Medical Hypotheses 138 (2020) 109574

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Geometry of the Poincaré plot can segregate the two arms of autonomic T
nervous system – A hypothesis
⁎
Soma Roya, Damodar Prasad Goswamib, Arnab Senguptac,
a
Dept. of Physiology, Rampurhat Govt. Medical College & Hospital Birbhum, 731224 WB, India
b
Dept. of Mathematics, Netaji Subhash Engineering College, Panchpota, Garia, Kolkata 700152, West Bengal, India
c
Dept. of Physiology, Calcutta Medical College, 88, College Street, Calcutta 700073, India

A R T I C LE I N FO A B S T R A C T

Keywords: Autonomic Nervous System (ANS) operates to achieve the optimum physiological functioning and maintains
Poincaré plot homeostasis in a tonic and continuous manner. Evaluation of ANS profile is crucial in assessing autonomic
Lorenz plot dysfunction. Conventional ANS evaluation procedures fail to capture minute dynamic alterations of ANS ac-
Recurrence plot tivities.
HRV
The ANS output pattern is appropriately reflected in the fine alteration of the resting heart rate (HR). HR is a
ANS profile
Diabetes mellitus
non-stationary variable, results from the dynamic interplay between the multiple physiologic mechanisms. The
DM control of cardiac rate or the chronotropic regulation of heart is considered as a coupled network of oscillators,
DAN each representing a specific facet of the cardiovascular reflex. The slower vasomotor oscillation via sympathetic
system is combined with rapid respiratory oscillation by parasympathetic system to modulate the intrinsic os-
cillation pattern of the SA Node.
Heart Rate Variability (HRV) is used to understand the autonomic influence on cardiovascular system in
health and disease. Fourier decomposition of HRV offers us mainly two different frequency components. High
frequency (HF) variation indicates parasympathetic variability due to respiration and Low frequency (LF) mainly
implicates tonic sympathetic influence, due to slower vasomotor modulation of heart rate. However, different
studies show conflicting results and direct recording of sympathetic nerve activity also failed to correlate with LF
power in either healthy subjects or in patients with increased cardiac sympathetic drive.
A scatter-plot where each R-R interval is plotted against the preceding R-R interval forms a distributed elliptic
point cloud in two dimensional plane. The phase space realization of this plot with dimension two and delay one
is referred to as Poincaré plot analysis, an emerging quantitative-visual technique where the shape of the plot is
categorized into different functional classes. The plot provides summary as well as detailed beat-to-beat in-
formation of the heart. This plot can be extended to three dimensions and with multi-lag, offering more insight
and information.
A mathematical expression was developed by an interventional study by Toichi et al., using pharmacological
blockers during different physiological variables that calculated the lengths of transverse and longitudinal axes
of the Poincaré plot to derive two quantitative expressions of sympathetic and vagal influence on HRV: ‘cardiac
sympathetic index’ (CSI)) and ‘cardiac vagal index’ (CVI).
In the present study, we emulate Poincaré plot patterns seen in normal range of sympatho-vagal balances and
also in Diabetes Mellitus (DM), known to cause autonomic dysfunction. The emerging pattern of R-R interval
time series would provide valuable insight into the altered temporal dynamics and also extract crucial features
embedded within. DM is a major public health crisis globally and particularly in Indian population.
We hypothesize that, CSI and CVI will effectively segregate the two arms of ANS and can be utilized as an
effective evaluation tool to explore the disease status in patients of Diabetes Mellitus.
We also propose that, the dynamics of fluctuations in physiological rhythms that exhibit long-term correlation
and memory, can also be explored and expressed quantitatively by incorporating various degrees of ‘lag’ in these
recurrence plots.

⁎
Corresponding author.
E-mail address: arnabseng@gmail.com (A. Sengupta).

https://doi.org/10.1016/j.mehy.2020.109574
Received 5 November 2019; Received in revised form 1 January 2020; Accepted 16 January 2020
0306-9877/ © 2020 Elsevier Ltd. All rights reserved.
S. Roy, et al.
Fig. 1. Poincaré Plot.
Introduction
Autonomic Nervous System (ANS) maintains a delicate balance
between exaltation and repression of the efferent control of the organ
system of the body. This operates to achieve the optimum physiological
functioning of the body and maintains homeostasis. The autonomic
output for maintenance of optimum organ function depends upon the
various afferent inputs originating from the somatic and visceral system
converged to the autonomic integrating centre in the Central Nervous
System.
ANS exerts characteristically its function on the effecter organ in
tonic and continuous manner. Accordingly, disease affecting ANS pri-
marily or secondarily lead to disturbance of homeostasis, manifested by
2
Medical Hypotheses 138 (2020) 109574
alteration of various physiological functions like blood pressure, heart
rate, GIT motility, urinary function, orthostatic stability etc. [1]. It is
evidenced that, change in the qualitative and quantitative parameters
of autonomic output patterns starts much earlier than the clinical and
biochemical manifestation of the disease process [1].
Accordingly, evaluation and assessment of ANS profile may have
important predictive value for risk assessment in various diseases af-
fecting ANS [2]. Apart from that, ANS profiling may also be utilized for
diagnosis of disease and also to assess the prognostic outcome of the
disease, characterization of therapeutic response and predicting mor-
bidity and mortality [3].
ANS profiling are not usually done in routine clinical practice. Even
the standard ANS evaluation procedures like, Tilt test, standing/lying
S. Roy, et al.
Fig. 2. The Chronotropic Regulation of Heart as a Coupled Network of
Oscillators.
ratio, cold pressure test, Valsalva maneuver, GSR etc are not yet uni-
versally standardized. Biochemical parameters used to assess ANS
function include Urinary Vanilyl Mandelic acid, Blood Epinephrine and
nor-epinephrine, etc. are also marred with standardization issues [4].
Also the clinical and biochemical evaluation of ANS profile have got
certain inherent limitations. ANS output pattern is a tonically active
and rapid physiologic parameter. It is delicately tuned with the finer
alteration of homeostatic state and is a rapidly changing dynamic
homeostatic parameter. So a biochemical estimation of ANS parameters
like VMA, Epinephrine, Norepinephrine, etc. or clinical evaluation as
mentioned, fail to reflect ever-changing temporal dynamicity of ANS
output pattern.
Assessment of cardiovascular autonomic reflexes is a critical ele-
ment in evaluation of autonomic function in humans [5]. It has already
been emphasized that, the ANS output is tuned with temporal alteration
of homeostatic state and this ever-changing dynamicity of ANS output
pattern is appropriately reflected in the fine and dynamic alteration of
the resting heart rate.
During normal sinus rhythm, the heart rate (HR) varies from beat to
beat. HR is a non-stationary signal and varies continuously in health
and in disease. Variability of heart rate results from the dynamic in-
terplay between the multiple physiologic mechanisms that regulate the
instantaneous HR. The pattern alteration in its variation may contain
indicators of current disease, or warnings about impending cardiac
diseases. The indicators may be present all the times or may occur
suddenly during certain intervals of the day. It is strenuous and time
consuming to study and pinpoint the abnormalities manually within the
voluminous data collected over several hours. Hence, HR variation
analysis (change of instantaneous HR against time axis) has become a
popular noninvasive tool for assessing the activities of the autonomic
nervous system [6].
Processing and analysis of the cardiac signal using mathematical
and statistical protocols and algorithms are presently in use.
Development in the technique of instrumentation and availability of
high frequency analogue to digital converters enable acquisition of
Table 1
Comparative Evaluation of a few Autonomic Parameters in Patients of DM with or without positive Family History of DM.
Autonomic Parameters DM with Positive Family History (n = 45)
(Mean ± SD)
Mean RR Interval (mSec) 734.39 ± 109.37
Low Frequency Peak (Hz) 0.070 ± 0.058
High Frequency Peak (Hz) 0.280 ± 0.079
CVI 0.036 ± 0.016
CSI 2.95 ± 1.02
3
Medical Hypotheses 138 (2020) 109574
physiological signal in digital format with desired precision provide
detail time series data of these signals. Many new parameters for eva-
luation of physiological functions have been developed; out of which
Heart Rate Variability (HRV) remains the most popular [6,7]. The HRV
is being used to understand the autonomic influence on cardiovascular
system in health and in disease [8]. This also has become an important
predictive tool in various disease outcomes, where autonomic system is
affected [7].
HRV, the variation of the period between consecutive heartbeats
over time, is predominantly dependent on the extrinsic regulation of the
heart rate. It is a reliable reflection of many physiological factors
modulating the normal rhythm of the heart. In fact, they provide a
powerful way of observing the interplay between the sympathetic and
parasympathetic nervous systems. Theoretically, it is thought that the
heart rate is generated with a nonlinear oscillator working behind it
[9]. HRV is thought to reflect the heart’s ability to adapt changing
circumstances by detecting and quickly responding to unpredictable
stimuli. HRV analysis is a way to assess overall cardiac health and the
state of the autonomic nervous system responsible for regulating car-
diac activity [3,4]. It is believed that HRV will become as common as
pulse, blood pressure or temperature in patient charts in near future. In
the last ten years more than 3000 articles have been published on HRV.
HRV has been used as a screening tool in many disease processes. In
diabetes and heart disease it has been proven to be a predictive measure
of the likelihood of future disease process [10].
Review of literature
The control of cardiac rate or the chronotropic regulation of heart is
considered as a coupled network of oscillators, each representing a
specific facet of the cardiovascular reflex and autonomic nervous
system [9]. The slower vasomotor oscillation via sympathetic system is
combined with rapid respiratory oscillation by Vegus nerve to modulate
the intrinsic oscillation pattern of the SA Node.
It is well known that perturbations to autonomic activity, such as
respiratory sinus arrhythmia and vasomotor oscillations, cause corre-
sponding fluctuations in heart rate [11,12]. HRV is usually assessed by
time domain, frequency domain and non-linear domain protocols with
a battery of tests and parameters (In frequency domain LF, HF mea-
surement, in time domain RMSSD, SDNN, RMSSD, NN50, in non-linear
domain Information entropy, Poincare SD1/SD2 etc.). Time-domain
indices quantify the time variation of the signal during monitoring
periods. Frequency-domain parameters calculate the absolute or re-
lative amount of signal energy within component bands and extract the
frequency components of the signal. Non-linear measurements quantify
the unpredictability, complexity and nonlinear behavior of the RR in-
terval time series [13].
Spectral analysis is a standard technique used to determine the
presence of respiratory sinus arrhythmia and vasomotor oscillations
[14]. While HF variation usually indicates Parasympathetic variability,
LF mainly implicates tonic sympathetic influence. The LF and HF bands,
effectively distinguishes between rapid respiratory modulator activity
and slow vasomotor modulation of heart rate. HF power is supposedly a
pure measure of parasympathetic activity, and LF power is a reflective
of sympathetic modulation and parasympathetic tone, although it is
DM without Positive Family History (n = 51) (Mean ± SD) P Value (2-tailed)
697.00 ± 108.11 0.0959
0.069 ± 0.027 0.8788
0.284 ± 0.080 0.7993
0.027 ± 0.011 0.0017
2.16 ± 1.11 0.0005
S. Roy, et al.
sometimes considered to reflect sympathetic tone also [15].
These have already been assessed widely and published in different
literatures. However, different studies show conflicting results.
Akselrod et al., Randall et al., and Houle & Billman showed that, the LF
peak of the heart rate power spectrum is reduced by at least 50% by
either cholinergic antagonists or selective parasympathectomy [16–18].
LF/HF ratio increased from a baseline value of 1.1 to 8.4 when selective
parasympathetic denervation was combined with β-adrenergic receptor
blockade, thus falsely suggesting a major shift to sympathetic dom-
inance.
Also direct recording of sympathetic nerve activity failed to corre-
late with LF power in either healthy subjects or in patients with heart
failure, a condition known to increase cardiac sympathetic drive
[19–26]. Carnethon found that, a reduced LF power was associated
with a 30% increased risk of developing diabetes [27]. Gustavoa (2013)
reported that, Vagal blockade reduces LF power by more than 90%,
while sympathetic blockade does not produce significant effects. Also,
physiological and psychological manipulations that markedly raise
sympathetic outflow do not increase LF power, but often reduce it. At
the same time, pharmacological manipulations inducing reflex changes
in sympathetic cardiac tone do not affect the LF component in the
predicted amount. It was also evidenced that, the group differences in
sympathetic autonomic control cannot be predicted from LF oscillations
and there are no associations between LF power and valid indicators of
sympathetic cardiac control [28]. Goldberger JJ et al. (2001) conducted
human experiments using autonomic blocker in order to study the re-
lationship of Heart Rate Variability with Parasympathetic Effect. They
described a function in which there is an ascending limb where HRV
increases as parasympathetic effect and increases until it reaches a
plateau level; HRV then decreases as parasympathetic effect increases
[29]. Billman (2013) in an extensive review emphasized the relative
inaccuracy of the spectral parameters of the frequency domain HRV
evaluation in delineating the autonomic profiles [30].
Thus apparently the LF component of HRV fails to provide an effi-
cient index of cardiac sympathetic drive and probably reflects a com-
plex and not so easily discernible mixture of sympathetic, para-
sympathetic, and other unidentified factors with parasympathetic
factors accounting for the largest portion of the variability in this fre-
quency range. As a consequence, the physiological basis for LF/HF ratio
has become difficult to explain. A possible non-linear effect of varying
cardiac sympathetic and cardiac parasympathetic nerve activity on LF/
HF was also proposed [30].
In this conflicting situation, Poincaré plot seems to be a savior.
Poincaré plot is basically a scatter plot where each RR interval is plotted
against the preceding RR interval resulting a formation of distributed
point cloud in the shape of an ellipse extended along the diagonal line
y = x.
The Poincaré plot which is also popularly known as recurrence plot
(Fig. 1) is a two-dimensional scatter plot which was originally designed
for application in meteorology [31]. It is a technique to quantify the
self-similarity taken from nonlinear dynamics, and has been applied in
the field of electrophysiology [32–35]. It is a plot of each R-R interval
plotted against the next interval. When the sequence of the consecutive
R–R intervals is expressed by I1, I2 ,…, In , the plot is constructed by
plotting Ik+1 against Ik (k = 1, 2, … n-1). From the analysis perspective,
Poincaré plot analysis is a quantitative visual technique, where the
shape of the plot is categorized into functional classes (21, 22). Points
above the line of identity indicate R-R intervals that are longer than the
preceding R-R interval, and points below the line of identity indicate a
shorter R-R interval than the previous one. Accordingly, the dispersion
of points perpendicular to the line of identity (the “width”) reflects the
level of short-term variability, and the dispersion of points along the
line of identity (the “length”) reflects the level of long-term variability.
The use of delay (also called return) maps is central to the qualitative
and quantitative analysis of dynamical systems [36,37]. The phase
space realization with dimension of two and delay of one is referred to
4
Medical Hypotheses 138 (2020) 109574
as a Poincaré plot [36–38]. This graphical method is widely used to
visualize and quantify short and longer variability. [38–46] and por-
trays the nature of R-R interval fluctuations. This plot provides a
summary information as well as detailed beat-to-beat information on
the behavior of the beating heart. A distinct advantage of Poincaré plots
is its ability to identify beat-to-beat cycles and patterns in data that are
difficult to identify with spectral analysis [47,48]. Also the dynamics of
fluctuations in physiological rhythms that exhibit long-term correlation
and memory [49], can also be visualized by incorporating various de-
grees of ‘lag’ in these recurrence plots, in order to quantify the self-
similarity features of nonlinear dynamics in the field of electro-
physiology.
Fig. 2 shows the Poincaré plots of two subjects: One of normal
control and another of a patient with autonomic dysfunction. In this
plot, the RR fluctuation is transformed into the points distributed on a
two-dimensional plane which usually form an elliptic configuration in
normal subjects.
Copie et al. (1996) undertook a correlation study between length,
width and area of the scatter plot with various time domain HRV
parameters (SDNN and SDANN as long term variability indices and
pNN50 as short term variability index). They found a strong correlation
between scatter plot length and long term parameters (r > 0.9) and
scatter plot width and short term parameters (r ˃ 0.9). They re-
commended this method of measuring scatter plot dimension as a
simple and accurate way of expressing short and long term HRV [50].
In the year 1997, Toichi et al. [51] confirmed and validated the
findings of Copie et al. and developed a mathematical representation
for quantitative expression of sympathetic and vagal influence on HRV.
They calculated two components of RR fluctuation from the plot: the
length of the transverse axis (T) which is vertical to the line Ik = Ik + 1,
and that of the longitudinal axis (L) which is parallel with the line
Ik = Ik + 1. When two adjacent intervals Im and Im+1 in the sequence
differ greatly (large beat-to-beat variation), the point (Im, Im+1) is
plotted distant from the line Ik = Ik + 1 on the plane, resulting in large
T. On the other hand, when the fluctuation is greater but continuous
(large amplitude, but small beat-to-beat variation), the plotted points
are distributed widely but along the line Ik = Ik + 1, resulting in large L
and small T. Thus the two components reflect different aspects of the
RR fluctuation.
They conducted an interventional study in 10 healthy volunteers,
and administered atropine (vagal blocker) and propanolol (β adrenergic
sympathetic blocker) in two consecutive days to block the effect of
vagus and sympathetic system respectively. In each experiment, RR
interval was measured in different postures and physiological condi-
tions. The RR interval time series data were analyzed by conducting
Poincaré plot, spectral analysis and coefficient of variation.
Each morphological component (L and T) is calculated to four times
the standard deviations of the plotted points along its axis in order to
approximate the visual image on the Poincaré plot.
To obtain the autonomic indices, they examined the four measures
of T, L, L*T, and L/T ratio. It was found that, while L was affected only
by parasympathetic blockade, T was affected by both sympathetic and
parasympathetic blockade under these limited conditions.
As the measure L*T is usually a large number, a logarithm in base 10
was employed to scale down and accommodate it. The measure log10
(L*T) was found to be a sensitive index of cardiac vagal function which
is not affected by sympathetic activity and was termed as the ‘cardiac
vagal index’ (CVI). The L/ T ratio is an index of cardiac sympathetic
function which is not affected by vagal activity: ‘cardiac sympathetic
index’ (CSI). Thus they derived two new parameters as CSI and CVI as
independent parametric expressions of two arms of ANS with necessary
mathematical formulation.
Discussion and hypothesis
The coupled network oscillator model of cardiac chronotrophy
S. Roy, et al.
(Fig. 2) describes two distinct dynamic regulatory systems of heart rate
that can be appropriately evaluated by the proposed sensitive indices.
When the results of the two indices are visually described, the area of
the ellipse on the Poincaré plot becomes larger as the vagal activity is
elevated and the configuration becomes longer and narrower as the
sympathetic activity is elevated. As these indices were developed by
rigorous and direct experimental procedures using pharmacological
blockers during resting as well as during different physiological vari-
ables and stresses, they are expected to be more effective than earlier
measures in evaluating and describing the patho-physiological states
from HRV.
We have proposed an application of these two indices in Diabetes
Mellitus (DM), where the autonomic activity is altered. DM is emerging
as a major public health crisis globally [52]. Indian population is known
to have greater susceptibility and preponderance of DM [53]. Apart
from affecting most of the organs and systems, somatic and autonomic
neuropathies are two common complications in DM and adversely af-
fect the outcome of the disease [54]. Appropriate and objective char-
acterization of Diabetic Autonomic Neuropathy (DAN) is a crucial issue
of current research.
As the assessment of ANS by conventional testing protocol has got
certain inherent limitations, due to the fact that they fail to elucidate
the moment to moment dynamic variability of autonomic tone [13], the
HRV assessment for characterization of DAN is becoming increasingly
popular among the scientific community [55,56].
A global reduction and alteration of circadian rhythm of autonomic
activity are present in offspring of type 2 diabetic patients with and
without insulin resistance [57]. Diabetes patients had lower values of
variability for time-domain and also for frequency-domain parameters
compared to controls. It was found that cardiac parasympathetic ac-
tivity was diminished in diabetic patients even before the onset of
clinical symptoms of neuropathy [58]. In frequency domain, the ana-
lysis of sympathetic (LF) and parasympathetic (HF) components evi-
denced an association between the offspring of type 2 diabetic subjects
and a sympathetic over activity [57].
However, as the efficiency of the spectral parameters raises certain
doubts, and are not corroborating with the established patho-physio-
logical parameters, it is prudent to revaluate the ANS profiles using
newer and less utilized tools and the model based on standard phy-
siological principles and mathematical formulation that permits in-
depth numerical and analytic investigations yielding valuable insight
into clinical R-R interval analysis techniques.
In the present study, we emulate the differing varieties of Poincaré
plot patterns seen in normal range of sympatho-vagal balances and also
in a standard pathological entity known to cause autonomic dysfunc-
tion, as in DM. The emerging pattern of R-R interval time series would
provide valuable insight into the altered temporal dynamics and also
extract crucial features embedded within.
We intend to explore these two less utilized parametric expressions
derived from Poincare plot namely CSI and CVI as sensitive indices of
cardiac autonomic profile in order to segregate the two arms of ANS in
patients of DM as compared to controls.
However, Toichi et al. warned that the CVI and CSI parameters were
obtained in physiologically normal subjects under mild autonomic
blockade and the change in the two indices suggests the shift in reg-
ulatory activity, not the degree of activity or tone of the ANS, and raised
a caution on the application and interpretation with these tools.
In the present endeavor, we proposed to use this model only to
segregate the two arms of ANS in health and in patients of DM.
We conducted a pilot observation to test the proposition as a com-
parison of a few autonomic profile parameters in two groups of DM
patients, with or without positive family history of their first degree
relatives. The preliminary data (Table 1) indicates that, while mean RR
interval, peak low frequency (LF) and peak high frequency (HF) failed
to discriminate the above two groups; but difference in CVI and CSI
among these groups is statistically significant, and they can be an
5
Medical Hypotheses 138 (2020) 109574
efficient tool of ANS classifier in the relatives of DM patients. However,
nothing can be concluded before a full-fledged analytical study is
conducted with matched controls.
In addition, the model provides a unique link between spectral
analysis techniques and the emerging analysis techniques that rely on
the shape and/or other morphological properties of the Poincaré plot.
We hypothesize that, Cardiac Sympathetic Index and Cardiac Vagal
Index, based on phase space realization with dimension of two and
delay of one in R-R interval time series will effectively segregate the
two arms of ANS and may be utilized as an effective evaluation and
research tool to explore the disease status in patients of Diabetes
Mellitus.
We can move a step further and hypothesize that we need not
confine ourselves within the proposed ‘dimension of two and delay of
one’ as mentioned above. Though ‘dimension of two and delay of one’ is
the most common and widely used parameters, higher dimensions and
higher lags may enlighten us with new information hidden in the R-R
interval time series which is not perceptible otherwise. This assumption
is quite reasonable because physiological systems often hold prolonged
association between events separated by time that characterizes the
intrinsic behavior of a complex system. Our cardiac system should not
be an exception.
Sources of support in the form of grants
None.
Conflict of interest
Nil.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.mehy.2020.109574.
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