Heart failure (HF) is a significant public health problem, as an estimated 5.1 million Americans are currently living with the condition, and this prevalence is expected to increase an additional 46% by 2030.1 Heart failure is associated with many adverse health outcomes, including functional decline, reduced quality of life,2 recurring hospitalization, and increased mortality.3 In addition to these health consequences, HF is an established risk factor for cognitive impairment,4 particularly in domains of memory, attention, and executive function.5,6 Cognitive deficits are found in up to 73% of HF patients4,7,8 and are independent predictors of premature mortality, rehospitalization, and functional decline.9,10
Much research has been devoted to elucidating gender differences in the etiology, presentation, and prognosis of HF. Data suggest that men are more likely to develop HF, do so at a younger age,11 and have poorer prognosis.12 However, women are more likely to exhibit reduced quality of life,13 depression,14 higher pain levels, and sleep difficulties.15 Less is known about possible gender differences in neurocognitive outcomes in HF.
Results from studies in healthy populations and other cognitively declining samples suggest that gender differences may exist in the context of HF. In healthy cohorts, gender differences in cognitive function are commonly reported, with women outperforming men on verbal learning and memory tasks.16–19 However, no differences are consistently found on measures of attention and executive functioning.18,19 Other work has found that women maintain this cognitive advantage in a cognitively declining sample with atherosclerosis.20
Despite these findings, few studies have directly examined possible gender differences in cognitive function in persons with HF. In 1 study of persons with HF (ejection fraction, 28.2 ± 10.3), men exhibited poorer test performance in multiple domains, including memory, psychomotor speed, and visuospatial recall, despite having less severe HF.6 Such findings encourage further examination, particularly in persons with milder forms of HF (eg, New York Heart Association [NYHA] class II and III). Based on the above study, we hypothesized that HF would be associated with poorer cognitive function in men relative to women.
The current sample was composed of 183 adults (116 men and 67 women) with HF who were enrolled in a larger project examining neurocognitive outcomes in HF.21 All participants were stable ambulatory patients receiving routine clinical care at Summa Health System in Akron, Ohio. To be eligible for the study, persons must have been between 50 and 85 years of age at the time of enrollment, be English-speaking, and have an NYHA class between II and IV (98.9% NYHA class II and III). Exclusion criteria included history of neurological disorder (eg, dementia, stroke), head injury with more than 10 minutes loss of consciousness, presence of a severe psychiatric disorder (eg, schizophrenia, bipolar disorder), substance abuse and/or dependence, and renal failure. See Table 1 for baseline demographic and clinical characteristics.
Commonly used neuropsychological measures were used to quantify cognitive test performance. These measures are well established, have strong psychometric properties, and have been recommended for use in persons with cardiovascular disease.22 Raw scores for each measure were used in the primary analyses and were categorized into 1 of 2 neuropsychological domains. Specific measures included the following:
Attention/executive function: Trail Making Test A23 has individuals rapidly draw a line connecting numbered circles, and completion time is used as a measure of complex visual scanning and psychomotor speed. Trail Making Test B24 asks individuals to quickly connect alternating numbers and letters in ascending order, and completion time is used as a measure of ability to shift and maintain cognitive set.
The Frontal Assessment Battery25 is a short measure consisting of 6 subtests that assess frontal mediated abilities. The Word and Color Word trials from the Stroop Color Word Test26,27 were administered. The Word trial has individuals rapidly read the names of colors printed in black ink. The Color Word trial asks participants to indicate the color of ink a word is written in, ignoring the actual word, which spells out a different color. The number of words read aloud in 45 seconds for each trial is used as a measure of selective attention and mental flexibility.
Memory: The California Verbal Learning Test-II requires participants learn, recall, and recognize a 16-item word list. Four indices from the California Verbal Learning Test-II were used to quantify memory, namely, Sum of Learning Trials 1–5, Short Delay Free Recall, Long Delay Free Recall, and Total Recognition Hits.28
The 2-minute step test (2MST) asks individuals to lift their knees above a marked target during a 2-minute period.29 This measure of physical fitness was included as a covariate, as research indicates that fitness levels are independently associated with cognitive function in people with HF.30 This fitness estimate has been found to correlate with standard treadmill stress testing in persons with HF.30
Medical and demographic characteristics were ascertained through a combination of self-report and medical record review.
Participants were informed of the research study by staff at Summa Health System. Interested participants then provided consent to be contacted by a research assistant. The local institutional review board approved the study procedures and all participants provided written informed consent before initiation of any activities. During a single assessment, participants completed the 2MST and demographic and psychosocial self-report measures. Participants were also administered the neuropsychological test battery. The visit occurred at a time convenient for the participant, typically in midmorning or early afternoon. Medical records were later examined to supplement self-report and corroborate all available information. All procedures were performed in a hospital setting by trained research assistants and under the supervision of a licensed clinical neuropsychologist.
Statistical differences in demographic and medical conditions between men and women were examined using t tests and χ2 tests. Before primary analyses, assumptions for inferential statistics were examined and met, including separately by gender. Multivariate analysis of covariance was used to compare cognitive test performance, adjusting for any demographic and medical characteristics that differed between groups. Raw scores from each neuropsychological test were used in the analyses. To further clarify gender differences in cognitive test performance, raw scores from each cognitive test were transferred to T scores using existing norms and used to calculate prevalence of cognitive impairment in the sample. Cognitive impairment on a specific test was defined as a T score of 35 or lower. χ2 Analyses compared the prevalence rates of impairment on a specific task within 1 of the primary cognitive domains (ie, attention/executive function, memory) or any impaired test performance.
Demographic and Medical Differences Between Men and Women
Women had lower educational attainment (t181 = 3.09, P = .002), were less likely to have a history of smoking (χ21 = 5.79, P = .02), had higher ejection fraction (t181 = 2.46, P = .02), and had poorer estimated fitness levels (2MST; t1 = 2.06, P = .04) than men did (see Table 1). Women also trended toward a higher likelihood of hypertension (χ21 = 3.77, P = .05) but were less likely to have history of bypass or valve surgery (χ21 = 3.01, P = .08) or history of myocardial infarction (χ21 = 3.26, P = .07). Given these findings, between-group comparisons for cognitive test performance were adjusted for age, education, ejection fraction, 2MST, hypertension, history of bypass/valve surgery, history of myocardial infarction, and history of smoking.
No Gender Differences in Attention/Executive Function
Multivariate analysis of covariance was conducted on tests of attention/executive function while adjusting for age, education, ejection fraction, 2MST, hypertension, history of bypass/valve surgery, history of myocardial infarction, and history of smoking. In terms of covariates, a significant influence of age (λ = 0.86, F5, 168 = 5.38, P < .001), education (λ = 0.90, F5, 168 = 3.90, P = .002), hypertension (λ = 0.92, F5, 168 = 2.90, P = .02), and 2MST (λ = 0.87, F5, 168 = 5.20, P < .001) emerged. However, analyses found no effect for gender, such that men and women with HF did not differ on tests of attention/executive function (λ = 0.97, F5, 168 = 0.96, P = .44; Table 2).
Gender Differences in Memory Performance
Multivariate analysis of covariance was then conducted on tests of memory while adjusting for age, education, ejection fraction, 2MST, hypertension, history of bypass/valve surgery, history of myocardial infarction, and history of smoking. In terms of these covariates, a significant influence of age (λ = 0.85, F4, 169 = 7333, P < .001) emerged. This analysis also found an effect for gender, such that men and women with HF differed on tests of memory (λ = 0.90, F4, 169 = 4.76, P = .001; see Table 2). Bonferroni-corrected post hoc tests showed that women performed better than men did on Sum of Trials 1–5 (F1, 172 = 18.10, P < .001), Short Delay Free Recall (F1, 172 = 9.80, P = .002), and Long Delay Free Recall (F1, 172 = 12.89, P < .001). No differences emerged for Total Recognition Hits (F1, 172 = 1.92, P = .17).
No Gender Differences in Prevalence of Cognitive Impairment
Analyses indicated that men and women with HF did not differ in prevalence rates of cognitive impairment in attention/executive function, memory, or any impaired test performance (P > .05 for all; see Table 3).
Past research demonstrated that gender differences in cognitive functioning exist in persons with moderate to severe HF.6 The current study sought to examine whether a similar pattern is found in a sample of HF patients with predominantly NYHA class II and III. After adjusting for possible confounds, results showed that women performed better than men did on multiple memory indices, although no differences emerged on measures of attention/executive function.
As hypothesized, women performed better than men did on tasks of memory in this sample of adults with HF. Women exhibit better memory test performance than men do in healthy older populations16,19,31 and APOE4 carriers,32 suggesting that the current findings may reflect this premorbid advantage. However, it is also possible that specific aspects of HF might contribute to gender differences in cognitive functioning. For example, men develop HF at a younger age,33 and the cognitive effects of some medical conditions (eg, type 2 diabetes, obesity, hypertension) are known to increase over time.34–36 Even though men and women were generally similar in their current HF status (and statistical adjustments were used for all analyses), it is possible that historical aspects of HF that vary by gender may also influence cognitive outcomes (ie, age at onset/duration, lowest ejection fraction, severity and number of myocardial infarctions, smoking history, combination of comorbid conditions, etc). It is also possible that HF leads to differential structural and functional brain changes in men and women. A series of projects from Woo and Kumar37–40 have revealed that HF is associated with abnormalities on neuroimaging, including greater atrophy (including structures like the hippocampus and caudate), reduced cortical thickness, and changes in mean diffusivity. Although gender differences have not yet been directly examined through these studies, preliminary findings suggested this possibility.40,41 Data from large, epidemiological studies will help clarify possible mechanisms for the observed gender differences in cognitive function and the reason they are limited to memory test performance.
Despite these group differences in performance, follow-up analyses found no differences in the prevalence of cognitive impairment (T score < 35) within domains. These findings suggest that men and women with HF are both susceptible to memory dysfunction, but men experience more severe levels of impairment. As above, the exact mechanism for this pattern is unclear and may involve novel risk factors for cognitive impairment in persons with HF. If confirmed, such findings may help to account for the increased mortality risk in men with HF,11 as cognitive impairment in HF populations is linked to diminished self-care behaviors and performance in instrumental activities of daily living,9,42,43 which are known to exacerbate HF symptoms and prognosis.44,45 Given that research suggests even mild cognitive dysfunction may impact self-care in this population46 and the high prevalence of cognitive impairment in both genders in this sample, routine cognitive screening in HF should be explored as a means of improving functional outcomes.
The current study is limited in several important ways. First, all data used for this study were cross-sectional, and a prospective study using a closely matched control group is needed to elucidate the pattern of cognitive decline in male and female HF patients. Results in this study may also be affected by the methodological and statistical limitations of the current study, including unequal sample of men and women and inclusion/exclusion criteria. For example, this study excluded individuals with history of known neurological disorder and lacked information on other factors (eg, HF duration, HF type, timing, and specific severity of cardiac events) that should be accounted for in future studies, as they may help to clarify the cognitive profile in this sample.
In summary, the current study found gender differences in cognitive function in persons with HF. Specifically, women had better performance than men did on measures of memory, although no differences were found in prevalence of cognitive impairment. The mechanisms underlying these findings are unclear and warrant further investigation. Better understanding the patterns of cognitive impairment in men and women with HF may help clarify the etiology of gender differences in the presentation and prognosis of HF. Elucidating these relationships is essential to improving clinical treatment and outcomes for both genders.
What News and Important
- Cognitive impairment is common in persons with HF.
- In this sample, men with HF exhibited poorer scores on measures of learning, short delay, and long delay free recall than women did.
- Routine cognitive screening in HF should be explored as a means of improving functional outcomes for both genders.
1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation
2. Zambroski CH, Moser DK, Bhat G, Ziegler C. Impact of symptom prevalence and symptom burden on quality of life in patients with heart failure
. Eur J Cardiovas Nurs
3. Steg PG, Dabbous OH, Feldman LJ, et al. Determinants and prognostic impact of heart failure
complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation
4. Pressler SJ. Cognitive functioning and chronic heart failure
: a review of the literature (2002–July 2007). J Cardiovasc Nurs
5. Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC. Cognitive impairment in heart failure
: a systematic review of the literature. Eur J Heart Fail
6. Pressler SJ, Subramanian U, Kareken D, et al. Cognitive deficits in chronic heart failure
. Nurs Res
7. Bennett SJ, Sauvé MJ. Cognitive deficits in patients with heart failure
: a review of the literature. J Cardiovasc Nurs
8. Harkness K, Demers C, Heckman GA, McKelvie RS. Screening for cognitive deficits using the Montreal cognitive assessment tool in outpatients ≥65 years of age with heart failure
. Am J Cardiol
9. Alosco ML, Spitznagel MB, Cohen R, et al. Cognitive impairment is independently associated with reduced instrumental activities of daily living in persons with heart failure
. J Cardiovasc Nurs
10. Zuccalà G, Pedone C, Cesari M, et al. The effects of cognitive impairment on mortality among hospitalized patients with heart failure
. Am J Med
11. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure
: the Framingham study. J Am Coll Cardiol
. 1993;22(4 suppl A):A6–A13.
12. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure
in Framingham Heart Study subjects. Circulation
13. Riedinger MS, Dracup KA, Brecht M; SOLVD Investigators. Studies of Left Ventricular Dysfunction. Quality of life in women with heart failure
, normative groups, and patients with other chronic conditions. Am J Crit Care
14. Gottlieb SS, Khatta M, Friedmann E, et al. The influence of age, gender, and race on the prevalence of depression in heart failure
patients. J Am Coll Cardiol
15. Regitz-Zagrosek V, Seeland U. Sex and gender differences in myocardial hypertrophy and heart failure
. Wien Med Wochenschr
16. Jorm AF, Anstey KJ, Christensen H, Rodgers B. Gender differences in cognitive abilities: the mediating role of health state and health habits. Intelligence
17. Maller JJ, Anstey KJ, Réglade-Meslin C, Christensen H, Wen W, Sachdev P. Hippocampus and amygdala volumes in a random community-based sample of 60–64 year olds and their relationship to cognition. Psychiatry Res
18. van Hooren SA, Valentijn AM, Bosma H, Ponds RW, van Boxtel MP, Jolles J. Cognitive functioning in healthy older adults aged 64–81: a cohort study into the effects of age, sex, and education. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn
19. Munro CA, Winicki JM, Schretlen DJ, et al. Sex differences in cognition in healthy elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn
20. Moore CS, Miller IN, Andersen RL, Arndt S, Haynes WG, Moser DJ. Gender differences in neuropsychological performance in individuals with atherosclerosis: impact of vascular function. J Clin Exp Neuropsychol
21. Alosco ML, Spitznagel MB, Cohen R, et al. Cardiac rehabilitation is associated with lasting improvements in cognitive function
in older adults with heart failure
. Acta Cardiol
22. Cohen R, Gunstad J, Benitez A. Clinical considerations in the neuropsychological assessment of patients with cardiovascular disease. In: Cohen R, Gunstad J, eds. Neuropsychology and Cardiovascular Disease
. New York, NY: Oxford University Press; 2010:123–146.
23. Spreen O, Strauss EA. Compendium of Neuropsychological Tests
. New York, NY: Oxford University Press; 1991.
24. Dikmen SS, Heaton RK, Grant I, Temkin NR. Test-retest reliability and practice effects of expanded Halstead-Reitan Neuropsychological Test Battery. J Int Neuropsychol Soc
25. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology
26. Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment
. 4th ed. New York, NY: Oxford University Press; 2004.
27. Uttl B, Graf P. Color-Word Stroop test performance across the adult life span. J Clin Exp Neuropsychol
28. Delis D, Kramer J, Kaplan E, Ober B. California Verbal Learning Test—Second edition: Adult Version. Manual
. San Antonio, TX: Psychological Corporation; 2000.
29. Jones CJ, Rikli RE. Measuring functional fitness of older adults. J Active Aging
30. Garcia S, Alosco ML, Spitznagel MB, et al. Cardiovascular fitness associated with cognitive performance in heart failure
patients enrolled in cardiac rehabilitation. BMC Cardiovasc Disord
31. Andreano JM, Cahill L. Sex influences on the neurobiology of learning and memory. Learn Mem
32. Caselli RJ, Dueck AC, Locke DE, Baxter LC, Woodruff BK, Geda YE. Sex-based memory advantages and cognitive aging: a challenge to the cognitive reserve construct? J Int Neuropsychol Soc
33. Mehta PA, Cowie MR. Gender and heart failure
: a population perspective. Heart
. 2006;93(suppl 3):iii14–iii18.
34. Gunstad J, Lhotsky A, Wendell CR, Ferrucci L, Zonderman AB. Longitudinal examination of obesity and cognitive function
: results from the Baltimore longitudinal study of aging. Neuroepidemiology
35. Yogi-Morren D, Galioto R, Strandjord SE, et al. Duration of type 2 diabetes and very low density lipoprotein levels are associated with cognitive dysfunction in metabolic syndrome. Cardiovasc Psychiatry Neurol
36. Li T, Bai Y, Xiang J, et al. Duration of hypertension is associated with cognitive function
: a cross-sectional study in Chinese adults. Chin Med J (Engl)
37. Woo MA, Ogren JA, Abouzeid CM, et al. Regional hippocampal damage in heart failure
. Eur J Heart Fail
38. Kumar R, Yadav SK, Palomares JA, et al. Reduced regional brain cortical thickness in patients with heart failure
. PLoS One
39. Woo MA, Palomares JA, Macey PM, Fonarow GC, Harper RM, Kumar R. Global and regional brain mean diffusivity changes in patients with heart failure
. J Neurosci Res
40. Woo MA, Kumar R, Macey PM, Fonarow GC, Hamilton MA, Harper RM. Brain gray matter loss in heart failure
is gender-dependent [abstract]. J Heart Lung Transplant
41. Woo MA, Abouzeid CM, Macey PM, et al. Greater brain hippocampal volume loss in female over male heart failure
patients [abstract]. Circulation
42. Alosco ML, Spitznagel MB, van Dulmen M, et al. Cognitive function
and treatment adherence in older adults with heart failure
. Psychosom Med
43. Harkness K, Heckman GA, Akhtar-Danesh N, Demers C, Gunn E, McKelvie RS. Cognitive function
and self-care management in older patients with heart failure
. Eur J Cardiovasc Nurs
44. Hauptman PJ. Medication adherence in heart failure
. Heart Fail Rev
45. Murad K, Goff DC Jr, Morgan TM, et al. Burden of comorbidities and functional and cognitive impairments in elderly patients at the initial diagnosis of heart failure
and their impact on total mortality: the Cardiovascular Health Study. JACC Heart Fail
46. Cameron J, Worrall-Carter L, Page K, Riegel B, Lo SK, Stewart S. Does cognitive impairment predict poor self-care in patients with heart failure
? Eur J Heart Fail