The pathobiology of vascular dementia

The retinal circulation allows one to visualize the microcirculation and investigate its relationship to systemic and ocular diseases Recent studies have shown that changes in retinal vascular caliber may predict a range of cardiovascular diseases, independent of established risk factors1,2 Generalized narrowing of retinal arterioles, for example, has been associated with incident stroke, coronary heart disease, and hypertension, independent of other risk factors3–8 Larger retinal venular caliber has been reported to predict progression of retinopathy and nephropathy in persons with type 1 diabetes9,10 Association between retinal vascular caliber and ocular disease, such as glaucoma, have also been reported11

Despite these data, the pathophysiological mechanisms underlying variations in retinal vascular caliber are unclear Retinal arteriolar narrowing is thought to reflect structural damage from chronic hypertension2,12–17 There is evidence that retinal venular caliber may be influenced by systemic inflammation,18–20 although not all studies have found consistent relationships,21 and most have only examined associations with nonspecific inflammatory markers (eg, white blood cell count, erythrocyte sedimentation rate)18,19 There have been no studies that have examined possible racial and ethnic differences in retinal vascular caliber

The purpose of this present study is to examine the relationship of retinal vascular caliber to a range of cardiovascular risk factors, including specific markers of inflammation (eg, high-sensitivity C-reactive protein, interleukin-6) and endothelial dysfunction (eg, soluble intercellular adhesion molecule-1, plasminogen activator inhibitor-1), in a multiethnic population of whites, blacks, Hispanics, and Chinese in the United States

/pdf/retinal-vascular-caliber-cardiovascular-risk-factors-and-cmjmfvc7en.pdf

Retinal Vascular Caliber, Cardiovascular Risk Factors, and Inflammation: The Multi-Ethnic Study of Atherosclerosis (MESA)

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60198-6.pdf

The eye in hypertension.

Retinal vascular caliber: systemic, environmental and genetic associations

Hypertension contributes significantly to worldwide cardiovascular morbidity and mortality. Hypertension appears to have a complex association with endothelial dysfunction, a phenotypical alteration of the vascular endothelium that precedes the development of adverse cardiovascular events and portends future cardiovascular risk. This review concentrates on recent findings with respect to the mechanisms of hypertension-associated endothelial dysfunction, the interrelationship between these two entities, and the relationship of the efficacy of antihypertensive therapies to improvements in vascular homeostasis beyond blood pressure reduction. Current evidence suggests that hypertension and endothelial dysfunction are integrally related with respect to pathophysiologic mechanisms. Future studies will need to identify the key connections between hypertension and endothelial dysfunction to allow novel interventions to be designed and promulgated.

/pdf/vascular-endothelial-function-and-hypertension-insights-and-15andw77zp.pdf

Vascular endothelial function and hypertension: insights and directions.

Background and Purpose— Arterial hypertension constitutes a central factor in the pathogenesis of stroke. We examined endothelial function of the retinal vasculature as a model of the cerebral circulation. Methods— Thirty-eight young subjects (19 hypertensive and 19 normotensive) were treated with the AT1-receptor blocker candesartan cilexetil and placebo, each over 7 days. Retinal capillary flow and blood flow velocity in the central retinal artery were assessed with scanning laser Doppler flowmetry and pulsed Doppler ultrasound, respectively. NG-monomethyl-l-arginine (l-NMMA) was infused to inhibit nitric oxide (NO) synthesis. Diffuse luminance flicker was applied to stimulate NO release. Results— In normotensive subjects, l-NMMA decreased retinal capillary flow by 8.2%±13% (P<0.05) and flickering light increased mean blood flow velocity in the central retinal artery by 19%±29% (P<0.01). In contrast, no significant change to these provocative tests was seen in hypertensive subjects. Treatment with cande...

Impaired Endothelial Function of the Retinal Vasculature in Hypertensive Patients

The impact of aldosterone in cardiovascular disease and hypertension has recently gained new interest. Aldosterone is now suggested to be a more common cause of hypertension than previously believed and has been linked to myocardial fibrosis, independent of its hypertensive effects. Finally, rapid nongenomic aldosterone effects have been proposed to be important in hypertension, in addition to its genomic effects. Forty-eight healthy male volunteers were examined in a randomized, placebo-controlled, double-blind crossover trial to elucidate the rapid nongenomic, vascular effects of aldosterone in humans. Forearm blood flow was measured by venous occlusion plethysmography. First, aldosterone (500 ng/min) and placebo were infused into the brachial artery for 8 minutes. The volunteers then received ascending doses of acetylcholine, N G -monomethyl-l-arginine (L-NMMA), sodium nitroprusside, or phenylephrine. Aldosterone increased forearm blood flow ( P P P P

Rapid nongenomic effects of aldosterone on human forearm vasculature.

Superoxide Scavenging Effects of N-Acetylcysteine and Vitamin C in Subjects With Essential Hypertension

BACKGROUND Reactive oxygen species play a major role in the development of endothelial dysfunction. It is as yet unspecified whether increased oxidative stress contributes to endothelial dysfunction of the renal vasculature in patients with type 2 diabetes. METHODS Renal haemodynamics were studied in 20 patients with type 2 diabetes and arterial hypertension (age 62 +/- 5 years) and 20 non-diabetic hypertensive patients at baseline and following infusions of the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg); the substrate of nitric oxide synthase, L-arginine (100 mg/kg); and the antioxidant, vitamin C (3 g, co-infused with L-arginine 100 mg/kg). RESULTS The response of renal plasma flow (RPF) to L-NMMA (-54 +/- 62 and -45 +/- 42 ml/min/1.73 m(2); P = NS) and L-arginine (+46 +/- 36 and +49 +/- 25 ml/min/1.73 m(2); P = NS) was not different between diabetic and non-diabetic patients. In contrast, vitamin C induced a more pronounced increase in RPF in diabetic than in non-diabetic patients when co-infused with L-arginine (+71+/-47 and +43+/-33 ml/min/1.73 m(2); P<0.05). CONCLUSIONS The difference in the response of renal perfusion to an antioxidant suggests increased formation of reactive oxygen species and thereby reduced nitric oxide bioavailability in the renal vasculature of patients with type 2 diabetes.

Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes

Oxidative stress plays a major pathogenetic role in cardiovascular disease. The C242T variant of the CYBA gene encoding the p22phox subunit of the NAD(P)H oxidase, a major source of superoxide production, has been shown to be associated with coronary artery disease and with vascular superoxide production in human veins ex vivo. Since superoxide degrades nitric oxide (NO), we hypothesized that the C242T variant influences endothelium-dependent vasodilation of the human forearm vasculature in vivo. In the present study, 90 subjects with elevated cholesterol levels were stratified for the C242T polymorphism of the CYBA p22phox gene. Endothelium-dependent and -independent vasodilation were assessed by plethysmographic monitoring of forearm blood flow responses to intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. N(G)-Monomethyl-L-arginine (L-NMMA) was infused to analyse NO-mediated basal vascular tone. Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. No differences in forearm blood flow responses to the intra-arterial infusion of acetylcholine, sodium nitroprusside or L-NMMA were found across the CYBA p22phox genotypes. Our sample size of n =90 had a power of >80% (beta=0.20) with a P value of <0.05 (alpha=0.05) to detect a difference greater than 156% in the forearm blood flow response to acetylcholine across genotypes (S.D. 336%; average increase in forearm blood flow=514%). In conclusion, at a power of 80%, our study excludes a major effect of the C242T CYBA p22phox polymorphism on acetylcholine-mediated endothelium-dependent vasodilation and basal NO-mediated vascular tone of the human forearm circulation in subjects with hypercholesterolaemia.

Sebastian Oehmer

Papers

Impaired Endothelial Function of the Retinal Vasculature in Hypertensive Patients

Rapid nongenomic effects of aldosterone on human forearm vasculature.

Superoxide Scavenging Effects of N-Acetylcysteine and Vitamin C in Subjects With Essential Hypertension

Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes

The C242T p22phox polymorphism and endothelium-dependent vasodilation in subjects with hypercholesterolaemia