Lower RHI was significantly associated with poorer verbal memory but not performance in other cognitive domains including visuospatial memory, processing speed, and executive function at baseline adjusting for potential confounders (Table 3). This model suggested that each unit lower in RHI was associated with a 0.65 SD lower in verbal memory performance (F = 2.94, p = .015, adjusted coefficient of determination (R2) = 0.16).
During CR, an increase in RHI was significantly associated with improvement in processing speed (Table 4). Specifically, a unit increase in RHI was associated with a 0.42 SD improvement in processing speed over time.
The present study assessed the relationships between peripheral measurements of microvascular endothelial function and cognitive performance at entry and after 3 months of CR in patients with CAD. Although RHI was not cross-sectionally associated with overall cognition, an increase in RHI during CR was associated with an improvement in overall cognition. Lower RHI, indicating poorer endothelial function, was significantly associated with poorer verbal memory performance at entry into CR, whereas an increase in RHI over CR was associated with improvement in processing speed. These findings suggest that RHI is a possible predictor of early cognitive changes in patients with CAD.
The role of vascular disease in the pathogenesis of cognitive impairment is an area of keen investigation. Although neurodegeneration is largely considered to underlie cognitive decline and dementia, coexistent or isolated cerebrovascular disease has also been suggested as an important contributor to these changes (3). Previously, FMD, a common proxy for endothelial function, was associated with performance in attention, executive function, and processing speed in hypertensive patients and those with cardiovascular disease (15). Recently, a community-based study reported significant associations between RHI, visuospatial ability, and executive function performance (36). Our findings identify novel associations between RHI and verbal memory in patients with CAD, a population at increased risk of cognitive decline.
A potential limitation of this study was the use of typical preventative drugs including antihypertensives, aldosterone antagonists, statins, antidiabetic agents, and aspirin, which may have attenuated associations between RHI and cognitive performance (51). Although the study sample was predominantly married white males who were highly educated, it was quite representative of CR participants, which may contribute to the generalizability of the results. Also, data were not available on those who declined to participate in the study to assess recruitment bias but comparison with an unselected sample suggested that the study sample was representative of the CR population. Practice effects may have contributed to the overall improvement in cognitive outcomes; however, a 3-month interval between testing would be expected to minimize such effects on cognitive tests (52). Even though the group as a whole improved, a substantial number of participants (97%) had a decrease on one or more cognitive tests at follow-up despite participation in CR. Subtle changes in cognitive test scores over CR though significant, may not reflect a clinically meaningful change. However, the importance of even subtle changes in cognitive performance in this population has been demonstrated with previous associations with poorer outcomes such as failure to complete CR (5). Future studies should include a control group to determine the independent effects of CAD on the association between RHI and cognition.
In patients with CAD, endothelial dysfunction was significantly associated with poor verbal memory and improvement in endothelial function during CR was significantly associated with improvements in overall cognition and processing speed. These findings suggest that RHI may be of clinical relevance in cognitively vulnerable populations such as those with CAD. Despite a lack of association with cardiopulmonary fitness, improvements in RHI over CR indicate the importance of lifestyle modifications and pharmacotherapy in modulating vascular health. Assessment of neuroimaging correlates in future studies will further clarify relationships with cognition and facilitate development of vascular health indices as clinically useful predictors of early cognitive changes.
Source of Funding and Conflicts of Interest: This study was supported by research grants from the Canadian Institutes of Health Research (LanctotMOP-114913) and Ontario Mental Health Foundation. Saleem reports doctoral support from Alzheimer's Society of Canada during the conduct of the study. The above institutions were not involved in study management, the collection, analysis, and interpretation of data, or the preparation, review, or approval of the manuscript. The authors report no conflicts of interest.
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