Algebraic formulas characterizing an alternative to Guyton's graphical analysis relevant for heart failure.

Although Guyton's graphical analysis of cardiac output-venous return has become a ubiquitous tool for explaining how circulatory equilibrium emerges from heart-vascular interactions, this classical model relies on a formula for venous return that contains unphysiological assumptions. Furthermore, Guyton's graphical analysis does not predict pulmonary venous pressure, which is a critical variable for evaluating heart failure patients' risk of pulmonary edema. Therefore, the purpose of the present work was to use a minimal closed-loop mathematical model to develop an alternative to Guyton's analysis. Limitations inherent in Guyton's model were addressed by 1) partitioning the cardiovascular system differently to isolate left ventricular function and lump all blood volumes together, 2) linearizing end-diastolic pressure-volume relationships to obtain algebraic solutions, and 3) treating arterial pressures as constants. This approach yielded three advances. First, variables related to morbidities associated with left ventricular failure were predicted. Second, an algebraic formula predicting left ventricular function was derived in terms of ventricular properties. Third, an algebraic formula predicting flow through the portion of the system isolated from the left ventricle was derived in terms of mechanical properties without neglecting redistribution of blood between systemic and pulmonary circulations. Although complexities were neglected, approximations necessary to obtain algebraic formulas resulted in minimal error, and predicted variables were consistent with reported values.

Adaptation of the hepatic transudation barrier to sinusoidal hypertension.

The role of the hepatic transudation barrier in determining ascites volume and protein content in chronic liver disease is poorly understood. Therefore, the purpose of the present study was to characterize how chronic sinusoidal hypertension impacts hepatic transudation barrier properties and the transudation rate. The suprahepatic inferior vena cava was surgically constricted, and animals were exposed to either short-term (SVH; 2-3 wk) or long-term venous hypertension (LVH; 5-6 wk). Compared with SVH, LVH resulted in lower peritoneal fluid pressure, ascites volume, and ascites protein concentration. The transudation barrier protein reflection coefficient was significantly higher, and the transudation barrier hydraulic conductivity, transudation rate, and transudate-to-lymph protein concentration ratio were significantly lower in LVH animals compared with SVH animals. The sensitivity of transudation rates to acute changes in interstitial fluid pressures was also significantly lower in LVH animals compared with SVH animals. In contrast, there was no detectable difference in hepatic lymph flow rate or sensitivity of lymph flow to acute changes in interstitial fluid pressures between SVH and LVH animals. Taken together, these data suggest that decreased hepatic transudation barrier permeability to fluid and protein and increased reflection coefficient led to a decrease in the hepatic contribution to ascites volume. The present work, to the best of our knowledge, is the first to quantify an anti-ascites adaptation of the hepatic transudation barrier in response to chronic hepatic sinusoidal hypertension.

Hepatic transudation barrier properties.

OBJECTIVE: Fluid and protein continuously transude from the surface of the liver. Despite a common understanding that transudation plays a critical role in hepatic interstitial and peritoneal fluid balance, transudation from the entire liver has not been studied. Therefore, the goal of the present work was to provide the first direct measurement of the hepatic transudation rate and transudation barrier properties. METHODS: Transudation rates were determined by collecting transudate from the entire liver. Hydraulic conductivity, and fluid transudation and protein reflection coefficients of the transudation barrier (formed by the subscapular interstitial matrix, capsule, and peritoneum) were determined from changes in fluid and protein transudation rates in response to hepatic venous pressure elevation. RESULTS: Following hepatic venous pressure elevation from 6.1 ± 0.9 to 11.1 ± 0.6 mm Hg, transudation rate increased from 0.13 ± 0.03 to 0.37 ± 0.03 mL/min·100 g. Transudation barrier hydraulic conductivity, fluid transudation and protein reflection coefficients (3.9 × 10-4  ± 5.7 × 10-5  mL/min·mm Hg·cm2 , 0.36 ± 0.04 mL/min·mm Hg, and 0.09 ± 0.03, respectively) were comparable to those reported for hepatic sinusoids. CONCLUSIONS: Taken together, these findings suggest that the hepatic transudation barrier is highly permeable at elevated sinusoidal pressures. These fundamental studies provide a better understanding of the hepatic transudation barrier properties and transudation under conditions that are physiologically and clinically relevant to ascites formation.

Aortic pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses.

Aortic pulse pressure arises from the interaction of the heart, the systemic arterial system, and peripheral microcirculations. The complex interaction between hemodynamics and arterial remodeling precludes the ability to experimentally ascribe changes in aortic pulse pressure to particular adaptive responses. Therefore, the purpose of the present work was to use a human systemic arterial system model to test the hypothesis that pulse pressure homeostasis can emerge from physiological adaptation of systemic arteries to local mechanical stresses. First, we assumed a systemic arterial system that had a realistic topology consisting of 121 arterial segments. Then the relationships of pulsatile blood pressures and flows in arterial segments were characterized by standard pulse transmission equations. Finally, each arterial segment was assumed to remodel to local stresses following three simple rules: 1) increases in endothelial shear stress increases radius, 2) increases in wall circumferential stress increases wall thickness, and 3) increases in wall circumferential stress decreases wall stiffness. Simulation of adaptation by iteratively calculating pulsatile hemodynamics, mechanical stresses, and vascular remodeling led to a general behavior in response to mechanical perturbations: initial increases in pulse pressure led to increased arterial compliances, and decreases in pulse pressure led to decreased compliances. Consequently, vascular adaptation returned pulse pressures back toward baseline conditions. This behavior manifested when modeling physiological adaptive responses to changes in cardiac output, changes in peripheral resistances, and changes in local arterial radii. The present work, thus, revealed that pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses.

The complex distribution of arterial system mechanical properties, pulsatile hemodynamics, and vascular stresses emerges from three simple adaptive rules.

Arterial mechanical properties, pulsatile hemodynamic variables, and mechanical vascular stresses vary significantly throughout the systemic arterial system. Although the fundamental principles governing pulsatile hemodynamics in elastic arteries are widely accepted, a set of rules governing stress-induced adaptation of mechanical properties can only be indirectly inferred from experimental studies. Previously reported mathematical models have assumed mechanical properties adapt to achieve an assumed target stress "set point." Simultaneous prediction of the mechanical properties, hemodynamics, and stresses, however, requires that equilibrium stresses are not assumed a priori. Therefore, the purpose of this work was to use a "balance point" approach to identify the simplest set of universal adaptation rules that simultaneously predict observed mechanical properties, hemodynamics, and stresses throughout the human systemic arterial system. First, we employed a classical systemic arterial system model with 121 arterial segments and removed all parameter values except vessel lengths and peripheral resistances. We then assumed vessel radii increase with endothelial shear stress, wall thicknesses increase with circumferential wall stress, and material stiffnesses decrease with circumferential wall stress. Parameters characterizing adaptive responses were assumed to be identical in all arterial segments. Iteratively predicting local mechanical properties, hemodynamics, and stresses reproduced five trends observed when traversing away from the aortic root towards the periphery: decrease in lumen radii, wall thicknesses, and pulsatile flows and increase in wall stiffnesses and pulsatile pressures. The extraordinary complexity of the systemic arterial system can thus arise from independent adaptation of vessels to local stresses characterized by three simple adaptive rules.

Functional adaptation of bovine mesenteric lymphatic vessels to mesenteric venous hypertension.

Lymph flow is the primary mechanism for returning interstitial fluid to the blood circulation. Currently, the adaptive response of lymphatic vessels to mesenteric venous hypertension is not known. This study sought to determine the functional responses of postnodal mesenteric lymphatic vessels. We surgically occluded bovine mesenteric veins to create mesenteric venous hypertension to elevate mesenteric lymph flow. Three days after surgery, postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 7) and sham surgery (Sham; n = 6) group animals were evaluated and compared. Contraction frequency (MVH: 2.98 ± 0.75 min(-1); Sham: 5.42 ± 0.81 min(-1)) and fractional pump flow (MVH: 1.14 ± 0.30 min(-1); Sham: 2.39 ± 0.32 min(-1)) were significantly lower in the venous occlusion group. These results indicate that postnodal mesenteric lymphatic vessels adapt to mesenteric venous hypertension by reducing intrinsic contractile activity.

Award article: Microcirculatory Society Award for Excellence in Lymphatic Research: time course of myocardial interstitial edema resolution and associated left ventricular dysfunction.

OBJECTIVE: Although the causal relationship between acute myocardial edema and cardiac dysfunction has been established, resolution of myocardial edema and subsequent recovery of cardiac function have not been established. The time to resolve myocardial edema and the degree that cardiac function is depressed after edema resolves are not known. We therefore characterized temporal changes in cardiac function as acute myocardial edema formed and resolved. METHODS: Acute myocardial edema was induced in the canine model by elevating coronary sinus pressure for three hours. Myocardial water content and cardiac function were determined before and during coronary sinus pressure elevation, and after coronary sinus pressure restoration. RESULTS: Although no change in systolic properties was detected, accumulation of water in myocardial interstitium was associated with increased diastolic stiffness. When coronary sinus pressure was relieved, myocardial edema resolved within 180 minutes. Diastolic stiffness, however, remained significantly elevated compared with baseline values, and cardiac function remained compromised. CONCLUSIONS: The present work suggests that the cardiac dysfunction caused by the formation of myocardial edema may persist after myocardial edema resolves. With the advent of new imaging techniques to quantify myocardial edema, this insight provides a new avenue for research to detect and treat a significant cause of cardiac dysfunction.

Increasing pulse wave velocity in a realistic cardiovascular model does not increase pulse pressure with age.

The mechanism of the well-documented increase in aortic pulse pressure (PP) with age is disputed. Investigators assuming a classical windkessel model believe that increases in PP arise from decreases in total arterial compliance (C(tot)) and increases in total peripheral resistance (R(tot)) with age. Investigators assuming a more sophisticated pulse transmission model believe PP rises because increases in pulse wave velocity (c(ph)) make the reflected pressure wave arrive earlier, augmenting systolic pressure. It has recently been shown, however, that increases in c(ph) do not have a commensurate effect on the timing of the reflected wave. We therefore used a validated, large-scale, human arterial system model that includes realistic pulse wave transmission to determine whether increases in c(ph) cause increased PP with age. First, we made the realistic arterial system model age dependent by altering cardiac output (CO), R(tot), C(tot), and c(ph) to mimic the reported changes in these parameters from age 30 to 70. Then, c(ph) was theoretically maintained constant, while C(tot), R(tot), and CO were altered. The predicted increase in PP with age was similar to the observed increase in PP. In a complementary approach, C(tot), R(tot), and CO were theoretically maintained constant, and c(ph) was increased. The predicted increase in PP was negligible. We found that increases in c(ph) have a limited effect on the timing of the reflected wave but cause the system to degenerate into a windkessel. Changes in PP can therefore be attributed to a decrease in C(tot).

Blood flow augmentation by intrinsic venular contraction in vivo.

Venomotion, spontaneous cyclic contractions of venules, was first observed in the bat wing 160 years ago. Of all the functional roles proposed since then, propulsion of blood by venomotion remains the most controversial. Common animal models that require anesthesia and surgery have failed to provide evidence for venular pumping of blood. To determine whether venomotion actively pumps blood in a minimally invasive, unanesthetized animal model, we reintroduced the batwing model. We evaluated the temporal and functional relationship between the venous contraction cycle and blood flow and luminal pressure. Furthermore, we determined the effect of inhibiting venomotion on blood flow. We found that the active venous contractions produced an increase in the blood flow and exhibited temporal vessel diameter-blood velocity and pressure relationships characteristic of a peristaltic pump. The presence of valves, a characteristic of reciprocating pumps, enhances the efficiency of the venular peristaltic pump by preventing retrograde flow. Instead of increasing blood flow by decreasing passive resistance, venular dilation with locally applied sodium nitroprusside decreased blood flow. Taken together, these observations provide evidence for active venular pumping of blood. Although strong venomotion may be unique to bats, venomotion has also been inferred from venous pressure oscillations in other animal models. The conventional paradigm of microvascular pressure and flow regulation assumes venules only act as passive resistors, a proposition that must be reevaluated in the presence of significant venomotion.

Nonlinear lymphangion pressure-volume relationship minimizes edema.

Lymphangions, the segments of lymphatic vessel between two valves, contract cyclically and actively pump, analogous to cardiac ventricles. Besides having a discernable systole and diastole, lymphangions have a relatively linear end-systolic pressure-volume relationship (with slope E(max)) and a nonlinear end-diastolic pressure-volume relationship (with slope E(min)). To counter increased microvascular filtration (causing increased lymphatic inlet pressure), lymphangions must respond to modest increases in transmural pressure by increasing pumping. To counter venous hypertension (causing increased lymphatic inlet and outlet pressures), lymphangions must respond to potentially large increases in transmural pressure by maintaining lymph flow. We therefore hypothesized that the nonlinear lymphangion pressure-volume relationship allows transition from a transmural pressure-dependent stroke volume to a transmural pressure-independent stroke volume as transmural pressure increases. To test this hypothesis, we applied a mathematical model based on the time-varying elastance concept typically applied to ventricles (the ratio of pressure to volume cycles periodically from a minimum, E(min), to a maximum, E(max)). This model predicted that lymphangions increase stroke volume and stroke work with transmural pressure if E(min) < E(max) at low transmural pressures, but maintain stroke volume and stroke work if E(min)= E(max) at higher transmural pressures. Furthermore, at higher transmural pressures, stroke work is evenly distributed among a chain of lymphangions. Model predictions were tested by comparison to previously reported data. Model predictions were consistent with reported lymphangion properties and pressure-flow relationships of entire lymphatic systems. The nonlinear lymphangion pressure-volume relationship therefore minimizes edema resulting from both increased microvascular filtration and venous hypertension.

Venomotion modulates lymphatic pumping in the bat wing.

In skin, it is believed that lymph must be pumped by intrinsic contraction of lymphatic muscle, since investigators have not considered that cyclical dilation of venules could compress adjacent lymphatic microvessels. Because lymphatic vessels are sensitive to stretch, we hypothesized that venomotion not only can cause extrinsic pumping of lymph in nearby lymphatic vessels, but also can stimulate intrinsic contractions. Bat wing venules have pronounced venomotion and are in close proximity to lymphatic microvessels, and can be studied noninvasively without the confounding effects of anesthesia, surgical trauma, or contrast agents. Therefore, the interaction between venules and their paired lymphatic vessels in unanesthetized Pallid bats (n = 8) was evaluated by recording the diameters of both vessels. Four sets of observations suggested that lymphatic and venous contractions were partially coupled. First, venous dilation and contraction produced a significant change in lymphatic microvascular cross-sectional area. Second, lymphatic microvascular contractions were immediately preceded by a change in venular diameter. Third, venular and lymphatic vessel contraction frequencies were positively correlated (r = 0.75). Fourth, time delays between peak venular systole and onset of lymphatic microvascular contraction were negatively correlated with venomotion magnitude (r = -0.55) and velocity (r = -0.64). In a separate experiment, inhibiting venomotion resulted in a 54.3 +/- 20.0% (n = 8) decrease in lymphatic contraction frequency. Furthermore, 85.7% (n = 56) of lymphatic vessels switch sides and lie adjacent to arterioles when venules were too small to exhibit venomotion. These results are consistent with both extrinsic pumping of lymph and stretch-induced lymphatic contraction and imply that intrinsic and extrinsic pumping can be coupled.

Lymphatic pump-conduit duality: contraction of postnodal lymphatic vessels inhibits passive flow.

Lymphangions, the segments of lymphatic vessels between valves, exhibit structural characteristics in common with both ventricles and arteries. Although once viewed as passive conduits like arteries, it has become well established that lymphangions can actively pump lymph against an axial pressure gradient from low-pressure tissues to the great veins of the neck. A recently reported mathematical model, based on fundamental principles, predicted that lymphangions can transition from pump to conduit behavior when outlet pressure falls below inlet pressure. In this case, the axial pressure gradient becomes the major source of energy for the propulsion of lymph, despite the presence of cyclical contraction. In fact, flow is augmented when cyclical contractions are abolished. We therefore used an in vitro preparation to confirm these findings and to test the hypothesis that lymphangion contraction inhibits flow when outlet pressure falls below inlet pressure. Bovine postnodal mesenteric lymphatic vessels harvested from an abattoir were subjected to an inlet pressure of 5.0 cmH(2)O and an outlet pressure that decreased from 6.5 to 3.5 cmH(2)O under control conditions, stimulated with U-46619 (a thromboxane analog) and relaxed with calcium-free solution. Under control conditions, lymphatic flow markedly increased as outlet pressure fell below inlet pressure. In this case, the slopes of the flow versus axial pressure gradient increased with calcium-free conditions (61%, n = 8, P = 0.016) and decreased with U-46619 stimulation (21%, n = 5, P = 0.033). Our findings indicate that the stimulation of lymphatic contractility does indeed inhibit lymphatic flow when vessels act like conduits.

Optimal postnodal lymphatic network structure that maximizes active propulsion of lymph.

The lymphatic system acts to return lower-pressured interstitial fluid to the higher-pressured veins by a complex network of vessels spanning more than three orders of magnitude in size. Lymphatic vessels consist of lymphangions, segments of vessels between two unidirectional valves, which contain smooth muscle that cyclically pumps lymph against a pressure gradient. Whereas the principles governing the optimal structure of arterial networks have been identified by variations of Murray's law, the principles governing the optimal structure of the lymphatic system have yet to be elucidated, although lymph flow can be identified as a critical parameter. The reason for this deficiency can be identified. Until recently, there has been no algebraic formula, such as Poiseuille's law, that relates lymphangion structure to its function. We therefore employed a recently developed mathematical model, based on the time-varying elastance model conventionally used to describe ventricular function, that was validated by data collected from postnodal bovine mesenteric lymphangions. From this lymphangion model, we developed a model to determine the structure of a lymphatic network that optimizes lymph flow. The model predicted that there is a lymphangion length that optimizes lymph flow and that symmetrical networks optimize lymph flow when the lymphangions downstream of a bifurcation are 1.26 times the length of the lymphangions immediately upstream. Measured lymphangion lengths (1.14 +/- 0.5 cm, n = 74) were consistent with the range of predicted optimal lengths (0.1-2.1 cm). This modeling approach was possible, because it allowed a structural parameter, such as length, to be treated as a variable.

Integrating research and education at research-extensive universities with research-intensive communities.

Although the Boyer Commission (1998) lamented the lack of research opportunities for all undergraduates at research-extensive universities, it did not provide a feasible solution consistent with the mandate for faculty to maintain sustainable physiology research programs. The costs associated with one-on-one mentoring, and the lack of a sufficient number of faculty members to give intensive attention to undergraduate researchers, make one-on-one mentoring impractical. We therefore developed and implemented the "research-intensive community" model with the aim of aligning diverse goals of participants while simultaneously optimizing research productivity. The fundamental organizational unit is a team consisting of one graduate student and three undergraduates from different majors, supervised by a faculty member. Undergraduate workshops, Graduate Leadership Forums, and computer-mediated communication provide an infrastructure to optimize programmatic efficiency and sustain a multilevel, interdisciplinary community of scholars dedicated to research. While the model radically increases the number of undergraduates that can be supported by a single faculty member, the inherent resilience and scalability of the resulting complex adaptive system enables a research-intensive community program to evolve and grow.

The origin of the biphasic flow response to local heat in skin.

OBJECTIVE: Although it is well established that the application of local heat causes a biphasic increase in skin blood flow, the responsible microvessels have not been identified. METHODS: A bifurcating network of arterioles (1st-5th orders, 60-15 mum, n = 10 per group) of the intact, unanesthetized, translucent bat wing were visualized on a transparent heat plate via intravital microscopy. Similar to previous bat wing studies, plate temperature was set at 25 degrees C for 10 min then increased to 37 degrees C for 20 min. Vessel diameter and red blood cell velocity were recorded and used to calculate resistance and blood flow. RESULTS: The average flow response in arterioles was biphasic (p = 0.02) and proportional to the temporal decrease in total resistance calculated from 1st-5th order arterioles. Metarteriole (i.e., 5th order arteriole) resistance had the greatest impact on total resistance (-67.0 +/- 20.7%) and exhibited a biphasic trend that was opposed by temporal changes in resistance of 1st-4th order arterioles. CONCLUSION: Metarterioles are not only necessary but sufficient to explain the origin of the biphasic flow response in skin blood flow.

Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema.

Myocardial interstitial edema forms as a result of several disease states and clinical interventions. Acute myocardial interstitial edema is associated with compromised systolic and diastolic cardiac function and increased stiffness of the left ventricular chamber. Formation of chronic myocardial interstitial edema results in deposition of interstitial collagen, which causes interstitial fibrosis. To assess the effect of myocardial interstitial edema on the mechanical properties of the left ventricle and the myocardial interstitium, we induced acute and chronic interstitial edema in dogs. Acute myocardial edema was generated by coronary sinus pressure elevation, while chronic myocardial edema was generated by chronic pulmonary artery banding. The pressure-volume relationships of the left ventricular myocardial interstitium and left ventricular chamber for control animals were compared with acutely and chronically edematous animals. Collagen content of nonedematous and chronically edematous animals was also compared. Generating acute myocardial interstitial edema resulted in decreased left ventricular chamber compliance compared with nonedematous animals. With chronic edema, the primary form of collagen changed from type I to III. Left ventricular chamber compliance in animals made chronically edematous was significantly higher than nonedematous animals. The change in primary collagen type secondary to chronic left ventricular myocardial interstitial edema provides direct evidence for structural remodeling. The resulting functional adaptation allows the chronically edematous heart to maintain left ventricular chamber compliance when challenged with acute edema, thus preserving cardiac function over a wide range of interstitial fluid pressures.

First-order approximation for the pressure-flow relationship of spontaneously contracting lymphangions.

To return lymph to the great veins of the neck, it must be actively pumped against a pressure gradient. Mean lymph flow in a portion of a lymphatic network has been characterized by an empirical relationship (P(in) - P(out) = -P(p) + R(L)Q(L)), where P(in) - P(out) is the axial pressure gradient and Q(L) is mean lymph flow. R(L) and P(p) are empirical parameters characterizing the effective lymphatic resistance and pump pressure, respectively. The relation of these global empirical parameters to the properties of lymphangions, the segments of a lymphatic vessel bounded by valves, has been problematic. Lymphangions have a structure like blood vessels but cyclically contract like cardiac ventricles; they are characterized by a contraction frequency (f) and the slopes of the end-diastolic pressure-volume relationship [minimum value of resulting elastance (E(min))] and end-systolic pressure-volume relationship [maximum value of resulting elastance (E(max))]. Poiseuille's law provides a first-order approximation relating the pressure-flow relationship to the fundamental properties of a blood vessel. No analogous formula exists for a pumping lymphangion. We therefore derived an algebraic formula predicting lymphangion flow from fundamental physical principles and known lymphangion properties. Quantitative analysis revealed that lymph inertia and resistance to lymph flow are negligible and that lymphangions act like a series of interconnected ventricles. For a single lymphangion, P(p) = P(in) (E(max) - E(min))/E(min) and R(L) = E(max)/f. The formula was tested against a validated, realistic mathematical model of a lymphangion and found to be accurate. Predicted flows were within the range of flows measured in vitro. The present work therefore provides a general solution that makes it possible to relate fundamental lymphangion properties to lymphatic system function.

Lymphangion coordination minimally affects mean flow in lymphatic vessels.

The lymphatic system returns interstitial fluid to the central venous circulation, in part, by the cyclical contraction of a series of "lymphangion pumps" in a lymphatic vessel. The dynamics of individual lymphangions have been well characterized in vitro; their frequencies and strengths of contraction are sensitive to both preload and afterload. However, lymphangion interaction within a lymphatic vessel has been poorly characterized because it is difficult to experimentally alter properties of individual lymphangions and because the afterload of one lymphangion is coupled to the preload of another. To determine the effects of lymphangion interaction on lymph flow, we adapted an existing mathematical model of a lymphangion (characterizing lymphangion contractility, lymph viscosity, and inertia) to create a new lymphatic vessel model consisting of several lymphangions in series. The lymphatic vessel model was validated with focused experiments on bovine mesenteric lymphatic vessels in vitro. The model was then used to predict changes in lymph flow with different time delays between onset of contraction of adjacent lymphangions (coordinated case) and with different relative lymphangion contraction frequencies (noncoordinated case). Coordination of contraction had little impact on mean flow. Furthermore, orthograde and retrograde propagations of contractile waves had similar effects on flow. Model results explain why neither retrograde propagation of contractile waves nor the lack of electrical continuity between lymphangions adversely impacts flow. Because lymphangion coordination minimally affects mean flow in lymphatic vessels, lymphangions have flexibility to independently adapt to local conditions.

Increase in pulse wavelength causes the systemic arterial tree to degenerate into a classical windkessel.

Two competing schools of thought ascribe vascular disease states such as isolated systolic hypertension to fundamentally different arterial system properties. The "windkessel school" describes the arterial system as a compliant chamber that distends and stores blood and relates pulse pressure to total peripheral resistance (R(tot)) and total arterial compliance (C(tot)). Inherent in this description is the assumption that arterial pulse wavelengths are infinite. The "transmission school," assuming a finite pulse wavelength, describes the arterial system as a network of vessels that transmits pulses and relates pulse pressure to the magnitude, timing, and sites of pulse-wave reflection. We hypothesized that the systemic arterial system, described by the transmission school, degenerates into a windkessel when pulse wavelengths increase sufficiently. Parameters affecting pulse wavelength (i.e., heart rate, arterial compliances, and radii) were systematically altered in a realistic, large-scale, human arterial system model, and the resulting pressures were compared with those assuming a classical (2-element) windkessel with the same R(tot) and C(tot). Increasing pulse wavelength as little as 50% (by changing heart rate -33.3%, compliances -55.5%, or radii +50%) caused the distributed arterial system model to degenerate into a classical windkessel (r(2) = 0.99). Model results were validated with analysis of representative human aortic pressure and flow waveforms. Because reported changes in arterial properties with age can markedly increase pulse wavelength, results suggest that isolated systolic hypertension is a manifestation of an arterial system that has degenerated into a windkessel, and thus arterial pressure is a function only of aortic flow, R(tot), and C(tot).

Lymphatic vessels transition to state of summation above a critical contraction frequency.

Although behavior of lymphatic vessels is analogous to that of ventricles, which completely relax between contractions, and blood vessels, which maintain a tonic constriction, the mixture of contractile properties can yield behavior unique to lymphatic vessels. In particular, because of their limited refractory period and slow rate of relaxation, lymphatic vessels lack the contractile properties that minimize summation in ventricles. We, therefore, hypothesized that lymphatic vessels transition to a state of summation when lymphatic vessel contraction frequency exceeds a critical value. We used an isovolumic, controlled-flow preparation to compare the time required for full relaxation with the time available to relax during diastole. We measured transmural pressure and diameter on segments of spontaneously contracting bovine mesenteric lymphatic vessels during 10 isovolumic volume steps. We found that beat-to-beat period (frequency(-1)) decreased with increases in diameter and that total contraction time was constant or slightly increased with diameter. We further found that the convergence of beat-to-beat period and contraction cycle duration predicted a critical transition value, beyond which the vessel does not have time to fully relax. This incomplete relaxation and resulting mechanical summation significantly increase active tension in diastole. Because this transition occurs within a physiological range, contraction summation may represent a fundamental feature of lymphatic vessel function.