Ghassan S. Kassab

Biomechanics of the gastrointestinal tract.

Abstract As the function of the gastrointestinal tract is to a large degree mechanical, it has become increasingly popular to acquire distensibility data in motility research based on various parameters. Hence it is important to know on which geometrical and mechanical assumptions the various parameters are based. Currently, compliance and tone derived from pressure‐volume curves are by far the most often used parameters. However, pressure‐volume relations obtained in tubular organs must be carefully interpreted as they provide no direct measure of luminal cross‐sectional area and other variables useful in plane stress and strain analysis. Thus, erroneous conclusions concerning tissue distensibility may be deduced. Other parameters, such as wall tension, stress and strain, give more useful information about mechanical behaviour. Distensibility data procure significance in fluid mechanics and in the study of tone, peristaltic reflexes, and mechanoreceptor kinematics. Such data are needed for the determination of the interaction between stimulus, electrical responses in neurons and the mechanical behaviour of the gut. Furthermore, from a clinical perspective, investigation of visco‐elastic properties is important because GI diseases are associated with growth and remodelling. For example, prestenotic dilatation, increased collagen synthesis, dysmotility and altered distensibility are common features of obstructive diseases. The purpose of this review is to discuss the physiological and clinical importance of acquiring biomechanical data, distensibility parameters and interpretation of these results and their associated errors. We will also discuss some aspects of the relationship between morphology, growth and biomechanics. Finally, we will outline a number of techniques to study the mechanical properties of the GI tract.

AMP-Activated Protein Kinase Is Involved in Endothelial NO Synthase Activation in Response to Shear Stress

Objective—The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK–eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner). Methods and Results—By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice. Conclusions—Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone.

On the design of the coronary arterial tree : a generalization of Murray's law

Murrays law has been generalized to provide morphometric relationships among various subtrees as well as between a feeding segment and the subtree it perfuses. The equivalent resistance of each subtree is empirically determined to be proportional to the cube of a subtrees cumulative arterial length (L) and inversely proportional to a subtrees arterial volume (V) raised to a power of approximately 2.6. This relationship, along with a minimization of a cost function, and a linearity assumption between flow and cumulative arterial length, provides a power law relationship between V and L. These results, in conjunction with conservation of energy, yield relationships between the diameter of a segment and the length of its distal subtree. The relationships were tested based on a complete set of anatomical data of the coronary arterial trees using two models. The first model, called the truncated tree model, is an actual reconstruction of the coronary arterial tree down to 500 microm in diameter. The second model, called the symmetric tree model, satisfies all mean anatomical data down to the capillary vessels. Our results show very good agreement between the theoretical formulation and the measured anatomical data, which may provide insight into the design of the coronary arterial tree. Furthermore, the established relationships between the various morphometric parameters of the truncated tree model may provide a basis for assessing the extent of diffuse coronary artery disease.

The pattern of coronary arteriolar bifurcations and the uniform shear hypothesis

By minimizing the cost function, which is the sum of the friction power loss and the metabolic energy proportional to blood volume, Murray derived an optimal condition for a vascular bifurcation. Murrays law states that the cube of the radius of a parent vessel equals the sum of the cubes of the radii of the daughters. We tested Murrays law against our data of pigs maximally vasodilated coronary arteriolar blood vessels at bifurcation points in control and hypertensive ventricles. Data were obtained from 7 farm pigs, 4 normal controls and 3 with right ventricular hypertrophy induced by stenosis of a pulmonary artery. Data on coronary arteriolar bifurcations were obtained from histological specimens by optical sectioning. The experimental results show excellent agreement with Murrays law in control and hypertensive hearts. Theoretically, we show that Murrays law can be derived alternatively as a consequence of the uniform vessel-wall shear strain rate hypothesis and a fluid mechanics equation based on conservation of mass and momentum. Conversely, the fluid mechanical equation, together with Murrays law, established as an empirical equation of actual measurements implies the uniformity of the shear strain rate of the blood at the vessel wall throughout the arterioles. The validity of these statements is discussed.

Nitric oxide is significantly reduced in ex vivo porcine arteries during reverse flow because of increased superoxide production

Oscillatory and negative flows occur normally in the cardiovascular system, which predispose those regions to atherosclerosis. Nitric oxide (NO) production increases in proportion to the magnitude of flow and is known to be athero‐protective. What is not known, however, is the effect of flow reversal on NO concentration ([NO]). The hypothesis of the present study is that [NO] is reduced in reverse flow. An additional hypothesis is that the reduction in [NO] is mediated through an increase in superoxide production during flow reversal. These hypotheses were tested in an ex vivo preparation of porcine elastic and muscular arteries. The flow of a physiological solution through the vessels was regulated in the forward and reverse direction and the effluent was assayed for nitrite levels using a combination of a diazo coupling method and high performance liquid chromatography. Our results show that [NO] is significantly reduced during reverse flow. Furthermore, addition of tempol (superoxide dismutase‐mimetic) which is a superoxide scavenger returns the [NO] during reverse flow to mirror those of forward flow. These results have important implications since the action of superoxide is implicated in many cardiovascular diseases, and the present finding suggests that flow reversal should be added to the list.

Scaling of myocardial mass to flow and morphometry of coronary arteries

There is no doubt that scaling relations exist between myocardial mass and morphometry of coronary vasculature. The purpose of this study is to quantify several morphological (diameter, length, and volume) and functional (flow) parameters of the coronary arterial tree in relation to myocardial mass. Eight normal porcine hearts of 117-244 g (mean of 177.5 +/- 32.7) were used in this study. Various coronary subtrees of the left anterior descending, right coronary, and left circumflex arteries were perfused at pressure of 100 mmHg with different colors of a polymer (Microfil) to obtain rubber casts of arterial trees corresponding to different regions of myocardial mass. Volume, diameter, and cumulative length of coronary arteries were reconstructed from casts to analyze their relationship to the perfused myocardial mass. Volumetric flow was measured in relationship with perfused myocardial mass. Our results show that arterial volume is linearly related to regional myocardial mass, whereas the sum of coronary arterial branch lengths, vessel diameters, and volumetric flow show an approximately 3/4, 3/8, and 3/4 power-law relationship, respectively, in relation to myocardial mass. These scaling laws suggest fundamental design principles underlying the structure-function relationship of the coronary arterial tree that may facilitate diagnosis and management of diffuse coronary artery disease.

Analysis of pig’s coronary arterial blood flow with detailed anatomical data

Blood flow to perfuse the muscle cells of the heart is distributed by the capillary blood vessels via the coronary arterial tree. Because the branching pattern and vascular geometry of the coronary vessels in the ventricles and atria are nonuniform, the flow in all of the coronary capillary blood vessels is not the same. This nonuniformity of perfusion has obvious physiological meaning, and must depend on the anatomy and branching pattern of the arterial tree. In this study, the statistical distribution of blood pressure, blood flow, and blood volume in all branches of the coronary arterial tree is determined based on the anatomical branching pattern of the coronary arterial tree and the statistical data on the lengths and diameters of the blood vessels. Spatial nonuniformity of the flow field is represented by dispersions of various quantities (SD/mean) that are determined as functions of the order numbers of the blood vessels. In the determination, we used a new, complete set of statistical data on the branching pattern and vascular geometry of the coronary arterial trees. We wrote hemodynamic equations for flow in every vessel and every node of a circuit, and solved them numerically. The results of two circuits are compared: oneasymmetric model satisfies all anatomical data (including the meanconnectivity matrix) and the other, asymmetric model, satisfies all mean anatomical data except the connectivity matrix. It was found that the mean longitudinal pressure drop profile as functions of the vessel order numbers are similar in both models, but the asymmetric model yields interesting dispersion profiles of blood pressure and blood flow. Mathematical modeling of the anatomy and hemodynamics is illustrated with discussions on its accuracy.

Role of shear stress and stretch in vascular mechanobiology

Blood vessels are under constant mechanical loading from blood pressure and flow which cause internal stresses (endothelial shear stress and circumferential wall stress, respectively). The mechanical forces not only cause morphological changes of endothelium and blood vessel wall, but also trigger biochemical and biological events. There is considerable evidence that physiologic stresses and strains (stretch) exert vasoprotective roles via nitric oxide and provide a homeostatic oxidative balance. A perturbation of tissue stresses and strains can disturb biochemical homeostasis and lead to vascular remodelling and possible dysfunction (e.g. altered vasorelaxation, tone, stiffness, etc.). These distinct biological endpoints are caused by some common biochemical pathways. The focus of this brief review is to point out some possible commonalities in the molecular pathways in response to endothelial shear stress and circumferential wall stretch.

Biomechanics of the cardiovascular system: the aorta as an illustratory example

Biomechanics relates the function of a physiological system to its structure. The objective of biomechanics is to deduce the function of a system from its geometry, material properties and boundary conditions based on the balance laws of mechanics (e.g. conservation of mass, momentum and energy). In the present review, we shall outline the general approach of biomechanics. As this is an enormously broad field, we shall consider a detailed biomechanical analysis of the aorta as an illustration. Specifically, we will consider the geometry and material properties of the aorta in conjunction with appropriate boundary conditions to formulate and solve several well-posed boundary value problems. Among other issues, we shall consider the effect of longitudinal pre-stretch and surrounding tissue on the mechanical status of the vessel wall. The solutions of the boundary value problems predict the presence of mechanical homeostasis in the vessel wall. The implications of mechanical homeostasis on growth, remodelling and postnatal development of the aorta are considered.

Intraspecific scaling laws of vascular trees

A fundamental physics-based derivation of intraspecific scaling laws of vascular trees has not been previously realized. Here, we provide such a theoretical derivation for the volume–diameter and flow–length scaling laws of intraspecific vascular trees. In conjunction with the minimum energy hypothesis, this formulation also results in diameter–length, flow–diameter and flow–volume scaling laws. The intraspecific scaling predicts the volume–diameter power relation with a theoretical exponent of 3, which is validated by the experimental measurements for the three major coronary arterial trees in swine (where a least-squares fit of these measurements has exponents of 2.96, 3 and 2.98 for the left anterior descending artery, left circumflex artery and right coronary artery trees, respectively). This scaling law as well as others agrees very well with the measured morphometric data of vascular trees in various other organs and species. This study is fundamental to the understanding of morphological and haemodynamic features in a biological vascular tree and has implications for vascular disease.