Associations of retinal microvascular caliber with intermediate phenotypes of large arterial function and structure: A systematic review and meta‐analysis

Abstract

Objective Intermediate phenotypes of microcirculation (retinal microvascular caliber) are associated with cardiovascular (CV) risk factors and independently predict CV events. However, the effect of microcirculation variation on the vascular system is unclear. We conducted a systematic review and meta‐analysis of observational studies to quantify associations of retinal microvascular caliber (arteriolar, venular caliber, arteriole‐to‐venule ratio) and preclinical CV measures (large arterial function and structure). Methods We identified studies in MEDLINE, EMBASE, and PubMed (1946 to March 2018) studying (a) general population samples and (b) patients with cardiometabolic disease. Study‐specific correlation estimates were combined into meta‐analysis where possible. Results Of 1294 studies identified, 26 met inclusion criteria (general population 16, patients 10), of which five studies were included in meta‐analysis. Most studied middle‐aged adults cross‐sectionally, with one childhood study. Large arterial function and structure were predominantly assessed by pulse wave velocity and carotid intima‐media thickness, respectively. Only arteriolar caliber was consistently associated with arterial function and structure, with stronger associations observed in cardiometabolic patients. Narrower (worse) arteriolar caliber was associated with faster (poorer) pulse wave velocity (correlation coefficient (r) −0.17, 95% CI −0.25 to −0.10) and greater (poorer) intima‐media thickness (r −0.05, 95%CI −0.09 to −0.02) across all adult participants. Conclusions Retinal arteriolar, but not venular caliber, was modestly associated with large arterial function and weakly associated with large arterial structure, with stronger evidence in patients with cardiometabolic disease. This suggests that preclinical changes in large arteries and the microcirculation have some shared but mainly unique pathways to associate with cardiovascular disease.

Associations of retinal microvascular caliber with large arterial function and structure: A population‐based study of 11 to 12 year‐olds and midlife adults

“…The explanatory power (ie, R 2 values) was small at age 11‐12 years and much stronger in adults. These results are consistent with our meta‐analysis of slightly older adults (mean age 54 years), which showed narrower retinal arteriolar caliber was associated with faster PWV ( r = −.17, 95% CI −0.25 to −0.10) 16 …”

“…By midlife, there is evidence of an association between the microvasculature and large artery structural phenotypes (ie, greater CIMT). It is likely that these associations will increase with age and with the development of manifest cardiometabolic disease 16 …”

“…However, the extent to which microvascular and macrovascular phenotypes co‐develop, and if so from what age and from what state of health, are unclear. We previously conducted a systematic review of 26 studies, including a meta‐analysis of five of these studies, to examine the association between retinal vascular caliber and intermediate phenotypes of large arteries (ie, CIMT, PWV) 16 . Most studies involved adults in later life, with only one study in children 17 .…”

“…Before this could take place, it is important to understand the small vessels' unique and shared contributions with more traditional large artery measures. Besides, most previous studies have only assessed one aspect of large arterial health (ie, functional or structural intermediate phenotypes), but not both in the same individuals 16 . Assuming that large arterial dysfunction precedes structural changes, retinal microvascular associations with large artery function might emerge earlier than with large artery structure 19 …”

Measuring the Interaction Between the Macro- and Micro-Vasculature

“…As a consequence, the outer retinal layers may be more exposed, and damaged by increased flow pulsatility related to increased large artery stiffness, although this hypothesis needs to be confirmed. Large artery stiffness has been shown to be related to diabetic retinopathy (58), age-related macular degeneration (59) and retinal microvascular impairment (60, 61). Exaggerated pulsed retinal capillary flow, in contrast to unchanged mean retinal capillary flow, and stiffer wall properties of retinal arterioles has been observed in patients with treated resistant hypertension compared with patients with grade 1–2 hypertension (62).…”