Wall shear stress as measured in vivo: consequences for the design of the arterial system

Based upon theory, wall shear stress (WSS), an important determinant of endothelial function and gene expression, has been assumed to be constant along the arterial tree and the same in a particular artery across species. In vivo measurements of WSS, however, have shown that these assumptions are far from valid. In this survey we will discuss the assessment of WSS in the arterial system in vivo and present the results obtained in large arteries and arterioles. In vivo WSS can be estimated from wall shear rate, as derived from non-invasively recorded velocity profiles, and whole blood viscosity in large arteries and plasma viscosity in arterioles, avoiding theoretical assumptions. In large arteries velocity profiles can be recorded by means of a specially designed ultrasound system and in arterioles via optical techniques using fluorescent flow velocity tracers. It is shown that in humans mean WSS is substantially higher in the carotid artery (1.1–1.3 Pa) than in the brachial (0.4–0.5 Pa) and femoral (0.3–0.5 Pa) arteries. Also in animals mean WSS varies substantially along the arterial tree. Mean WSS in arterioles varies between about 1.0 and 5.0 Pa in the various studies and is dependent on the site of measurement in these vessels. Across species mean WSS in a particular artery decreases linearly with body mass, e.g., in the infra-renal aorta from 8.8 Pa in mice to 0.5 Pa in humans. The observation that mean WSS is far from constant along the arterial tree implies that Murray’s cube law on flow-diameter relations cannot be applied to the whole arterial system. Because blood flow velocity is not constant along the arterial tree either, a square law also does not hold. The exponent in the power law likely varies along the arterial system, probably from 2 in large arteries near the heart to 3 in arterioles. The in vivo findings also imply that in in vitro studies no average shear stress value can be taken to study effects on endothelial cells derived from different vascular areas or from the same artery in different species. The cells have to be studied under the shear stress conditions they are exposed to in real life

Dimensions of compartments and membrane surfaces in the intact rabbit heart of importance in studies on intramyocardial transfer of blood-borne substances

Cardiac studies on the uptake, storage and intramyocardial transfer of blood-borne substances require detailed information on the geometric ultrastructural dimensions of myocardial compartments and parts thereof, and the membranes separating these compartments. Such a specific ultrastructural set of data of the heart is yet lacking. In the present study, we quantitatively assessed these dimensions in glutaraldehyde-perfusion fixed rabbit hearts by means of histological and tailored mathematical techniques. We showed the true ellipsoid nature of the myocardial capillary cross section and estimated the mean capillary diameter dcap. After correction for the ellipsoid shape, dcap was found to be 5.21±1.41 μm. Effective widths of the endothelial cell and the pericapillary interstitium (is1), dimensions of importance in diffusion, amounted to 187±7 and 160±10 nm, respectively. The fractional volume of the large vessels (arteries and veins larger than 10 µm), capillaries, endothelium, is1, cardiomyocytes, non-pericapillary interstitium is2, t-tubular compartment and interstitial cells amounted on average to 5.92%, 9.36%, 1.83%, 1.94%, 73.07%, 5.97%, 0.95% and 0.96%, respectively, of total myocardial volume, defined as the cardiac tissue volume, the large blood vessels included. Normalized to total myocardial volume, the surface area of the luminal and abluminal endothelial membranes and of the cardiomyocyte membrane opposing the endothelial cells amounted to 75.2±5.5x103, 82.2±6.0x103 and 89.1±6.5x103 m2/m3, respectively. The present study provides quantitative information about ultrastructural dimensions of the adult rabbit heart, among others, of importance for studies on cardiac uptake, and intramyocardial transfer and storage of blood-supplied substances

Intra-cardiac transfer of fatty acids from capillary to cardiomyocyte

Blood-borne fatty acids (Fa) are important substrates for energy conversion in the mammalian heart. After release from plasma albumin, Fa traverse the endothelium and the interstitial compartment to cross the sarcolemma prior to oxidation in the cardiomyocytal mitochondria. The aims of the present study were to elucidate the site with lowest Fa permeability (i.e., highest Fa resistance) in the overall Fa trajectory from capillary to cardiomyocyte and the relative contribution of unbound Fa (detach pathway, characterized by the dissociation time constant τ(AlbFa)) and albumin-bound Fa (contact pathway, characterized by the membrane reaction rate parameter d(Alb)) in delivering Fa to the cellular membranes. In this study, an extensive set of 34 multiple indicator dilution experiments with radiolabeled albumin and palmitate on isolated rabbit hearts was analysed by means of a previously developed mathematical model of Fa transfer dynamics. In these experiments, the ratio of the concentration of palmitate to albumin was set at 0.91. The analysis shows that total cardiac Fa permeability, P(tot), is indeed related to the albumin concentration in the extracellular compartment as predicted by the mathematical model. The analysis also reveals that the lowest permeability may reside in the boundary zones containing albumin in the microvascular and interstitial compartment. However, the permeability of the endothelial cytoplasm, P(ec,) may influence overall Fa permeability, P(tot), as well. The model analysis predicts that the most likely value of τ(AlbFa) ranges from about 200 to 400 ms. In case τ(AlbFa) is fast, i.e., about 200 ms, the extracellular contact pathway appears to be of minor importance in delivering Fa to the cell membrane. If Fa dissociation from albumin is slower, e.g. τ(AlbFa) equals 400 ms, the contribution of the contact pathway may vary from minimal (d(Alb)≤5 nm) to substantial (d(Alb) about 100 nm). In the latter case, the permeability of the endothelial cytoplasm varies from infinite (no hindrance) to low (substantial hindrance) to keep the overall Fa flux at a fixed level. Definitive estimation of the impact of endothelial permeability on P(tot) and the precise contribution of the contact pathway to overall transfer of Fa in boundary zones containing albumin requires adequate physicochemical experimentation to delineate the true value of, among others, τ(AlbFa), under physiologically relevant circumstances. Our analysis also implies that concentration differences of unbound Fa are the driving force of intra-cardiac Fa transfer; an active, energy requiring transport mechanism is not necessarily involved. Membrane-associated proteins may facilitate Fa transfer in the boundary zones containing albumin by modulating the membrane reaction rate parameter, d(Alb), and, hence, the contribution of the contact pathway to intra-cardiac Fa transfer