The intraaortic balloon pump: a nonlinear digital computer model

A computer based model for in-series cardiac assistance by intraaortic balloon pumping was developed in this study. The model, obtained from the Navier-Stokes and Continuity equations, was capable of computing pressures, volumetric flow rates and radii through the arterial system. The model was used to study the effects of a wide range of assist device timing adjustments on the benefits of ventricular assistance under conditions corresponding to those measured during animal experiments. The model was also used to study the relationship between device timing adjustments and the benefits of ventricular assistance under constant cardiovascular state conditions. Such studies are important in isolating the response of the system to assist device phasing from the response associated with system state. The results obtained in this study demonstrate that the hemodynamic response of the cardiovascular system to intraaortic balloon pumping is a sensitive function of both the state of the cardiovascular system and phasing of the assist device.     

A new integrated method for analyzing heart mechanics using a cell-hemodynamics-autonomic nerve control coupled model of the cardiovascular system

A model of the cardiovascular system coupling cell, hemodynamics, and autonomic nerve control function is proposed for analyzing heart mechanics. We developed a comprehensive cardiovascular model with multi-physics and multi-scale characteristics that simulates the physiological events from membrane excitation of a cardiac cell to contraction of the human heart and systemic blood circulation and ultimately to autonomic nerve control. A lumped parameter model is used to compute the systemic and pulmonary circulations interacting with the cardiac cell mechanism. For autonomic control of the cardiovascular system, we used the approach suggested by Heldt et al. [2002. Computational modeling of cardiovascular response to orthostatic stress. J. Appl. Physiol. 92, 1239–1254] (Heldt model), including baroreflex and cardiopulmonary reflexes. We assumed sympathetic and parasympathetic pathways for the nerve control system. The cardiac muscle response to these reflex control systems was implemented using the activation-level changes in the L-type calcium channel and sarcoplasmic/endoplasmic reticulum calcium ATPase function based on experimental observations. Using this model, we delineated the cellular mechanism of heart contractility mediated by nerve control function. To verify the integrated method, we simulated a 10% hemorrhage, which involves cardiac cell mechanics, circulatory hemodynamics, and nerve control function. The computed and experimental results were compared. Using this methodology, the state of cardiac contractility, influenced by diverse properties such as the afterload and nerve control systems, is easily assessed in an integrated manner.     

A cardiovascular-respiratory control system model including state delay with application to congestive heart failure in humans

This paper considers a model of the human cardiovascular-respiratory control system with one and two transport delays in the state equations describing the respiratory system. The effectiveness of the control of the ventilation rate is influenced by such transport delays because blood gases must be transported a physical distance from the lungs to the sensory sites where these gases are measured. The short term cardiovascular control system does not involve such transport delays although delays do arise in other contexts such as the baroreflex loop (see [46]) for example. This baroreflex delay is not considered here. The interaction between heart rate, blood pressure, cardiac output, and blood vessel resistance is quite complex and given the limited knowledge available of this interaction, we will model the cardiovascular control mechanism via an optimal control derived from control theory. This control will be stabilizing and is a reasonable approach based on mathematical considerations as well as being further motivated by the observation that many physiologists cite optimization as a potential influence in the evolution of biological systems (see, e.g., Kenner [29] or Swan [62]). In this paper we adapt a model, previously considered (Timischl [63] and Timischl et al. [64]), to include the effects of one and two transport delays. We will first implement an optimal control for the combined cardiovascular-respiratory model with one state space delay. We will then consider the effects of a second delay in the state space by modeling the respiratory control via an empirical formula with delay while the the complex relationships in the cardiovascular control will still be modeled by optimal control. This second transport delay associated with the sensory system of the respiratory control plays an important role in respiratory stability. As an application of this model we will consider congestive heart failure where this transport delay is larger than normal and the transition from the quiet awake state to stage 4 (NREM) sleep. The model can be used to study the interaction between cardiovascular and respiratory function in various situations as well as to consider the influence of optimal function in physiological control system performance.Supported by FWF (Austria) under grant F310 as a subproject of the Special Research Center F003 Optimization and ControlMathematics Subject Classification (2000): 92C30, 49J15     

Theoretical and clinical assessment of the sensitivity of heart rate variability indices

The application of modern methods of mathematical processing of non-stationary quasi-periodic data to the analysis of heart-rate variability is considered. Methods for the assessment of new parameters in non-linear variability analysis are described in detail. Mathematical models of heart rhythm are developed with the presence of various noise processes taken into account. A model of the state of the cardiovascular system based on the analysis of heart-rate variability has been developed. A theoretical estimate of the sensitivity of heart-rate variability indices to changes in the state of the cardiovascular system has been obtained for model data. Clinical studies of the parameters of heart-rate variability included in the analysis have been performed within the framework of cardiological screening for coronary heart disease.     

Use of principles of prenosological diagnosis for assessing the functional state of the body under stress conditions as exemplified by bus drivers

The functional state of the body was assessed in healthy subjects performing their daily work under stress conditions. The study sample comprised bus drivers aged 25–65 years. A prenosological approach was used to assess the borderline between the physiologically normal state and pathological conditions. At the first stage of the study (prenosological screening), the subjects were divided into four groups with different adaptive capacities of the body. At the second stage of the study, a detailed prenosological examination was performed to determine the causes and mechanisms of evolution of prenosological conditions into premorbid conditions and further into adaptation failure, resulting in diseases. It was found that the bus drivers experienced chronic occupational stress leading to the overtension and exhaustion of regulatory mechanisms and to the rapid development of cardiovascular pathology. Long-term mental and psychoemotional tension in drivers associated with occupational stress leads to the activation of suprasegmental structures involved in the control of physiological functions; to a decrease in the functional reserves; and, consequently, to the worsening of the psychophysiological and cardiorespiratory function of the body. As a result of the study, a group of bus drivers with an increased risk of diseases, including cardiovascular, was determined and recommendations on workforce health protection were developed for the managers of the motor transport enterprise.     

Aspects of control of the cardiovascular-respiratory system during orthostatic stress induced by lower body negative pressure

This paper considers a model developed to study the cardiovascular control system response to orthostatic stress as induced by two variations of lower body negative pressure (LBNP) experiments. This modeling approach has been previously applied to study control responses to transition from rest to aerobic exercise, to transition to non-REM sleep and to orthostatic stress as produced by the head up tilt (HUT) experiment. LBNP induces a blood volume shift because negative pressure changes the volume loading characteristics of the compartment which is subject to the negative pressure. This volume shift induces a fall in blood pressure which must be counteracted by a complicated control response involving a variety of mechanisms of the cardiovascular control system. There are a number of medical issues connected to these questions such as orthostatic intolerance in the elderly resulting in dizziness or fainting during the transition from sitting to standing. The model presented here is used to study the interaction of changes in systemic resistance, unstressed venous volume, venous compliance, heart rate, and contractility in the control of orthostatic stress. The overall short term response depends on a combination of these physiological reactions which may vary from individual to individual. There remain open questions about which factors have greater importance. The model simulations are compared to experimental data collected for LBNP exerted from the hips to feet and from ribs to feet.     

The coronary bed and its role in the cardiovascular system: a review and an introductory single-branch model

To investigate cardiovascular haemodynamics under normal and pathological conditions, a closed-loop model of the cardiovascular system already presented in the literature¹, has been complemented by a model of the coronary bed. Oxygen available to the myocardium is strictly related to the coronary blood flow; we have developed threshold criteria which correlate cardiac output with the coronary flow. The system utilizes control systems related to the cardiac contractility and frequency, and imitates feedback mechanisms peculiar to the heart. The work exemplifies the autoregulation of events that occur when the equilibrium of the system is disturbed. It is suggested that the heart plays an active role in trying to restore the haemodynamic parameters to their physiological values.     

Patient-specific modeling of cardiovascular and respiratory dynamics during hypercapnia

This study develops a lumped cardiovascular–respiratory system-level model that incorporates patient-specific data to predict cardiorespiratory response to hypercapnia (increased CO₂ partial pressure) for a patient with congestive heart failure (CHF). In particular, the study focuses on predicting cerebral CO₂ reactivity, which can be defined as the ability of vessels in the cerebral vasculature to expand or contract in response CO₂ induced challenges. It is difficult to characterize cerebral CO₂ reactivity directly from measurements, since no methods exist to dynamically measure vasomotion of vessels in the cerebral vasculature. In this study we show how mathematical modeling can be combined with available data to predict cerebral CO₂ reactivity via dynamic predictions of cerebral vascular resistance, which can be directly related to vasomotion of vessels in the cerebral vasculature. To this end we have developed a coupled cardiovascular and respiratory model that predicts blood pressure, flow, and concentration of gasses (CO₂ and O₂) in the systemic, cerebral, and pulmonary arteries and veins. Cerebral vascular resistance is incorporated via a model parameter separating cerebral arteries and veins. The model was adapted to a specific patient using parameter estimation combined with sensitivity analysis and subset selection. These techniques allowed estimation of cerebral vascular resistance along with other cardiovascular and respiratory parameters. Parameter estimation was carried out during eucapnia (breathing room air), first for the cardiovascular model and then for the respiratory model. Then, hypercapnia was introduced by increasing inspired CO₂ partial pressure. During eucapnia, seven cardiovascular parameters and four respiratory parameters was be identified and estimated, including cerebral and systemic resistance. During the transition from eucapnia to hypercapnia, the model predicted a drop in cerebral vascular resistance consistent with cerebral vasodilation.     

Laser-scanning velocimetry: A confocal microscopy method for quantitative measurement of cardiovascular performance in zebrafish embryos and larvae

Background  

The zebrafish Danio rerio is an important model system for drug discovery and to study cardiovascular development. Using a laser-scanning confocal microscope, we have developed a non-invasive method of measuring cardiac performance in zebrafish embryos and larvae that obtains cardiovascular parameters similar to those obtained using Doppler echocardiography in mammals. A laser scan line placed parallel to the path of blood in the dorsal aorta measures blood cell velocity, from which cardiac output and indices of vascular resistance and contractility are calculated.     

Modeling the Cardiovascular-Respiratory Control System: Data,Model Analysis,and Parameter Estimation

Several key areas in modeling the cardiovascular and respiratory control systems are reviewed and examples are given which reflect the research state of the art in these areas. Attention is given to the interrelated issues of data collection, experimental design, and model application including model development and analysis. Examples are given of current clinical problems which can be examined via modeling, and important issues related to model adaptation to the clinical setting.     

个体化康复运动训练联合八段锦运动对冠心病PCI术后患者心功能、生活质量和心境状态的影响

目的:观察个体化康复运动训练联合八段锦运动对冠心病患者经皮冠状动脉介入术(PCI)术后心功能、心境状态和生活质量的影响。方法:选取2017年9月-2018年9月期间来我院接受治疗的100例冠心病PCI术后患者,根据随机数字表法分为对照组和研究组,各50例。对照组患者在常规治疗的基础上接受个体化康复运动训练,研究组患者在对照组的基础上联合八段锦运动。观察两组心功能、生活质量和心境状态变化情况。统计两组6个月内心血管不良事件发生率。结果:干预后,两组患者6 min步行试验(6MWT)距离、左心室射血分数(LVEF)均较干预前升高,且研究组的变化程度优于对照组(P<0.05)。干预后,两组患者紧张-焦虑、抑郁-沮丧、愤怒-敌意、疲乏-迟钝、迷惑-混乱评分均较干预前下降,精力-活力、与自我有关的情绪评分较干预前升高,且研究组的变化程度优于对照组(P<0.05)。研究组6个月内的心血管不良事件发生率低于对照组,但是两组组间对比无统计学差异(P>0.05)。干预后,两组总体/精神健康、精力、情感/生理职能、躯体疼痛、生理/社会功能各维度评分升高,且研究组较对照组高(P<0.05)。结论:八段锦运动联合个体化康复运动训练可促进冠心病PCI术后患者心功能、生活质量和心境状态改善,同时还可控制心血管不良事件发生风险。     

Cardiovascular autonomic imbalance and baroreflex dysfunction in the apolipoprotein E-deficient mouse

Genetically engineered mouse models and advances in molecular biotechnology have given extensive aid to experimental studies of cardiovascular mechanisms and dysfunction in pathological states such as atherosclerosis. Among the available animal models that have been developed to study atherosclerosis, the apolipoprotein E-deficient (apoE(-/-)) mouse is the most ideal genetically modified animal presently available. The apoE(-/-)mouse develops spontaneous severe hypercholesterolemia in a short-time and subsequently develops atherosclerotic lesions similar to those found in humans. Since its creation two decades ago, the apoE(-/-)mouse has greatly contributed to the understanding of atherosclerosis, but the consequences of hypercholesterolemia and atherosclerosis for the autonomic control of cardiovascular function in this mouse model have not been reviewed. In this article, we provide an overview of abnormalities of the parasympathetic and sympathetic nervous systems controlling heart rate and blood pressure and emphasize the dysfunction of the baroreflex control of cardiovascular function and how this dysfunction is influenced by nitric oxide, reactive oxygen species, aging and an atherogenic diet in the apoE(-/-)mouse.     

Effect of motor load on the course of functional maturation of the autonomic control of the cardiovascular system of adolescents

A comparative study of the state of the cardiovascular systems of adolescents not engaged in sports and young athletes of the same age has been performed. According to the indices recorded in the resting state, a relative lag of the functional development of the systems of autonomic control of the cardiovascular system was shown for adolescent nonathletes at an age of 13–14 years as compared with young athletes. This lag is compensated by the age of 15–16 years, but the adequate level of autonomic activity is reached through the activation of central regulatory mechanisms (sympathetic and humoral), with a relatively low contribution of the peripheral vagal and baroreflex mechanisms. This conclusion is confirmed by the results of assessment of the reactivity of the cardiovascular system of adolescents with different levels of motor activity in a functional test with limited pulmonary ventilation.     

Lipotoxicity and cardiac dysfunction in mammals and Drosophila

The lipotoxic effects of obesity are important contributing factors in cancer, diabetes, and cardiovascular disease (CVD), but the genetic mechanisms, by which lipotoxicity influences the initiation and progression of CVD are poorly understood. Hearts, of obese and diabetic individuals, exhibit several phenotypes in common, including ventricular remodeling, prolonged QT intervals, enhanced frequency of diastolic and/or systolic dysfunction, and decreased fractional shortening. High systemic lipid concentrations are thought to be the leading cause of lipid-related CVD in obese or diabetic individuals. However, an alternative possibility is that obesity leads to cardiac-specific steatosis, in which lipids and their metabolites accumulate within the myocardial cells themselves and thereby disrupt normal cardiovascular function. Drosophila has recently emerged as an excellent model to study the fundamental genetic mechanisms of metabolic control, as well as their relationship to heart function. Two recent studies of genetic and diet-induced cardiac lipotoxicity illustrate this. One study found that alterations in genes associated with membrane phospholipid metabolism may play a role in the abnormal lipid accumulation associated with cardiomyopathies. The second study showed that Drosophila fed a diet high in saturated fats, developed obesity, dysregulated insulin and glucose homeostasis, and severe cardiac dysfunction. Here, we review the current understanding of the mechanisms that contribute to the detrimental effects of dysregulated lipid metabolism on cardiovascular function. We also discuss how the Drosophila model could help elucidate the basic genetic mechanisms of lipotoxicity- and metabolic syndrome-related cardiomyopathies in mammals.     

Etiologic heterogeneity in the familial aggregation of congenital cardiovascular malformations.

Recent data indicate that there is increased risk of congenital cardiovascular malformations (CCVM) within families of probands diagnosed with congenital cardiovascular malformations that are due to altered embryonic blood flow (flow lesions). In the present study, regressive models recently developed by Bonney were used to compare specific models of inheritance and to test for etiologic heterogeneity among three subgroups of 375 flow-lesion families identified by the Baltimore-Washington Infant Study. When all families were analyzed as a single group, the best-fitting model was a simple recessive model with Mendelian transmission; race did not have a significant effect on estimated risk. Separate analyses of families of probands with left heart defects, right heart defects, and ventricular septal defects (VSD) confirmed this simple Mendelian recessive model as the model of choice. However, when race was included as a covariate in these genetic models, there was evidence for significant heterogeneity among the three subgroups. There was an increased risk to relatives of white probands with right heart defects and to relatives of black probands with VSD, while there was no effect of race among relatives of probands with left heart defects. These results strongly suggest that there is etiologic heterogeneity in the control of CCVM among flow-lesion families and that the patterns of familial aggregation differ among the races.     

In vivo interpretation of model predicted inhibition in acrylate pathway engineered Lactococcus lactis

To maximize the productivity of engineered metabolic pathway, in silico model is an established means to provide features of enzyme reaction dynamics. In our previous study, Escherichia coli engineered with acrylate pathway yielded low propionic acid titer. To understand the bottleneck behind this low productivity, a kinetic model was developed that incorporates the enzymatic reactions of the acrylate pathway. The resulting model was capable of simulating the fluxes reported under in vitro studies with good agreement, suggesting repression of propionyl-CoA transferase (Pct) by carboxylate metabolites as the main limiting factor for propionate production. Furthermore, the predicted flux control coefficients of the pathway enzymes under steady state conditions revealed that the control of flux is shared between Pct and lactoyl-CoA dehydratase. Increase in lactate concentration showed gradual decrease in flux control coefficients of Pct that in turn confirmed the control exerted by the carboxylate substrate. To interpret these in silico predictions under in vivo system, an organized study was conducted with a lactic acid bacteria strain engineered with acrylate pathway. Analysis reported a decreased product formation rate on attainment of inhibitory titer by suspected metabolites and supported the model.     

Announcing the call for the Special Issue on “Cardiovascular mechanobiology—a special issue to look at the state of the art and the newest insights into the role of mechanical forces in cardiovascular development,physiology, and disease”

This Commentary describes a call for submissions for the upcoming special issue focused on the state of the art of cardiovascular mechanobiology research and the newest insights into the role of mechanical forces in cardiovascular development, physiology, and disease

Cells in the human body are exposed to a variety of different forces which they sense and respond to. This is especially true for the cardiovascular system, where cells react for instance to blood flow, stretching forces from the filling of the heart with blood, or extracellular matrix stiffness. These parameters change throughout development and further in disease, which can dramatically impact the behavior of the sensing cells and the disease progression: blood flow and wall stress are sensed by endothelial cells in the arteries and determine the sites of atherosclerotic plaque formation; reduced ejection fraction leads to excessive stretching of cardiomyocytes in the ventricle with detrimental effects on cardiomyocyte signaling and function; and the cardiac extracellular matrix and also cardiomyocytes themselves stiffen as a response to injuries or diseases and lead to a loss of contractile function.Detailed knowledge of the source and the parameters of the forces as well as the mechanisms used by cells to sense and respond to them can help to understand disease mechanisms and identify to new paths of treating cardiovascular and other diseases. Unsurprisingly, mechanobiology as a discipline dedicated to the study of (sub-) cellular forces, topographies, and mechanically responsive molecules or complexes has been growing in importance. Methods initially being developed and used by only a few specialty labs have become standard techniques in cell and developmental biology. Similarly, the field of cardiovascular biology has seen a strong increase in publications related to mechanobiology over the past decades. This special issue is aiming to take stock at the recent developments and current state of the art of cardiovascular mechanobiology and will cover all topics related to the investigation into the role of mechanical forces in cardiovascular development, physiology, and disease.The Special Issue will be prepared and edited by the current authors (Pamela Swiatlowska and Thomas Iskratsch).     

A computational model for understanding the micro-mechanics of collagen fiber network in the tunica adventitia

Abdominal aortic aneurysm is a prevalent cardiovascular disease with high mortality rates. The mechanical response of the arterial wall relies on the organizational and structural behavior of its microstructural components, and thus, a detailed understanding of the microscopic mechanical response of the arterial wall layers at loads ranging up to rupture is necessary to improve diagnostic techniques and possibly treatments. Following the common notion that adventitia is the ultimate barrier at loads close to rupture, in the present study, a finite element model of adventitial collagen network was developed to study the mechanical state at the fiber level under uniaxial loading. Image stacks of the rabbit carotid adventitial tissue at rest and under uniaxial tension obtained using multi-photon microscopy were used in this study, as well as the force–displacement curves obtained from previously published experiments. Morphological parameters like fiber orientation distribution, waviness, and volume fraction were extracted for one sample from the confocal image stacks. An inverse random sampling approach combined with a random walk algorithm was employed to reconstruct the collagen network for numerical simulation. The model was then verified using experimental stress–stretch curves. The model shows the remarkable capacity of collagen fibers to uncrimp and reorient in the loading direction. These results further show that at high stretches, collagen network behaves in a highly non-affine manner, which was quantified for each sample. A comprehensive parameter study to understand the relationship between structural parameters and their influence on mechanical behavior is presented. Through this study, the model was used to conclude important structure–function relationships that control the mechanical response. Our results also show that at loads close to rupture, the probability of failure occurring at the fiber level is up to 2%. Uncertainties in usually employed rupture risk indicators and the stochastic nature of the event of rupture combined with limited knowledge on the microscopic determinants motivate the development of such an analysis. Moreover, this study will advance the study of coupling microscopic mechanisms to rupture of the artery as a whole.

     

Nitric oxide donor-based FFA1 agonists: Design,synthesis and biological evaluation as potential anti-diabetic and anti-thrombotic agents

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Thus, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of FFA1 agonist and NO donor were design to obtain dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the induced-fit docking study suggested that it is feasible for our design strategy to hybrid NO donor with compound 1. These hybrids exhibited moderate FFA1 agonistic activities and anti-platelet aggregation activities, and their anti-platelet effects mediated by NO were also confirmed in the presence of NO scavenger. Moreover, compound 3 revealed significantly hypoglycemic effect and even stronger than that of TAK-875 during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 3, is expected as a potential candidate with additional cardiovascular benefits for the treatment of T2DM.