Dynamic Assessment of Baroreflex Control of Heart Rate During Induction of Propofol Anesthesia Using a Point Process Method

In this article, we present a point process method to assess dynamic baroreflex sensitivity (BRS) by estimating the baroreflex gain as focal component of a simplified closed-loop model of the cardiovascular system. Specifically, an inverse Gaussian probability distribution is used to model the heartbeat interval, whereas the instantaneous mean is identified by linear and bilinear bivariate regressions on both the previous R−R intervals (RR) and blood pressure (BP) beat-to-beat measures. The instantaneous baroreflex gain is estimated as the feedback branch of the loop with a point-process filter, while the RRBP feedforward transfer function representing heart contractility and vasculature effects is simultaneously estimated by a recursive least-squares filter. These two closed-loop gains provide a direct assessment of baroreflex control of heart rate (HR). In addition, the dynamic coherence, cross bispectrum, and their power ratio can also be estimated. All statistical indices provide a valuable quantitative assessment of the interaction between heartbeat dynamics and hemodynamics. To illustrate the application, we have applied the proposed point process model to experimental recordings from 11 healthy subjects in order to monitor cardiovascular regulation under propofol anesthesia. We present quantitative results during transient periods, as well as statistical analyses on steady-state epochs before and after propofol administration. Our findings validate the ability of the algorithm to provide a reliable and fast-tracking assessment of BRS, and show a clear overall reduction in baroreflex gain from the baseline period to the start of propofol anesthesia, confirming that instantaneous evaluation of arterial baroreflex control of HR may yield important implications in clinical practice, particularly during anesthesia and in postoperative care.National Institutes of Health (U.S.) (Grant R01-HL084502)National Institutes of Health (U.S.) (Grant K25-NS05758)National Institutes of Health (U.S.) (Grant DP2- OD006454)National Institutes of Health (U.S.) (Grant T32NS048005)National Institutes of Health (U.S.) (Grant T32NS048005)National Institutes of Health (U.S.) (Grant R01-DA015644)Massachusetts General Hospital (Clinical Research Center, UL1 Grant RR025758

Instantaneous monitoring of heart beat dynamics during anesthesia and sedation

Anesthesia-induced altered arousal depends on drugs having their effect in specific brain regions. These effects are also reflected in autonomic nervous system (ANS) outflow dynamics. To this extent, instantaneous monitoring of ANS outflow, based on neurophysiological and computational modeling, may provide a more accurate assessment of the action of anesthetic agents on the cardiovascular system. This will aid anesthesia care providers in maintaining homeostatic equilibrium and help to minimize drug administration while maintaining antinociceptive effects. In previous studies, we established a point process paradigm for analyzing heartbeat dynamics and have successfully applied these methods to a wide range of cardiovascular data and protocols. We recently devised a novel instantaneous nonlinear assessment of ANS outflow, also suitable and effective for real-time monitoring of the fast hemodynamic and autonomic effects during induction and emergence from anesthesia. Our goal is to demonstrate that our framework is suitable for instantaneous monitoring of the ANS response during administration of a broad range of anesthetic drugs. Specifically, we compare the hemodynamic and autonomic effects in study participants undergoing propofol (PROP) and dexmedetomidine (DMED) administration. Our methods provide an instantaneous characterization of autonomic state at different stages of sedation and anesthesia by tracking autonomic dynamics at very high time-resolution. Our results suggest that refined methods for analyzing linear and nonlinear heartbeat dynamics during administration of specific anesthetic drugs are able to overcome nonstationary limitations as well as reducing inter-subject variability, thus providing a potential real-time monitoring approach for patients receiving anesthesia

Mathematical models for educational simulation of cardiovascular pathophysiology

Tese de doutoramento. Engenharia Biomédica. Faculdade de Engenharia. Universidade do Porto, Instituto de Engenharia Biomédica, Faculdade de Medicina. Universidade do Porto. 200

The Effects of Exercise Training on Indices of Cardiovascular Autonomic Neuropathy in STZ-Induced Type 1 Diabetic Rats Treated with Insulin

This study investigated whether regular aerobic exercise training could prevent the dysregulation of autonomic cardiovascular (CV) control in a streptozotocin (STZ)-diabetes model designed to represent clinical type 1 diabetes mellitus (T1DM). Rats were divided into control (C), control exercise (CX), diabetic (D) and diabetic exercise (DX) groups. Baroreflex sensitivity (BRS), heart rate variability (HRV) and vascular sympathetic tone (VST) were measured following 10 weeks of exercise. Parasympathetic-mediated bradycardia BRS was reduced in D compared to C and DX (

Assessment and Mechanisms of Autonomic Function in Health and Disease

The autonomic nervous system is a master regulator of homeostasis, and the conviction that autonomic outflow is important on a patient-by-patient, minute-to-minute basis in both health and disease is the motivation for this thesis. The dissertation explores three aims that advance our understanding of the autonomic nervous system by elucidating the molecular mechanisms of autonomic regulation, validating widely used techniques for autonomic assessment, and developing and applying a new method to assess sympathetic vascular control. The first aim of the dissertation was to investigate the role of the Rho kinase pathway as a mediator of the autonomic effects of central angiotensin-II. This study was performed in conscious, chronically instrumented rabbits that received intracerebroventricular infusions of angiotensin-II, angiotensin-II with the specific Rho kinase inhibitor Fasudil, Fasudil alone, or a vehicle control over two weeks. Baseline hemodynamics were assessed daily, and cardiac and global vasomotor sympathetic tone was assessed by the hemodynamic response to autonomic blockers. Angiotensin-II raised blood pressure and cardiac and global vasomotor sympathetic outflow in a Rho-kinase dependent manner. In a separate cohort, renal sympathetic nerve activity was directly recorded and sympathetic baroreflex sensitivity was assessed, providing clear evidence that angiotensin-II increases renal sympathetic nerve activity and impairs baroreflex control thereof via a Rho kinase-dependent mechanism. In summary, the pressor, sympatho-excitatory, and baroreflex dysfunction caused by central angiotensin-II depend on Rho kinase activation. The second aim was to investigate the relationship between measures of pulse rate variability obtained by a chronically implanted arterial pressure telemeter with measures of heart rate variability derived by the standard electrocardiogram and the ability of pulse rate variability to reflect the autonomic contributions of heart rate variability. This study was conducted in conscious rabbits chronically instrumented with epicardial leads and arterial pressure telemeters. The autonomic contribution to pulse rate variability was assessed by pharmacological blockade, and the intrinsic variability of pulse rate was assessed by ventricular pacing. This study showed that pulse rate variability is a generally acceptable surrogate for heart rate variability for time- and frequency-domain measures, but the additional contribution of respiration to and the differing nonlinear properties of pulse rate variability should be considered by investigators. The third aim was to critically test the idea that the renal sympathetic nerves do not participate in the physiological control of renal blood flow. This study was conducted in conscious rabbits that underwent unilateral renal denervation and chronic instrumentation with arterial pressure telemeters and bilateral renal blood flow probes. Using time-varying transfer function analysis, this study showed active, rhythmic vasoconstriction of the renal vasculature with baroreflex properties in normally innervated kidneys, consistent with sympathetic vasomotion, which was absent in denervated kidneys. This refutes the long-held idea that sympathetic control of the renal vasculature is not physiological and has important applications to the burgeoning field of therapeutic renal denervation for cardiovascular disease

The Role of Central ACE2 and Nrf2 in Sympatho-Excitation: Responses to Central Angiotensin II

Sympatho-excitation is a key characteristic in cardiovascular diseases such as chronic heart failure (CHF) and primary Hypertension (HTN). Evidence suggests that increased sympathetic tone is closely related to activation of the Renin-Angiotensin-Aldosterone system (RAAS) in the central nervous system. An underlying mechanism for sympatho-excitation is thought to be oxidative stress resulting from Angiotensin II (AngII) type 1 receptor (AT1R) activation. Over the past several decades, pharmacological targeting of components of the RAAS have been used as standard therapy in CHF and HTN. However, additional therapeutic strategies are necessary to control these diseases. Oxidative stress is regulated, in part, by the balance between components of the RAAS and the ability of the system to scavenge oxygen radicals. Over the past decade, Nuclear factor E2-related factor 2 (Nrf2) has emerged as an important transcriptional regulator that maintains redox homeostasis by governing a broad array of antioxidant genes in response to oxidant stress. Central Nrf2 dysregulation has been found in animals with CHF and HTN. To determine if Nrf2 contributes to decreased antioxidant defense and increased sympathetic nerve activity (SNA) in CHF, we upregulated Nrf2 in the rostral ventrolateral medulla (RVLM) in C57BL/6 mice and evaluated their hemodynamic and sympathetic function in the CHF state. We found that (1) Nrf2 and two target proteins, NAD(P)H dehydrogenase [quinone] 1 (NQO1) and Heme oxygenase (HO-1) in the RVLM were significantly lower in CHF compared to Sham mice; (2) Urinary norepinephrine (NE) excretion in CHF mice was markedly reduced following Nrf2 upregulation; (3) CHF mice overexpressing Nrf2 exhibited an enhancement in spontaneous baroreflex gain and a decrease in basal renal SNA. In an attempt to understand the antioxidant function of the RAAS we examined the role of Angiotensin converting enzyme 2 (ACE2) in a model of central AngII-induced HTN. Despite its direct enzymatic effect on AngII, ACE2 has been shown to reduce oxidative stress and to be sympatho-inhibitory. It has been demonstrated that animals with CHF exhibit increased Angiotensin converting enzyme (ACE) and decreased ACE2 in the RVLM. We hypothesized that overexpression of ACE2 in the brain reduces the sympathetic and blood pressure (BP) responses to central AngII by activation of Nrf2 and enhancing antioxidant enzyme expression. To illuminate the role of Nrf2 in the central regulation of SNA in response to central AngII, we assessed Nrf2 changes in the RVLM in SynhACE2 mice treated with ICV AngII infusion. Mice with central overexpression of ACE2 inhibited the pressor and sympathetic responses to central AngII. We found that Nrf2 was upregulated in the RVLM in SynhACE2 mice, and that pharmacological upregulation of central Nrf2 had a significant impact on BP in response to central AngII. Overall, the experiments described in this dissertation showed that selectively upregulating Nrf2 in the RVLM attenuates sympatho-excitation in CHF mice. We also describe a novel role of interplay between central AngII, ACE2 and Nrf2 in the regulation of sympatho-excitation in central HTN. While not definitive, these studies suggest a role for ACE2 and Nrf2 as targets for therapy in CHF and HTN

Changes in Cardiac Autonomic Regulation after Acute Lung Exposure to Carbon Nanotubes: Implications for Occupational Exposure

Carbon nanotubes (CNTs) are among the most relevant engineered nanomaterials (ENMs). Given the expected rise of exposure to ENMs, there is concern that they may adversely affect health of exposed people. Aim of the study was to test the hypothesis that single wall carbon nanotubes (SWCNTs) pulmonary exposure acutely affect the autonomic cardiovascular regulation in conscious rats. We studied Wistar-Kyoto rats in which a telemetry transmitter for continuous arterial pressure (AP) and heart rate (HR) recordings was surgically implanted. SWCNTs dispersed in phosphate buffer saline (PBS) or PBS alone were randomly administered intratracheally. Immediately before, and 24 hours after each instillation a 30 min AP recording was performed. The sequence analysis was performed to evaluate the baroreflex function. In the control group, PBS instillation did not induce any significant changes. At variance the SWCNT exposure induced a significant reduction of baroreflex system (BRS) (3.5 \ub1 0.6 versus 2.6 \ub1 0.40\u2009msec/mmHg) without significant changes in the occurrence of baroreflex sequences (7.5 \ub1 0.47 % versus 7.4 \ub1 0.38 %). Our results show that SWCNT pulmonary exposure might affect the cardiovascular autonomic regulation thus contributing to cardiac and arrhythmic events

Activity Dependent Changes In Functional And Morphological Characteristics Among Presympathetic Neurons Of The Rostral Ventrolateral Medulla

A sedentary lifestyle is a major risk factor for the development of cardiovascular disease (CVD), the leading cause of death among Americans. Increasing evidence implicates increased sympathetic nerve activity (SNA) as the link between a sedentary lifestyle and CVD. The research presented in this dissertation examines the region of the brainstem known as the rostral ventrolateral medulla (RVLM) and how its regulation of SNA changes as a result of sedentary conditions. Our group has previously reported that sedentary conditions enhance splanchnic SNA in response to pharmacologically induced decreases in blood pressure or by direct activation of the RVLM via microinjection of the amino acid glutamate. More recently, our group has published the first evidence of overt structural differences in phenotypically identified RVLM neurons from sedentary versus physically active rats. Although collectively these studies suggest that a sedentary lifestyle results in increased activity and sensitivity of presympathetic RVLM neurons involved in blood pressure regulation, direct evidence of this proposed mechanism for the observed increased splanchnic SNA is lacking. The studies presented in this dissertation use in vivo characterization and juxtacellular labeling of RVLM neurons to examine the potential mechanistic connection and physiological relevance of overt changes in their structure and function and how they relate to enhanced SNA in sedentary versus physically active rats. These cross sectional studies are complemented by longitudinally based studies of in vivo neuronal activity in the RVLM utilizing manganese-enhanced magnetic resonance imaging (MEMRI). The information gained from these studies will contribute to our understanding of how a sedentary lifestyle contributes to the development of CVD and may provide information on new therapeutic targets in the brain to prevent or slow the progression of CVD

Instantaneous Transfer Entropy for the Study of Cardiovascular and Cardio-Respiratory Nonstationary Dynamics

Objective: Measures of Transfer Entropy (TE) quantify the direction and strength of coupling between two complex systems. Standard approaches assume stationarity of the observations, and therefore are unable to track time-varying changes in nonlinear information transfer with high temporal resolution. In this study, we aim to define and validate novel instantaneous measures of transfer entropy to provide an im- proved assessment of complex non-stationary cardio-respiratory interactions