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Quantitative Assessment of Autonomic Regulation of the Cardiac System

Quantitative Assessment of Autonomic Regulation of the Cardiac System Hindawi Journal of Healthcare Engineering Volume 2019, Article ID 4501502, 8 pages https://doi.org/10.1155/2019/4501502 Research Article Quantitative Assessment of Autonomic Regulation of the Cardiac System 1,2 1 3 4 Jian Kang Wu , Zhipei Huang , Zhiqiang Zhang , Wendong Xiao , and Hong Jiang e University of Chinese Academy of Sciences, Beijing, China Institute of Healthcare Technologies, Chinese Academy of Sciences, Nanjing, China University of Leeds, West Yorkshire, UK Beijing University of Science and Technology, Beijing, China China-Japan Friendship Hospital, Beijing, China Correspondence should be addressed to Jian Kang Wu; jkwu@ucas.ac.cn and Zhipei Huang; zhphuang@ucas.ac.cn Received 8 January 2019; Accepted 27 March 2019; Published 21 April 2019 Guest Editor: Jilong Kuang Copyright © 2019 Jian Kang Wu et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autonomic neural system (ANS) regulates the circulation to provide optimal perfusion of every organ in accordance with its metabolic needs, and the quantitative assessment of autonomic regulation is crucial for personalized medicine in cardiovascular diseases. In this paper, we propose the Dystatis to quantitatively evaluate autonomic regulation of the human cardiac system, based on homeostatis and probabilistic graphic model, where homeostatis explains ANS regulation while the probability graphic model systematically defines the regulation process for quantitative assessment. -e indices and measurement methods for three well- designed scenarios are also illustrated to evaluate the proposed Dystatis: (1) heart rate variability (HRV), blood pressure variability (BPV), and respiration synchronization (Synch) in resting situation; (2) chronotropic competence indices (CCI) in graded exercise testing; and (3) baroreflex sensitivity (BRS), sympathetic nerve activity (SNA), and parasympathetic nerve activity (PNA) in or- thostatic testing. -e previous clinical results have shown that the proposed method and indices for autonomic cardiac system regulation have great potential in prediction, diagnosis, and rehabilitation of cardiovascular diseases, hypertension, and diabetes. and (2) Axelrod [3], Von Euler [4], and Del and Katz [5] 1. Introduction identified acetylcholine (ACh) as a transmitter for the Autonomic neural system (ANS) regulates the circulation to parasympathetic nerves, norepinephrine (NE), and sympa- provide optimal perfusion of every organ in accordance with thetic nerves. However, the ANS regulation of the cardiac its metabolic needs. Together with the endocrine and im- system can be viewed as a complex dynamic system, and it munological systems, it adjusts the internal environment of can be well described by “Homeostasis” [6], which is now the organism to respond the changes in the external envi- regarded as one of the core competencies by the American Association of Medical Colleges and Howard Hughes Medical ronment [1]. -erefore, understanding the ANS and the way it regulates body circulation is crucial for personalized Institute and a core concept necessary for future physicians medicine in cardiovascular diseases. -e understanding of the [7]. ANS regulation in the cardiac system can be traced back to the In clinical settings, autonomic dysfunction has been findings of two Nobel Prize winners: (1) Corneille Heymans in linked to direct detrimental effects towards heart failure and 1938 identified the carotid sinus nerves [2], which are tiny chronic kidney disease [8]; thus, quantitative methods to baroreceptor and chemoreceptor nerves and can sense evaluate the ANS regulation has great potential to generate changes in hemodynamic pressure and humoral factors and innovative diagnostic and treatment approaches that limit send output to the sympathetic and parasympathetic nerves, hypertension and target end-organ damage. Recent research 2 Journal of Healthcare Engineering effects from other internal and external in- has shown that the autonomic neurohumoral system can dramatically influence morbidity and mortality from car- teractions. -ese are minor compared to graded exercises. diovascular disease through influences on the innate and adaptive immune systems [9]. Due to the high metabolic rate (3) BRS, SNA, and PNA in orthostatic testing: based of brain tissue, the precise regulation of cerebral blood flow on Dystatis, orthostatic testing creates a large (CBF) is critical for maintenance of constant nutrient and blood pressure drop and then a large BRS output oxygen supply to the brain [10]. -e metabolic syndrome is to sympathetic and parasympathetic nerves. As characterized by the clustering of various common meta- such, the mathematical model for solution of bolic abnormalities in an individual, which is also associated BRS, SNA, and PNA can be greatly simplified by with increased risk for the development of type 2 diabetes neglecting other internal and external in- and cardiovascular diseases. -e augmented sympathetic teractions in the ANS regulation. activity in individuals with metabolic syndrome worsens prognosis of this high-risk population [11]. Experimental 2. Dystasis:SystematicQuantitativeAssessment and clinical investigations have validated the hypothesis: the Methodology for ANS Regulation of the origin, progression, and outcome of human hypertension Cardiac System are related to dysfunctional autonomic cardiovascular control, which is particularly true for abnormal activation of Human body is a complex biological system, of which the sympathetic division [12]. homeostasis is a crucial property in maintaining the life. It is Since the quantitative assessment of the autonomic reg- the self-regulating process by which biological systems ulation is tremendously important for clinical and healthcare maintain stability in order to adjust to conditions that are applications, there is urgent need to quantitatively evaluate optimal for survival. -e stability attained is a dynamic the ANS regulation status. Unfortunately, there are only two equilibrium, in which continuous change occurs yet rela- invasive methods to measure certain aspects of the ANS thus tively uniform conditions prevail. far: (1) microneurography to assess muscle sympathetic nerve Dystasis is built up on homeostasis and defined as fol- activity and (2) the norepinephrine isotope dilution to de- lows: ANS regulation of the cardiac system is a part of body’s termine noradrenalin in the blood to evaluate spillover of the complex biological system. -rough ANS self-regulating sympathetic nervous system [13]. Although HRV is an in- process, the cardiac system tends to reach and maintain a direct biomarker of the cardiac autonomic nervous system dynamic equilibrium state, in order to supply cells and activity [14], ANS regulation of the cardiac system is complex organs with their metabolic needs, e.g., oxygen, nutrients, in nature and existing HRV assessment is rather ad hoc and removal of waste, survive in various internal and ex- without any theoretical model. -erefore, HRV indices ob- ternal environments, and support various physical and tained in different settings and by different persons are often mental activities. -e characteristics of Dystasis are (1) inconsistent, resulting in difficulties for clinical interpretation. equilibrium: the ANS self-regulating process of the cardiac In summary, ANS regulation of the cardiac system plays system reaches and maintains an “equilibrium” state in a a central role in both research and clinical practices, and we relative steady internal and external environment, with no or will focus on the quantitative assessment of autonomic minor changes in terms of physical and mental activities. -e regulation of the cardiac system in this paper. -e main property and its numerical measures of the state of this contributions are as follows: equilibrium of the individual’s ANS self-regulating process shall provide quantitative performance evaluation of how (i) We propose the Dystatis to quantitatively evaluate well one’s ANS regulation system works; (2) dynamic: the autonomic regulation of the human cardiac system, ANS self-regulating process of cardiac system should be based on homeostatis and the probabilistic graphic “dynamic” enough, being able to work in dynamic envi- model, where homeostatis explains ANS regulation ronment, support various physical and mental activities of while the probability graphic model systematically the body, and defend virus invasions. In other words, it defines the regulation process for quantitative should be able to reach new equilibrium state as soon as assessment. possible when there is a change of internal/external envi- (ii) -e Dystatis is elaborated in three well-designed ronment or physical/mental activities. For instance, ANS scenarios, where indices and measurement methods regulation interacts with the immune system to control for each scenario are also proposed and illustrated by inflammation [15] and ANS regulation of the cardiac system clinical applications: increases oxygen supply and reaches a new equilibrium (1) HRV, BRV, and Synch in resting situation: when the intensity of physical activity increases to a new Dystatis provides theoretical model and guide- level. -e capability of ANS regulation to accommodate lines for the test design and data processing and changes of internal and external environment, as well as interpretations, in order to solve existing in- activity needs, is another important measure. consistence problems. In order to quantitatively evaluate the state and capa- (2) CCI in graded exercise testing: Dystatis meta- bility of ANS regulation of the cardiac system, one feasible bolic requirement is enlarged by graded exercise approach is the probabilistic graphic model-based approach so that CCI can be obtained without considering [16], as shown in Figure 1. Principally, the interactions of Journal of Healthcare Engineering 3 (1) Variability of the heart rate and blood pressure (HRV Immune Metabolism system and BPV) while the subject is in resting or other Vascular Viscera steady state: the ideal measurement scenario is zero or known steady physical activity, minimal mental ac- Lung Mental tivity, and minimal viscera disturbance. -e vari- ability indices are used to characterize the state of ANS equilibrium of individual’s ANS self-regulating pro- cess, which directly reflects states of immune system, linking with inflammation biomarkers. Heart (2) CCI in graded exercise testing: the effect of physical activity on ANS is maximized so that the influences Figure 1: Probabilistic graphic model of autonomic regulation of from the rest sources can be neglected. CCI provide the cardiac system with internal and external influences. numerical measures to characterize the capability of ANS regulation to accommodate changes of exercise ANS with cardiac, respiration, vascular, metabolic, immune, intensity. viscera, and mental systems are bidirectional [17]. Here, in (3) BRS, SNA, and PNA are obtained by model-based Figure 1, the objective is to estimate ANS state through all analysis of blood pressure (BP) and heart rate (HR) possible observations, in case of ANS regulation of the heart pairs acquired in orthostatic testing: Via orthostatic rate with major internal and external influences; i.e., RSA is a test, large blood pressure drops around 30 mmh is terminology for heart rate modulation by respiration; blood obtained. -e input from baroreflex to SNA and pressure formed in the vascular system and sensed by PNA becomes the major effect, and the rest can be baroreflex which then affects the heartbeat; physical activ- neglected. As such, the mathematical model for the ities stimulate metabolic needs and increase the heart rate; solution can be simplified as a subgraph of the inflammation in the immune system breaks the stability of graphic model in Figure 1. ANS regulation and then heart rate variations; the dorsal vagal complex is responsible for the interaction between viscera organs and ANS; and the ventral vagal complex is 3. Variabilities in Resting or Steady responsible for mental activities [17]. -e observation of Testing Scenario ANS regulation here is variations of the heart rate, blood pressure, and respiration. -e sympathetic innervation of -e indices of HRV and BPV consist of time-domain second- the heart and blood vessels is excitatory. It stimulates va- order statistics, for example, standard deviation of ECG soconstriction and increases the heart rate and cardiac normal-to-normal intervals (SDNN) and standard deviation contraction. On contrary, the parasympathetic vagal in- of differences of neighboring normal-to-normal intervals nervation is inhibitory, which decreases the heart rate and (SDSD). Frequency-domain indices are calculated at very low cardiac contraction. -e balance of the two appears as frequency band (VLF, 0.004–0.04 Hz), low frequency band variations of the heart rate and blood pressure and can be (LF, 0.04–0.15 Hz), and high frequency band (0.15–0.4 Hz). characterized by indices which represent properties and -e problem is then to quantitatively evaluate the state of rules of those variations caused by regulation: -e sympa- ANS and infer the physiological and psychological implica- thetic activity increases during the flight-or-fight response, tions, given measured variabilities of the heart rate, blood whereas parasympathetic activity increases to calm the heart pressure, respiration, and assessment scenario that the when there appears emotionally driven high blood pressure. physical activity is zero or constant. Based on Dystasis For the estimation purpose and from Figure 1, we can framework, according to equation (1) and graphic model in obtain the following formula, via probabilistic graphic Figure 1, there are still three nodes: mental activities and the model: states of viscera organs are not known or unmeasurable and inflammations in the immune system are the ones to be P � p(heart/A) p(A/mental) p(A/viscera) inferred. Now, in this assessment scenario, in order to obtain · p(A/immune) p(A/metabolic) p(A/vascular) the stable and consistent quantitative measures, we have to · p(A/lung), minimize the influences of mental activities and viscera or- gans. To fulfill this requirement, variabilities are best to be (1) measured when the subject is in deep sleep or in a coherence where A is the state of ANS to be estimated through ob- state between respiration and heart rate where mental ac- servations connected with ANS in the graph of Figure 1. tivities and viscera influences are purposely minimized. However, not all nodes connected with the ANS node are HRV has been studied for a long time to reflect the states observable or measurable. For the quantitative assessment of ANS regulation [14, 18]. In clinical practice, HRV is purpose, it is the best to intentionally create assessment usually evaluated using Holter device and software, without scenario where the influences of the measurable nodes are consideration of physical activities and other influences. -is maximized whilst minimizing those of the unmeasurable has resulted in inconsistences in various studies and limited nodes. -erefore, we designed the following three assess- the clinical applications of HRV. To quantitatively evaluate ment scenarios: the physical activities and define the testing scenario, in case 4 Journal of Healthcare Engineering of using Holter device, a three-dimensional accelerometer A review of research literature [24] tells that affected sensor is used to detect and classify posture and activity into central nervous system structures and implicated autonomic nervous system regulation coexist in Alzheimer’s disease. laying, sitting or standing, walking, or running. HRV indices are then calculated when any of those postures and activities Assessment of autonomic dysfunction can be used as an keeps for more than 10 minutes [19]. early marker of Alzheimer’s disease and used for differential -e interaction between heartbeat and respiration is the diagnosis among dementia subtypes. well-known respiratory sinus arrhythmia (RSA). -e wis- dom of the body to maintain the homeostasis is achieved by 4. Chronotropic Competence Indices in Graded synchronizing heartbeats with breathing and consequently Exercise Testing Scenario to maximize the efficiency of the cardiopulmonary system in metabolic and circulation process. -is equilibrium state is Graded exercise tests, such as cardiopulmonary exercise test the result of resonance of the cardiopulmonary system. (CPX), have been used in clinical practice to test the exercise -ere are indices proposed to evaluate the degree of the capability in terms of maximum oxygen metabolism [25]. In resonance of the cardiopulmonary system. -e most com- Dystasis family, CCI are designed to evaluate the capability mon used one is coherence measure (Coh), the cross power of the ANS regulation of the cardiac system in response to spectral density of the heart rate and respiration signals [20]. exercise, where the subject does not necessarily reach the -e resonance of the cardiopulmonary system represents maximum exercise intensity. the equilibrium of ANS regulation, where one reaches both Chronotropic incompetence (CI) is a terminology de- physiological and psychological healthy state. -erefore, Coh scribing the status of attenuated heart rate response to exer- can be used to compose numerical measures to visually rep- cises. CI has been studied for the last 50 years [26]. Typical CI- resent one’s health state, especially psychological health state, related measurements include the maximum heart rate and and then, variability-biofeedback training is used to help one to heart rate recovery after exercise. -ere have been a lot of gain resonance state. A clinic trial was conducted in the Uni- research efforts to explore the usefulness of CI parameters in versity of Chinese Academy of Sciences (UCAS) Hospital to test clinical applications, i.e., their diagnosis value of coronary the effectiveness of HRV biofeedback (HRVB) for pregnant artery [27], prognosis and management of heart failure women in managing anxiety and depression [21]. 20 pregnant [28, 29], diabetes [30, 31], and hypertension [32, 33]. Although th women at last trimester (28–32 week) without pregnancy- CI is an independent predictor of major adverse cardiovascular induced hypertension and diabetes were randomly assigned to events and overall mortality, the importance of CI is under- the HRVB group and the control group. Participants in the estimated [34]; this may be in part due to multiple definitions, HRVB group practiced HRVB for 30 minutes per day, while the confounding effects of aging and medications, and the participants in the control group did not. Following checks are need for formal exercise testing for definitive diagnosis. conducted for all participants every two weeks: blood pressure We have formally defined CCI as part of Dystasis in a (BP), fasting blood glucose (FBG), HRV of pregnant women systematic way and in terms of ANS regulation capabilities (PHRV) and their fetuses (FRHV), and subjective assessment and endowed CCI with clear physiological and clinical on pressure using Pregnancy Pressure Scale (PPS), depression implications. CCI are defined as follows: using Edinburgh Postnatal Depression Scale (EPDS), and sleep (1) Resting heart rate (HRrest) and resting blood pressure quality using Pittsburgh Sleep Quality Index (PSQI). -e clinical (BPrest): -e resting heart rate and resting blood trial continued for subjects until they are in hospital for delivery. pressure are defined as the heart rate and blood pressure In the trial, the HRVB group has shown significant improve- when a person is awake, in a neutrally temperate en- ment over the control group with respect to blood pressure vironment, and has not been subject to any recent stability (p> 0.05), depression reduction (p � 0.013), and sleep exertion or stimulation, such as stress or surprise. quality improvement, while fetuses in the HRVB group has shown significant improvement with respect to HRV SDNN (2) Chronotropic rate (CR and CR ): chronotropic HR BP (p< 0.01) and LF spectrum power (p< 0.01). rate represents the rate at which the heart rate and HRV and BPV can be used as a noninvasive assessment blood pressure increase as exercise intensity increases. tool for autonomic nervous system function, and reduced It is measured as the amount of heart rate or blood and/or abnormal HRV and BPV are associated with in- pressure increase in response to every unit of meta- creased risk of mortality in cardiac patients. For both adults bolic equivalent (MET) exercise intensity increase. In and children, increased blood pressure variability (BPV) practice, it can be measured and calculated as appears to be directly related to sympathetic overactivity 􏼐HR − HR 􏼑 stage rest with increased risk of end-organ damage and cardiovascular CR � , HR MET − 1 events. Decreased HRV has been observed in adults and 􏼐 􏼑 stage children with chronic kidney disease and is an independent (2) predictor of mortality [22]. 􏼐BP − BP 􏼑 stage rest Autonomic dysfunctions are the most common non- CR � . BP 􏼐MET − 1􏼑 motor symptoms of Parkinson’s disease (PD) and often stage precede the motor symptoms of the disease. Clinical study has shown that HRV and BPV can be used as markers to indicate CR is similar with the “Exercise HR” in EACPR/ HR the treatment progress and stages of the disease [23]. AHA Joint Scientific Statement [25]. It directly Journal of Healthcare Engineering 5 relates to sympathetic nerves activation and provides example, Dhoble et al. [36] examined conventional insight into chronotropic competence and cardiac cardiovascular risk factors and exercise test pa- response to exercise. It normally increases ∼10 beats rameters in 6546 individuals (mean age 49 years, 58% per MET. -e chronotropic rate is an important men) between 1993 and 2003. A total of 285 patients parameter to provide personalized quantitative re- died during the follow-up period. HR < 12 recovery1 lation between HR and exercise intensity so that the beats were found independently associated with target heart rate (THR) can be used to prescribe mortality (P< 0.001). exercise intensity in exercise training. However, the A clinical trial in cardiac rehabilitation was conducted in chronotropic rate of a person may vary due to Jiangsu Provincial Hospital to evaluate the usability of CCI medication or rehab progress; it is recommended to [37], which are measured by Cardiac Chronotropic Com- measure the chronotropic rate promptly or monitor petence Testing (3CT), a device produced by SmartHealth chronotropic rate changes in order to keep exercise Electronics Ltd. 61 participants were recruited, including prescription updated [35]. patients of unilateral ischemic or hemorrhagic stroke within (3) Chronotropic limit (CL): chronotropic limit repre- the previous 6 months with some voluntary movement and sents the maximal heart rate an individual can preserved cognitive function. Participates are randomly achieve without severe problems through exercise assigned to the rehab group (30) and control group (31). stress, as well as the blood pressure measured at the Each patient from both groups was evaluated at the be- same time. It is measured as heart rate reserve and ginning and after 3 months using both subjective/qualitative calculated as and objective/quantitative measures, namely, the In- ternational Classification of Functioning, Disability and HR − HR 􏼁 max rest CL � HRR � , (3) Health (ICF), and chronotropic competence indices (CCI) HR − HR 􏼁 PredM rest and 6 minute walking test (6MWT). Patients in the control group were given personalized rehab advices after the where HR is the maximal heart rate one achieves max during the exercise test and HR is the predicted baseline test. Patients in the rehab group were equipped with PredM maximal heart rate, usually calculated as 220− age. a Microsens rehab assistant for regular rehab exercise at -e maximal heart rate is usually obtained when home. Personalized exercise prescription based on CCI is reaching peak exercise, which can be identified downloaded into MicroSens rehab assistant, which consists during CPX testing. In this case, the normal value of of rehab app on a smartphone and a wearable device. CL is 0.8–1.3. However, when CPX testing or peak Comparison between control and rehab groups after exercise is not achievable, then CL normal values are 3 months of rehab training using the t-test shows that, different for types of exercises. For example, in a 6- through out the rehab training, all the four ICF measure- ments, namely, walking, doing house-hold work, in- minute walking test, CL � 0.4 for a 60-year-old person should be considered normal. With a rest- terpersonal interactions, and muscle power, have significant ing heart rate of 75 bpm, CR would be 10 beats per improvement (p � 0.0070, 0.0209, 0.0089, and 0.0000, re- MET and the maximal heart rate would be 109 bpm spectively). Consistently, after 3 months of rehab training, with an exercise intensity of 4.4 MET. the rehab group is significantly better over the control group with respect to all three 3CT objective measures: 6-minute (4) Chronotropic acceleration (CA): ANS requires cer- walking distance, chronotropic rate, and 1-minute heart rate tain time to adjust the heart rate and blood pressure recovery (p � 0.0445, 0.0121, and 0.0414, respectively). to reach a new stable state or equilibrium when the exercise intensity increases to a new level in the graded exercise test. CA is defined as the time taken 5. BRS, SNA, and PNA in Orthostatic to reach new equilibrium after exercise intensity Testing Scenario increases. CA is measured in seconds and represents the ability of the ANS regulation of the cardiac Estimation of BRS, SNA, and PNA is carried out in orthostatic system in fulfilling metabolic needs. testing scenario where the subject is requested to suddenly (5) Chronotropic recovery at 1 minute after exercise stand up from a sitting position. As a result, blood pools in the (HR and BP ): it is defined as the re- vessels of the legs for a longer period and less is returned to the recovery1 recovery1 duction in the heart rate and blood pressure 1 minute heart, thereby leading to a reduced cardiac output and fall in after stopping exercise. -e measurement of HR blood pressure. In order to counteract these changes, the re- and BP requires the testee to try his frequency of afferent impulses in the aortic and carotid sinus covery1 recovery1 best in the exercise, but not necessarily to reach one’s nerves is reduced, which leads to parasympathetic withdrawal maximum capacity. EACPR/AHA Joint Scientific and sympathetic activation. Here, the nerve activity will be Statement [25] considers that HR provides referred to as the baroreflex firing rate or simply the firing recovery1 insight into speed of parasympathetic reactivation rate. Sympathetic activation leads to a growing release of and that the normal value of HR should norepinephrine which contributes to restoration of BP by recovery1 be> 12 beats. -ere have been a number of clinical increasing HR, cardiac contractility, and vasoconstrictor tone. studies on prognosis value of HR . For In addition, parasympathetic withdrawal leads to decreased recovery1 6 Journal of Healthcare Engineering Average BP Heart rate 20 40 60 80 100 120 140 Time (second) Acceleration X (front-back) Acceleration Y (left-right) Acceleration Z (up-down) –5 20 40 60 80 100 120 140 Time (second) Figure 2: Curves of measured acceleration data (low), average blood pressure (up, blue), and heart rate (up, green). -e stands up at the 47th second, when acceleration Z component (red) has a sudden drop, followed by average blood pressure fall and recovery and heart rate increase and recovery. release of acetylcholine which also causes the increase of HR. (c) Concentrations of noradrenaline and acetyl- -is whole ANS regulation process can be described by a choline are computed as functions of the sym- pathetic and parasympathetic outflows mathematical model [29, 38]. In the measurement, the subject wears a device which (d) Heart rate is computed as a function of these two measures ECG, radial artery pulse wave and branchial artery chemical concentrations pulse wave, and acceleration data to locate phases of the or- (e) Computed HR is compared with the measured thostatic posture. -e orthostatic testing protocol is as follows: HR (1) -e subject wears the device and sits on a chair, with (ii) For all BP and HR pairs, optimization for the the upper body straight up until reaching a stable minimizing error is performed between computed state of heart rate HR and measured HR to get curves of baroreflex firing rate and sympathetic and parasympathetic (2) -e subject stands up and keeps standing for 40 seconds outflows. Figure 3 shows these curves for a healthy th young person and a 50 hypertension person. Other (3) -e above process is repeated for three times parameters, such as baroreflex sensitivity, can be -e device records all the data and sends the data to the derived from those curves and BP and HR data. computer wirelessly. -e heart rate is calculated from ECG Noninvasive measurement of BRS, SNA, and PNA signal. -e average blood pressure is estimated via pulse provides useful meanings to discover mechanisms that act to transmission time from radial artery pulse wave and branchial keep cerebral blood flow (CBF) constant, to understand artery pulse wave with assumption that the physical properties immune system, for better management of metabolic syn- of the blood vessel and the blood do not change within the drome and hypertension. -e quantitative estimation of measurement time. Figure 2 shows a sample of the mea- baroreflex sensitivity has been regarded as a synthetic index surement data. of neural regulation at the sinus atrial node, which has been -e blood pressure change in the orthostatic test is shown to provide clinical and prognostic information in a maximized, and the mathematical model defining the ANS variety of cardiovascular diseases, including myocardial regulation of heart rate due to blood pressure changes can then be simplified as a small subgraph of the probability infarction and heart failure [39]. Chronic hyperglycemia is graphic model in Figure 1. Based on the mathematical the primary risk factor for the development of complications model, using a series of blood pressure and heart rate data in diabetes mellitus (DM). Postprandial spikes in blood pairs obtained in the orthostatic testing, we can perform the glucose, as well as hypoglycemic events, are blamed for following. increased cardiovascular events in DM. Glycemic variability (GV) includes both of these events. However, defining GV (i) For each BP and HR pair, the following is performed: remains a challenge primarily due to the difficulty of (a) BP is used to calculate the baroreflex firing rate measuring it [40]. A multicenter, prospective, open-label clinical trial including a total of 102 patients with type 2 (b) With baroreflex firing rate, sympathetic and parasympathetic outflows are predicted diabetes [41] has found that GV was inversely related to BRS Journal of Healthcare Engineering 7 Baroreflex firing rate Conflicts of Interest -e authors declare that they have no conflicts of interest. References [1] A. Zygmunt and J. Stanczyk, “Methods of evaluation of au- tonomic nervous system function,” Archives of Medical Sci- ence, vol. 1, pp. 11–18, 2010. [2] C. Heymans, “Reflexogenic areas of the cardiovascular sys- tem,” Perspectives in Biology and Medicine, vol. 3, no. 3, pp. 409–417, 1960. [3] J. 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Quantitative Assessment of Autonomic Regulation of the Cardiac System

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Copyright © 2019 Jian Kang Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Healthcare Engineering Volume 2019, Article ID 4501502, 8 pages https://doi.org/10.1155/2019/4501502 Research Article Quantitative Assessment of Autonomic Regulation of the Cardiac System 1,2 1 3 4 Jian Kang Wu , Zhipei Huang , Zhiqiang Zhang , Wendong Xiao , and Hong Jiang e University of Chinese Academy of Sciences, Beijing, China Institute of Healthcare Technologies, Chinese Academy of Sciences, Nanjing, China University of Leeds, West Yorkshire, UK Beijing University of Science and Technology, Beijing, China China-Japan Friendship Hospital, Beijing, China Correspondence should be addressed to Jian Kang Wu; jkwu@ucas.ac.cn and Zhipei Huang; zhphuang@ucas.ac.cn Received 8 January 2019; Accepted 27 March 2019; Published 21 April 2019 Guest Editor: Jilong Kuang Copyright © 2019 Jian Kang Wu et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autonomic neural system (ANS) regulates the circulation to provide optimal perfusion of every organ in accordance with its metabolic needs, and the quantitative assessment of autonomic regulation is crucial for personalized medicine in cardiovascular diseases. In this paper, we propose the Dystatis to quantitatively evaluate autonomic regulation of the human cardiac system, based on homeostatis and probabilistic graphic model, where homeostatis explains ANS regulation while the probability graphic model systematically defines the regulation process for quantitative assessment. -e indices and measurement methods for three well- designed scenarios are also illustrated to evaluate the proposed Dystatis: (1) heart rate variability (HRV), blood pressure variability (BPV), and respiration synchronization (Synch) in resting situation; (2) chronotropic competence indices (CCI) in graded exercise testing; and (3) baroreflex sensitivity (BRS), sympathetic nerve activity (SNA), and parasympathetic nerve activity (PNA) in or- thostatic testing. -e previous clinical results have shown that the proposed method and indices for autonomic cardiac system regulation have great potential in prediction, diagnosis, and rehabilitation of cardiovascular diseases, hypertension, and diabetes. and (2) Axelrod [3], Von Euler [4], and Del and Katz [5] 1. Introduction identified acetylcholine (ACh) as a transmitter for the Autonomic neural system (ANS) regulates the circulation to parasympathetic nerves, norepinephrine (NE), and sympa- provide optimal perfusion of every organ in accordance with thetic nerves. However, the ANS regulation of the cardiac its metabolic needs. Together with the endocrine and im- system can be viewed as a complex dynamic system, and it munological systems, it adjusts the internal environment of can be well described by “Homeostasis” [6], which is now the organism to respond the changes in the external envi- regarded as one of the core competencies by the American Association of Medical Colleges and Howard Hughes Medical ronment [1]. -erefore, understanding the ANS and the way it regulates body circulation is crucial for personalized Institute and a core concept necessary for future physicians medicine in cardiovascular diseases. -e understanding of the [7]. ANS regulation in the cardiac system can be traced back to the In clinical settings, autonomic dysfunction has been findings of two Nobel Prize winners: (1) Corneille Heymans in linked to direct detrimental effects towards heart failure and 1938 identified the carotid sinus nerves [2], which are tiny chronic kidney disease [8]; thus, quantitative methods to baroreceptor and chemoreceptor nerves and can sense evaluate the ANS regulation has great potential to generate changes in hemodynamic pressure and humoral factors and innovative diagnostic and treatment approaches that limit send output to the sympathetic and parasympathetic nerves, hypertension and target end-organ damage. Recent research 2 Journal of Healthcare Engineering effects from other internal and external in- has shown that the autonomic neurohumoral system can dramatically influence morbidity and mortality from car- teractions. -ese are minor compared to graded exercises. diovascular disease through influences on the innate and adaptive immune systems [9]. Due to the high metabolic rate (3) BRS, SNA, and PNA in orthostatic testing: based of brain tissue, the precise regulation of cerebral blood flow on Dystatis, orthostatic testing creates a large (CBF) is critical for maintenance of constant nutrient and blood pressure drop and then a large BRS output oxygen supply to the brain [10]. -e metabolic syndrome is to sympathetic and parasympathetic nerves. As characterized by the clustering of various common meta- such, the mathematical model for solution of bolic abnormalities in an individual, which is also associated BRS, SNA, and PNA can be greatly simplified by with increased risk for the development of type 2 diabetes neglecting other internal and external in- and cardiovascular diseases. -e augmented sympathetic teractions in the ANS regulation. activity in individuals with metabolic syndrome worsens prognosis of this high-risk population [11]. Experimental 2. Dystasis:SystematicQuantitativeAssessment and clinical investigations have validated the hypothesis: the Methodology for ANS Regulation of the origin, progression, and outcome of human hypertension Cardiac System are related to dysfunctional autonomic cardiovascular control, which is particularly true for abnormal activation of Human body is a complex biological system, of which the sympathetic division [12]. homeostasis is a crucial property in maintaining the life. It is Since the quantitative assessment of the autonomic reg- the self-regulating process by which biological systems ulation is tremendously important for clinical and healthcare maintain stability in order to adjust to conditions that are applications, there is urgent need to quantitatively evaluate optimal for survival. -e stability attained is a dynamic the ANS regulation status. Unfortunately, there are only two equilibrium, in which continuous change occurs yet rela- invasive methods to measure certain aspects of the ANS thus tively uniform conditions prevail. far: (1) microneurography to assess muscle sympathetic nerve Dystasis is built up on homeostasis and defined as fol- activity and (2) the norepinephrine isotope dilution to de- lows: ANS regulation of the cardiac system is a part of body’s termine noradrenalin in the blood to evaluate spillover of the complex biological system. -rough ANS self-regulating sympathetic nervous system [13]. Although HRV is an in- process, the cardiac system tends to reach and maintain a direct biomarker of the cardiac autonomic nervous system dynamic equilibrium state, in order to supply cells and activity [14], ANS regulation of the cardiac system is complex organs with their metabolic needs, e.g., oxygen, nutrients, in nature and existing HRV assessment is rather ad hoc and removal of waste, survive in various internal and ex- without any theoretical model. -erefore, HRV indices ob- ternal environments, and support various physical and tained in different settings and by different persons are often mental activities. -e characteristics of Dystasis are (1) inconsistent, resulting in difficulties for clinical interpretation. equilibrium: the ANS self-regulating process of the cardiac In summary, ANS regulation of the cardiac system plays system reaches and maintains an “equilibrium” state in a a central role in both research and clinical practices, and we relative steady internal and external environment, with no or will focus on the quantitative assessment of autonomic minor changes in terms of physical and mental activities. -e regulation of the cardiac system in this paper. -e main property and its numerical measures of the state of this contributions are as follows: equilibrium of the individual’s ANS self-regulating process shall provide quantitative performance evaluation of how (i) We propose the Dystatis to quantitatively evaluate well one’s ANS regulation system works; (2) dynamic: the autonomic regulation of the human cardiac system, ANS self-regulating process of cardiac system should be based on homeostatis and the probabilistic graphic “dynamic” enough, being able to work in dynamic envi- model, where homeostatis explains ANS regulation ronment, support various physical and mental activities of while the probability graphic model systematically the body, and defend virus invasions. In other words, it defines the regulation process for quantitative should be able to reach new equilibrium state as soon as assessment. possible when there is a change of internal/external envi- (ii) -e Dystatis is elaborated in three well-designed ronment or physical/mental activities. For instance, ANS scenarios, where indices and measurement methods regulation interacts with the immune system to control for each scenario are also proposed and illustrated by inflammation [15] and ANS regulation of the cardiac system clinical applications: increases oxygen supply and reaches a new equilibrium (1) HRV, BRV, and Synch in resting situation: when the intensity of physical activity increases to a new Dystatis provides theoretical model and guide- level. -e capability of ANS regulation to accommodate lines for the test design and data processing and changes of internal and external environment, as well as interpretations, in order to solve existing in- activity needs, is another important measure. consistence problems. In order to quantitatively evaluate the state and capa- (2) CCI in graded exercise testing: Dystatis meta- bility of ANS regulation of the cardiac system, one feasible bolic requirement is enlarged by graded exercise approach is the probabilistic graphic model-based approach so that CCI can be obtained without considering [16], as shown in Figure 1. Principally, the interactions of Journal of Healthcare Engineering 3 (1) Variability of the heart rate and blood pressure (HRV Immune Metabolism system and BPV) while the subject is in resting or other Vascular Viscera steady state: the ideal measurement scenario is zero or known steady physical activity, minimal mental ac- Lung Mental tivity, and minimal viscera disturbance. -e vari- ability indices are used to characterize the state of ANS equilibrium of individual’s ANS self-regulating pro- cess, which directly reflects states of immune system, linking with inflammation biomarkers. Heart (2) CCI in graded exercise testing: the effect of physical activity on ANS is maximized so that the influences Figure 1: Probabilistic graphic model of autonomic regulation of from the rest sources can be neglected. CCI provide the cardiac system with internal and external influences. numerical measures to characterize the capability of ANS regulation to accommodate changes of exercise ANS with cardiac, respiration, vascular, metabolic, immune, intensity. viscera, and mental systems are bidirectional [17]. Here, in (3) BRS, SNA, and PNA are obtained by model-based Figure 1, the objective is to estimate ANS state through all analysis of blood pressure (BP) and heart rate (HR) possible observations, in case of ANS regulation of the heart pairs acquired in orthostatic testing: Via orthostatic rate with major internal and external influences; i.e., RSA is a test, large blood pressure drops around 30 mmh is terminology for heart rate modulation by respiration; blood obtained. -e input from baroreflex to SNA and pressure formed in the vascular system and sensed by PNA becomes the major effect, and the rest can be baroreflex which then affects the heartbeat; physical activ- neglected. As such, the mathematical model for the ities stimulate metabolic needs and increase the heart rate; solution can be simplified as a subgraph of the inflammation in the immune system breaks the stability of graphic model in Figure 1. ANS regulation and then heart rate variations; the dorsal vagal complex is responsible for the interaction between viscera organs and ANS; and the ventral vagal complex is 3. Variabilities in Resting or Steady responsible for mental activities [17]. -e observation of Testing Scenario ANS regulation here is variations of the heart rate, blood pressure, and respiration. -e sympathetic innervation of -e indices of HRV and BPV consist of time-domain second- the heart and blood vessels is excitatory. It stimulates va- order statistics, for example, standard deviation of ECG soconstriction and increases the heart rate and cardiac normal-to-normal intervals (SDNN) and standard deviation contraction. On contrary, the parasympathetic vagal in- of differences of neighboring normal-to-normal intervals nervation is inhibitory, which decreases the heart rate and (SDSD). Frequency-domain indices are calculated at very low cardiac contraction. -e balance of the two appears as frequency band (VLF, 0.004–0.04 Hz), low frequency band variations of the heart rate and blood pressure and can be (LF, 0.04–0.15 Hz), and high frequency band (0.15–0.4 Hz). characterized by indices which represent properties and -e problem is then to quantitatively evaluate the state of rules of those variations caused by regulation: -e sympa- ANS and infer the physiological and psychological implica- thetic activity increases during the flight-or-fight response, tions, given measured variabilities of the heart rate, blood whereas parasympathetic activity increases to calm the heart pressure, respiration, and assessment scenario that the when there appears emotionally driven high blood pressure. physical activity is zero or constant. Based on Dystasis For the estimation purpose and from Figure 1, we can framework, according to equation (1) and graphic model in obtain the following formula, via probabilistic graphic Figure 1, there are still three nodes: mental activities and the model: states of viscera organs are not known or unmeasurable and inflammations in the immune system are the ones to be P � p(heart/A) p(A/mental) p(A/viscera) inferred. Now, in this assessment scenario, in order to obtain · p(A/immune) p(A/metabolic) p(A/vascular) the stable and consistent quantitative measures, we have to · p(A/lung), minimize the influences of mental activities and viscera or- gans. To fulfill this requirement, variabilities are best to be (1) measured when the subject is in deep sleep or in a coherence where A is the state of ANS to be estimated through ob- state between respiration and heart rate where mental ac- servations connected with ANS in the graph of Figure 1. tivities and viscera influences are purposely minimized. However, not all nodes connected with the ANS node are HRV has been studied for a long time to reflect the states observable or measurable. For the quantitative assessment of ANS regulation [14, 18]. In clinical practice, HRV is purpose, it is the best to intentionally create assessment usually evaluated using Holter device and software, without scenario where the influences of the measurable nodes are consideration of physical activities and other influences. -is maximized whilst minimizing those of the unmeasurable has resulted in inconsistences in various studies and limited nodes. -erefore, we designed the following three assess- the clinical applications of HRV. To quantitatively evaluate ment scenarios: the physical activities and define the testing scenario, in case 4 Journal of Healthcare Engineering of using Holter device, a three-dimensional accelerometer A review of research literature [24] tells that affected sensor is used to detect and classify posture and activity into central nervous system structures and implicated autonomic nervous system regulation coexist in Alzheimer’s disease. laying, sitting or standing, walking, or running. HRV indices are then calculated when any of those postures and activities Assessment of autonomic dysfunction can be used as an keeps for more than 10 minutes [19]. early marker of Alzheimer’s disease and used for differential -e interaction between heartbeat and respiration is the diagnosis among dementia subtypes. well-known respiratory sinus arrhythmia (RSA). -e wis- dom of the body to maintain the homeostasis is achieved by 4. Chronotropic Competence Indices in Graded synchronizing heartbeats with breathing and consequently Exercise Testing Scenario to maximize the efficiency of the cardiopulmonary system in metabolic and circulation process. -is equilibrium state is Graded exercise tests, such as cardiopulmonary exercise test the result of resonance of the cardiopulmonary system. (CPX), have been used in clinical practice to test the exercise -ere are indices proposed to evaluate the degree of the capability in terms of maximum oxygen metabolism [25]. In resonance of the cardiopulmonary system. -e most com- Dystasis family, CCI are designed to evaluate the capability mon used one is coherence measure (Coh), the cross power of the ANS regulation of the cardiac system in response to spectral density of the heart rate and respiration signals [20]. exercise, where the subject does not necessarily reach the -e resonance of the cardiopulmonary system represents maximum exercise intensity. the equilibrium of ANS regulation, where one reaches both Chronotropic incompetence (CI) is a terminology de- physiological and psychological healthy state. -erefore, Coh scribing the status of attenuated heart rate response to exer- can be used to compose numerical measures to visually rep- cises. CI has been studied for the last 50 years [26]. Typical CI- resent one’s health state, especially psychological health state, related measurements include the maximum heart rate and and then, variability-biofeedback training is used to help one to heart rate recovery after exercise. -ere have been a lot of gain resonance state. A clinic trial was conducted in the Uni- research efforts to explore the usefulness of CI parameters in versity of Chinese Academy of Sciences (UCAS) Hospital to test clinical applications, i.e., their diagnosis value of coronary the effectiveness of HRV biofeedback (HRVB) for pregnant artery [27], prognosis and management of heart failure women in managing anxiety and depression [21]. 20 pregnant [28, 29], diabetes [30, 31], and hypertension [32, 33]. Although th women at last trimester (28–32 week) without pregnancy- CI is an independent predictor of major adverse cardiovascular induced hypertension and diabetes were randomly assigned to events and overall mortality, the importance of CI is under- the HRVB group and the control group. Participants in the estimated [34]; this may be in part due to multiple definitions, HRVB group practiced HRVB for 30 minutes per day, while the confounding effects of aging and medications, and the participants in the control group did not. Following checks are need for formal exercise testing for definitive diagnosis. conducted for all participants every two weeks: blood pressure We have formally defined CCI as part of Dystasis in a (BP), fasting blood glucose (FBG), HRV of pregnant women systematic way and in terms of ANS regulation capabilities (PHRV) and their fetuses (FRHV), and subjective assessment and endowed CCI with clear physiological and clinical on pressure using Pregnancy Pressure Scale (PPS), depression implications. CCI are defined as follows: using Edinburgh Postnatal Depression Scale (EPDS), and sleep (1) Resting heart rate (HRrest) and resting blood pressure quality using Pittsburgh Sleep Quality Index (PSQI). -e clinical (BPrest): -e resting heart rate and resting blood trial continued for subjects until they are in hospital for delivery. pressure are defined as the heart rate and blood pressure In the trial, the HRVB group has shown significant improve- when a person is awake, in a neutrally temperate en- ment over the control group with respect to blood pressure vironment, and has not been subject to any recent stability (p> 0.05), depression reduction (p � 0.013), and sleep exertion or stimulation, such as stress or surprise. quality improvement, while fetuses in the HRVB group has shown significant improvement with respect to HRV SDNN (2) Chronotropic rate (CR and CR ): chronotropic HR BP (p< 0.01) and LF spectrum power (p< 0.01). rate represents the rate at which the heart rate and HRV and BPV can be used as a noninvasive assessment blood pressure increase as exercise intensity increases. tool for autonomic nervous system function, and reduced It is measured as the amount of heart rate or blood and/or abnormal HRV and BPV are associated with in- pressure increase in response to every unit of meta- creased risk of mortality in cardiac patients. For both adults bolic equivalent (MET) exercise intensity increase. In and children, increased blood pressure variability (BPV) practice, it can be measured and calculated as appears to be directly related to sympathetic overactivity 􏼐HR − HR 􏼑 stage rest with increased risk of end-organ damage and cardiovascular CR � , HR MET − 1 events. Decreased HRV has been observed in adults and 􏼐 􏼑 stage children with chronic kidney disease and is an independent (2) predictor of mortality [22]. 􏼐BP − BP 􏼑 stage rest Autonomic dysfunctions are the most common non- CR � . BP 􏼐MET − 1􏼑 motor symptoms of Parkinson’s disease (PD) and often stage precede the motor symptoms of the disease. Clinical study has shown that HRV and BPV can be used as markers to indicate CR is similar with the “Exercise HR” in EACPR/ HR the treatment progress and stages of the disease [23]. AHA Joint Scientific Statement [25]. It directly Journal of Healthcare Engineering 5 relates to sympathetic nerves activation and provides example, Dhoble et al. [36] examined conventional insight into chronotropic competence and cardiac cardiovascular risk factors and exercise test pa- response to exercise. It normally increases ∼10 beats rameters in 6546 individuals (mean age 49 years, 58% per MET. -e chronotropic rate is an important men) between 1993 and 2003. A total of 285 patients parameter to provide personalized quantitative re- died during the follow-up period. HR < 12 recovery1 lation between HR and exercise intensity so that the beats were found independently associated with target heart rate (THR) can be used to prescribe mortality (P< 0.001). exercise intensity in exercise training. However, the A clinical trial in cardiac rehabilitation was conducted in chronotropic rate of a person may vary due to Jiangsu Provincial Hospital to evaluate the usability of CCI medication or rehab progress; it is recommended to [37], which are measured by Cardiac Chronotropic Com- measure the chronotropic rate promptly or monitor petence Testing (3CT), a device produced by SmartHealth chronotropic rate changes in order to keep exercise Electronics Ltd. 61 participants were recruited, including prescription updated [35]. patients of unilateral ischemic or hemorrhagic stroke within (3) Chronotropic limit (CL): chronotropic limit repre- the previous 6 months with some voluntary movement and sents the maximal heart rate an individual can preserved cognitive function. Participates are randomly achieve without severe problems through exercise assigned to the rehab group (30) and control group (31). stress, as well as the blood pressure measured at the Each patient from both groups was evaluated at the be- same time. It is measured as heart rate reserve and ginning and after 3 months using both subjective/qualitative calculated as and objective/quantitative measures, namely, the In- ternational Classification of Functioning, Disability and HR − HR 􏼁 max rest CL � HRR � , (3) Health (ICF), and chronotropic competence indices (CCI) HR − HR 􏼁 PredM rest and 6 minute walking test (6MWT). Patients in the control group were given personalized rehab advices after the where HR is the maximal heart rate one achieves max during the exercise test and HR is the predicted baseline test. Patients in the rehab group were equipped with PredM maximal heart rate, usually calculated as 220− age. a Microsens rehab assistant for regular rehab exercise at -e maximal heart rate is usually obtained when home. Personalized exercise prescription based on CCI is reaching peak exercise, which can be identified downloaded into MicroSens rehab assistant, which consists during CPX testing. In this case, the normal value of of rehab app on a smartphone and a wearable device. CL is 0.8–1.3. However, when CPX testing or peak Comparison between control and rehab groups after exercise is not achievable, then CL normal values are 3 months of rehab training using the t-test shows that, different for types of exercises. For example, in a 6- through out the rehab training, all the four ICF measure- ments, namely, walking, doing house-hold work, in- minute walking test, CL � 0.4 for a 60-year-old person should be considered normal. With a rest- terpersonal interactions, and muscle power, have significant ing heart rate of 75 bpm, CR would be 10 beats per improvement (p � 0.0070, 0.0209, 0.0089, and 0.0000, re- MET and the maximal heart rate would be 109 bpm spectively). Consistently, after 3 months of rehab training, with an exercise intensity of 4.4 MET. the rehab group is significantly better over the control group with respect to all three 3CT objective measures: 6-minute (4) Chronotropic acceleration (CA): ANS requires cer- walking distance, chronotropic rate, and 1-minute heart rate tain time to adjust the heart rate and blood pressure recovery (p � 0.0445, 0.0121, and 0.0414, respectively). to reach a new stable state or equilibrium when the exercise intensity increases to a new level in the graded exercise test. CA is defined as the time taken 5. BRS, SNA, and PNA in Orthostatic to reach new equilibrium after exercise intensity Testing Scenario increases. CA is measured in seconds and represents the ability of the ANS regulation of the cardiac Estimation of BRS, SNA, and PNA is carried out in orthostatic system in fulfilling metabolic needs. testing scenario where the subject is requested to suddenly (5) Chronotropic recovery at 1 minute after exercise stand up from a sitting position. As a result, blood pools in the (HR and BP ): it is defined as the re- vessels of the legs for a longer period and less is returned to the recovery1 recovery1 duction in the heart rate and blood pressure 1 minute heart, thereby leading to a reduced cardiac output and fall in after stopping exercise. -e measurement of HR blood pressure. In order to counteract these changes, the re- and BP requires the testee to try his frequency of afferent impulses in the aortic and carotid sinus covery1 recovery1 best in the exercise, but not necessarily to reach one’s nerves is reduced, which leads to parasympathetic withdrawal maximum capacity. EACPR/AHA Joint Scientific and sympathetic activation. Here, the nerve activity will be Statement [25] considers that HR provides referred to as the baroreflex firing rate or simply the firing recovery1 insight into speed of parasympathetic reactivation rate. Sympathetic activation leads to a growing release of and that the normal value of HR should norepinephrine which contributes to restoration of BP by recovery1 be> 12 beats. -ere have been a number of clinical increasing HR, cardiac contractility, and vasoconstrictor tone. studies on prognosis value of HR . For In addition, parasympathetic withdrawal leads to decreased recovery1 6 Journal of Healthcare Engineering Average BP Heart rate 20 40 60 80 100 120 140 Time (second) Acceleration X (front-back) Acceleration Y (left-right) Acceleration Z (up-down) –5 20 40 60 80 100 120 140 Time (second) Figure 2: Curves of measured acceleration data (low), average blood pressure (up, blue), and heart rate (up, green). -e stands up at the 47th second, when acceleration Z component (red) has a sudden drop, followed by average blood pressure fall and recovery and heart rate increase and recovery. release of acetylcholine which also causes the increase of HR. (c) Concentrations of noradrenaline and acetyl- -is whole ANS regulation process can be described by a choline are computed as functions of the sym- pathetic and parasympathetic outflows mathematical model [29, 38]. In the measurement, the subject wears a device which (d) Heart rate is computed as a function of these two measures ECG, radial artery pulse wave and branchial artery chemical concentrations pulse wave, and acceleration data to locate phases of the or- (e) Computed HR is compared with the measured thostatic posture. -e orthostatic testing protocol is as follows: HR (1) -e subject wears the device and sits on a chair, with (ii) For all BP and HR pairs, optimization for the the upper body straight up until reaching a stable minimizing error is performed between computed state of heart rate HR and measured HR to get curves of baroreflex firing rate and sympathetic and parasympathetic (2) -e subject stands up and keeps standing for 40 seconds outflows. Figure 3 shows these curves for a healthy th young person and a 50 hypertension person. Other (3) -e above process is repeated for three times parameters, such as baroreflex sensitivity, can be -e device records all the data and sends the data to the derived from those curves and BP and HR data. computer wirelessly. -e heart rate is calculated from ECG Noninvasive measurement of BRS, SNA, and PNA signal. -e average blood pressure is estimated via pulse provides useful meanings to discover mechanisms that act to transmission time from radial artery pulse wave and branchial keep cerebral blood flow (CBF) constant, to understand artery pulse wave with assumption that the physical properties immune system, for better management of metabolic syn- of the blood vessel and the blood do not change within the drome and hypertension. -e quantitative estimation of measurement time. Figure 2 shows a sample of the mea- baroreflex sensitivity has been regarded as a synthetic index surement data. of neural regulation at the sinus atrial node, which has been -e blood pressure change in the orthostatic test is shown to provide clinical and prognostic information in a maximized, and the mathematical model defining the ANS variety of cardiovascular diseases, including myocardial regulation of heart rate due to blood pressure changes can then be simplified as a small subgraph of the probability infarction and heart failure [39]. Chronic hyperglycemia is graphic model in Figure 1. Based on the mathematical the primary risk factor for the development of complications model, using a series of blood pressure and heart rate data in diabetes mellitus (DM). Postprandial spikes in blood pairs obtained in the orthostatic testing, we can perform the glucose, as well as hypoglycemic events, are blamed for following. increased cardiovascular events in DM. Glycemic variability (GV) includes both of these events. However, defining GV (i) For each BP and HR pair, the following is performed: remains a challenge primarily due to the difficulty of (a) BP is used to calculate the baroreflex firing rate measuring it [40]. A multicenter, prospective, open-label clinical trial including a total of 102 patients with type 2 (b) With baroreflex firing rate, sympathetic and parasympathetic outflows are predicted diabetes [41] has found that GV was inversely related to BRS Journal of Healthcare Engineering 7 Baroreflex firing rate Conflicts of Interest -e authors declare that they have no conflicts of interest. References [1] A. Zygmunt and J. Stanczyk, “Methods of evaluation of au- tonomic nervous system function,” Archives of Medical Sci- ence, vol. 1, pp. 11–18, 2010. [2] C. Heymans, “Reflexogenic areas of the cardiovascular sys- tem,” Perspectives in Biology and Medicine, vol. 3, no. 3, pp. 409–417, 1960. [3] J. 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