with relatively short disease duration. Furthermore, the mean Webster scores in our sample were around 13 (out of 30) implying moderate disease. All of these may have been responsible for lack of correlation between HRV and disease severity in our study.
Sympathetic outflow regulation by Baroreflex-receptor mediated mechanisms is responsible for maintaining postural blood pressure and peripheral vasoconstriction responses.[37] The early loss of postganglionic cardiovascular sympathetic neurons may result in autonomic dysfunction and loss of the normal “dipping” pattern of blood pressure responses.[38],[39] In our study, 50 out of the 60 PD patients showed a non-dipping pattern in ambulatory blood pressure recording. Thus, 83% of the patients in our study showed a non-dipping pattern in ambulatory blood pressure monitoring. Similar to our results, Sommer et al.[10] and Oh et al.[40] have reported a non-dipping pattern in 88% and 80% of PD patients, respectively. Furthermore, 53% of PD patients showed supine hypertension with the majority being in those having a non-dipping pattern. The exact pathophysiology of supine hypertension is not known, though it could be due to the effect of vasoactive agents given to treat orthostatic hypotension among PD or MSA patients.[41] However, our study had a small sample size, recruited mild to moderate early PD cases with a mean disease duration of 1.7 ± 1.1 years. In addition, most of our patients were newly diagnosed or undiagnosed patients of PD. Hence, the supine hypertension observed in our study might have resulted from autonomic dysfunction rather than the effects of drugs given to treat orthostatic hypotension or other confounding factors (such as drugs). Similar to our study findings, Umehara et al.[42] reported 45% prevalence of supine hypertension in early-stage PD.
The low percentage of orthostatic hypotension (8.3%) may be due to small sample size, inclusion of only mild-moderate cases with short disease duration, inclusion of drug naive patients in our study, and lack of detailed autonomic function testing for orthostatic hypotension (assessment done only by single clinical measurement of blood pressures in supine and within 3 minutes of standing).
The results of our study showed that mean ambulatory systolic and diastolic blood pressures had a positive correlation with age of onset and disease duration. This result should be interpreted with caution as the sample size of our study was relatively small and the confounding effect of age on BP recordings cannot be ruled out due to the lack of a control group. As most of the patients were non-dippers in our study which may have led to the increased ambulatory blood pressure recordings.
There were limitations to our study. The study design was cross-sectional, no control group was present for comparison, the sample size of this study was relatively small, and autonomic function tests were not compared before and after the onset of disease. Furthermore, the confounding effect of age on HRV and ABPM recordings cannot be ruled out in a cross-sectional study design.
Conclusions In conclusion, the study showed that HRV parameters and ambulatory blood pressure monitoring are of significant help in the detection of cardiovascular autonomic dysfunction with respect to age and duration of idiopathic PD. These autonomic tests may help in early detection of autonomic dysfunction among PD patients and may aid in early modulation of treatment plan by determining blood pressure fluctuations and supine hypertension. Moreover, supine hypertension was quite common among Indian PD patients, and it is therefore important to detect and possibly treat supine hypertension among these patients. To the best of our knowledge, this is the first study to holistically assess time and frequency based HRV domains along with ambulatory blood pressure recording patterns and attempted to correlate these parameters with age of onset, disease duration, and severity among Indian PD patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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