A Cardiovascular Mathematical Model of Graded Head-Up Tilt

A lumped parameter model of the cardiovascular system has been developed and optimized using experimental data obtained from 13 healthy subjects during graded head-up tilt (HUT) from the supine position to . The model includes descriptions of the left and right heart, direct ventricular interaction through the septum and pericardium, the systemic and pulmonary circulations, nonlinear pressure volume relationship of the lower body compartment, arterial and cardiopulmonary baroreceptors, as well as autoregulatory mechanisms. A number of important features, including the separate effects of arterial and cardiopulmonary baroreflexes, and autoregulation in the lower body, as well as diastolic ventricular interaction through the pericardium have been included and tested for their significance. Furthermore, the individual effect of parameter associated with heart failure, including LV and RV contractility, baseline systemic vascular resistance, pulmonary vascular resistance, total blood volume, LV diastolic stiffness and reflex gain on HUT response have also been investigated. Our fitted model compares favorably with our experimental measurements and published literature at a range of tilt angles, in terms of both global and regional hemodynamic variables. Compared to the normal condition, a simulated congestive heart failure condition produced a blunted response to HUT with regards to the percentage changes in cardiac output, stroke volume, end diastolic volume and effector response (i.e., heart contractility, venous unstressed volume, systemic vascular resistance and heart rate) with progressive tilting.

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title: Circulatory Response to the Upright Posture
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title: Hemodynamic Response to the Upright Posture
abstract: The authors' objective was to review previous studies of immediate (first 30 seconds) and stabilized (30 seconds to 20 minutes) hemodynamic responses of healthy adults to the head‐up posture, with particular reference to alteration of such responses in the elderly and the usefulness of such data in the diagnosis of orthostatic hypotension. The immediate response in healthy young adults is characterized by a prompt rise in heart rate, which peaks at about 8 to 15 seconds and then tapers; the arterial pressure and total vascular resistance decrease sharply at 5 to 10 seconds, followed by a rapid rebound and overshoot. Over the first 30 seconds there is a steady parallel decline of thoracic blood volume and stroke volume; there is also an initial surge of cardiac output followed by a steady decrease. During the stabilized response (30 seconds to 20 minutes), the hemodynamic variables are relatively steady, showing average increases in heart rate of about 15 to 30%, in diastolic pressure of 10 to 15%, and in total vascular resistance of 30 to 40%; during the 5th to 20th minutes there are also decreases in thoracic blood volume averaging about 25 to 30%, in cardiac output 15 to 30%, and in pulse pressure about 5 to 10%. It is evident that in normal human subjects, assumption of the upright posture results in profound hemodynamic changes, most of them occurring during the first 30 seconds. In elderly subjects (aged 60–69 years), there are, in the upright posture, lesser increments of heart rate and diastolic pressure, but no significant differences from younger age groups in the response of thoracic blood volume, cardiac output or total vascular resistance. However, beginning at about age 75, there is an increasing incidence of orthostatic hypotension, which averages about 14 to 20% at age 75 and older. The tendency toward orthostatic hypotension in the elderly is due (1) to the structural and functional changes in the circulation itself, (2) to a decline in autonomic function, and (3) to a probable functional deficiency of the skeletal muscle pump. The authors believe that closer hemodynamic monitoring of orthostatic hypotension patients would considerably increase our understanding and aid in the diagnosis of this condition.

title: An Integrative Cardiovascular Model of the Standing and Reclining Sheep
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title: Blood pressure and blood flow variation during postural change from sitting to standing: model development and validation.
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title: Sensitivity Analysis and Model Assessment: Mathematical Models for Arterial Blood Flow and Blood Pressure
abstract: The complexity of mathematical models describing the cardiovascular system has grown in recent years to more accurately account for physiological dynamics. To aid in model validation and design, classical deterministic sensitivity analysis is performed on the cardiovascular model first presented by Olufsen, Tran, Ottesen, Ellwein, Lipsitz and Novak ( 2005). This model uses 11 differential state equations with 52 parameters to predict arterial blood flow and blood pressure. The relative sensitivity solutions of the model state equations with respect to each of the parameters is calculated and a sensitivity ranking is created for each parameter. Parameters are separated into two groups: sensitive and insensitive parameters. Small changes in sensitive parameters have a large effect on the model solution while changes in insensitive parameters have a negligible effect. This analysis was successfully used to reduce the effective parameter space by more than half and the computation time by two thirds. Additionally, a simpler model was designed that retained the necessary features of the original model but with two-thirds of the state equations and half of the model parameters.

title: Mathematical modeling of gravitational effects on the circulation: importance of the time course of venous pooling and blood volume changes in the lungs.
abstract: A dip in blood pressure (BP) in response to head-up tilt (HUT) or active standing might be due to rapid pooling in the veins below the heart (preload) or muscle activation-induced drop in systemic vascular resistance (afterload). We hypothesized that, in the cardiovascular response to passive HUT, where, in contrast to active standing, little BP dip is observed, features affecting the preload play a key role. We developed a baroreflex model combined with a lumped-parameter model of the circulation, including viscoelastic stress-relaxation of the systemic veins. Cardiac contraction is modeled using the varying-elastance concept. Gravity affects not only the systemic, but also the pulmonary, circulation. In accordance with the experimental results, model simulations do not show a BP dip on HUT; the tilt-back response is also realistic. If it is assumed that venous capacities are steady-state values, the introduction of stress-relaxation initially reduces venous pooling. The resulting time course of venous pooling is comparable to measured impedance changes. When venous pressure-volume dynamics are neglected, rapid (completed within 30 s) venous pooling leads to a drop in BP. The direct effect of gravity on the pulmonary circulation influences the BP response in the first approximately 5 s after HUT and tilt back. In conclusion, the initial BP response to HUT is mainly determined by the response of the venous system. The time course of lower body pooling is essential in understanding the response to passive HUT.

title: Simulation of cardiovascular response to lower body negative pressure from 0 to -40 mmHg.
abstract: This paper presents a mathematical model for simulation of the human cardiovascular response to lower body negative pressure (LBNP) up to -40 mmHg both under normal conditions and when arterial baroreflex sensitivity or leg blood capacity (LBC) is altered. Development of the model assumes that the LBNP response could be explained solely on the bases of 1) blood volume redistribution, 2) left ventricular end-diastolic filling, 3) interaction between left ventricle and peripheral circulation, and 4) modulations of peripheral resistances and heart rate by arterial and cardiopulmonary baroreflexes. The model reproduced well experimental data obtained both under normal conditions and during complete autonomic blockade; thus it is validated for simulation of the cardiovascular response from 0 to -40 mmHg LBNP. We tested the ability of the model to simulate the changes in LBNP response due to a reduction in LBC. To assess these changes experimentally, six healthy men were subjected to LBNP of -15, -30, and -38 mmHg with and without wearing elastic compression stockings. Stockings significantly reduced LBC (from 3.9 +/- 0.3 to 1.8 +/- 0.4 ml/100 ml tissue at -38 mmHg LBNP; P < 0.01) and attenuated the change in heart rate (from 23 +/- 4 to 8 +/- 3% at -38 mmHg LBNP; P < 0.05). The model accurately reproduced this result. The model is useful for assessing the influence of LBC or other parameters such as arterial baroreflex sensitivity in diminishing the orthostatic tolerance of humans after spaceflight, bed rest, or endurance training.

title: Mathematical modeling of human cardiovascular system for simulation of orthostatic response.
abstract: This paper deals with the short-term response of the human cardiovascular system to orthostatic stresses in the context of developing a mathematical model of the overall system. It discusses the physiological issues involved and how these issues have been handled in published cardiovascular models for simulation of orthostatic response. Most of the models are stimulus specific with no demonstrated capability for simulating the responses to orthostatic stimuli of different types. A comprehensive model incorporating all known phenomena related to cardiovascular regulation would greatly help to interpret the various orthostatic responses of the system in a consistent manner and to understand the interactions among its elements. This paper provides a framework for future efforts in mathematical modeling of the entire cardiovascular system.

title: Dynamic time course of hemodynamic responses after passive head-up tilt and tilt back to supine position.
abstract: Mechanisms involved in the control of arterial pressure during postural changes were studied by analysis of the dynamic time course of cardiovascular changes during head-up tilt (HUT) and tilt back to supine position (TB). Beat-to-beat values of cardiovascular variables were recorded continuously before, during, and after passive HUT to 30 degrees in seven healthy humans. Left cardiac stroke volume (SV, Doppler ultrasound), mean arterial blood pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral conductance (TPC) were recorded. During HUT, MAP at the level of the carotid baroreceptors decreased by approximately 5 mmHg. There was a striking asymmetry between the time courses of cardiovascular changes on HUT and on TB. Adjustments generally took up to 30 s after HUT, whereas most changes were completed during the first 10 s after TB. Cardiovascular reflex adjustments of HR and TPC were more symmetrical. After HUT, SV was maintained during the first 4-6 s and then decreased steadily during the next 30 s to a stable level approximately 25% below its pretilt value. However, after TB, SV increased rapidly to its pretilt value in <10 s. This asymmetry in SV dynamics may be explained in part by a more rapid change in left cardiac filling after TB than after HUT. On TB, there must be a rapid inflow of stagnant blood from the legs, whereas venous valves will impede backward filling of veins in the lower body on HUT. In conclusion, we have revealed a characteristic asymmetry in cardiovascular responses to inverse variations in gravity forces in humans. This asymmetry can be explained in part by nonlinear, hydrodynamic factors, such as the one-way effect of venous valves in the lower part of the body.

title: Simulating transient ventricular interaction using a minimal cardiovascular system model.
abstract: A minimal closed-loop cardiovascular system (CVS) model has been developed that can simulate ventricular interaction due to both direct interaction through the septum and series interaction through the circulation system. The model is used to simulate canine experiments carried out to study the transient response of the left ventricle due to changes in right ventricle pressures and volumes. The model-simulated trends in left and right ventricle pressures and volumes, septum deflection and arterial flow rates are compared with the experimental results. In spite of the limited physiological data available describing the animals, the model is shown to capture all the transient trends in the experimental data. This is the first known example of a physiological model that can capture all these trends. The model is then used to illustrate the separate effects of direct and series interactions independently. This study proves the value of this modelling method to be used in conjunction with experimental data for delineating and understanding the factors that contribute to ventricular dynamics.

title: Parameter-Optimized Model of Cardiovascular–Rotary Blood Pump Interactions
abstract: A lumped parameter model of human cardiovascular-implantable rotary blood pump (iRBP) interaction has been developed based on experimental data recorded in two healthy pigs with the iRBP in situ. The model includes descriptions of the left and right heart, direct ventricular interaction through the septum and pericardium, the systemic and pulmonary circulations, as well as the iRBP. A subset of parameters was optimized in a least squares sense to faithfully reproduce the experimental measurements (pressures, flows and pump variables). Our fitted model compares favorably with our experimental measurements at a range of pump operating points. Furthermore, we have also suggested the importance of various model features, such as the curvilinearity of the end systolic pressure-volume relationship, the Starling resistance, the suction resistance, the effect of respiration, as well as the influence of the pump inflow and outflow cannulae. Alterations of model parameters were done to investigate the circulatory response to rotary blood pump assistance under heart failure conditions. The present model provides a valuable tool for experiment designs, as well as a platform to aid in the development and evaluation of robust physiological pump control algorithms.

title: Cardiovascular response to dynamic aerobic exercise: A methematical model
abstract: An original mathematical model of the cardiovascular response to dynamic exercise is presented. It includes the pulsating heart, the pulmonary and systemic circulation, a separate description of the vascular bed in active tissues, the local metabolic vasodilation in these tissues and the mechanical effects of muscular contractions on venous return. Moreover, the model provides a description of the ventilatory response to exercise and various neural regulatory mechanisms working on cardiovascular parameters. These mechanisms embrace the so-called central command, the arterial baroreflex and the lung inflation reflex. All parameters in the model have been given in accordance with physiological data from the literature. In this work, the model has been used to simulate the steady-state value of the main cardiorespiratory quantities at different levels of aerobic exercise and the temporal pattern in the transient phase from rest to moderate exercise. Results suggest that, with suitable parameter values the model is able accurately to simulate the cardio-respiratory response in the overall range of aerobic exercise. This response is characterised by a moderate hypertension (10–30%) and by a conspicuous increase in systemic conductance (80–130%), heart rate (64–150%) and cardiac output (100–200%). The transient pattern exhibits three distinct phases (lasting approximately 5 s, 15 s and 2 min), that reflect the temporal heterogeneity of the mechanisms involved. The model may be useful to improve understanding of exercise physiology and as an educational tool to analyse the complexity of cardiovascular and respiratory regulation.

title: Interaction between carotid baroregulation and the pulsating heart: a mathematical model.
abstract: A mathematical model of short-term arterial pressure control by the carotid baroreceptors in pulsatile conditions is presented. The model includes an elastance variable description of the left and right heart, the systemic (splanchnic and extrasplanchnic) and pulmonary circulations, the afferent carotid baroreceptor pathway, the sympathetic and vagal efferent activities, and the action of several effector mechanisms. The latter mechanisms work, in response to sympathetic and vagal action, by modifying systemic peripheral resistances, systemic venous unstressed volumes, heart period, and end-systolic elastances. The model is used to simulate the interaction among the carotid baroreflex, the pulsating heart, and the effector responses in different experiments. In all cases, there has been satisfactory agreement between model and experimental results. Experimental data on heart rate control can be explained fairly well by assuming that the sympathetic-parasympathetic systems interact linearly on the heart period. The carotid baroreflex can significantly modulate the cardiac function curve. However, this effect is masked in vivo by changes in arterial and atrial pressures. During heart pacing, cardiac output increases with frequency at moderate levels of heart rate and then fails to increase further because of a reduction in stroke volume. Shifting from nonpulsatile to pulsatile perfusion of the carotid sinuses decreases the overall baroreflex gain and significantly modifies operation of the carotid baroreflex. Finally, a sensitivity analysis suggests that venous unstressed volume control plays the major role in the early hemodynamic response to acute hemorrhage, whereas systemic resistance and heart rate controls are a little less important.

title: Theoretical analysis of rest and exercise hemodynamics in patients with total cavopulmonary connection.
abstract: The objective of this study was to determine the impact of a total cavopulmonary connection on the main hemodynamic quantities, both at rest and during exercise, when compared with normal biventricular circulation. The analysis was performed by means of a mathematical model of the cardiovascular system. The model incorporates the main parameters of systemic and pulmonary circulation, the pulsating heart, and the action of arterial and cardiopulmonary baroreflex mechanisms. Furthermore, the effect of changes in intrathoracic pressure on venous return is also incorporated. Finally, the response to moderate dynamic exercise is simulated, including the effect of a central command, local metabolic vasodilation, and the "muscle pump" mechanism. Simulations of resting conditions indicate that the action of baroreflex regulatory mechanisms alone can only partially compensate for the absence of the right heart. Cardiac output and mean systemic arterial pressure at rest show a large decrease compared with the normal subject. More acceptable hemodynamic quantity values are obtained by combining the action of regulatory mechanisms with a chronic change in parameters affecting mean filling pressure. With such changes assumed, simulations of the response to moderate exercise show that univentricular circulation exhibits a poor capacity to increase cardiac output and to sustain aerobic metabolism, especially when the oxygen consumption rate is increased above 1.2-1.3 l/min. The model ascribes the poor response to exercise in these patients to the incapacity to sustain venous return caused by the high resistance to venous return and/or to exhaustion of volume compensation reserve.

title: Comparison of cardiovascular responses between lower body negative pressure and head-up tilt.
abstract: To investigate local blood-flow regulation during orthostatic maneuvers, 10 healthy subjects were exposed to -20 and -40 mmHg lower body negative pressure (LBNP; each for 3 min) and to 60 degrees head-up tilt (HUT; for 5 min). Measurements were made of blood flow in the brachial (BF(brachial)) and femoral arteries (BF(femoral)) (both by the ultrasound Doppler method), heart rate (HR), mean arterial pressure (MAP), cardiac stroke volume (SV; by echocardiography), and left ventricular end-diastolic volume (LVEDV; by echocardiography). Comparable central cardiovascular responses (changes in LVEDV, SV, and MAP) were seen during LBNP and HUT. During -20 mmHg LBNP, -40 mmHg LBNP, and HUT, the following results were observed: 1) BF(brachial) decreased by 51, 57, and 41%, and BF(femoral) decreased by 40, 53, and 62%, respectively, 2) vascular resistance increased in the upper limb by 110, 147, and 85%, and in the lower limb by 76, 153, and 250%, respectively. The increases in vascular resistance were not different between the upper and lower limbs during LBNP. However, during HUT, the increase in the lower limb was much greater than that in the upper limb. These results suggest that, during orthostatic stimulation, the vascular responses in the limbs due to the cardiopulmonary and arterial baroreflexes can be strongly modulated by local mechanisms (presumably induced by gravitational effects).

title: Differential effects of lower body negative pressure and upright tilt on splanchnic blood volume.
abstract: Upright posture and lower body negative pressure (LBNP) both induce reductions in central blood volume. However, regional circulatory responses to postural changes and LBNP may differ. Therefore, we studied regional blood flow and blood volume changes in 10 healthy subjects undergoing graded lower-body negative pressure (-10 to -50 mmHg) and 8 subjects undergoing incremental head-up tilt (HUT; 20 degrees , 40 degrees , and 70 degrees ) on separate days. We continuously measured blood pressure (BP), heart rate, and regional blood volumes and blood flows in the thoracic, splanchnic, pelvic, and leg segments by impedance plethysmography and calculated regional arterial resistances. Neither LBNP nor HUT altered systolic BP, whereas pulse pressure decreased significantly. Blood flow decreased in all segments, whereas peripheral resistances uniformly and significantly increased with both HUT and LBNP. Thoracic volume decreased while pelvic and leg volumes increased with HUT and LBNP. However, splanchnic volume changes were directionally opposite with stepwise decreases in splanchnic volume with LBNP and stepwise increases in splanchnic volume during HUT. Splanchnic emptying in LBNP models regional vascular changes during hemorrhage. Splanchnic filling may limit the ability of the splanchnic bed to respond to thoracic hypovolemia during upright posture.

title: Effect of different degrees of tilt on cardiac output, heart rate, and blood pressure in normal man.
abstract: Many workers have shown that the cardiac output in normal man is less in the upright than in the recumbent position (McMichael and SharpeySchafer, 1944; Stead et al., 1945; Coe, Best, and Lawson, 1950; Wang, Marshall, and Shepherd, 1960; Chapman, Fisher, and Sproule, 1960; Reeves et al., 1961). The physiological events underlying this change are complex and depend on many variables, such as the angle of tilt and length of time the patient remains at a given angle and whether the change is from recumbency to an upright position or vice versa. Posture and its relation to cardiac output here becomes increasingly important with the introduction of hypotensive drugs. The purpose of this study was to determine the relation ofthe angle oftilting to the changes in cardiac output, blood pressure, and pulse rate in normal man.

title: Regional blood flow response to orthostasis in patients with congestive heart failure.
abstract: To investigate the central and regional circulatory response to orthostasis in congestive heart failure, hemodynamic variables and forearm and hepatic blood flow were measured in 22 patients at supine rest and during a 65 degrees head-up tilt. Results were compared with those in nine normal subjects. Heart rate and mean arterial blood pressure increased during tilt in normal subjects, but not in patients with heart failure. Forearm blood flow decreased in normal subjects from 3.7 +/- 1.1 to 2.7 +/- 1.5 ml/min per 100 g (probability [p] less than 0.02), but did not change from a lower baseline (1.65 +/- 0.78 ml/min per 100 g) in patients. Forearm vascular resistance increased in normal subjects but not in patients. Hepatic blood flow did not change during tilt in either group, but hepatic vascular resistance increased in normal subjects from 0.37 +/- 0.13 to 0.47 +/- 0.15 U, (p less than 0.02). The increase was not seen in patients (1.2 +/- 1.1 to 1.4 +/- 1.0 U, p = not significant [NS] ). Total systemic resistance increased in patients from 1,848 +/- 560 to 2,132 +/- 731 dynes.s.cm-5 (p less than 0.005) indicating that resistance did increase in some vascular beds. Plasma norepinephrine also increased modestly in these patients from 665 +/- 377 to 761 +/- 379 pg/ml (p = 0.035), but individual changes in plasma norepinephrine did not correlate with changes in hepatic or forearm resistance. Thus, both the overall hemodynamic response and the regulation of regional blood flow and resistance differ in several respects in patients with congestive heart failure when compared with normal subjects. Changes in heart rate, blood pressure, forearm flow and forearm and hepatic vascular resistance are all blunted in patients. Reasons for the differences are not yet clear, but may be associated with abnormalities in reflex control of the circulation in patients with congestive heart failure.

title: The Neurohumoral and Hemodynamic Response to Orthostatic Tilt in Patients with Congestive Heart Failure
abstract: Thirty-five patients with varying degrees of congestive heart failure were subjected to 60° upright tilt. Eight of the patients with normal resting hemodynamics had elevated resting plasma norepinephrine levels (PNE) (p < 0.001), but their response to upright tilt was similar to that in normal subjects: All had increases in heart rate, plasma norepinephrine (from 263 ± 32 to 483 ± 78 pg/mg, p < 0.02) and plasma renin activity (from 4.8 ± 0.9 to 13.7 ± 7.6 ng/ml/hour, p < 0.05). In 27 patients with high resting pulmonary wedge pressure and low cardiac index, resting PNE was higher (668 ± 71 ng/ml), but PNE, plasma renin activity and heart rate did not increase significantly during tilt despite a fall in pulmonary capillary wedge pressure and cardiac index. In 18 of these patients, PNE rose during tilt, whereas in nine it did not change or fell; the regting hemodynamics and the hemodynamic response to tilt were not significantly different in these two groups. These data suggest that an abnormality of mechanoreceptor or baroreceptor function is common in patients with CHF. This abnormality corresponds in part to the severity of the resting hemodynamic abnormality, but among patients with severe CHF, the reflex neurohumoral abnormality may provide independent information about the severity of the disease.

title: Stroke volume of the heart and thoracic fluid content during head‐up and head‐down tilt in humans
abstract: The stroke volume (SV) of the heart depends on the diastolic volume but, for the intact organism, central pressures are applied widely to express the filling of the heart.

title: Cardiovascular response to orthostatic tilt in patients with severe congestive heart failure.
abstract: Baroreflex mediated haemodynamic responses and aortic pulsatile stretch were studied in patients with congestive heart failure due to ischaemia. Seven patients with severe congestive heart failure (baseline angiographic ejection fraction 21(3)% (mean(SEM); left ventricular end diastolic volume and pressure 351(43) ml and 22(3) mmHg respectively) were compared with seven control subjects whose angiographic ejection fraction was 74(3)%. Passive 45 degrees upright tilt was used to unload baroreceptors. Aortic pulsatile stretch (pulsatile distension as percentage of diastolic diameter) was calculated from echocardiographic measurements of aortic diameters. Upright tilt caused a significant decrease in cardiac filling pressures in patients with congestive heart failure, as in control subjects. During tilt control subjects had substantially increased systemic vascular resistance and heart rate and decreased stroke volume, but arterial pressure, cardiac index, and aortic pulsatile stretch were maintained constant. Patients with congestive heart failure developed peripheral vasodilatation, had no increase in heart rate, and failed to maintain arterial mean and systolic pressures in the tilted position. They had, however, maintained a constant pulse pressure and increased cardiac index, stroke volume, and aortic pulsatile stretch. The response to upright tilt in patients with congestive heart failure may be explained by faulty sympathetic reflexes, causing vasodilatation and hypotension rather than vasoconstriction, and a rise in stroke volume due to the decrease in afterload.

title: Abnormal Baroreceptor‐Mediated Vasodilation of the Peripheral Circulation in Congestive Heart Failure Secondary to Idiopathic Dilated Cardiomyopathy
abstract: BackgroundPeripheral edema is a major clinical problem in congestive heart failure (CHF). The function of the edema-protective baroreceptor-mediated and local nervous vasoconstrictor reflexes of the lower leg during orthostasis in moderate and severe CHF has largely been unexplored.  Blood flow was measured by the local ‘33Xe washout method in the supine position and during 45$ head-up tilt. When the central baroreceptor reflex alone was activated, the changes in subcutaneous blood flow of the heart failure patients in both groups were significantly different from those of the eleven control subjects: blood flow increased 48±26% in 10 severe and 3±24% in nine moderate CHF patients compared with the decrease in blood flow of -36±15% observed in 11 control subjects (p<0.0001 for both). A highly significant direct association was demonstrated between changes in blood flow and New York Heart Association functional class (p=0.007) and the left ventricular ejection fraction (p=0.01). Activation of the baroreceptor and local venoarteriolar axon reflexes simultaneously increased blood flow significantly (30±9%o) in 14 patients with severe CHF, compared with the decrease found in 14 control subjects (-53±9%1) and in the group of 14 patients with moderate CHF (-17±25%) (p<0.0001 for both). ConclusionsPatients with CHF secondary to idiopathic dilated cardiomyopathy have an abnormal baroreceptor-mediated vasodilation in subcutaneous tissue of the lower leg during the upright position, which increases with the severity of the disease. The hemodynamic consequence is capillary hypertension and hyperemia in the leg during the upright position that may contribute to the development ofedema and to the initiation of structural changes (microangiopathy) demonstrated in the microcirculation.

title: Decreased left ventricular distensibility in response to postural change in older patients with heart failure and preserved ejection fraction.
abstract: Most elderly persons with heart failure have a preserved left ventricular (LV) ejection fraction (HFPEF). The pathophysiology of this disorder is not well understood, and there are conflicting data regarding the role of decreased LV distensibility. To assess LV distensibility over a range of preload conditions while minimizing the large, confounding changes in contractility, afterload, and heart rate characteristic of exercise, we measured LV end-diastolic volume (EDV), stroke volume (SV), and cardiac output (CO) using two-dimensional echocardiography in 48 elderly (mean age, 69 yr) HFPEF patients and 25 healthy age-matched controls during quiet supine rest, 45 degrees head-up tilt (HUT), and 45 degrees head-down tilt (HDT). As a result, when compared with controls, HFPEF patients had reduced percent changes in EDV (-7 +/- 2 vs. -17 +/- 2%; P = 0.003), SV (-7 +/- 3 vs. -27 +/- 2%; P = 0.003), and CO (-6 +/- 4 vs. -34 +/- 4%; P = 0.001) during the transition from supine to HUT. HFPEF also had reduced percent changes in EDV (8 +/- 2 vs. 15 +/- 2%; P = 0.02), SV (11 +/- 3 vs. 21 +/- 3%; P = 0.002), and CO (1 +/- 4 vs. 12 +/- 4%; P = 0.04) during the transition from HUT to HDT. In conclusion, HFNEF patients have reduced LV distensibility in response to postural change, resulting in blunted EDV, SV, and CO. This provides further support for the hypothesis that a blunted Frank-Starling mechanism may contribute to the pathophysiology of HFPEF.

title: Diastolic ventricular interaction in normal and dilated heart during head‐up tilting
abstract: The normal human heart behaves as a single functional unit during preload reduction; adaptations of the left ventricle to head‐up tilting is mediated through ventricular interdependence and biventricular—lung interaction.

title: Investigation of a Hemodynamic Basis for Syncope in Hypertrophic Cardiomyopathy: Use of a Head‐Up Tilt Test
abstract: BackgroundSyncope and sudden death in hypertrophic cardiomyopathy may have a hemodynamic basis. The presence of a small ventricular cavity with high intracavity pressures may activate left ventricular baroreceptors and cause reflex hypotension as described in other populations with syncope. Methods and ResultsTo investigate this potential mechanism of syncope in hypertrophic cardiomyopathy, we studied 17 patients with a history of syncope (syncopal), 19 without syncope (nonsyncopal), and nine normal control subjects by using a head-up tilt test. Head-up tilt at 60° for 45 minutes was followed by 10-minute tilts during incremental doses of isoprenaline. Heart rate, blood pressure, and twodimensional and Doppler echocardiography were monitored throughout. On tilting, hypertrophic cardiomyopathy patients showed a decline in mean arterial pressure of −5±6 mm Hg (p<0.001) compared with no change in control subjects (0.2±6 mm Hg, p=0.9). Left ventricular outflow tract velocity decreased on tilting in control subjects (−8±6 cm/sec, p=0.004) but increased in the syncopal and nonsyncopal patients (20±50 cm/sec, p=0.05). Reflex hypotension with or without bradycardia, associated with syncope or presyncope, was induced in seven syncopal patients, two nonsyncopal patients, and two control subjects (p=0.05). The early response to tilt in these subjects was characterized by maintenance of blood pressure but a greater increase in left ventricular fractional shortening than in the other subjects (10±8% versus 1±1%, p=0.002). The onset of hypotension was associated with a trend toward further decreases in left ventricular diameters, outflow tract velocity, and transmitral flow velocities. In the remaining patients who had a negative test, transient hypotension (systolic pressure <100 mm Hg) occurred in seven syncopal patients and three nonsyncopal patients compared with none of the control subjects (p=0.01). In total, hypotension was demonstrated in 82% of syncopal patients compared with 26% of nonsyncopal patients and 22% of control subjects (p=0.001). ConclusionsPatients with hypertrophic cardiomyopathy and a history of syncope frequently display hypotension during head-up tilt. In some cases, sudden hypotension occurs and is usually associated with bradycardia and a reduced cavity size, findings compatible with activation of a ventricular baroreflex. In other cases, transient hypotension occurs and could be explained by an impairment of baroreceptor function. These mechanisms may contribute to the occurrence of syncope in daily life.

title: Diastolic ventricular interaction: a possible mechanism for abnormal vascular responses during volume unloading in heart failure.
abstract: Baroreflex dysfunction is common in chronic heart failure and contributes to the associated sympathoexcitation. Baroreceptor activity normally decreases during volume unloading, causing an increase in sympathetic outflow and resulting in forearm vasoconstriction. Some heart failure patients develop attenuated vasoconstriction or paradoxical vasodilation. The mechanism for this is unknown. We have recently demonstrated diastolic ventricular interaction in some patients with chronic heart failure as evidenced by increases in left ventricular (LV) end-diastolic volume in association with decreases in right ventricular (RV) volume during volume unloading. We reasoned that such an increase in LV volume, by increasing LV mechanoreceptor activity, would decrease sympathetic outflow and could therefore explain the abnormal vascular responses seen in such patients.



We assessed changes in forearm vascular resistance (FVR) during application of -20 and -30 mm Hg lower-body negative pressure (LBNP) in 24 patients with chronic heart failure and 16 control subjects. Changes in LV and RV end-diastolic volumes were assessed during -30 mm Hg LBNP in all heart failure patients. Diastolic ventricular interaction was demonstrated in 12 patients as evidenced by increases in LV end-diastolic volume in association with decreases in RV end-diastolic volume during LBNP. Changes in FVR during LBNP (-20 and -30 mm Hg) were markedly attenuated in these 12 patients (-1.6+/-11.2 and -0.9+/-12.5 U) compared with both the remaining patients (11.9+/-10.0 and 17.0+/-12.3 U) and the control subjects (16.5+/-9.5 and 23.1+/-13.9 U) (P<.01 for both comparisons at each level of LBNP). FVR decreased in 5 of these 12 patients during -30 mm Hg LBNP, a response seen in none of the remaining patients (P=.01).



Diastolic ventricular interaction in patients with chronic heart failure is associated with attenuated forearm vasoconstriction or paradoxical vasodilation during LBNP. This may explain the apparent derangement in baroreflex control of sympathetic outflow during acute volume unloading in heart failure.

title: Human Baroreflexes in Health and Disease
abstract: Part A: General considerations: Introduction History Baroreflex anatomy Part B: Methods for Human Research: Valvalva's manoeuvre Selective methods Part C: Physiology: Afferent baroreceptor activity Reflex interactions Efferent baroreflex responses Effector responses to baroreceptor forcings Part D: Pathophysiology: Baroreflex malfunction in cardiovascular patients: general principles Hypertension Myocardial ischaemia Dysrhythmias Congestive heart failure Carotid sinus reflex hypersensitivity.

title: The role of diastolic ventricular interaction in abnormal cardiac baroreflex function in chronic heart failure.
abstract: Baroreflex abnormalities have been well documented in both patients with chronic heart failure and experimental animal models of heart failure. These abnormalities are associated with increased mortality and probably contribute to neurohumoral activation. While it is likely that several mechanisms contribute to reduced baroreflex sensitivity, it has been difficult to explain why baroreflex control mechanisms during acute volume unloading in patients with severe chronic heart failure should be directionally opposite to those in normal subjects. Volume unloading normally causes a reduction in baroreceptor activity, and hence an increase in sympathetic outflow; however, patients with chronic heart failure develop attenuated increases or paradoxical reductions in forearm vascular resistance, muscle sympathetic nerve activity, and noradrenaline spillover. It has been suggested that this probably represents paradoxical activation of left ventricular (LV) mechanoreceptors, but why LV receptors should behave in such a fashion has not been determined. In the setting of diastolic ventricular interaction, the filling of the left ventricle is constrained by the surrounding pericardium and right ventricle. In these patients, the reduction in right ventricular (RV) volume that normally occurs during acute volume unloading allows for an increase in LV end-diastolic volume (as opposed to the reduction in LV volume that normally occurs). We have demonstrated this to be important in some patients with chronic heart failure, and observed that baroreflex control of forearm vascular resistance was markedly impaired in these patients. We propose that the increase in LV volume that occurred during volume unloading would increase LV mechanoreceptor activity, and could therefore explain the paradoxical reductions in sympathetic outflow. As discussed, this has important therapeutic implications.

title: Interaction of cardiopulmonary and carotid baroreflex control of vascular resistance in humans.
abstract: Previous studies in experimental animals indicate an important inhibitory interaction between cardiopulmonary and arterial baroreflexes. In the dog, for example, cardiopulmonary vagal afferents modulate carotid baroreflex control of vascular resistance. On the other hand, previous studies in human subjects have not produced convincing evidence of a specific interaction between these baroreceptor reflexes. The purpose of this study was to determine whether unloading of cardiopulmonary baroreceptors in humans with nonhypotensive lower body negative pressure selectively augments the reflex vasoconstrictor responses to simulated carotid hypotension produced by neck pressure. In nine healthy subjects, we measured forearm vascular responses with plethysmography during lower body negative pressure alone (cardiopulmonary baroreflex), during neck pressure alone (carotid baroreflex), and during concomitant lower body negative pressure and neck pressure (baroreflex interaction). Lower body negative pressure produced a greater than twofold augmentation of the forearm vasoconstrictor response to neck pressure. This increase in resistance was significantly greater (P less than 0.05) than the algebraic sum of the increase in resistance from lower body negative pressure alone plus that from neck pressure alone. In contrast, lower body negative pressure did not potentiate the forearm vasoconstrictor responses either to intra-arterial norepinephrine or to the cold pressor test. Thus, the potentiation of the vasoconstrictor response to neck pressure by lower body negative pressure cannot be explained by augmented reactivity to the neurotransmitter or to a nonspecific augmentation of responses to all reflex vasoconstrictor stimuli. In conclusion, nonhypotensive lower body negative pressure selectively augments carotid baroreflex control of forearm vascular resistance. These experiments demonstrate a specific inhibitory cardiopulmonary-carotid baroreflex interaction in humans.