In this study of a community dwelling cohort of ambulatory adults, we found that cardiac index was associated with total brain volume and lateral ventricular volume, both markers of accelerated brain aging;17,42
however, when analyses excluded participants with prevalent CVD, only the association between cardiac index and total brain volume remained. The association was stronger for individuals less than 60 years of age, which coincides with a period in the lifespan with reduced risk for abnormal brain changes, possibly allowing the influence of cardiac index on brain health to be more prominent. Individuals in the top tertile of cardiac index had a higher mean total brain volume equivalent to nearly two years of healthy brain aging as compared to those participants in either the middle or bottom tertile of cardiac index. Though cardiac index as a continuous variable was unrelated to neuropsychological performances, when clinical cut-offs were applied, low cardiac index was related to information processing speed, a finding that was modestly attenuated when participants with prevalent CVD were excluded from analyses.
Collectively, these results suggest that even in the absence of prevalent CVD, cardiac index is related to total brain volume, a neuroimaging marker of brain health, and low cardiac index is related to information processing speed. Prior research relating cardiac output to neuroimaging and neuropsychological phenotypes of maladaptive brain aging in clinical cohorts have yielded significant associations.2,4,5
For instance, among patients with severe cardiomyopathies2
reduced cardiac output is related to cognitive impairment. Among elders with prevalent CVD, reduced cardiac output is related to both executive dysfunction4
The current findings enhance prior research in two important ways. First, these data extend past reports by demonstrating that cardiac output is related to brain aging markers in the absence of clinical CVD
in a community-based cohort. Second, based on the cohort under investigation, the point at which cardiac index is significantly related to abnormal brain health appears to differ from the clinical threshold for abnormal cardiac function (i.e., a cardiac index value <2.5 is often used to define impaired cardiac function40
). The illustrates that the level at which cardiac index is associated with differences in brain health
(defined as total brain volume) appears to be higher than 2.5 (i.e., closer to 2.9), suggesting that a range of normal cardiac index values (i.e., 2.5-2.9) may be related to compromised brain health integrity. These findings require further study, but if replicated, such results may have significant clinical implications, including the early identification of individuals with low (<2.5) or low normal (2.5-2.9) cardiac index for treatment to prevent abnormal brain changes.
The mechanism accounting for associations between cardiac index and markers of brain aging is unknown; however, reduced systemic
blood flow may contribute to subclinical brain injury because of its impact on cerebral
blood flow homeostasis.43,44
Despite auto-regulatory mechanisms to preserve blood flow to the brain, research in macaque monkeys has demonstrated that lowering systemic blood flow via reduced cardiac output directly reduces cerebral perfusion.7
Similar findings have been reported in heart transplant candidates with severe cardiomyopathies, such that cerebral blood flow values return to healthy levels following restoration of cardiac function.45
Alterations in cerebral
blood flow homeostasis can contribute to clinical or subclinical brain injury by propagating or exacerbating microvascular damage or Alzheimer’s disease neuropathology. For instance, alterations in cerebral perfusion lead to microvessel structure changes, expression of vascular cell receptors, alterations in microvessel permeability, and vascular remodeling.46,47
Furthermore, rats develop Alzheimer’s disease-related neuropathology following acute cessation of blood flow, including diffuse beta-amyloid peptide and amyloid precursor protein expression in the hippocampus, entorhinal cortex, and neocortex.48
In transgenic mouse models of Alzheimer’s disease, chronic cerebral hypoperfusion places the brain at risk for amyloid deposition, resulting in neuronal death.49
Thus, reductions in cardiac function and systemic blood flow may lead to subclinical or clinical brain injury by affecting cerebral blood flow homeostasis. Future studies are needed to understand the mechanism(s) accounting for the preliminary epidemiological associations reported here and clinical findings reported elsewhere.2,4,5,44
Beyond the primary findings described above, an unanticipated finding was the number of community-dwelling adults with cardiac index values below standard clinical cut-off criteria. That is, approximately 30% of participants had low resting cardiac index (i.e., values <2.5 L/min/m2
When individuals with prevalent CVD were excluded, 30% of participants still had resting cardiac index values below 2.5 L/min/m2
. In light of the current observation that cardiac index is associated with cross-sectional markers of accelerated brain aging, such a high proportion of cardiac index values below clinical criteria warrants further investigation.
Our study has a number of strengths, including the large community-based cohort free of clinical dementia and stroke, comprehensive ascertainment of potential confounding variables, an innovative and precise cardiac imaging technique, stringent quality control procedures for measurement of cardiac and brain MRI, and core reading laboratory for processing measurements. However, the present findings must be tempered by several caveats. First, multiple comparisons were made, raising the possibility of a false positive finding. Next, the age and racial makeup of the Framingham Offspring Study is predominantly white, of European descent, and middle-aged to elderly, so the generalizability to other races, ethnicities, and age-groups is unknown. The exclusion of institutionalized individuals and participants with clinical stroke and the inclusion of individuals willing to undergo MRI yielded a generally healthy sample, thereby reducing the likelihood of finding relations that may be present in the general population that includes individuals with cognitive impairment or stroke. The lack of an association between cardiac index and most of the neuropsychological measures may be due to inadequate power. Similarly, the smaller dataset available for analyses relating cardiac index to hippocampal volume may have been insufficiently powered. The observational design limits inferences about causality. The brain MRI data were temporally acquired before the cardiac MRI data, which limits interpretation of directionality. Finally, the cross-sectional design increases the likelihood of residual confounding despite attempts to thoroughly adjust for confounders, including current systolic blood pressure and hypertension medication use, in analytical models. Our results are preliminary and our findings require replication in other samples.
In summary, cardiac index is associated with brain volume, even in individuals without diagnosed prevalent CVD. Though our analyses are based on an observational design and we are unable to establish a causal relation or temporality for the associations observed, we propose that subtle reductions in cardiac index, as well as cardiac index values in the low end of the normal range, may be implicated in accelerating age-related changes in the brain. However, we cannot rule out the possibility that the findings are due to some epiphenomenon. Further investigation into the mechanisms and clinical significance of the association between cardiac index and brain aging is merited.