Cerebral Perfusion is Associated with White Matter Hyperintensities in Older Adults with Heart Failure

Abstract

1. Introduction

Heart failure (HF) is a chronic disease that affects nearly six million Americans and is associated with significant economic burden,¹ recurrent hospitalizations,² and elevated mortality risk.³ Heart failure patients are also at risk for conditions like Alzheimer’s disease, and up to 75% exhibit deficits on neuropsychological tests assessing attention, executive function, memory, and language.^4–7 Past work has identified medical and clinical contributors to cognitive impairment in older adults with HF. For instance, hypertension can be found in up to 75% of HF patients and has been linked with impairments in attention/executive function in HF.^1,8 Other common comorbid conditions in HF such as depression, obesity, and diabetes have also been shown to negatively impact cognition in this population.^9–11

Recent work shows that structural brain changes, including the development of white matter hyperintensities (WMH), are important contributors to cognitive impairment in HF. Indeed, WMH are associated with decline in global cognition as well as increased risk for depression, anxiety, cerebrovascular events, and mortality in cardiac and cognitively impaired populations.^12–13 Heart failure patients also have more severe WMH relative to healthy and cardiac controls and such white matter damage has been linked with cognitive dysfunction in this population.^14–15 There is extant evidence that demonstrates the adverse effects of WMH on cognitive outcomes in cardiovascular disease and aging populations.^{12, 16–19}

It is hypothesized that WMH—and resulting cognitive impairment—in HF is a manifestation of cerebral hypoperfusion and subsequent ischemia secondary to the effects of reduced cardiac pumping efficiency and comorbid medical conditions.^20–21 Past findings showing cerebral hypoperfusion is common in this population (i.e., reduced by as much as 30%) and associated with impairments in global cognitive functioning^22–25 support this hypothesis. In addition, reduced cardiac function, as measured by ejection fraction and/or cardiac output, has also been shown to be related to increased WMH in other cardiac populations.^{20, 26–27} Moreover, cerebral hypoperfusion quantified with neuroimaging techniques has been linked with WMH in healthy elderly and patients with type 2 diabetes.^28–30

Despite these findings, past work examining the relationship between cerebral blood flow and WMH in HF has mainly relied on measures of cardiac function to operationalize cerebral perfusion. Thus, the objective of the current study was to examine the association between cerebral perfusion measured by transcranial Doppler sonography (TCD) and WMH among older adults with HF. We further sought to investigate the independent association between WMH and global cognitive status in this sample of HF patients.

2. Methods

3. Results

4. Discussion

Past work suggests that cognitive impairment in HF is a manifestation of cerebral hypoperfusion and subsequent cerebral structural damage (e.g., WMH). Previous investigations of these proposed mechanisms in HF and other cardiac samples are limited due to use of indirect perfusion measures (e.g., indices of cardiac function). In the current study, we found that lower TCD measured cerebral perfusion of the MCA was associated with higher WMH volume in a sample of older adults with HF.

Although brief changes in cerebral blood flow are maintained in healthy individuals through autoregulatory mechanisms, such mechanisms can become compromised in the presence of chronic hypoperfusion that results from HF.^{21, 24, 36} This pattern of decreased cerebral blood flow is theorized to produce WMH through declines in oxygenation and subsequent ischemic injury.^21,44 Indeed, WMH are believed to reflect ischemic related injury, including axonal loss, rarefaction of myelin, gliosis, spongiosis, and fiber loss.^45–46 The strong relationship between vascular risk factors common to HF patients that impact cerebral hemodynamics, such as reduced cardiac output, hypertension, atherosclerosis, and reduced endothelial functioning, and WMH provides further evidence for their ischemic nature.^{26, 44, 47–51}

Contrary to the findings of the current study, Vogels and colleagues³⁶ did not find a significant relationship between cerebral blood flow velocity and WMH in HF patients. The exact reason for the discrepancy between our findings and Vogels et al.³⁶ is not entirely clear. One possible explanation involves the possibility of a threshold effect. On average, the sample in Vogels et al.³⁶ exhibited rather preserved levels of cerebral blood flow velocity relative to the sample in the current study. Thus, cerebral perfusion might need to fall below a certain level to disrupt autoregulatory mechanisms and produce subsequent insult. Some evidence for this notion may be found in the Vogels et al.,³⁶ study in that a relationship between cerebral blood flow and WMH emerged in the subset of most severe HF patients in their sample but not in the overall, generally healthier, sample. Prospective studies in larger samples with a wide range of HF severity are needed to clarify the relationship between cerebral perfusion and WMH in HF.

Finally, the current study found that greater WMH was independently associated with reduced global cognitive status in HF patients. White matter hyperintensities are prevalent in vascular populations and associated with increased dementia risk and reduced performance on cognitive testing among aging and cardiovascular disease populations.^{12, 15, 52} It seems likely that WMH may also serve as a sensitive predictor of cognitive test outcomes in HF patients. Prospective studies are needed to clarify the predictive validity of WMH to cognitive impairment in HF, including risk for dementia.

Our findings are limited in several ways. First, although past work in other populations supports the directionality of our findings,^53–54 the current study consisted of cross-sectional analyses and prospective studies are needed to confirm our findings. Future studies with larger samples are also needed to determine whether WMH mediate the relationship between cerebral hypoperfusion and cognitive impairment. In addition, the current study also did not utilize a healthy control or comparison group and case-controlled studies are also needed to confirm the association between reduced cerebral blood flow, WMH, and neurocognitive outcomes in HF. If our findings are replicated with the above limitations addressed, interventions that modify cerebral blood flow (e.g., cardiac rehabilitation) in HF may lead to better neurocognitive outcomes in this population. Support for this hypothesis may be found in the concept of cognitive reserve. For instance, recent work shows that higher cognitive reserve mitigates the effects of HF on cognitive abilities such as attention, executive function, and language.⁵⁵ These findings may in part be explained by the protective effects of greater brain reserve on altered cerebral hemodynamics.⁵⁶

Several other limitations warrant further discussion. Although TCD is a valid measure of cerebral blood flow,³⁴ it does not directly assess perfusion within the brain and blood flow velocity may be compromised by conditions that negatively impact the arterial diameter (e.g., artheroscelorosis). Thus, future studies should also examine WMH and cerebral perfusion using other methods that assess cerebral blood flow (e.g., arterial spin labeling (ASL) magnetic resonance imaging or positron emission tomography (PET) imaging). Specifically, ASL MRI imaging has become increasingly popular to assess cerebral blood flow because it is non-invasive and associated with decreased patient risk.⁵⁷ More importantly, ASL provides a direct measure of cerebral blood flow through the use of an endogenous tracer that consists of magnetically-labeled arterial blood water.^57,58 Consistent with this notion, the current findings may also be limited by the MRI parameters implemented. For instance, the use of a slice thickness of 5 mm slice may have underestimated white matter lesion load relative to thinner slices.⁵⁹ Finally, future work should examine the association between cerebral blood flow and WMH with cognitive function using comprehensive neuropsychological test batteries that assesses attention, executive function, memory, and language.⁶ Such work would help to clarify the possibility of differential effects of WMH on cognition in HF.

In brief summary, the current study suggests that reduced cerebral perfusion is associated with greater WMH in HF. These findings may in part explain the high rates of cognitive impairment observed in HF populations. Prospective studies are needed to confirm our findings using additional measures of cerebral blood flow (e.g., ASL from MRI, PET scan imaging).

Acknowledgments

Footnotes

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