Allometric scaling relations, including the 3/4 power law for metabolic rates, are characteristic of all organisms and are here derived from a general model that describes how essential materials are transported through space-filling fractal networks of branching tubes. The model assumes that the energy dissipated is minimized and that the terminal tubes do not vary with body size. It provides a complete analysis of scaling relations for mammalian circulatory systems that are in agreement with data. More generally, the model predicts structural and functional properties of vertebrate cardiovascular and respiratory systems, plant vascular systems, insect tracheal tubes, and other distribution networks.

https://science.sciencemag.org/content/sci/276/5309/122.full.pdf

A general model for the origin of allometric scaling laws in biology

Atherosclerosis, the leading cause of death in the developed world and
nearly the leading cause in the developing world, is associated with systemic
risk factors including hypertension, smoking, hyperlipidemia, and diabetes
mellitus, among others. Nonetheless, atherosclerosis remains a geometrically
focal disease, preferentially affecting the outer edges of vessel bifurcations.
In these predisposed areas, hemodynamic shear stress, the frictional force
acting on the endothelial cell surface as a result of blood flow, is weaker
than in protected regions. Studies have identified hemodynamic shear stress
as an important determinant of endothelial function and phenotype. Arterial-level
shear stress (>15 dyne/cm2) induces endothelial quiescence and
an atheroprotective gene expression profile, while low shear stress (<4
dyne/cm2), which is prevalent at atherosclerosis-prone sites, stimulates
an atherogenic phenotype. The functional regulation of the endothelium by
local hemodynamic shear stress provides a model for understanding the focal
propensity of atherosclerosis in the setting of systemic factors and may help
guide future therapeutic strategies.

/pdf/hemodynamic-shear-stress-and-its-role-in-atherosclerosis-1u0na41ojd.pdf

Hemodynamic shear stress and its role in atherosclerosis.

Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.

/pdf/flow-mediated-endothelial-mechanotransduction-281f54bq52.pdf

Flow-mediated endothelial mechanotransduction

Fluid velocities were measured by laser Doppler velocimetry under conditions of pulsatile flow in a scale model of the human carotid bifurcation. Flow velocity and wall shear stress at five axial and four circumferential positions were compared with intimal plaque thickness at corresponding locations in carotid bifurcations obtained from cadavers. Velocities and wall shear stresses during diastole were similar to those found previously under steady flow conditions, but these quantities oscillated in both magnitude and direction during the systolic phase. At the inner wall of the internal carotid sinus, in the region of the flow divider, wall shear stress was highest (systole = 41 dynes/cm2, diastole = 10 dynes/cm2, mean = 17 dynes/cm2) and remained unidirectional during systole. Intimal thickening in this location was minimal. At the outer wall of the carotid sinus where intimal plaques were thickest, mean shear stress was low (-0.5 dynes/cm2) but the instantaneous shear stress oscillated between -7 and +4 dynes/cm2. Along the side walls of the sinus, intimal plaque thickness was greater than in the region of the flow divider and circumferential oscillations of shear stress were prominent. With all 20 axial and circumferential measurement locations considered, strong correlations were found between intimal thickness and the reciprocal of maximum shear stress (r = 0.90, p less than 0.0005) or the reciprocal of mean shear stress (r = 0.82, p less than 0.001). An index which takes into account oscillations of wall shear also correlated strongly with intimal thickness (r = 0.82, p less than 0.001). When only the inner wall and outer wall positions were taken into account, correlations of lesion thickness with the inverse of maximum wall shear and mean wall shear were 0.94 (p less than 0.001) and 0.95 (p less than 0.001), respectively, and with the oscillatory shear index, 0.93 (p less than 0.001). These studies confirm earlier findings under steady flow conditions that plaques tend to form in areas of low, rather than high, shear stress, but indicate in addition that marked oscillations in the direction of wall shear may enhance atherogenesis.

Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress.

Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell dysfunction, in its broadest sense, encompasses a constellation of various nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone and redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. In this review, we trace the evolution of the concept of endothelial cell dysfunction, focusing on recent insights into the cellular and molecular mechanisms that underlie its pivotal roles in atherosclerotic lesion initiation and progression; explore its relationship to classic, as well as more recently defined, clinical risk factors for atherosclerotic cardiovascular disease; consider current approaches to the clinical assessment of endothelial cell dysfunction; and outline some promising new directions for its early detection and treatment.

Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis

On the basis of various observations, we argue that there is spatial variation of the time-averaged wall shear rate in arteries, both overall and locally. From our own observations, and those of others, we show that the distribution of early atheroma in man is coincident with those regions in which arterial wall shear rate is expected to be relatively low, while the development of lesions is inhibited or retarded in those regions in which wall shear rate is expected to be relatively high. Such a correlation is inconsistent with a proposal, made by several workers, that there is a causative relation between arterial blood mechanics and the development of atheroma, i.e. that atheroma is associated with wall damage due to the motion of blood. Instead it immediately suggests that the process is associated with shear dependent mass transport phenomena. It has been demonstrated by others that mass transport, in the inner part of the arterial wall, is dominantly to and from blood flowing within the lumen. We review theory relevant to diffusional mass transport across such a sheared interface, and examine available experimental evidence, relating to normally occurring (quasi-steady state) and experimentally induced (transient-type) atheroma, as well as the distribution of cholesterol in arteries. These results are considered in the light of simple theoretical schemes which we develop for the movement of cholesterol, in particular, although the arguments may also be relevant to other diffusing species. Shear enhances mass transport by means of a steepening effect on the concentration gradient, thus diffusion of material from a wall is promoted when material which has already diffused is swept rapidly away, so that the concentration gradient leading to further diffusion remains steep. However, the influence of shear on the diffusion of a species, say, from just within the wall of an artery to fluid in the main stream, depends upon the relative resistances to its diffusion from within the wall to surface fluid (wall phase) and from surface fluid to fluid in the main stream (blood phase); diffusion is not appreciably shear dependent if the latter resistance is small compared with the former. Assuming simplified flow conditions and that as suggested by others cholesterol is transported in blood in association with plasma protein, we can estimate resistance for diffusion of this species in the blood phase, for different stations in the arterial system. However, we possess no definite comparable information for the wall phase; we conjecture that this resistance is relatively small, and assume shear dependence of diffusional transport of cholesterol between arterial walls and intraluminal blood. We find that a net flux of cholesterol from blood to wall, as has been suggested by others, cannot account, in terms of the proposed schemes, for the observed normally occurring (quasi-steady state) distribution of atheromatous lesions in man and in animals; mass transport is inhibited in low shear regions by the thick diffusional boundary layer. Instead it appears that cholesterol, which has been shown by others to be synthesized in arterial walls, accumulates in low shear regions because its local diffusional efflux from wall to blood is inhibited by the reduced concentration gradient. Given suitable values for relevant parameters, the theoretical schemes are also able to account for adequacy of supply of precursor to the wall for cholesterol synthesis, for the preferential occurrence that we now recognize of lesions in high shear regions in response to sudden natural or experimental elevation of blood cholesterol, and for the responses to administration of labelled cholesterol (transient type phenomena); it appears therefore possible, in terms of these schemes, to unify naturally occurring and experimentally induced atheroma. It is reported by others that platelets are associated only with advanced lesions; the correlation of naturally occurring atheroma with low shear regions, and transient type lesions with high shear regions, with the fluid mechanics being unaltered in the two situations, provides no support for the implication of platelets in the development of early atheroma. It appears that wall shear rate may be a major controlling factor in the development of atheroma, i.e. that high shear, such as is associated for example with increased cardiac output in exercise, will retard progression of the process. Its progression will also be retarded by any means which reduces the accumulation of atheromatous material, by influencing its rate of net production or diffusion.

Atheroma and arterial wall shear. Observation, correlation and proposal of a shear dependent mass transfer mechanism for atherogenesis.

Continuing demand for this book confirms that it remains relevant over 30 years after its first publication. The fundamental explanations are largely unchanged, but in the new introduction to this second edition the authors are on hand to guide the reader through major advances of the last three decades. With an emphasis on physical explanation rather than equations, Part I clearly presents the background mechanics. The second part applies mechanical reasoning to the component parts of the circulation: blood, the heart, the systemic arteries, microcirculation, veins and the pulmonary circulation. Each section demonstrates how an understanding of basic mechanics enhances our understanding of the function of the circulation as a whole. This classic book is of value to students, researchers and practitioners in bioengineering, physiology and human and veterinary medicine, particularly those working in the cardiovascular field, and to engineers and physical scientists with multidisciplinary interests.

https://assets.cambridge.org/97805211/51771/frontmatter/9780521151771_frontmatter.pdf

The Mechanics of the Circulation

THE patchy distribution of fatty streaking and early atheroma has been associated with arterial blood mechanics. Mustard et al.1 have noted occurrence of atheroma at sites which are thought to experience particle (platelet) deposition as the result of local rapid flow fluctuations (turbulence) or eddies. Others have proposed platelet deposition in regions of flow separation2. Texon3 invoked damage due to Bernoulli-type suction forces in areas of locally increased blood velocity; but this is considered implausible because the forces are negligible in physiological conditions in comparison with normal variations of mean blood pressure. Mitchell and Schwartz4 reported the sparing of fatty streaking in localized areas, at which they suggest low wall shear rate (the product of velocity gradient and fluid viscosity) is experienced. Fry5,6 has shown that acute elevation of shear rate on the aortic wall causes endothelial damage and increased permeability to lipids. These theories assign to fluid mechanics a causative role in atherogenesis.

Arterial Wall Shear and Distribution of Early Atheroma in Man

/pdf/physiological-factors-affecting-airway-resistance-in-normal-19cb4ccr2p.pdf

Physiological factors affecting airway resistance in normal subjects and in patients with obstructive respiratory disease

Certain alterations in pulmonary mechanics occur in man when an inspiration is taken from below the resting lung volume (1) and during shallow breathing (2). Some effects of a sustained reduction of the total lung capacity on respiration have been studied previously (3-5), yet the effects of chest strapping on pulmonary mechanics have received relatively little attention. In the preliminary experiments we tightly bound the chest in the expiratory position with either adhesive tape or a long strip of rubber. Subsequently we designed a special chest corset that permitted us to reduce the resting lung volume and inspiratory capacity at will. The entire pressure-volume curve of the lung was altered by these procedures, but was restored to normal when a deep inspiration was taken after release of the restricting apparatus. Simultaneously, the escape of gas from poorly ventilated regions of the lung was detected. The effect of these changes on other aspects of pulmonary and circulatory function was examined and our findings, together with a consideration of their physiological and clinical significance, form the basis of this report.

/pdf/some-effects-of-restriction-of-chest-cage-expansion-on-195qxzdv7l.pdf

C. G. Caro

Papers

Atheroma and arterial wall shear. Observation, correlation and proposal of a shear dependent mass transfer mechanism for atherogenesis.

The Mechanics of the Circulation

Arterial Wall Shear and Distribution of Early Atheroma in Man

Physiological factors affecting airway resistance in normal subjects and in patients with obstructive respiratory disease

Some effects of restriction of chest cage expansion on pulmonary function in man: an experimental study