Turning an eye towards cardiovascular health: the retina in public health research

Abstract

Air pollution exposure and physical inactivity are risk factors for cardiovascular morbidity and mortality. The vascular effects are the result of complex molecular and physiological changes that also occur in the microcirculation, which is the network of smallest blood vessels. These vessels make up the bulk of the cardiovascular system and ensure delivery of nutrients, removal of metabolites and gas exchange. The microcirculation is the primary site of resistance and plays an important role in blood pressure regulation. Cardiovascular risk factors such as air pollution and physical inactivity can induce microvascular functional and structural changes that can play a role in cardiovascular disease development. The retina offers an unique possibility to visualize the microvasculature in vivo using fundus photography and quantify effects using image analysis. The retinal blood vessels share anatomical, physiological and pathological features with cerebral and coronary blood vessels. In epidemiological studies, retinal arteriolar narrowing and venular widening are associated with cardio- and cerebrovascular risk factors and outcomes. However, the evidence on the impact of air pollution or physical (in)activity on the retinal blood vessels is scarce and not much is known about the short-term impact of these risk factors. The question whether repeated fundus photography can be used to investigate the association between ambient air pollution exposure or physical (in)activity and retinal blood vessel changes is addressed in this PhD project. The specific objectives of the project were to investigate:

The association between personal or short-term air pollution exposure and retinal arteriolar narrowing and venular widening in healthy adults. The effects of bedrest, an experimental model for physical inactivity, on the retinal microvasculature. The retinal microvascular responses after acute exercise in cardiac patients and investigate whether these responses were changed after completion of a cardiac rehabilitation program. The association between short-term air pollution exposure and retinal microvascular changes were studied in three panel studies in Flanders. In the first panel study (n=84, mean age= 37±9, 60% females; January 2012-May 2012; 3 repeated measurements), each 10 µg/m³ increase in PM10 or each 1 µg/m³ increase in black carbon was associated with retinal arteriolar narrowing of respectively 0.93 µm (95%CI: -1.42 to -0.45) and 1.84 µm (95%CI: -3.18 to -0.15). These changes in retinal arteriolar diameter were equivalent to a 1.5 year increase in age (Chapter 3). These observations are in line with experimental controlled exposure studies in which brachial artery endothelial dysfunction or vasoconstriction was observed after air pollution exposure. In the second panel study (n=50, mean age=32±8, 50% females; December 2014-April 2015; 5 repeated measurements), each 10 µg/m³ increase in PM10 was associated with a decrease in CRAE of 0.72 µm (95%CI: -1.38 to -0.06), an increase in CRVE of 0.99 µm (95%CI: 0.18 to 1.80) and a downregulation of 6.62% (95%CI: -11.07 to -2.17) and 6.71% (95%CI: -10.68 to -2.75) in respectively miR-21 and miR-222 expression. Changes in microRNA expression were associated with air pollution exposure and retinal microvascular changes. These microRNAs are involved in inflammatory reactions and endothelial dysfunction, suggesting their potential role in mediating the effects of air pollution on the retinal blood vessels (Chapter 4). Short-term air pollution exposure can induce endothelial dysfunction. In this process, the potent vasodilator nitric oxide is lost and inflammatory reactions are upregulated. This may lead to arteriolar vasoconstriction and venular widening. In the third panel (n=56, mean age=41±10; 93% females; April 2013-May 2013; 4 repeated measurements during one week), each 425 ng/m³ increase in subchronic (long-term) traffic-related air pollution exposure was associated with increases in systolic and diastolic blood pressure and venular widening of respectively 2.77 mm Hg (95% CI: 0.39 to 5.15), 2.35 mm Hg (95% CI: 0.52 to 4.19) and 4.76 µm (95% CI: 0.27 to 9.24). Since the exposure levels and variation in personal exposure between study subjects were very limited during the study period, we were unable to reproduce our associations between short-term traffic-related air pollution exposure and retinal microvascular changes (Chapter 5).

The retinal microvascular responses to physical inactivity were addressed in 14 healthy adult males during a 21-day bedrest cross-over study in normoxic and hypoxic conditions. Normoxic bedrest caused retinal arteriolar vasoconstriction that remained for the whole study period. The maximal decrease in retinal arteriolar diameter was 7.47 µm (95% CI: -10.78 to -4.15). Hypoxic bedrest caused an initial increase in retinal arteriolar diameter of 4.49 µm (95% CI: 1.23 to 7.75) that was attenuated during the study period. These responses were probably due to the autoregulatory properties of the retinal vessels. Under hypoxic conditions, myogenic vasoconstriction attenuated metabolic vasodilation in the retinal arterioles. This mechanism might contribute to the predisposition of physically inactive individuals for cardiovascular disease development or progression (Chapter 6).

The retinal microvascular responses to physical activity were also addressed in 53 cardiac rehabilitation patients. These individuals participated in a rehabilitation program in which they conducted two maximal endurance tests. We observed that retinal microvascular reactivity was preserved in these patients as the blood vessels dilated after exercise and remained dilated for up to 30 minutes after exercise cessation. The microvascular reactivity was assessed again after a 6-week rehabilitation program, but there were no indications that retinal vascular responses were improved (Chapter 7).

Our results suggest that short-term effects exposure to air pollution and physical (in)activity are associated with retinal microvascular changes. The studies on air pollution performed as part of this PhD project contribute to international research investigating the cardiovascular effects of environmental pollutants at the current exposure levels. The experimental studies on physical (in)activity add to our understanding of the detrimental vascular effects of a sedentary lifestyle and the need for regular physical exercise to maintain vascular health.

In conclusion, retinal imaging is a convenient tool to study the microvasculature in epidemiological and (pre-)clinical settings. Dedicated image analysis software is able to quantify functional and structural retinal blood vessel changes that are important on the trajectory of cardiovascular disease development.