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Am J Physiol Heart Circ Physiol 298: H158-H162, 2010. First published October 23, 2009; doi: 10.1152/ajpheart.00654.2009.--In the failing myocardium a subendocardial plexus can develop. Detection of the presence or function, however, of such a plexus does not form part of the present diagnostic spectrum for heart failure. This may now change as new methods for high-resolution imaging of myocardial perfusion distribution are being developed. A severely hypertrophic heart was harvested during transplantation and analyzed for morphology of the intramural coronary arterial vasculature. The heart only had one coronary ostium, and the main branches of the coronary artery were cannulated. A fluorescent casting material was infused that was allowed to harden under physiological pressure. The entire heart was frozen and placed in a novel imaging cryomicrotome and sequentially cut in 25-[micro]m slices. High-resolution images of each cutting plane were acquired, allowing a detailed three-dimensional reconstruction of the arterial vasculature. The epicardial layer of the free wall demonstrated a normal vasculature with penetrating branching arteries. The endocardial layer and the septum revealed a highly interconnected vascular plexus with large vessels oriented parallel to the apicobasal axis. An extensive endocardial network with collaterals was detected, forming connections between the main epicardial branches. We conclude that an outward remodeling of transmural vessels did not prevent the generation and growth of subendocardial conduit arteries. The orientation and vascular volume in the plexus provides an opportunity for detection by novel techniques of MRI contrast imaging currently developed. Knowledge of the effect on perfusion studies is required to prevent a misinterpretation of subendocardial perfusion images in heart failure. imaging cryomicrotome; collateral; vascular plexus; hypertrophy

The effect of [[alpha].sub.1]-receptor blockade with urapidil on coronary blood flow and left ventricular function has been attributed to relief of diffuse coronary vasoconstriction following percutaneous coronary intervention (PCI). We hypothesized that an increase in diastolic time fraction (DTF) contributes to the beneficial action of urapidil. In eleven patients with a 63% (SD 13) diameter stenosis, ECG, aortic pressure ([P.sub.a]) and distal intracoronary pressure ([P.sub.d], and blood flow velocity were recorded at baseline and throughout adenosine-induced hyperemia. Measurements were obtained before and after PCI and after subsequent [[alpha].sub.1]-receptor blockade with urapidil (10 mg ic). DTF was determined from the ECG and the [P.sub.a] waveform. Functional parameters such as coronary flow velocity reserve, fractional flow reserve, and an index of hyperemic microvascular resistance (HMR) were assessed. Urapidil administration after PCI induced an upward shift in the DTF-heart rate relationship, resulting in a 3.1% (SD 2.7) increase in hyperemic DTF at a constant heart rate (P < 0.005) due to a shorter duration of systole. Hyperemic [P.sub.a] and [P.sub.d] decreased, respectively, by 6.1% (SD 6.6; P < 0.05) and 5.7% (SD 5.8; P < 0.01) after [[alpha].sub.1]-blockade. Although epicardially measured functional parameters were on average not altered by [[alpha].sub.1]-blockade due to concurrent changes in pressure and heart rate, HMR decreased by urapidil in those patients where coronary pressure remained constant. In conclusion, [[alpha].sub.1]-receptor blockade after PCI produced a modest but significant prolongation of DTF at a given heart rate, thereby providing an adjunctive beneficial mechanism for improving subendocardial perfusion, which critically depends on DTF. coronary circulation; angioplasty; microcirculation; diastole; [alpha]-adrenergic receptors

A novel single-point technique to calculate local arterial wave speed (SPc) has recently been presented and applied in healthy human coronary arteries at baseline flow. We investigated its applicability for conditions commonly encountered in the catheterization laboratory. Intracoronary pressure (Pa) and Doppler velocity (U) were recorded in 29 patients at rest and during adenosine-induced hyperemia in a distal segment of a normal reference vessel and downstream of a single stenosis before and after revascularization. Conduit vessel tone was minimized with nitroglycerin. Microvascular resistance (MR) and SPc were calculated from Pd and U. In the reference vessel, SPc decreased from 21.5 m/s (SD 8.0) to 10.5 m/s (SD 4.1) after microvascular dilation (P < 0.0001). SPc was substantially higher in the presence of a proximal stenosis and decreased from 34.4 m/s (SD 18.2) at rest to 27.5 m/s (SD 13.4) during hyperemia (P < 0.0001), with a concomitant reduction in Pa by 20 mmHg and MR by 55.4%. The stent placement further reduced hyperemic MR by 26% and increased [P.sub.d] by 26 mmHg but paradoxically decreased SPc to 13.1 m/s (SD 7.7) (P < 0.0001). Changes in SPc correlated strongly with changes in MR (P < 0.001) but were inversely related to changes in Pd (P < 0.01). In conclusion, the single-point method yielded erroneous predictions of changes in coronary wave speed induced by a proximal stenosis and distal vasodilation and is therefore not appropriate for estimating local wave speed in coronary vessels. Our findings are well described by a lumped reservoir model reflecting the 'windkesselness' of the coronary arteries. coronary hemodynamics; pulse wave velocity; microvascular resistance; intramyocardial pump; stenosis

The aim of this study was to assess the influence of a second guidewire on the diagnostic accuracy of functional parameters of coronary lesion severity. Sixty-five patients with intermediate coronary lesions underwent myocardial perfusion scintigraphy. Fractional flow reserve (FFR), coronary flow velocity reserve (CFVR), and hyperemic stenosis resistance (HSR) index (HSR = stenosis pressure gradient / velocity) were determined in 77 lesions. Distal pressure and velocity were acquired simultaneously (dual wire) and sequentially (single wire) with two sensor-equipped guidewires. Overall, functional parameters deteriorated from single-to dual-wire assessment. In patients without ischemia, the good diagnostic performance of FFR, CFVR, and HSR deteriorated significantly (P < 0.001) when assessed by dual wires, with an increase in the number of false-positive results. This trend was more pronounced for HSR, since the presence of a second wire reduced maximal velocity and increased the pressure gradient. The presence of two guidewires, especially across a myocardial perfusion scintigraphy-induced nonsignificant lesion, is associated with overestimation of the hemodynamically assessed lesion severity and, therefore, is likely to have a major impact on clinical decision making. This underscores the advantage of a dual-sensor-equipped guidewire for the evaluation of stenosis severity by combined pressure and velocity measurements. hemodynamics; microcirculation; pressure; coronary disease; stenosis doi:10.1152/ajpheart.01042.2006

We investigated the quantitative contribution of all local conduit arterial, blood, and distal load properties to the pressure transfer function from brachial artery to aorta. The model was based on anatomical data, Young's modulus, wall viscosity, blood viscosity, and blood density. A three-element wind-kessel represented the distal arterial tree. Sensitivity analysis was performed in terms of frequency and magnitude of the peak of the transfer function and in terms of systolic, diastolic, and pulse pressure in the aorta. The root mean square error (RMSE) described the accuracy in wave-shape prediction. The percent change of these variables for a 25% alteration of each of the model parameters was calculated. Vessel length and diameter are found to be the most important parameters determining pressure transfer. Systolic and diastolic pressure changed blood pressure; transfer function; personalization; brachial artery; aorta

The capacity for myocardial perfusion depends on the structure of the coronary microvascular bed. Coronary microvessels may adapt their structure to various stimuli. We tested whether the local pressure profile affects tone and remodeling of porcine coronary microvessels. Subendocardial vessels (~160 [micro]m, n = 53) were cannulated and kept in organoid culture for 3 days under different transvascular pressure profiles: Osc 80: mean 80 mmHg, 60 mmHg peak-peak sine wave pulsation amplitude at 1.5 Hz; St 80: steady 80 mmHg; Osc 40: mean 40 mmHg, 30 mmHg amplitude; St 40: steady 40 mmHg. Under the Osc 80 profile, modest tone developed, reducing the diameter to 81 [+ or -] 14% (mean [+ or -] SE, n = 6) of the maximal, passive diameter. No inward remodeling was found here, as determined from the passive pressure-diameter relation after 3 days of culture. Under all other profiles, much more tone developed (e.g., Osc 40: to 26 [+ or -] 3%, n = 7). In addition, these vessels showed eutrophic (i.e., without a change in wall cross-sectional area) inward remodeling (e.g., Osc 40: passive diameter reduction by 24 [+ or -] 3%). The calcium blocker amlodipine induced maintained dilation in St 40 vessels and reversed the 22 [+ or -] 3% (n = 6) inward remodeling to 15 [+ or -] 3% (n = 8) outward remodeling toward day 3. Vessels required a functional endothelium to maintain structural integrity in culture. Our data indicate that reduction of either mean pressure or pulse pressure leads to microvascular constriction followed by inward remodeling. These effects could be reversed by amlodipine. Although microvascular pressure profiles distal to stenoses are poorly defined, these data suggest that vasodilator therapy could improve subendocardial microvascular function and structure in coronary artery disease. coronary circulation; microcirculation; vascular remodeling; amlodipine doi:10.1152/ajpheart.00711.2005

It was hypothesized that endothelial glycocalyx perturbation contributes to increased vulnerability of the arterial wall exposed to atherogenic risk factors. Glycocalyx and intima-to-media ratios (IMR) were studied at a low- and a high-risk region within the murine carotid artery (common region) and internal carotid branch (sinus region) in control C57BL/6J (C57BL6) and age-matched C57BL/6J/apoE*3-Leiden (apoE*3; on an atherogenic diet) mice. Electron micrographs revealed significantly thinner glycocalyces [73 (SD 36) vs. 399 (SD 174) nm, P < 0.05] and greater IMR [0.096 (SD 0.045) vs. 0.044 (SD 0.023), P < 0.05] at the sinus region of C57BL6 mice than in the common region. Thinner glycocalyces [100 (SD 27) vs. 399 (SD 174) nm, P < 0.05] and greater IMR [0.071 (SD 0.024) vs. 0.044 (SD 0.023), P < 0.05] were also observed in the common region of age-matched apoE*3 mice on an atherogenic diet for 6 wk vs. C57BL6 mice on a normal diet. Greater IMR were due to greater intima layers, without significant changes in media layer dimension. In addition, atherogenic diet resulted in increased endothelial cell thickness at the sinus region [0.85 (SD 0.49) vs. 0.53 (SD 0.28) [micro]m, P < 0.05] but not at the common region [0.66 (SD 0.37) vs. 0.62 (SD 0.32) [micro]m]. It is concluded that both regional and diet-induced increases in atherogenic risk are associated with smaller glycocalyx dimensions and greater IMR and that vascular sites with diminished glycocalyx are more vulnerable to proinflammatory and atherosclerotic sequelae. flow; permeability

Vascular endothelial cells are shielded from direct exposure to flowing blood by the endothelial glycocalyx, a highly hydrated mesh of glycoproteins, sulfated proteoglycans, and associated glycosaminoglycans (GAGs). Recent data indicate that the incorporation of the unsulfated GAG hyaluronan into the endothelial glycocalyx is essential to maintain its permeability barrier properties, and we hypothesized that fluid shear stress is an important stimulus for endothelial hyaluronan synthesis. To evaluate the effect of shear stress on glycocalyx synthesis and the shedding of its GAGs into the supernatant, cultured human umbilical vein endothelial ceils (i.e., the stable cell line EC-RF24) were exposed to 10 dyn/[cm.sup.2] nonpulsatile shear stress for 24 h, and the incorporation of [[sup.3]H]glucosamine and [Na.sub.2][[sup.35]S][O.sub.4] into GAGs was determined. Furthermore, the amount of hyaluronan in the glycocalyx and in the supernatant was determined by ELISA. Shear stress did not affect the incorporation of [sup.35]S but significantly increased the amount of glucosamine-containing GAGs incorporated in the endothelial glycocalyx [168 (SD 17)% of static levels, P < 0.01] and shedded into the supernatant [231 (SD 41)% of static levels, P < 0.01]. Correspondingly with this finding, shear stress increased the amount of hyaluronan in the glycocalyx [from 26 (SD 24) x [l0.sup.-4] to 46 (SD 29) x [10.sup.-4] ng/cell, static vs. shear stress, P < 0.05] and in the supernatant [from 28 (SD 11) x [10.sup.-4] to 55 (SD 16) x [10.sup.-4] ng x [cell.sup.1] x [h.sup.-1], static vs. shear stress, P < 0.05]. The increase in the amount of hyaluronan incorporated in the glycocalyx was confirmed by a threefold higher level of hyaluronan binding protein within the glycocalyx of shear stress-stimulated endothelial cells. In conclusion, fluid shear stress stimulates incorporation of hyaluronan in the glycocalyx, which may contribute to its vasculoprotective effects against proinflammatory and pro-atherosclerotic stimuli. endothelial surface layer; endothelium

The mechanisms of flow-induced vascular remodeling are poorly understood, especially in the coronary microcirculation. We hypothesized that application of flow in small coronary arteries in organoid culture would cause a nitric oxide (NO)-mediated dilation and inhibit inward remodeling. We developed an organoid culture setup to drive a flow through cannulated arterioles at constant luminal pressure via a pressure gradient between the pipettes. Subepicardial porcine coronary arterioles with diameter at full dilation and 60 mmHg ([D.sub.0]) of 168 [+ or -] 10 (SE) [micro]m were cannulated. Vessels treated with [N.sup.[omega]]-nitro-l-arginine (L-NNA) to block NO production and untreated vessels were pressurized at 60 mmHg for 3 days with and without flow. Endothelium-dependent dilation to [10.sup.-7] M bradykinin was preserved in all groups. Tone was significantly less in vessels cultured under flow conditions in the last half of the culture period. Untreated and l-NNA-treated vessels regulated their diameter to yield shear stresses of 10.3 [+ or -] 2.1 and 14.0 [+ or -] 2.4 (SE) dyn/[cm.sup.2], respectively (not significantly different). Without l-NNA, passive pressure-diameter curves at the end of the culture period revealed inward remodeling in the control group [to 92.3 [+ or -] 1.3% of [D.sub.0] (SE)] and no remodeling in the vessels cultured under flow conditions (100.2 [+ or -] 1.3% of [D.sub.0]); with l-NNA, the group subjected to flow showed inward remodeling (92.1 [+ or -] 2.5% of [D.sub.0]). We conclude that pressurized coronary resistance arteries could be maintained in culture for several days with flow. Vessels cultured under flow conditions remained more dilated when NO synthesis was blocked. Inward remodeling occurred in vessels cultured under no-flow conditions and was inhibited by flow-dependent NO synthesis. vascular remodeling; shear stress; nitric oxide

Because adenosine is commonly used for inducing maximal coronary hyperemia in the clinic, it is imperative that adenosine-induced hyperemia (AH) resembles coronary hyperemia that can be attained by endogenous stimuli. In the present study we hypothesized that coronary reactive hyperemia (RH) is limited compared with AH due to the presence of the glycocalyx and that the AH response is therefore unable to detect glycocalyx modifications. In anesthetized open-chest dogs, blood flow and pressure were measured in the left circumflex artery. RH after 15-s occlusion was compared with an intracoronary infusion of adenosine (650 [micro]g; AH) during control conditions and after intracoronary treatment of the glycocalyx with hyaluronidase (20.000 U, 2 X 20 min; n = 6) or heat-inactivated hyaluronidase (n = 5). During control, coronary conductance during RH was 1.49 [+ or -] 0.15 ml*mm[Hg.sup.-1]*. [min.sup.-1] and 76 [+ or -] 7% of coronary conductance during AH (P < 0.05). After hyaluronidase, RH conductance increased (P < 0.01) by 43 [+ or -] 13% and became 93 [+ or -] 4% of AH conductance (P = NS). Heatinactivated hyaluronidase had no effect on RH and AH conductance. Our results demonstrate that adenosine-induced coronary hyperemia profoundly exceeds RH and that the difference is virtually abolished on selective removal of the glycocalyx. It is concluded that, compared with RH, adenosine-induced coronary hyperemia is not affected by modification of the glycocalyx. This glycocalyx insensitivity should be taken into account when using adenosine-induced coronary hyperemia as a marker for vasodilating capacity to an ischemic stimulus. coronary circulation; hyaluronidase; dogs

We hypothesized that modulation of the effective charge density of the endothelial surface layer (ESL) results in altered arterial barrier properties to transport of anionic solutes. Rat mesenteric small arteries (diameter ~190 [micro]m) were isolated, cannulated, perfused, and superfused with MOPS-buffered physiological salt solutions. MOPS-solutions were of normal ionic strength (162 mM, MOPS), low ionic strength (81 mM, LO-MOPS), or high ionic strength (323 mM, HI-MOPS), to modulate ESL charge density (normal, high, or low ESL charge, respectively). Osmolarity of MOPS, LO-MOPS, and HI-MOPS was kept constant at 297 mosmol/1, using additional glucose when necessary. Perfusate solutions were supplemented with 1% BSA. Arteries were cannulated with a double-barreled theta-pipet on the inlet side and a regular pipet on the outlet side. After infusion of FITC-labeled dextran of 50 kDa (FITC-[DELTA]50) and the endothelial membrane dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, the dynamics of arterial dye tilting were determined with confocal microscopy. ESL thickness, as determined from the initial exclusion zone for FITC-[DELTA]50 on the luminal endothelial surface, was 6.3 [+ or -] 1.4 [micro]M for LO-MOPS, 2.7 [+ or -] 1.0 [micro]m for MOPS, and 1.1 [+ or -] 1.3 [micro]M for HI-MOPS. At low ionic strength, FITC-[DELTA]50 permeated into the ESL with a total ESL permeation time ([[tau].sub.ESL]) of 26 min, and at normal ionic strength with a [[tau].sub.ESL] of 20 min. No apparent exclusion of FITC-[DELTA]50 from the ESL could be observed at high ionic strength. In conclusion, we demonstrate that the modulation of solvent ionic strength influences the thickness and barrier properties of the ESL. vascular permeability; isolated artery; ionic strength; glycocalyx

Hypercholesterolemia and atherosclerosis have been associated with changes in the microvasculature, in particular with endothelial dysfunction. In the present study, the impact of atherogenic conditions on arteriolar vasomotor control was determined. Arteriolar [second-order (2A) and third-order (3A) arterioles; diameter range: 9-37 [micro] m] responses during reactive hyperemia (RH) were determined in cremaster muscle of anesthetized mice. C57B1/6 mice on normal rodent chow were used as controls and high-fat/high-cholesterol (HFC)-fed C57B1/6 and ApoE3-Leiden mice as hypercholesterolemic mice. The HFC diet resulted in time-dependent increases in plasma cholesterol and triglyceride concentrations (P < 0.001), which were more pronounced in ApoE3-Leiden mice (P < 0.001). In control mice, inhibition of nitric oxide (NO) synthesis with N [omega] -nitro-L-arginine (LNNA) reduced baseline diameter from 17.9 [+ or-] 1.2 to 15.9 [+ or -] 1.3 [micro] m (P < 0.05) and decreased the duration of RH [time to 50% ([t.sub.50]) of recovery: 23.3 [+ or -] 3.6 vs. 12.5 [+ or -] 1.3 s (P = 0.003)]. [t.sub.50] was longer in 2A versus 3A arterioles (33 [+ or -] 3 vs. 18 [+ or -] 2 s, P < 0.001) and increased with wall shear rate at the beginning of RH in 2A arterioles only. Compared with control mice, RH duration was reduced in 2A arterioles of HFC mice ([t.sub.50]: 11 [+ or -] 2 s, P < 0.001 vs. control) but not affected in 3A vessels. L-NNA did not affect baseline diameter in HFC mice and reduced [t.sub.50] only in 'slow' responders ([t.sub.50] [greater than or equal to] 10 s). It is concluded that hypercholesterolemia results in an impairment of NO-mediated vasomotor control in 2A but not 3A arterioles during dynamic changes of perfusion like RH. 2A arterioles likely therefore represent the functional locus of endothelial dysfunction during atherogenic conditions. endothelial dysfunction; shear-dependent dilation; arteriolar heterogeneity; ApoE3-Leiden

Diastolic time fraction (DTF) has been recognized as an important determinant for subendocardial perfusion, but microsphere studies in which DTF was the independent variable are practically absent. In 21 anesthetized goats, the left coronary main stem was artificially perfused at controlled pressure. DTF was varied by pacing the heart, vagus stimulation, or administration of dobutamine. Regional coronary flow was measured with fluorescent microspheres under full adenosine dilation. Perfusion pressure ([P.sub.c]) was defined as mean coronary arterial pressure minus minimal left ventricular pressure. Regional flow conductances (flow/[P.sub.c]) were as follows: for the subendocardium, [C.sub.endo] = -0.103 + 0.197 DTF + 0.00074 [P.sub.c] (P < 0.001); for the midmyocardium, conductance = -0.048 + 0.126 DTF + 0.00049 [P.sub.c] (P < 0.001); and for the subepicardium. [C.sub.epi] was not significant. [C.sub.endo]-DTF relations demonstrated a finite value for DTF at which flow is zero, implying that, at physiological pressures, systolic subendocardial flow limitation extends into diastole. The DTF corresponding to an equal conductance in subendocardium and subepicardium (DT[F.sub.1]) was inversely related to [P.sub.c]: DT[F.sub.1] = 0.78 0.003 [P.sub.c] (P < 0.01). When heart rate and [P.sub.c] were held constant and dobutamine was administered (5 goats), contractility doubled and DTF increased by 39%, resulting in an increase of [C.sub.endo] of 40%. It is concluded that 1) DTF is a determinant of subendocardial perfusion, 2) systolic compression exerts a flow-limiting effect into diastole, and 3) corresponding to clinical findings on inducible ischemia we predict that, under hyperemic conditions, [C.sub.endo] < [C.sub.epi] if [P.sub.c] is lower than ~75% of a normal aortic pressure and heart rate >80 beats/min. systolic flow limitation; coronary reserve; steal; heart; microspheres; regional conductance

Remodeling of resistance arteries in organoid culture is modulated by pressure and pressure pulsation and depends on vasomotion. Am J Physiol Heart Circ Physiol 286: H2052-H2056, 2004. First published February 12, 2004; 10.1152/ajpheart.00978.2003.--The hypothesis was tested that pressure and pressure pulsation modulate vascular remodeling. Arterioles (~200 [micro]m lumen diameter) were dissected from rat cremaster muscle and studied in organoid culture. In the first series, arterioles were kept at a stable pressure level of either 50 or 100 mmHg for 3 days. Both groups showed a progressive increase in myogenic tone during the experiment. Arterioles kept at 50 mmHg showed larger endothelium-dependent dilation, compared with vessels kept at 100 mmHg on day 3. Remodeling, as indicated by the reduction in maximally dilated diameter at 100 mmHg, was larger in arterioles kept at 50 mmHg compared with 100 mmHg: 34 [+ or -] 4.5 versus 10 [+ or -] 4.8 [micro]m (P < 0.05). In the second series, arterioles were subjected to a stable pressure of 60 mmHg or oscillating pressure of 60 [+ or -] 10 mmHg (1.5 Hz) for 4 days. Pressure pulsation induced partial dilation and was associated with less remodeling: 34 [+ or -] 4.0 versus 19 [+ or -] 4.5 [micro]m (P < 0.01) for stable pressure versus oscillating pressure. Vasomotion was frequently observed in all groups, and inward remodeling was larger in vessels with vasomotion: 30 [+ or -] 2.5 [micro]m compared with vessels that did not exhibit vasomotion: 8.0 [+ or -] 5.0 [micro]m (P < 0.01). In conclusion, these results indicate that remodeling is not enhanced by high pressure. Pressure pulsation causes partial dilation and reduces inward remodeling. The appearance of vasomotion is associated with enhanced inward remodeling. myogenic regulation; vascular adaptation; hypertension

Endothelial cells are covered by a surface layer of membrane-associated proteoglycans, glycosaminoglycans, glycoproteins, glycolipids, and associated plasma proteins. This layer may limit transendothelial solute transport. We determined dimension and transport properties of this endothelial surface layer (ESL) in isolated arteries. Rat mesenteric small arteries (diameter ~150 [micro]m) were isolated and cannulated with a double-barreled [theta]-pipette on the inlet side and a regular pipette on the outlet side. Dynamics and localization of intra-arterial fluorescence by FITC-labeled dextrans (FITC-[DELTA]s) and the endothelial membrane dye DiI were determined with confocal microscopy. Large FITC-[DELTA] (148 kDa) filled a core volume inside the arteries within 1 min but was excluded from a 2.6 [+ or -] 0.5-[micro]m-wide region on the luminal side of the endothelium during 30 min of dye perfusion. Medium FITC-[DELTA] (50.7 kDa) slowly penetrated this ESL within 30 min but did not permeate into the arterial wall. Small FITC-[DELTA] (4.4 kDa) quickly passed the ESL and accumulated in the arterial wall. Prolonged luminal fluorochrome illumination with a bright mercury lamp destroyed the ~3-[micro]m exclusion zone for FITC-[DELTA]148 within a few minutes. This study demonstrates the presence of a thick ESL that contributes to the permeability barrier to solutes. The layer is sensitive to phototoxic stress, and its damage could form an early event in atherosclerosis. vascular permeability; isolated artery; endothelial surface layer; confocal microscopy; glycocalyx

Chamuleau, Steven A. J., Maria Siebes, Martijn Meuwissen, Karel T. Koch, Jos A. E. Spaan, and Jan J. Piek. Association between coronary lesion severity and distal microvascular resistance in patients with coronary artery disease. Am J Physiol Heart Circ Physiol 285: H2194-H2200, 2003. First published June 26, 2003; 10.1152/ajpheart.01021.2002.-Homogeneity of microvascular resistance in different perfusion areas of the same heart is generally assumed. We investigated the effect of the severity of an epicardial stenosis on microvascular resistance in 27 patients with coronary artery disease and stable angina. All patients had an angiographically normal coronary, artery, an artery with an intermediate lesion, and an artery with a severe lesion; the latter was treated with angioplasty. In each patient, distal blood flow velocity and pressure were measured during baseline and maximal hyperemia (induced by intracoronary adenosine) using a Doppler and pressure guide wire, respectively. The ratio of mean distal pressure to average peak blood flow velocity was used as an index for the microvascular resistance (MR[nu]). Within patients, the hyperemic MR[nu] was higher in arteries with more severe stenosis (P = 0.021). After percutaneous transluminal coronary angioplasty (PTCA), the hyperemic MR[nu] decreased (pre-PTCA, 2.6 vs. postPTCA, 1.9 mmHg * [cm.sup.-1][s.sup.-1], P < 0.01) toward the value of the reference artery (1.7 mmHg * [cm.sup.-1][s.sup.-1]; P = 0.67). We conclude that there is a positive association between coronary lesion severity and variability of distal microvascular resistance that normalizes after angioplasty. This study challenges the concept of uniform distribution of hyperemic MR[nu] that is relevant for the interpretation of both noninvasive and invasive diagnostic tests. microcirculation; coronary disease; physiology; blood flow; blood pressure

VanBavel, Ed, Pier Siersma, and Jos A.E. Spaan. Elasticity of passive blood vessels: a new concept. Am J Physiol Heart Circ Physiol 285: H1986-H2000, 2003. First published July 3, 2003; 10.1152/ajpheart.00248.2003.--The mechanical properties of passive blood vessels are generally thought to depend on the parallel arrangement of elastin and collagen with linear elasticity and collagen recruitment depending on vessel strain [hook-on (HO) model]. We evaluated an alternative model [serial element (SE) model] consisting of the series arrangement of an infinite number of elements, each containing elastin with a constant elastic modulus and collagen that switches stepwise from slack (zero stress) to fully rigid (infinite stiffness) on ongoing element strain. Both models were implemented with Weibull distributions for collagen recruitment strain (HO model) and collagen tightening strain (SE model). The models were tested in experiments on rat mesenteric small arteries. Strain-tension relations were obtained before and after two rounds of digestion by collagenase. Both models fitted the data prior to digestion. However, for the HO model, this required unrealistically low estimates for collagen recruitment or elastic modulus and unrealistically high estimates for distension of collagen fibers. Furthermore, the data after digestion were far better predicted by the SE model compared with the HO model. Finally, the SE model required one parameter less (collagen elastic modulus). Therefore, the SE model provides a valuable starting point for the understanding of vascular mechanics and remodeling of vessels. biomechanics; vascular remodeling; collagen; elastin

Endothelium-derived nitric oxide (NO) is synthesized in response to chemical and physical stimuli. Here, we investigated a possible role of the endothelial cell glycocalyx as a biomechanical sensor that triggers endothelial NO production by transmitting flow-related shear forces to the endothelial membrane. Isolated canine femoral arteries were perfused with a Krebs-Henseleit solution at a wide range of perfusion rates with and without pretreatment with hyaluronidase to degrade hyaluronic acid glycosaminoglycans within the glycocalyx layer. NO production rate was evaluated as the product of nitrite concentration in the perfusate and steady-state perfusion rate. The slope that correlates the linear relation between perfusion rate and NO production rate was taken as a measure for flow-induced NO production. Hyaluronidase treatment significantly decreased flow-induced NO production to 19 [+ or -] 9% of control (mean [+ or -] SD; P < 0.0001 vs. control; n = 11), whereas it did not affect acetylcholine-induced NO production (88 [+ or -] 17% of pretreatment level, P = not significant; n = 10). We conclude that hyaluronic acid glycosaminoglycans within the glycocalyx play a pivotal role in detecting and amplifying the shear force of flowing blood that triggers endothelium-derived NO production in isolated canine femoral arteries. glycocalyx; canine femoral artery; hyaluronidase; nitrite; shear stress

Pressure-based fractional flow reserve (FFR) is used clinically to evaluate the functional severity of a coronary stenosis, by predicting relative maximal coronary flow ([Q.sub.s]/[Q.sub.n]). It is considered to be independent of hemodynamic conditions, which seems unlikely because stenosis resistance is flow dependent. Using a resistive model of an epicardial stenosis (0-80% diameter reduction) in series with the coronary microcirculation at maximal vasodilation, we evaluated FFR for changes in coronary microvascular resistance ([R.sub.cor] = 0.2-0.6 mmHg*[ml.sup.-1]*min), aortic pressure ([P.sub.a] = 70-130 mmHg), and coronary outflow pressure ([P.sub.b] = 0-15 mmHg). For a given stenosis, FFR increased with decreasing [P.sub.a] or increasing [R.sub.cor]. The sensitivity of FFR to these hemodynamic changes was highest for stenoses of intermediate severity. For [P.sub.b] > 0, FFR progressively exceeded [Q.sub.s/[Q.sub.n] with increasing stenosis severity unless [P.sub.b] was included in the calculation of FFR. Although the [P.sub.b]-corrected FFR equaled [Q.sub.s]/[Q.sub.n] for a given stenosis, both parameters remained equally dependent on hemodynamic conditions, through their direct relationship to both stenosis and coronary resistance. coronary artery stenosis; coronary circulation; coronary stenosis evaluation; coronary flow reserve

Myogenic response, flow-dependent dilation, and direct metabolic control are important mechanisms controlling coronary flow. A model was developed to study how these control mechanisms interact at different locations in the arteriolar tree and to evaluate their contribution to autoregulatory and metabolic flow control. The model consists of 10 resistance compartments in series, each representing parallel vessel units, with their diameters determined by tone depending on either flow and pressure [flow-dependent tone reduction factor (TR[F.sub.flow]) x [Tone.sub.myo]] or directly on metabolic factors ([Tone.sub.meta]). The pressure-[Tone.sub.myo] and flow-TR[F.sub.flow] relations depend on the vessel size obtained from interpolation of data on isolated vessels. Flow-dependent dilation diminishes autoregulatory properties compared with pressure-flow lines obtained from vessels solely influenced by [Tone.sub.myo]. By applying [Tone.sub.meta] to the four distal compartments, the autoregulatory properties are restored and tone is equally distributed over the compartments. Also, metabolic control and blockage of nitric oxide are simulated. We conclude that a balance is required between the flow-dependent properties upstream and the constrictive metabolic properties downstream. Myogenic response contributes significantly to flow regulation. myogenic response; flow-dependent dilation; metabolic control; autoregulation; mathematical model

Pulsation-induced dilation of subendocardial and subepicardial arterioles: effect on vasodilator sensitivity. Am J Physiol Heart Circ Physiol 282: H311-H319, 2002.--Coronary vessels are squeezed by the surrounding myocardium during systole, impeding blood flow specifically in the subendocardium. To study the myocardial compression effect, we applied pulsatile transvascular pressure to isolated, cannulated subendocardial (Endo) and subepicardial (Epi) resistance arteries. Pressure pulsation at 0.5 to 2.5 Hz between 20 and 100 mmHg induced dilation of preconstricted vessels that was somewhat larger in Epi arterioles. In four Epi and five Endo arterioles loaded with fura 2, pulsation led to a small increase in intracellular calcium. Pulsation induced a significant decrease in I[C.sub.50] for bradykinin (BK) (5.9 [+ or -] 0.6 vs. 27.3 [+ or -] 3.2 nM in Epi vessels and 7.6 [+ or -] 0.3 vs. 302 [+ or -] 9 nM in Endo vessels), compared with steady pressure. The adenosine (Ado) sensitivity was not significantly affected (2.21 [+ or -] 0.08 vs. 3.76 [+ or -] 0.4 [micro]M) in Epi arteries but was enhanced during pulsations in Endo vessels (3.1 [+ or -] 0.3 vs. 10.1 [+ or -] 0.6 [micro]M). When pulsation-induced dilation was compensated by a higher concentration of the preconstrictor (U-46619), a significantly larger dilation to BK or Ado was found during pulsations. In conclusion, pulsation-induced dilation occurs at physiologically relevant frequencies and amplitudes in Endo vessels. The process does not involve intracellular calcium reduction and increases vasodilator sensitivity. coronary artery; pulsatile pressure; intracellular calcium

Cornelissen, Annemiek J. M., Jos A. E. Spaan, Jenny Dankelman, Charles C. Chan, and Frank C. P. Yin. Evidence for stretch-induced resistance increase of proximal coronary microcirculation. Am J Physiol Heart Circ Physiol 281: H2687-H2696, 2001.--We investigated the influence of stretch on regional hemodynamic parameters of the septal circulation. We used a similar experimental setup and mathematical model, as described previously (14). Five ventricular septa were isolated from anesthetized dogs, sutured to a biaxial stretching apparatus, and perfused with an, oxygenated perfluorochemical emulsion at maximal vasodilation. Under unloaded and biaxially stretched conditions, flow and septal thickness (to index vascular volume) were measured continuously. Pressure was varied sinusoidally at 30, 50, and 70 mmHg with amplitude of 7.5 mmHg over frequencies ranging between 0.015 and 7 Hz. Admittance (flow/pressure) and capacitance (thickness/pressure) transfer functions were calculated and interpreted in terms of a two-compartmental model with volume-dependent resistances. Parameter estimation showed that the proximal resistance and compliance were unaffected, whereas the resistance of the proximal part of the microcirculation, including the small arterioles, increased with stretch. The effect of stretch on the distal resistance and capacitance, however, could not be determined unequivocally. coronary resistance distribution; admittance; intramyocardial compliance; model; pressure-dependent resistance Received 21 July 2000; accepted in final form 20 August 2001

Research was conducted to examine the relationship between contractility and the derivative of left ventricular pressure (PLV) on epicardial lymph pressure generation. A left thoracotomy was carried out in the fifth intercostal space while the heart was exposed and suspended in a pericardial cradle. Results indicated that the transmission of PLV to the cardiac lymphatic vasculature is influenced by the impairment of regional contraction.

Open-chest anesthetized dogs were analyzed to determine the effects of altered fluid balance and increased fluid filtration on the rate of interstitial volume change. Analysis of open-chest anesthetized dogs after histamine infusion indicated the presence of increased systolic and diastolic peak in stopped-flow epicardial lymph pressure. Furthermore, the effects of histamine on lymph pressure were mediated by interstitial and lymph filling indicating the role of cardiac contraction in preventing myocardial edema.