Heart Failure and Cognitive Impairment in the Atherosclerosis Risk in Communities (ARIC) Study

INTRODUCTION

Over five million Americans suffer from heart failure (HF).¹ Approximately 25–50% of patients with HF are estimated to have cognitive impairment, commonly reporting deficits in attention, reduced executive function, slowed processing speed, and memory loss.^2–4 Mild deficits can be classified as mild cognitive impairment (MCI), while the American Psychiatric Association defines dementia as a multidomain impairment in cognitive ability that interferes with everyday activities.⁵ Cerebral hypo-perfusion due to decreased cardiac output and HF-related cardioembolic stroke may be mechanisms for the reported association of HF with cognitive impairment.^{6, 7} Atherosclerotic vascular disease, whether from the cumulative exposure to cardiovascular risk factors (elevated glucose and blood pressure) or subclinical atherosclerosis, affects cognitive function and is often related to HF.^8–15 Furthermore, alterations in circulatory hormones due to a failing heart or medication side effects may also lead to HF-related cognitive impairment.^16–18 Given that the risk factors for atherosclerosis, HF, and stroke (such as hypertension, diabetes, and smoking) are intertwined and overlapping, it is difficult to analyze the root cause of this HF-cognition association. Compounding this low left ventricular ejection fraction (EF) may be associated with worse cognitive performance, particularly in the presence of lower mean arterial pressure and the decompensated HF state.^19–21

The Atherosclerosis Risk in Communities (ARIC) study cohort provides an opportunity to elucidate the association between HF and cognitive dysfunction. Our study examines whether those with HF have a higher prevalence of dementia or MCI compared to those without HF. To bolster our assessment and identify more subtle changes in mental status, we also investigate the association between incident HF and change in cognitive function over time.

METHODS

This study uses multivariate regression to assess the relationship between HF and neurocognitive status in older adults through two analyses: (1) a cross-sectional analysis examining the association of HF with a categorical measure of cognition at a single point in time and (2) the association between onset of HF and the change in a continuous measure of cognition over a 15-year period.

RESULTS

Table 1 presents clinical characteristics for participants who attended visit 5. Included cohort members had a mean age of 76 years (SD 5.3) and most were female (59%). A total of 953 (15%) individuals had prevalent HF at visit 5, of whom 38% were classified as having dementia or MCI (compared to 24% of those without HF). The sample included only 105 cases of HFrEF, 11% of those with HF, while 184 (19%) individuals with HF were missing ejection fraction data. Compared to those with HF, those without HF (n = 5542) were more likely to be female and better educated. They were also more likely to be current drinkers. Among those with HFrEF, the average EF was 40% (SD 6.5) and only 33 had EF ≤ 35%. Those with HF had worse scores on standardized tests (DWR, WFT, DSST) at visit 5 compared to those without HF even when comparing only those with a diagnosis of dementia or MCI to each other (online appendix).

DISCUSSION

Heart failure is associated with an increased prevalence of dementia and mild cognitive impairment independent of conventional risk factors for either diagnosis. Similarly, those participants who developed incident HF showed greater cognitive decline over the same period as compared to those who did not develop HF. Given that this study controls for disease states proposed to contribute to cognitive dysfunction in the HF population (such as stroke, hypertension, diabetes, and depression), these findings suggest that HF itself may directly predispose individuals to a range of cognitive impairments.

The mechanism of this association is currently unknown and cannot be explained purely on the basis of decreased EF, as those with HFrEF showed similar results to those with HFpEF in both the cross-sectional and the change over time analyses. The relationship between EF and cognitive function has been described as nonlinear, with a steeper association between EF and decreased cognition at lower levels of EF than at higher levels;^{20, 40} however, our small sample of HFrEF participants limits our analysis of this relationship, especially since only 3.5% had LVEF ≤ 35%. Proposed pathways connecting HF to cognitive decline include cerebral atrophy from hypo-perfusion, infarction due to decreased blood flow, subclinical cardioembolic phenomena, and an association between natriuretic peptides and the deposition of amyloid plaques in the brain.^{16, 17, 41, 42} Other possible causes include the interplay between decreased cardiac output and previously described co-morbidities including microvascular damage from diabetes, vascular damage from hypertension, and arterial disease.^{2, 43, 44} Finally, the association might be non-causal, e.g., the result of confounding by the use of certain medications. The relationship between HF and cognitive decline is possibly bidirectional as those with HF may suffer cognitive decline as shown in our study; however, baseline poor cognition may lead to poor medication adherence for chronic diseases such as HTN and CHD further pre-disposing them to HF.⁴⁵

Previous studies have described a similar relationship between HF and cognitive impairment. Jefferson et al. examined a small cohort of elderly individuals (n = 72) and found that those with worse executive functioning were more likely to have low cardiac output.¹⁹ When examining a cohort of decompensated HF patients (n = 20) compared to healthy controls, Kindermann and colleagues noted worse cognition in those with HF.²¹ Gottesman and colleagues examined 234 individuals with coronary arterial disease and found that those with lower EF had lower global functioning scores and worsened motor function.²⁰ A systematic review published in 2007 by Vogels et al. pooled analyses of case-control studies examining almost 3000 patients with HF. This analysis showed that patients with HF had increased prevalence of cognitive impairment (odds ratio 1.62, 95% CI 1.48–1.79) than those without HF.¹⁷ All these studies suggest a strong cross-sectional relationship between HF and cognitive impairment, though the studies varied in their control for cardiovascular risk factors and other potential confounders.

Although prior longitudinal studies have demonstrated the relationship between more pronounced cognitive decline and heart failure, our multi-center ARIC cohort study is unique in its combination of size, detailing of cognitive status, and its lengthy follow-up of over 15 years.⁴⁶ All elderly participants in this large cohort were originally recruited at home and assessed in the ARIC field centers. Thus, this analysis refers to a group of individuals most of whom were healthy enough to attend nearly daylong in-person visits. Also, because of our unique outpatient setting, the observed association between HF and cognitive impairment is less likely to be confounded by delirium or situational depression, which was noted in studies consisting primarily of hospitalized patients.¹⁷ Additionally, our study’s neuropsychological assessment included a wide range of cognitive abilities: executive functioning, spatial reasoning, and ability to perform activities of daily living. The extensive neuropsychological evaluations undertaken in this analysis and examination of an elderly population from the community is only matched by European studies including the Rotterdam Study and Three-City Study. Furthermore, ARIC includes a more racially diverse population than these other analyses.^{47, 48} Our study details a clear association between HF and MCI as well as dementia, which is less well described in current literature.

Several limitations pertain to this study. Importantly, although we examine a wider range of health and disease than is possible in hospital-based studies, due to the physical and temporal requirements of the comprehensive in-person examination, ARIC participants who completed visit 5 were inherently healthier than those who refused or were unable to participate. This healthy-participant effect likely contributes to the low observed prevalence of dementia and limits our ability to examine the very sickest HF patients or those with severe dementia. Additionally, our analysis examines the relationship of the change in cognition over time and concurrent development of HF. While this design works to avoid confounding by factors which are stable over time in participants (such as educational or intellectual background), the data did not allow us to determine which occurred first (cognitive decline or development of HF), so causal interpretations are not possible. Prior studies have demonstrated a predisposition to develop heart failure as cognitive function declines, and it is possible that this relationship is bidirectional which may falsely strengthen the observed relationship.²⁷ HF medications have also been proposed to interact with or contribute to cognitive decline. Only limited information was available regarding medication usage, adherence, and temporality between visits 4 and 5, limiting inclusion of potential medication effects in our analysis. Finally, the observational nature of the study means that we cannot be sure of freedom from residual unmeasured confounding.

Despite these limitations, this analysis highlights associations between HF and neurocognitive decline that cannot be explained by known and observed risk factors. These findings can aid clinicians when caring for HF patients and ensure they are attuned to the risk of cognitive decline associated with this disease. It also provides potential areas for further analysis and therefore intervention to prevent cognitive decline, whether by improved HF treatment, increasing cardiac output, or adjusting medications.

Future studies should aim to observe changes in cognitive function occurring after HF develops, with possible neurologic imaging and more detailed examinations of disease states that may contribute to cognitive decline. Similarly, potential differences in cognitive status among those with HFrEF as compared to those with HFpEF warrant additional investigation, given a potential relationship between cardiac output and cognitive decline.

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