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Hemodynamic Risk Factors in the Development of Vision Threatening Diabetic Retin

Paul Chous, M.A., O.D. Doctor of Optometry Type 1 diabetic since 1968 Diabetic retinopathy is the leading cause of new blindness for persons under age 74 in the US. Recognized risk factors for the development and progression of diabetic retinopathy include disease duration, poor glycemic control, hypertension and disease sub-type. , , Tight glycemic and hypertensive control comprise the mainstay of efforts to prevent and/or delay retinopathy , whereas laser photocoagulation is the current gold standard for ameliorating the risk of severe vision loss due to proliferative diabetic retinopathy (PDR) and clinically significant diabetic macular edema (CSDME). A variety of models have been tested and elaborated with regard to the development of vision threatening retinopathy (PDR and CSDME), including: hormonal, biochemical (sketched previously by myself last year, and much more comprehensively and beautifully in the last few weeks by Stephen Setter, R. Keith Campbell and Clifton Cahoon for diabetesincontrol.com), and hemodynamic/autoregulatory. Here, I would like to consider some evidence for the latter.

Elevated blood pressure is a definitive risk for poor microvascular and macrovascular outcomes of diabetes. In Type 2 diabetes, blood pressure status was shown to be even more important than blood glucose status in predicting and preventing significant vision loss from diabetic retinopathy.1 The significance of systemic hypertension for diabetic eye disease may derive from the concept of “retinal perfusion pressure” (RPP), a parameter describing the net force of blood flow into the eye and derived from the opposing forces of pulse pressure pushing blood into the eye and internal eye pressure (intraocular pressure) resisting blood flow.

It is well established that diabetic patients have increased retinal blood flow (measured as volume per unit of time) as a function of hyperglycemia, hypertension, pregnancy, and defective retinal vascular auto-regulation. , , Vascular auto-regulation is defined as the intrinsic ability of an organ to maintain a constant blood flow despite changes in perfusion pressure. Hyperglycemia impairs the retina’s ability to compensate for increased perfusion pressure, resulting in unchecked increase of retinal blood flow.

Hyperglycemic damage to retinal endothelial pericytes impairs homeostatic vasoconstriction in response to excess oxygenation, setting the stage for increased blood flow and hemodynamic injury. , Increased retinal perfusion pressure and blood flow, in turn, cause “shear stress” on vascular endothelium that may contribute to capillary defects (i.e. leakage as in diabetic macular edema) and closure (ischemia). High volume blood flow also results in effective shunting of blood away from capillaries into larger caliber vessels. Shear stress and shunting caused by elevated RPP results in capillary nonperfusion, the sine qua non of proliferative diabetic retinopathy. Coupled with the metabolic insult of chronic hyperglycemia that biochemically injures retinal vasculature, increased RPP may represent the hemodynamic/mechanical straw that breaks the camel’s back, so to speak.

RPP has been determined classically by measuring pulse pressure of the central retinal artery via a technique called ophthalmodynamometry (ODM); a calibrated foot plate is applied to the sclera that increases intraocular pressure (IOP) to a point that it collapses the central retinal artery as viewed by an ophthalmoscope. The patients IOP (which resists blood flow into the eye) is then subtracted from her pulse pressure to determine the effective net pressure of blood flow into the eye (RPP = PP – IOP). In fact, the technique is uncomfortable and prone to subjective inconsistency by the examiner. As a result, a close approximation of RPP has been developed using mean arterial pressure of the brachial artery as a function of conventional blood pressure measurement:

RPP = 2/3 (MAP) – IOP

where MAP = Mean Arterial Pressure = (Systolic BP – Diastolic BP)/3 + Diastolic BP

As it turns out, RPP rises, non-linearly, faster than BP. Moreover, higher intraocular pressure moderates RPP, consistent with the clinical finding that patients with ocular hypertension may have relative protection against more severe forms of diabetic retinopathy. Let’s consider two examples:

(1) BP = 120/80 with an IOP of (a) 20mm versus (b) 10mm
For case (a), MAP = 93.3mm and RPP = 42.2mm
For case (b), MAP = 93.3mm and RPP = 52.2mm

(2) BP = 150/100 with an IOP of (c) 20mm versus (d) 10mm
For case (c), MAP = 116.7mm and RPP = 57.8mm
For case (d), MAP = 116.7mm and RPP = 67.8mm

Comparing examples (1) and (2), we see that a 25% increase in blood pressure results in a 25% increase in MAP but a 30-37% increase in RPP (depending on IOP level). This non-linear rise in RPP may help explain why retinal micro-circulation is so sensitive to blood pressure status. Furthermore, we see that intraocular pressure tempers RPP and that that relatively high IOPs may moderate hemodynamic stresses on diabetic eyes (the development of glaucoma notwithstanding).

Is there evidence that RPP has predictive value for the development of severe diabetic retinopathy? One population-based study of 891 “younger onset” diabetics (dx before age 30) and 987 “older onset” diabetics showed that RPP (aka Ocular Perfusion Pressure) was significantly associated with incidence of retinopathy over four years in the younger onset group only; there was, interestingly, no association found with intraocular pressure. Another prospective study of patients receiving care at a diabetic retinopathy clinic demonstrated that RPP was highly correlated with the development of PDR and CSDME amongst 457 Type 1 patients (p < 0.001), more so than disease duration (p = 0.008). In Type 2 diabetes, mean arterial pressure and diastolic blood pressure were most predictive of sight threatening retinopathy (n = 927, with p

Panja et al compare the relative risk of developing sight threatening retinopathy by RPP quartiles, and the data show that RPPs above 50mm substantially elevate the risk of both proliferative diabetic retinopathy and clinically significant diabetic macular edema. In fact, in patients with non-proliferative diabetic retinopathy, the relative risk of developing PDR, CSDME, or both was 5-6 times greater for retinal perfusion pressures above 50mm than for those below 50mm. The take home message is, of course, that clinicians should be determining RPP for all diabetic patients and identifying high risk individuals for both more aggressive (blood pressure) intervention and more frequent retinal evaluation.

It appears there is a complex interaction amongst biochemical, hemodynamic and hormonal factors in the development and progression of diabetic retinopathy. Clinical attention to each of these factors, where measurable and/or remediable, may help us lessen one of the most dreaded complications of this disease.

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Dr. Paul Chous received his undergraduate education at Brown University and the University of California at Irvine, where he was elected to Phi Beta Kappa in 1985. He received his Masters Degree in 1986 and his Doctorate of Optometry in 1991, both with highest honors from the University of California at Berkeley. Dr. Chous was selected as the Outstanding Graduating Optometrist in 1991. He has practiced in Renton, Kent, Auburn and Tacoma, Washington for the last 12 years, emphasizing diabetic eye disease and diabetes education. Dr. Chous has been a Type 1 diabetic since 1968. He lives in Maple Valley, Washington with his wife and son.