Retinal microvascular function predicts chronic kidney disease in patients with cardiovascular risk factors.

BACKGROUND AND AIMS: Endothelial dysfunction is a precursor to atherosclerosis and is implicated in the coexistence between cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined whether retinal microvascular dysfunction is present in subjects with renal impairment and predictive of long-term CKD progression in patients with CVD. METHODS: In a single centre prospective observational study, 253 subjects with coronary artery disease and CVD risk factors underwent dynamic retinal vessel analysis. Retinal microvascular dysfunction was quantified by measuring retinal arteriolar and venular dilatation in response to flicker light stimulation. Serial renal function assessment was performed over a median period of 9.3 years using estimated GFR (eGFR). RESULTS: Flicker light-induced retinal arteriolar dilatation (FI-RAD) was attenuated in patients with baseline eGFR <90 mL/min/1.73 m2, compared to those with normal renal function (eGFR ≥90 mL/min/1.73 m2) (1.0 [0.4-2.1]% vs. 2.0 [0.8-3.6]%; p < 0.01). In patients with normal renal function, subjects with the lowest FI-RAD responses exhibited the greatest annual decline in eGFR. In uni- and multivariable analysis, among subjects with normal renal function, a 1% decrease in FI-RAD was associated with an accelerated decline in eGFR of 0.10 (0.01, 0.15; p = 0.03) and 0.07 mL/min/1.73 m2 per year (0.00, 0.14; p = 0.06), respectively. FI-RAD was not predictive of CKD progression in subjects with baseline eGFR <90 mL/min/1.73 m2. CONCLUSIONS: Retinal arteriolar endothelial dysfunction is present in patients with CVD who have early-stage CKD, and serves as an indicator of long-term CKD progression in those with normal renal function.

Impaired retinal microvascular function predicts long-term adverse events in patients with cardiovascular disease.

AIMS: Endothelial dysfunction is a precursor to the development of symptomatic atherosclerosis. Retinal microvascular reactivity to flicker light stimulation is a marker of endothelial function and can be quantified in vivo. We sought to determine whether retinal microvascular endothelial dysfunction predicts long-term major adverse cardiovascular events (MACE). METHODS AND RESULTS: In a single-centre prospective observational study, patients with coronary artery disease (CAD) or cardiovascular risk factors underwent dynamic retinal vessel assessment in response to flicker light stimulation and were followed up for MACE. Retinal microvascular endothelial dysfunction was quantified by measuring maximum flicker light-induced retinal arteriolar dilatation (FI-RAD) and flicker light-induced retinal venular dilatation (FI-RVD). In total, 252 patients underwent dynamic retinal vessel assessment and 242 (96%) had long-term follow-up. Of the 242 patients, 88 (36%) developed MACE over a median period of 8.6 years (interquartile range 6.0-9.1). After adjustment for traditional risk factors, patients within the lowest quintile of FI-RAD had the highest risk of MACE [odds ratio (OR) 5.21; 95% confidence interval (CI) 1.78-15.28]. Patients with lower FI-RAD were also more likely to die (OR 2.09; 95% CI 1.00-4.40, per standard deviation decrease in FI-RAD). In Kaplan-Meier analysis, patients with FI-RAD responses below the cohort median of 1.4% exhibited reduced MACE-free survival (55.5 vs. 71.5%; log-rank P = 0.004). FI-RVD was not predictive of MACE. CONCLUSION: Retinal arteriolar endothelial dysfunction is an independent predictor of MACE in patients with CAD or cardiovascular risk factors. Dynamic retinal vessel analysis may provide added benefit to traditional risk factors in stratifying patients at risk for cardiovascular events.

Plasma endothelin-1 and adrenomedullin are associated with coronary artery function and cardiovascular outcomes in humans.

BACKGROUND: Endothelin-1 (ET-1) is a vasoconstrictor associated with cardiovascular disease, whereas adrenomedullin (ADM) is a vasorelaxant with cardioprotective properties. We sought to determine the relationship between plasma ET-1 and ADM with coronary circulatory function and long-term major adverse cardiovascular events (MACE). METHODS: Thirty-two patients undergoing coronary angiography for chest pain were recruited. Baseline plasma ET-1 and ADM levels were measured. The index of microcirculatory resistance (IMR), coronary flow mediated dilatation (cFMD) and coronary flow reserve (CFR) were measured in a non-obstructed coronary artery. Patients were assessed for MACE over a median period of 8.8 years. RESULTS: Plasma ET-1 levels correlated with IMR (r = 0.57; p < 0.01) and ADM levels correlated with CFR (r = 0.50; p = 0.04) and cFMD (r = 0.62; p = 0.01). After adjustment for age, gender and cardiovascular risk factors, the association between ADM and cFMD (ß = 0.79; p < 0.01) and between ET-1 and IMR (ß = 5.7; p = 0.01) remained significant. IMR was higher, although not statistically significant, in patients with long-term MACE (17.9 ±â€¯5.3 vs. 13.1 ±â€¯6.0 units; p = 0.14). In patients free of MACE, cFMD (9.3 ±â€¯7.6 vs. 2.8 ±â€¯5.0%; p = 0.01) and plasma ADM levels (7.6 ±â€¯5.3 vs. 4.0 ±â€¯1.9 pmol/L; p = 0.07) were higher. CONCLUSIONS: Plasma ET-1 and ADM were associated with measures of coronary microvascular and coronary conduit vessel function, respectively. Increased cFMD and elevated plasma ADM were associated with a cardioprotective effect.

Usefulness of retinal microvascular endothelial dysfunction as a predictor of coronary artery disease.

Endothelial dysfunction is a key feature of atherosclerosis. Retinal microvascular endothelial function can be assessed using noninvasive dynamic vessel imaging techniques. Whether it is impaired in subjects with coronary artery disease (CAD) is unknown. The aim of this study was to examine the relation of retinal microvascular endothelial function with CAD. Vascular studies were performed in 197 prospectively recruited subjects divided into 2 groups: those without CAD but ≥2 cardiovascular risk factors (non-CAD controls; n = 119) and those with stable CAD (n = 78). Retinal microvascular endothelial dysfunction was assessed by measuring retinal arteriolar and venular dilatation to flicker light, a nitric oxide-dependent phenomenon, expressed as percentage increase over baseline diameter. Fingertip pulse-volume amplitude was measured to calculate reactive hyperaemia index and brachial artery flow-mediated dilatation assessed as measures of peripheral microvascular and conduit vessel endothelial function, respectively. Mean retinal arteriolar dilatation was attenuated in patients with CAD compared with non-CAD controls (1.51 ± 1.51% vs 2.37 ± 1.95%, p = 0.001). Retinal arteriolar dilatation was independently associated with CAD after adjustment for age, gender, cardiovascular risk factors, and medication use (odds ratio 1.60, 95% confidence interval 1.14 to 2.25, p = 0.007). Reactive hyperaemia index and flow-mediated dilatation were not different. In conclusion, the capacity of retinal arterioles to dilate in response to flicker light is an independent predictor of the presence of CAD and suggests that retinal microvascular endothelial dysfunction is a marker for underlying CAD.

Retinal microvascular structure and function in patients with risk factors of atherosclerosis and coronary artery disease.

OBJECTIVE: Retinal microvascular signs are markers of cardiovascular disease risk. There are limited data, on relationships between retinal microvascular signs and retinal microvascular endothelial function. We sought to determine the relationship of retinal vascular signs with retinal microvascular endothelial function in patients with or at high risk of coronary artery disease. METHODS: Participants with atherosclerosis risk factors and coronary disease (n=258; mean age 57±11 years) were recruited to have static and dynamic retinal vascular assessment. Retinal arteriolar dilatation in response to flicker light (FI-RAD) was measured using the Digital Vessel Analyser and expressed as percentage increase over baseline diameter. Static retinal photographs were acquired utilising a digital fundus camera for measurement of central retinal artery and vein equivalent (CRAE and CRVE), arteriovenous nicking (AVN) and focal arteriolar narrowing (FAN). RESULTS: Intra-class correlation coefficient was 0.82 for flicker-light induced retinal arteriolar dilatation. There were modest associations in retinal vascular measurements between eyes. For each 10 µm decrease in retinal arteriolar diameter, the absolute increase in FI-RAD was 0.28% (95% CI 0.11, 0.45; p=0.002) independent of age, gender and atherosclerosis risk factors. AVN and FAN were associated with attenuated FI-RAD (ß=-0.67%; 95% CI -1.20, -0.15; p=0.012) and (ß=-0.83%; 95% CI -1.44, -0.23; p=0.007) respectively after adjustment for age and gender. CONCLUSION: Assessment of retinal microvascular endothelial function is reproducible and correlated with retinal microvascular structure and signs, independent of atherosclerosis risk factors. Assessment of retinal vascular structure and function may provide insights into atherosclerotic disease.

Contemporary outcomes in women undergoing percutaneous coronary intervention for acute coronary syndromes.

BACKGROUND: Uncertainty remains as to whether females benefit as much as males from percutaneous coronary intervention (PCI) in the setting of an acute coronary syndrome (ACS). METHODS: We compared 802 women with 2151 men presenting with ACS, undergoing PCI from April 2004 to October 2006 from the Melbourne Interventional Group registry. Clinical characteristics, in-hospital, 30-day and 1-year outcomes were compared. RESULTS: Women were older (69.6 ± 11.6 vs. 62.17 ± 12.3 years, p<0.001), and had more diabetes (27.1% vs. 19.6%, p<0.001) and hypertension (70.3% vs. 53.9%, p<0.001) than men. Women were less likely to present with ST-elevation myocardial infarction (30.5% vs. 37.9%, p<0.001). Bleeding (3.6% vs. 0.8%, p<0.001) was higher among women. Thirty-day mortality (4.7 vs. 2.4%, p<0.001) and MACE (10.1 vs. 6.4%, p<0.001) were higher in women. Gender was an independent predictor of overall MACE at 30 days (OR 1.45, 95% CI 1.04-2.02, p=0.03) but not death. At 12 months, there were no significant differences in mortality (6.4% vs. 4.8%, p=0.09), myocardial infarction (5.5% vs. 5.0%, p=0.64), target vessel revascularization (7.9% vs. 7.0%, p=0.42) and MACE (16.3% vs. 14%, p=0.13) between women and men. CONCLUSIONS: There is an early hazard amongst women undergoing PCI for ACS, but not at 12 months. These data suggest that gender should not affect the decision to offer PCI but further gender specific studies are warranted.