M Baker

Retinal Signs and Stroke Revisiting the Link Between the Eye and Brain

Background and Purpose— The retinal and cerebral vasculature share similar anatomic, physiological, and embryological characteristics. We reviewed the literature, focusing particularly on recent population-based studies, to examine the relationship between retinal signs and stroke. Summary of Review— Hypertensive retinopathy signs (eg, focal retinal arteriolar narrowing, arterio-venous nicking) were associated with prevalent stroke, incident stroke, and stroke mortality, independent of blood pressure and other cerebrovascular risk factors. Diabetic retinopathy signs (eg, microaneurysms, hard exudates) were similarly associated with incident stroke and stroke mortality. Retinal arteriolar emboli were associated with stroke mortality but not incident stroke. There were fewer studies on the association of other retinal signs such as retinal vein occlusion and age-related macular degeneration with stroke, and the results were less consistent. Conclusion— Many retinal conditions are associated with stroke, reflecting possible concomitant pathophysiological processes affecting both the eye and the brain. However, the incremental value of a retinal examination for prediction of future stroke risk remains to be determined.

A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families.

Background: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. Methods: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. Results: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 3′ untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3–5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. Conclusions: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.

Genotype at the −174G/C Polymorphism of the Interleukin-6 Gene Is Associated With Common Carotid Artery Intimal-Medial Thickness Family Study and Meta-Analysis

Background and Purpose— Studies in unrelated individuals have produced conflicting findings concerning the putative association between the interleukin-6 (IL-6) −174G/C polymorphism and carotid intimal-medial thickness (IMT). We have used a family-based genetic association design to assess the heritability of carotid IMT and to investigate the hypothesized association of carotid IMT with the IL-6 to −174G/C polymorphism. Methods— We studied 854 members of 224 white British families. The heritability of carotid IMT was determined using Multipoint Engine for Rapid Likelihood Inference. Genetic association analyses were carried out using ANOVA and family-based tests of association implemented in Quantitative Transmission Disequilibrium Test. A meta-analysis of previous studies of the association was conducted to place our result in context. Results— The heritability of carotid IMT was 24%. Under a recessive model (GG+GC versus CC), there was significant evidence of association between IL-6 to the −174G/C genotype and adjusted loge maximal carotid IMT (F=5.469; P=0.02). Family-based analyses using Quantitative Transmission Disequilibrium Test showed no evidence of population stratification as a cause of the observed association (&khgr;21=0.469; P=0.4934). The CC genotype was associated with a 4.8% increase in maximal carotid IMT and accounted for 0.6% of the observed variation in the trait, which is equivalent to 2.5% of the heritable component. A meta-analysis of the present and 2 previous large studies, which enrolled a total of 2930 subjects, confirmed the recessive effect of the C allele on carotid IMT (P=0.0014). Conclusions— The genotype at the IL-6 to −174G/C polymorphism is associated with common carotid artery IMT, although the size of the genetic effect is small.

Retinal Vascular Caliber and Extracranial Carotid Disease in Patients With Acute Ischemic Stroke The Multi-Centre Retinal Stroke (MCRS) Study

Background and Purpose— Previous studies show that both retinal vascular caliber and carotid disease predict incident stroke in the general population, but the exact relationship between these 2 microvascular and macrovascular structural risk factors is unclear. We studied the relationship between retinal vascular caliber and carotid disease in patients presenting with acute ischemic stroke. Methods— We conducted a cross-sectional study of patients with acute ischemic stroke recruited from 3 centers (Melbourne, Sydney, Singapore). The caliber of retinal arterioles and venules was measured from digital retinal photographs. Severe extracranial carotid disease was defined as stenosis ≥75% or occlusion determined by carotid Doppler using North American Symptomatic Carotid Endarterectomy Trial-based criteria. Results— Among the 1029 patients with acute stroke studied, 7% of the population had severe extracranial carotid disease. Retinal venular caliber was associated with ipsilateral severe carotid disease (P<0.001 in multivariate models). Patients with wider retinal venular caliber were more likely to have severe ipsilateral carotid disease (multivariable-adjusted OR, 3.81; 95% CI, 1.80 to 8.07, comparing the largest and smallest venular caliber quartiles). The retinal venular caliber–carotid disease association remained significant in patients with large artery stroke. Conclusions— In patients with acute stroke, retinal venular widening was strongly associated with ipsilateral severe extracranial carotid disease. Our findings suggest concomitant retinal and cerebral microvascular disease may be present in patients with carotid stenosis or occlusion disease. The pathogenesis of stroke due to carotid disease may thus be partially mediated by microvascular disease.

Transient Ischemic Attack and Acute Ischemic Stroke Associations With Retinal Microvascular Signs

Background and Purpose— Small vessel disease plays a role in cerebral events. We aimed to investigate the prevalence and patterns of retinal microvascular signs (surrogates for cerebral small vessel disease) among patients with transient ischemic attack (TIA) or acute stroke and population control subjects. Methods— Patients with TIA or acute stroke aged ≥49 years admitted to hospitals in Melbourne and Sydney, Australia, were recruited to the Multi-Centre Retina and Stroke Study (n=693, 2005 to 2007). Control subjects were Blue Mountains Eye Study participants aged ≥49 years without TIAs or stroke (n=3384, 1992 to 1994, west of Sydney). TIA, ischemic stroke, or primary intracerebral hemorrhage was classified using standardized neurological assessments, including neuroimaging. Retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar light reflex) were assessed from retinal photographs masked to clinical information. Results— Patients with TIA or acute stroke were older than control subjects and more likely to have stroke risk factors. After adjustment for study site and known risk factors, all retinal microvascular signs were more common in patients with TIA or acute stroke than in control subjects (OR, 1.9 to 8.7; P<0.001). Patients with TIA and those with ischemic stroke had similar prevalences of nondiabetic retinopathy (26.9% versus 29.5%; OR, 0.8; 95% CI, 0.5 to 1.6), diabetic retinopathy (55.5% versus 50.0%; OR, 1.3; 95% CI, 0.4 to 3.6), focal arteriolar narrowing (15.6% versus 18.4%; OR, 0.8; 95% CI, 0.4 to 1.5), and arteriovenous nicking (23.0% versus 17.8%; OR, 1.4; 95% CI, 0.7 to 2.7). Conclusions— Patients with TIA and acute stroke may share similar risk factors or pathogenic mechanisms.

Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study.

The endothelins are among the most potent vasoconstrictors known. Pharmacological inhibition of endothelin receptors lowers blood pressure (BP). It is unknown whether naturally occurring genetic variation in the endothelin receptors influences BP. We have evaluated the type A endothelin receptor (EDNRA) as a candidate gene for hypertension in a large family study. A total of 1425 members of 248 families selected via a proband with hypertension were studied. Ambulatory BP monitoring was conducted using the A&D TM2421 device. Four haplotype-tagging single nucleotide polymorphisms (SNPs) spanning the EDNRA gene were typed. There was evidence of association between genotype at the rs5335 (C+70G) SNP and night systolic blood pressure (+1.24% (s.e. 0.64) per G allele; P=0.05); night diastolic blood pressure (+1.64% (s.e. 0.71) per G allele; P=0.021) and night mean BP (+1.51% (s.e. 0.64) per G allele; P=0.017). Borderline significant trends in the same direction were seen for daytime BPs. Proportions of hypertensives in each of the three genotype groups were C/C 34.7%, C/G 37.9%, G/G 42.4% yielding an odds ratio for hypertension per G allele of 1.19 (95% confidence interval 1.00–1.41; P=0.05). In conclusion, the rs5335 (C+70G) polymorphism of the EDNRA gene has small effects on the risk of hypertension. Natural variation in other genes in the endothelin-signalling pathway should be explored to identify additional influences on BP regulation.

Retinopathy and Lobar Intracerebral Hemorrhage Insights Into Pathogenesis

BACKGROUND The vascular pathogenesis underlying lobar intracerebral hemorrhage (ICH) is unclear. OBJECTIVE To determine whether certain retinal microvascular signs are associated with lobar ICH to improve understanding of its underlying cerebral vasculopathy. DESIGN Prospective cohort study. SETTING Royal Melbourne Hospital and Westmead Hospital. PATIENTS Of 655 patients with acute stroke, 25 had lobar ICH, 51 had deep ICH, 93 had lacunar infarction, and 486 had nonlacunar cerebral infarction. MAIN OUTCOME MEASURES Retinal photographs were assessed for retinopathy lesions (microaneurysms, retinal hemorrhages, cotton-wool spots, and hard exudates) and retinal arteriolar wall signs (focal arteriolar narrowing, arteriovenous nicking, and enhanced arteriolar wall light reflex) masked to the cerebral pathologic abnormalities and the study hypothesis. RESULTS In patients without diabetes mellitus, retinopathy lesions were more likely to be present in persons with lobar ICH than in those with either lacunar infarction (47.8% vs 30.4%; adjusted odds ratio, 3.5; 95% confidence interval, 1.1-10.9) or nonlacunar cerebral infarction (47.8% vs 24.6%; 3.3;1.4-8.1). Most retinal arteriolar wall signs were less frequent in lobar ICH than in deep ICH, although this difference was significant only for focal arteriolar narrowing. CONCLUSIONS Patients with lobar ICH were more likely than patients with lacunar or nonlacunar cerebral infarction to have retinopathy lesions, suggesting breakdown of the blood-retina barrier in patients with lobar ICH. These findings support a distinct vasculopathy in lobar ICH compared with other acute stroke subtypes resulting from cerebral small vessel disease or ischemic infarction.