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The Microcirculation: Changes in Diabetes Mellitus

1988; Elsevier BV; Volume: 63; Issue: 5 Linguagem: Inglês

10.1016/s0025-6196(12)65652-3

1942-5546

D. E. McMillan,

Acute Ischemic Stroke Management

The microvessels of the retina are commonly examined in patients with diabetes, but except for recognizing the presence of hypertensive retinopathy, diabetic retinopathy, or severe lipemia, rarely are any conclusions drawn about the patient's general microvascular status. The microvascular changes in the retina in diabetes differ in several ways from those present in other body areas. Subtlety is inherent in the microcirculation, both in its function and its history. Because the microscope had not yet been invented, William Harvey had to conduct and report numerous unequivocal experiments to have the scientific world accept the existence of the "pores of the flesh" that were needed to connect arteries and veins to allow the blood to circulate.1Harvey W An anatomical disquisition on the motion of the heart and blood in animals.in: Willis R The Works of William Harvey. The Sydenham Society, London1847: 54-55Google Scholar The motion of blood is based on physical principles, the most central of which was discerned first by Thomas Young, a physician who also made important contributions to elasticity of solids and to optics. In 1808, Young2Young T The heart and arteries: Croonian Lecture of 1808.in: Peacock G Miscellaneous Works of the Late Thomas Young. John Murray, London1855: 511-535Google Scholar calculated the viscosity of the blood with reasonable accuracy by estimating the size and the number of resistance arterioles present in the human body and knowing the blood pressure. The pressure gradient must be sufficient to force the blood through the vessels in each local microcirculatory area. The measurement of pressure and its distribution in the microcirculation has been a major preoccupation of microcirculatory physiologists in the past 2 decades. They have shown that local arteriolar pressure is linked to vessel diameter;3Zweifach BW Lipowsky H Pressure-flow distribution and relationships in the microcirculation.in: Baan J Noordergraaf A Raines J Cardiovascular System Dynamics. MIT Press, Cambridge, Massachusetts1979: 187-193Google Scholar it is kept stable in microvessels over a wide range of flow rates by changes in the diameter of vessels upstream. Because local pressure gradients are necessary to deliver blood to the tissues, probable mechanisms by which the pressure stabilization is accomplished will underlie much of the rest of this discussion. Long-standing diabetes is associated with accumulation of collagen in the walls of the microvasculature, which somehow interferes with the adjustment process and causes various problems in different organs. The anatomic correlate of pressure distribution is arteriolar branching. Branching allows the blood to be widely distributed and is also responsible for linking flow and pressure to each other. The more branches each arteriole has, the greater decline in pressure that arteriole will produce for the same amount of flow in the individual distant branches. A smaller number of large arterioles and a larger number of branches are reported to be present in skeletal muscle in rats with hereditary hypertension.4Engelson ET Schmid-Schönbein GW Zweifach BW Quantitative description of the arteriolar network in normotensive and hypertensive skeletal muscle (abstract).Microvasc Res. 1984; 27: 241-242Google Scholar The veins and venules have attracted less physiologic attention than areas of greater pressure decrease, but they play a major role in disease. Their role tends to be related to the slowing of blood flow and the associated lower pressure gradients present. Many granulocytes tend to be maintained in venules because of these features. Granulocytes in venules impair local passage of erythrocytes. Injected epinephrine produces a substantial increase in leukocyte count by raising the venular pressure gradient. A damaging role for granulocytes is envisioned in the "no reflow" phenomenon. When the perfusion pressure of an organ is lowered to a marginal level, leukocytes accumulate progressively in the microvessels, and restoration of pressure fails to dislodge them.5Schmid-Schönbein GW Engler RL Granulocytes as active participants in acute myocardial ischemia and infarction.Am J Cardiovasc Pathol. 1986; 1: 15-30Google Scholar Their stasis, in combination with toxic oxygen compounds and enzymes they release, contributes to the progression from tissue ischemia to infarction. The exact microvessel-leukocyte interaction responsible for the phenomenon is not completely understood. Poorly controlled diabetes tends to impair granulocyte function, but an effect on the "no reflow" phenomenon has not yet been reported. Erythrocytes interact nonadhesively with small microvessels. In resting muscle, their entrance into the long and narrow capillaries that supply oxygen to the active fibers is orchestrated to maintain a low vessel hematocrit. A subtle erythrocyte problem that may play a role in generating microvascular stiffening in patients with diabetes is linked to their tendency to aggregate when a person is standing. The plasma proteins that promote erythrocyte aggregation are high both in adult patients with diabetes6McMillan DE Physical factors important in the development of atherosclerosis in diabetes.Diabetes. 1981; 30: 97-104Crossref PubMed Google Scholar and in nondiabetic adults predisposed to coronary disease.7Kannel WB D'Agostino RB Belanger AJ Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham study.Am Heart J. 1987; 113: 1006-1010Abstract Full Text PDF PubMed Scopus (414) Google Scholar, 8Stone MC Thorp JM Plasma fibrinogen—a major coronary risk factor.J R Coll Gen Pract. 1985; 35: 565-569PubMed Google Scholar Some blood in the large arteries undergoes periods of shearing, and aggregates form. These aggregates pass into the microcirculation, where they must ultimately be disrupted. Their disruption necessitates unusually large short-lived local pressure gradients in patients with diabetes because of reduced erythrocyte deformability.9McMillan DE Relationship of abnormalities in blood viscosity to early vascular changes in diabetic children and adolescents.Pediatr Adolesc Endocrinol. 1988; 17: 1-6Google Scholar Shunt vessels are an anatomic feature that causes confusion. These specialized microvessels play a central role in blood flow in muscle and skin, being placed in parallel with capillaries. When ophthalmic artery pressure is reduced by disease, they become prominent in the retina. Leukocytes usually use shunt vessels to pass through the microcirculation, and in resting muscle, they carry most of the erythrocytes. In skin, flow through these vessels helps mediate loss of heat. The major contrast between capillaries and shunt vessels is that in true capillaries the erythrocytes deform as they pass and thereby produce a disproportionately high pressure gradient. In shunt vessels, the erythrocytes flow near the vessel axis and offer little resistance to flow. The reduction in flow resistance seems to be central to the function of shunt vessels, allowing flow at lower pressure gradients than occurs in true capillaries. Glomerular "capillaries" are actually shunt vessels, as are choroidal "capillaries." In these cases, special functions—plasma filtration and removal of local retinal heat—seem responsible. Local flow may be controlled by the unique function of a particular organ. For example, the plasma filtration rate determines flow in the kidney, making it high in polycythemia and low in anemia. The body's need for heat dissipation raises blood flow in the skin. The commonest determinant of blood flow, however, is the local metabolic need for oxygen consumption. In most tissues, oxygen demand and local flow vary over time. Many organs actually have the ability to receive the same blood flow over a wide range of arterial pressure, an attribute called autoregulation. As previously indicated, local microvessel pressure is kept stable during wide variations in local blood flow; thus, a means of precisely establishing the diameter of the supply vessel must be present. This result is accomplished by myogenic autoregulation. This process is a complex local smooth muscle response in which each vessel wall adjusts itself by contraction or relaxation so that the microcirculatory unit maintains its proper pressure gradient. Myogenic autoregulation creates a redundant control system; if one vessel wall area or even one smooth muscle cell fails to behave appropriately, the adjacent cells can easily compensate for the loss. Such redundancy makes early microcirculatory failure extremely difficult to detect. Studies of the microcirculation usually begin in the physiology laboratory. The skin area around the fingernails of humans was an early target, studied more than 50 years ago. Direct microscopic observation of flow of erythrocytes and local pressure measurement with use of inserted micro-pipettes were performed. Recently, this technique was applied to adult patients with diabetes; local pressures were observed to be normal except at extremes of flow rate.10Tooke JE A capillary pressure disturbance in young diabetics.Diabetes. 1980; 29: 815-819Crossref PubMed Google Scholar The nearly normal pressures contrast with well-defined abnormalities in vessel morphologic features11Redisch W Rouen LR Terry EN Oppermann W Kuthan F Clauss RH Microvascular changes in early diabetes mellitus.Adv Metab Disorders. 1973; : 383-390PubMed Google Scholar and permeability12Bollinger A Frey J Jäger K Furrer J Seglias J Siegenthaler W Patterns of diffusion through skin capillaries in patients with long-term diabetes.N Engl J Med. 1982; 307: 1305-1310Crossref PubMed Scopus (95) Google Scholar in the same vascular bed in patients with diabetes. Study of local flow rates by noninvasive means (water plethysmography) also began 50 years ago. Venous occlusion by partial inflation of a blood pressure cuff causes a rapidly progressive increase in limb volume that is determined by the rate of entry of blood. In recent years, water has been replaced by a mercury-filled silicone rubber strain gauge coupled with a resistance bridge. This technique can measure both the local flow rate in the distal forearm or leg and the slower rate of movement of fluid from the plasma space into the extravascular space produced by the elevated venous pressure. The slower transfer of fluid is referred to as the capillary filtration coefficient. Several studies of limb flow and the capillary filtration coefficient in patients with diabetes have been conducted. In these subjects, resting flow is commonly normal and the capillary filtration coefficient is normal or depressed early but tends to increase with duration and become elevated in long-standing diabetes.13Poulsen HL Nielsen SL Water filtration of the forearm in short- and long-term diabetes mellitus.Diabetologia. 1976; 12: 437-440Crossref PubMed Scopus (19) Google Scholar, 14Katz MA Janjan N Forearm hemodynamics and responses to exercise in middle-aged adult-onset diabetic patients.Diabetes. 1978; 27: 726-731Crossref PubMed Google Scholar Recent technologic advances have introduced two flow-measuring capabilities based on laser light. Blood enters the retina principally through two large arterioles, and a technique has been developed that assesses the rate of flow in these vessels. Both age and diabetes have been shown to affect primarily the ratio of systolic to diastolic flow rate in the major retinal arterioles.15Grunwald JE Riva CE Sinclair SH Brucker AJ Petrig BL Laser Doppler velocimetry study of retinal circulation in diabetes mellitus.Arch Ophthalmol. 1986; 104: 991-996Crossref PubMed Scopus (199) Google Scholar More widely applicable is a laser reflection technique that measures local flow velocity and can be applied to the skin. In the toes of patients with diabetes, dilated capillaries and a delay in return of local flow after ischemia have been found.16Fagrell B Hermansson I-L Karlander S-G Ostergren J Vital capillary microscopy for assessment of skin viability and microangiopathy in patients with diabetes mellitus.Acta Med Scand [Suppl]. 1984; 687: 25-28PubMed Google Scholar Another option necessitates radioisotope injection (xenon-133) and local detection. This gas is introduced into a tissue space, and its rate of local disappearance is characterized to measure local blood flow.17Lassen NA Lindbjerg J Munck O Measurement of blood-flow through skeletal muscle by intramuscular injection of xenon-133.Lancet. 1964; 1: 686-689Abstract PubMed Scopus (314) Google Scholar The xenon technique has been combined with injection of low-molecular-weight ionic isotopes to study vessel-tissue exchange. Studies in the legs of patients with diabetes have shown normal local blood flow, increased "diffusion" of local ions from the extravascular space to the microcirculation, and more rapid return of flow after ischemia.18Trap-Jensen J Alpert JS del Rio G Lassen NA Capillary diffusion capacity for sodium in skeletal muscle in long-term juvenile diabetes mellitus.Acta Med Scand [Suppl]. 1967; 476: 135-146PubMed Google Scholar Xenon-133 has also been used to assess local changes in cerebral blood flow after its intra-arterial injection. Cerebral activity raises local brain blood flow, but no impairment of local flow in patients with diabetes has yet been reported by the investigative group that has already demonstrated defective autoregulation of total cerebral blood flow in diabetes.19Bentsen N Larsen B Lassen NA Chronically impaired autoregulation of cerebral blood flow in long-term diabetics.Stroke. 1975; 6: 497-502Crossref PubMed Google Scholar Because the delivery of oxygen to cells for metabolic use is a primary function of the circulation, techniques to assess the local tissue oxygen level have engrossed several investigators. Demonstration of low tensions has been infrequent, probably because of the redundancy in control of local flow in combination with metabolic accommodation to modest hypoxia. Platinum electrodes that can sense the oxygen level in small areas have been developed; this type of electrode was used to demonstrate sural nerve hypoxia in diabetic neuropathy.20Newrick PG Wilson AJ Jakubowski J Boulton AJM Ward JD Sural nerve oxygen tension in diabetes.Br Med J [Clin Res]. 1986; 293: 1053-1054Crossref PubMed Scopus (244) Google Scholar Preretinal vitreous studies with similar electrodes were less successful in demonstrating low oxygen levels.21Ernest JT Goldstick TK Engerman RL Hyperglycemia impairs retinal oxygen autoregulation in normal and diabetic dogs.Invest Ophthalmol Vis Sci. 1983; 24: 985-989PubMed Google Scholar An attractive correlate of cellular oxygen availability that has not yet been fully exploited is the variation in fluorescence of mitochondria as their metabolic state changes. Difficulties in obtaining abnormal data at rest have led to a series of studies in which a provocation has been used to expose a latent problem. The type of provocation chosen is influenced by the physiologic features of the tissue. Different techniques used to maximize local blood flow demonstrate this concept. Blood flow in muscle is stimulated by use of the muscle and the associated increased metabolic demand. Blood flow in skin is increased by raising body temperature. In long-standing diabetes, both maximal muscle22Christensen NJ Muscle blood flow, measured by xenon133 and vascular calcifications in diabetics.Acta Med Scand. 1968; 183: 449-454Crossref PubMed Scopus (49) Google Scholar and maximal skin23Sigroth K Reflux vasodilatation of the fingers in the study of peripheral vascular disorders: with special reference to diabetes mellitus.Acta Med Scand [Suppl]. 1957; 325: 1-116PubMed Google Scholar blood flow are impaired. In contrast to the delay in return of blood flow in the skin of the toes,15Grunwald JE Riva CE Sinclair SH Brucker AJ Petrig BL Laser Doppler velocimetry study of retinal circulation in diabetes mellitus.Arch Ophthalmol. 1986; 104: 991-996Crossref PubMed Scopus (199) Google Scholar blood flow in leg muscle returned more rapidly in patients with diabetes.22Christensen NJ Muscle blood flow, measured by xenon133 and vascular calcifications in diabetics.Acta Med Scand. 1968; 183: 449-454Crossref PubMed Scopus (49) Google Scholar In addition to maximal flow testing, physiologic reflex evaluation has importance. In diabetes for instance, the more than 80% reduction in blood flow in the foot that normally occurs when one stands is impaired when neuropathy is present.24Rayman G Hassan A Tooke JE Blood flow in the skin of the foot related to posture in diabetes mellitus.Br Med J [Clin Res]. 1986; 292: 87-90Crossref PubMed Scopus (215) Google Scholar The retina is another site in which provocation can be used. The oxygen content of blood can be manipulated by changing respiratory gas mixtures. The hypoxemia present at an altitude of 12,000 feet (3,658 m) dilates retinal vessels and generates retinal hemorrhages.25Shults WT Swan KC High altitude retinopathy in mountain climbers.Arch Ophthalmol. 1975; 93: 404-408Crossref PubMed Scopus (52) Google Scholar A high oxygen tension normally causes retinal vasoconstriction; this response is blocked by acute hyperglycemia.22Christensen NJ Muscle blood flow, measured by xenon133 and vascular calcifications in diabetics.Acta Med Scand. 1968; 183: 449-454Crossref PubMed Scopus (49) Google Scholar, 26Atherton A Hill DW Keen H Young S Edwards EJ The effect of acute hyperglycaemia on the retinal circulation of the normal cat.Diabetologia. 1980; 18: 233-237Crossref PubMed Scopus (83) Google Scholar In the future, even more ingenious provocative circulatory assessments may be expected. The impaired control of resting cutaneous blood flow in the neuropathic foot27Archer AG Roberts VC Watkins PJ Blood flow patterns in painful diabetic neuropathy.Diabetologia. 1984; 27: 563-567Crossref PubMed Scopus (135) Google Scholar and its inability to suppress flow when the patient with diabetes stands erect24Rayman G Hassan A Tooke JE Blood flow in the skin of the foot related to posture in diabetes mellitus.Br Med J [Clin Res]. 1986; 292: 87-90Crossref PubMed Scopus (215) Google Scholar seem culpable in generating the popliteal branch atherosclerosis found almost uniquely in the middle-life adult patient with diabetes. Clearly, a need exists to move from our current exploratory studies to a test or set of tests that can be applied to patients with diabetes as part of a periodic evaluation. In addition, if a convenient test is to have full clinical value, it should indicate to what extent it measures a general more than a local circulatory abnormality. In this regard, it is important to link the physiologic abnormality measured to an anatomic one. With success, physicians may actually be speaking much more exactly about the microcirculatory status of patients with diabetes in another decade.