Chronic hyperglycemia underlies microvascular complications in patients with type 1 diabetes. The mechanisms leading to these vascular complications are not fully understood. Recently, we observed that acute hyperglycemia results in endothelial glycocalyx damage. To establish whether glycocalyx is associated with microvascular damage, we performed glycocalyx perturbation volume measurements in type 1 diabetic patients with microalbuminuria (DM1-MA group; n ‫؍‬ 7), without microalbuminuria (DM1-NA group; n ‫؍‬ 7), and in age-matched control subjects (CON; n ‫؍‬ 7). Systemic glycocalyx volume was determined comparing intravascular distribution volume of a glycocalyxpermeable tracer (dextran 40) to that of a glycocalyximpermeable tracer (labeled erythrocytes). Sublingual capillaries were visualized using orthogonal polarization spectral microscopy to estimate microvascular glycocalyx. Patients and control subjects were matched according to age and BMI. Glycocalyx volume decreased in a stepwise fashion from CON, DM1-NA, and finally DM1-MA subjects (1.5 ؎ 0.1, 0.8 ؎ 0.4, and 0.2 ؎ 0.1 l, respectively, P < 0.05). Microvascular glycocalyx in sublingual capillaries was also decreased in type 1 diabetes versus the control group (0.5 ؎ 0.1 vs. 0.9 ؎ 0.1 m, P < 0.05). Plasma hyaluronan, a principal glycocalyx constituent, and hyaluronidase were increased in type 1 diabetes. In conclusion, type 1 diabetic patients are characterized by endothelial glycocalyx damage, the severity of which is increased in presence of microalbuminuria.

Myocardial tissue edema attributable to increased microvascular fluid loss contributes to cardiac dysfunction after myocardial ischemia, cardiopulmonary bypass, hypertension, and sepsis. Recent studies suggest that carbohydrate structures on the luminal surface of microvascular endothelium are essential to prevent tissue edema. We carefully preserved these structures for visualization with electron microscopy, revealing that the rat myocardial capillary endothelial surface is coated with a 0.2-to 0.5-m-thick carbohydrate layer and that its degradation instantly results in notable myocardial tissue edema.

Objective-A thick endothelial glycocalyx provides the endothelial surface with a nonadherent shield. Oxidized LDL (Ox-LDL) degrades the endothelial glycocalyx. We hypothesized that glycocalyx degradation stimulates leukocyteendothelial cell adhesion, whereas intravascular supplementation with sulfated polysaccharides reconstitutes the endothelial glycocalyx and attenuates Ox-LDL-induced leukocyte-endothelial cell adhesion. Methods and Results-Degradation of the endothelial glycocalyx by local microinjection of heparitinase (10 to 50 U/mL) into mouse cremaster venules dose-dependently increased the number of adherent leukocytes. Systemic administration of Ox-LDL (0.4 mg/100 g body weight) induced 10.1Ϯ0.9 adherent leukocytes/100 m at 60 minutes. In the venules perfused with 500-kDa dextran sulfate (1 mg/mL), the number of adherent leukocytes at 60 minutes after Ox-LDL bolus application was not influenced (9.2Ϯ1.0 leukocytes/100 m). However, the venules locally perfused with heparan sulfate (10 mg/mL) or heparin (1 mg/mL) displayed a significantly lower number of adherent leukocytes induced by Ox-LDL: 5.1Ϯ0.7 and 5.4Ϯ0.9 leukocytes/100 m, respectively (PϽ0.05). Fluorescently labeled heparan sulfate and heparin, but not dextran sulfate, attached to the venule luminal surface after Ox-LDL administration. Key Words: glycocalyx Ⅲ leukocytes Ⅲ oxidized LDL Ⅲ heparin T he endothelial glycocalyx provides the endothelial surface with a negatively charged coating that contributes to the antiadhesive nature of the endothelial cell surface. 1,2 In the presence of inflammatory stimuli, the endothelial surface loses its nonadhesiveness because of the activation of adhesion molecules and becomes accessible to leukocytes. There is evidence that activation of adhesion molecules is associated with changes in the cell-surface glycocalyx. 2-4 Indeed, the glycocalyx occupies a large domain at the endothelial surface, 5,6 which most probably influences the adhesion process. In this investigation, we studied the effect of endothelial glycocalyx condition on leukocyte-endothelial cell adhesion. Conclusions-EndothelialUnderstanding the role of the endothelial glycocalyx in leukocyte-endothelial cell adhesion has direct relevance for atherosclerosis-related conditions, such as hypercholesterolemia and the plasma presence of oxidized lipoproteins, which are associated with increased leukocyte recruitment 7,8 and degradation of the endothelial glycocalyx. 9 -11 Noteworthy, early modifications of endothelial cells during diet-induced hypercholesterolemia are represented by a decreased thickness and anionic charge of the endothelial glycocalyx and by changes in its biochemical composition. 9,10 Degradation of the endothelial glycocalyx is also induced by oxidized LDL (Ox-LDL in clinically relevant doses and is associated with a parallel increase in endothelial surface adhesiveness. 11 The first aim of the present study was to induce a primary alteration of the thickness and charge of the endothelial glycocalyx by enzyme treatment and to inves...

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 +/- 9% of control (mean +/- SD; P < 0.0001 vs. control; n = 11), whereas it did not affect acetylcholine-induced NO production (88 +/- 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.

This comprehensive core laboratory analysis comparing iFR and Pd/Pa with FFR demonstrated an overall accuracy of ~80% for both nonhyperemic indices, which can be improved to ≥90% in a subset of lesions. Clinical outcome studies are required to determine whether the use of iFR or Pd/Pa might obviate the need for hyperemia in selected patients.

The blood vessels that run on the surface of the heart and through its muscle are compliant tubes that can be affected by the pressures external to them in at least two ways. If the pressure outside these vessels is higher than the pressure at their downstream ends, the vessels may collapse and become Starling resistors or vascular waterfalls. If this happens, the flow through these vessels depends on their resistance and the pressure drop from their inflow to the pressure around them and is independent of the actual downstream pressure. In the first part of this review, the physics of collapsible tubes is described, and the possible occurrences of vascular waterfalls in the body is evaluated. There is good evidence that waterfall behavior is seen in collateral coronary arteries and in extramural coronary veins, but the evidence that intramural coronary vessels act like vascular waterfalls is inconclusive. There is no doubt that in systole there are high tissue pressures around the intramyocardial vessels, particularly in the subendocardial muscle of the left ventricle. The exact nature and values of the forces that act at the surface of the small intramural vessels, however, are still not known. We are not certain whether radial (compressive) or circumferential and longitudinal (tensile) stresses are the major causes of vascular compression; the role of collagen struts in modifying the reaction of vessel walls to external pressures is unknown but possibly important; direct examination of small subepicardial vessels has failed to show vascular collapse. One of the arguments in favor of intramyocardial vascular waterfalls has been that during a long diastole the flow in the left coronary artery decreases and reaches zero when coronary arterial pressure is still high: it can be as much as 50 mmHg in the autoregulating left coronary arterial bed and approximately 15-20 mmHg even when the vessels have been maximally dilated. These high zero flow pressures, especially during maximal vasodilatation, have been regarded as indicating a high back pressure to flow that is due to waterfall behavior of vessels that are exposed to tissue pressures.(ABSTRACT TRUNCATED AT 400 WORDS)

Background-Discordance between fractional flow reserve (FFR) and coronary flow velocity reserve (CFVR) may reflect important coronary pathophysiology but usually remains unnoticed in clinical practice. We evaluated the physiological basis and clinical outcome associated with FFR/CFVR discordance. Methods and Results-We studied 157 intermediate coronary stenoses in 157 patients, evaluated by FFR and CFVR between April 1997 and September 2006 in which revascularization was deferred. Long-term follow-up was performed to document the occurrence of major adverse cardiac events: cardiac death, myocardial infarction, or target vessel revascularization. Discordance between FFR and CFVR occurred in 31% and 37% of stenoses at the 0.75, and 0.80 FFR cut-off value, respectively, and was characterized by microvascular resistances during basal and hyperemic conditions. Follow-up duration amounted to 11.7 years (Q1-Q3, 9.9-13.3 years). Compared with concordant normal results of FFR and CFVR, a normal FFR with an abnormal CFVR was associated with significantly increased major adverse cardiac events rate throughout 10 years of follow-up, regardless of the FFR cut-off applied. In contrast, an abnormal FFR with a normal CFVR was associated with equivalent clinical outcome compared with concordant normal results: ≤3 years when FFR <0.75 was depicted abnormal and throughout 10 years of follow-up when FFR ≤0.80 was depicted abnormal. Conclusions-Discordance of CFVR with FFR originates from the involvement of the coronary microvasculature. Importantly, the risk for major adverse cardiac events associated with FFR/CFVR discordance is mainly attributable to stenoses where CFVR is abnormal. This emphasizes the requirement of intracoronary flow assessment in addition to coronary pressure for optimal risk stratification in stable coronary artery disease. (Circ Cardiovasc Interv. 2014;7:301-311.)Key Words: coronary flow velocity reserve ◼ coronary microcirculation ◼ fractional flow reserve ◼ stable coronary artery disease

SUMMARYThe effect of cardiac contraction on coronary arterial flow has been described in terms of an intramyocardiaJ pump, which displaces blood backward and forward during systole and diastole, respectively. Normally, the mean forward flow exceeds, and consequently conceals, this backflow. The main left coronary artery of six anesthetized open-chest dogs was perfused with a Gregg cannula from a constant pressure source via a pcrfusion line containing an adjustable stenosis. At mean left main arterial pressures, P^, of 65, 90, 125, and 155 mm Hg, the hearts were perfused via different grades of stenosis, while a constant mean perfusion pressure (Pu,) distal to the stenosis was maintained. Mean coronary flow was then independent of stenosis grade. However, with increasing stenosis grade, the systolic-diastolic coronary flow difference decreased, whereas the dlastolic-systolic coronary pressure difference increased. By varying the stenosis grade at constant P^ linear relationships between diastolic-systolic pressure difference and flow difference were obtained and were interpreted as being a result of an electrical analog potential-source equivalent. From the potential-source equivalent, the diastolic-systolic pressure changes of the intramyocadial pump, pi_, can be determined as well as the coronary resistance, R., impeding the flow variations originated by p^. We found p^ = 53.1 ± 7.02 (SD) nun Hg, and independent of P^. R. was correlated with the resistance to coronary flow, Re, via R. = 0.63 x R,. -12.9 mm Hg»s/ml (r -0.939, n -25). R* was defined as (Pic -14 nun Hg)/mean coronary flow. The waterfall model extended to allow for autoregulation to achieve an equal division of mean flow over the myocardium could not explain these results. From a decay curve of coronary arterial pressure following clamping of the perfusion line, intramyocardial coronary capacitance was estimated to be approximately 0.07 ml/mm rig/100 g LV. This value is in agreement with published volume pressure relationships of the intramyocardial blood compartment. The phasic coronary blood flow component requires intramyocardial arterial volume. We conclude that systolic-diastolic variations in coronary blood flow are not due to varying resistances but are caused by an active intramyocardial pump. Circ Res 49.-SS4-593, 1981THREE centuries have elapsed since Scaramucci (Porter, 1898) first speculated on the phasic nature of coronary blood flow. In modern physiological thinking, two more or less parallel lines of reasoning developed: Sabiston and Gregg (1957) held that contraction of the heart impedes coronary arterial flow, whereas Wiggers (1954) believed that systole and diastole were inseparable. In the second volume of Circulation Research, Wiggers states, "The volume of blood that can enter intramural vessels during diastole must depend to some extent on the degree to which they are emptied during preceding systole," supporting this opinion with the observation that systole enhances coronary venous outflow.From the Department of Physiology ...