Cerebrovascular Damage and Memory (p 176)
Hypertension and aortic stiffness are well-known causes of dementia. Although the vascular hypothesis of Alzheimer disease is supported by studies of risk factors, few have examined specific vascular properties that may underlie these associations. We evaluated carotid-femoral pulse wave velocity, measures of microvascular structure, and cognitive scores and their relations in 1820 participants of the community-based Age, Gene/Environment Susceptibility–Reykjavik Study. Measures of microvascular damage and remodeling—cerebrovascular resistance and white matter hyperintensities—were each associated with carotid-femoral pulse wave velocity and memory. In addition, cerebrovascular resistance and white matter hyperintensities attenuated the direct relationship between carotid-femoral pulse wave velocity and memory in regression and mediation models adjusted for confounding factors. Together, cerebrovascular resistance and white matter hyperintensities accounted for ≈41% of the observed effect of carotid-femoral pulse wave velocity on memory (total indirect effect). Our results suggest that microvascular and white matter damage contribute to the observed associations between higher aortic stiffness and lower memory function in older adults. Because memory is the key functional measure impaired in amnestic mild cognitive impairment and Alzheimer disease, our findings support potential vascular and microvascular targets for the prevention of dementia and Alzheimer disease, particularly when individuals may have evidence of more subtle, subclinical disease. Thus, novel treatment approaches that target excessive aortic stiffness and prevent small vessel damage in the brain may delay the onset of memory decline with advancing age.
Gene Expression and Arterial Stiffness (p 70)
Stiffening of large arteries is a hallmark of vascular aging and an important determinant of the age-related increase in blood pressure and cardiovascular events. Candidate gene and genome-wide association studies have identified genes potentially implicated in this process. However, genetic variants described to date account for small amounts of variance in arterial phenotypes and often do not replicate. This is a common problem with polygenic conditions, and thus there is interest in examining whether phenotypes may relate more closely to gene expression in accessible tissue such as blood-based cells rather than to individual gene variants. In the present study, we investigated whether expression of genes previously implicated in arterial stiffening associates with cross-sectional and longitudinal measures of arterial stiffness in the Twins UK cohort. Expression of ENPP1, involved in vascular calcification, was correlated with arterial stiffness in both cross-sectional and longitudinal analysis, and expression of COL4A1, which encodes for 1 component of type IV collagen, was associated with arterial stiffening. These genes, which are implicated in regulation of the extracellular matrix and arterial calcification, may be functional mediators of a genetic association, and not just a marker for alternative genomic events. A hypothesized pathway linking COL4A1 and ENPP1 to arterial stiffening is shown in Figure 1 (see page 74). Combining knowledge from genetic association studies with that obtained from gene expression in accessible tissues may yield new insights into molecular mechanisms of disease.
Rac1 Activates Cardiac Mineralocorticoid Receptors (p 99)
Mineralocorticoid receptor (MR) has been shown to have pathological roles in the development of cardiovascular disease, and MR blockade significantly improved prognosis of patients with heart failure. However, the mechanisms for MR activation in cardiovascular diseases are still unclear. Although ligand excess is an important stimulus, evidence indicates that MR activity is affected by factors other than its ligands. Our demonstration that a Rho family, small GTPase Rac1, is involved in pathogenic MR activation has 2 potential implications. One is that circulating levels of ligand, namely aldosterone, need not be elevated for cardiac damage to occur. The other is that the Rac1-MR-NOX4 pathway may offer a novel therapeutic target for the treatment of heart failure and chronic kidney disease. Whereas MR blockers carry a risk of causing hyperkalemia, an effective dose of Rac1 inhibitor could avoid hyperkalemia by blocking both MR activity and NOX2-reactive oxygen species production.
- © 2015 American Heart Association, Inc.