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European Journal of Heart Failure 2007 9(5):440-449; doi:10.1016/j.ejheart.2006.11.001
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© 2006 European Society of Cardiology

Cognitive impairment in heart failure: A systematic review of the literature

Raymond L.C. Vogelsa,*, Philip Scheltensb, Jutta M. Schroeder-Tankac and Henry C. Weinsteina

a Department of Neurology, Sint Lucas-Andreas Hospital Jan Tooropstraat 164, 1061 AE Amsterdam, The Netherlands
b Department of Neurology and Alzheimer Center, VU University Medical Center Amsterdam, The Netherlands
c Department of Cardiology, Sint Lucas-Andreas Hospital Amsterdam, The Netherlands

* Corresponding author. Tel.: +31 205108911; fax: +31 206837198. E-mail address: r.vogels{at}vumc.nl


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Outcomes
 5. Discussion
 6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
 References
 
Background: Heart failure (HF) and cognitive impairment are common medical conditions that are becoming increasingly prevalent in the aging Western population. They are associated with frequent hospitalisation and increased mortality, particularly when they occur simultaneously. Evidence from a number of studies suggests that HF is independently associated with impairment in various cognitive domains.

Aims: This systematic literature review evaluates the relation between cognitive deterioration and heart failure.

Methods: We searched electronic databases from 1966 to May 2006 for studies that investigated cognitive function in HF patients. Twenty-two controlled studies that met the inclusion criteria were selected for analysis. Study characteristics and data on global cognitive performance, memory scores, psychomotor speed and depression scores were extracted and analysed using the Cochrane Review Manager software.

Results: Pooled analysis shows diminished neuropsychological performance in HF patients, as compared to control subjects. In a pooled sample of 2937 heart-failure patients and 14,848 control subjects, the odds ratio for cognitive impairment was 1.62 (95% confidence interval:1.48–1.79, p<0.0001) among subjects with HF.

Conclusion: This review confirms the relationship between HF and cognitive impairment, but it also stresses the need for additional systematic neuropsychological data and adequate neuro-imaging from representative populations of HF patients.

Key Words: Review • Heart failure • Cognitive impairment

Received July 10, 2006; Revised September 21, 2006; Accepted November 1, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Outcomes
 5. Discussion
 6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
 References
 
The clinical syndrome of heart failure (HF) is an increasingly important and frequent complication of most diseases that affect the heart. It is one of the leading causes of hospitalisation, morbidity and mortality in Western countries, with a reported incidence of 1-2% [1-5]. The prevalence of chronic HF is estimated to be 10% among those over the age of 75, rising to 15-20% among the elderly population over the age of 80 [6]. Due to the aging population in Western countries, the prevalence of HF is expected to double within the next 40 years. Some authors even predict that it will become the epidemic of the near future [7].

Since 1977, HF has been proposed as a possible cause of cognitive dysfunction, expressed by the term ‘cardiogenic dementia’ [8]. In the past three decades, however, only a limited number of clinical studies have systematically assessed cognitive performance in HF patients. Although cognitive impairment or dementia may coincide with chronic HF for some individuals, an increasing body of evidence suggests that decreased heart function, as measured by indices of low cardiac output, is independently associated with impairment in various cognitive domains [9,10]. The prevalence of mild cognitive impairment (MCI) exceeds the prevalence of dementia, ranging from 53% to 58% in older patients with mild to moderate HF [11]. MCI is a general term most commonly used to describe a subtle but measurable deficit in one or multiple cognitive domains, most often memory. These deficits are greater than normally expected with aging, but a person does not show other symptoms of dementia, such as impaired judgment or reasoning and difficulties in performing activities of daily living. In the majority of cases it represents a transitional state between the cognitive changes of aging and the earliest clinical manifestations of dementia [12].

Cognitive dysfunction has been reported in patients who suffer from a variety of cardiovascular disorders. It is well documented among hypertensive patients, after coronary artery bypass graft (CABG) surgery [13-16] and among the survivors of sudden cardiac arrest [17]. Because of the heterogeneity in reported samples of HF patients, where a variety of vascular risk factors and co-morbidity contribute to the development of cognitive decline, the underlying pathophysiological mechanisms are difficult to identify and yet unknown. Common conditions in chronically ill patients that cause significant functional limitations like depression and extreme fatigue have been linked to cognitive dysfunction, but still need further evaluation in this patient group [18].

Although the documentation of neuropsychological changes in patients who are affected by HF has been recognised as an increasingly important feature in the development of treatment regimes for individual patients, there is still no generally accepted guideline for cognitive screening in HF patients.

We performed a literature review to evaluate the results of systematic studies on the relationship between cognitive deterioration and HF. The purpose of this article is to review these results critically and identify the shortcomings of previous studies. Finally we recommend priority areas for further research.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Outcomes
 5. Discussion
 6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
 References
 
2.1. Search strategy and selection criteria
We used MEDLINE, the National Research Register, Embase (1980-2006, OVID online) and the Cochrane Controlled Trials Register of the Cochrane Library (edition 2002, no. 4) to search for studies that investigated the relationship between HF and cognition, and which were published between 1966 and May 2006. The search included the following key words: heart failure, congestive; cognitive impairment, dysfunction, deficit; neuropsychological functions; cardiac transplantation; neuro-imaging, magnetic resonance imaging. In addition, we manually scanned the bibliographies of the articles that were found in the electronic search to identify studies that met our Inclusion criteria.

2.2. Inclusion criteria
We included in our analysis only those studies that met the following criteria: 1) they addressed randomised clinical trials or case-control surveys designed to investigate the association between HF and cognitive impairment; 2) they assessed cognitive function using validated neuropsychological methods. These methods include a range of standardised neuropsychological tests and rating scales that have either age-corrected or age- and educationally corrected normative data in the investigated population; 3) the reported data were suitable for analysis; 4) they were published in English.

Studies were evaluated according to their methods of investigation, data collection, sample characteristics, neuropsychological measures and interpretation of outcomes. Pathophysiological mechanisms causing cognitive impairment in HF patients in relation to diagnostic tests of cardiovascular and brain functions (e.g., brain imaging) were of particular interest, as they may point out directions for future research. Although not a formal neuropsychological measure, depression scores were also included in this review. Depressive symptoms are known to be an important confounder on neuropsychological functioning in patients affected by fatigue, breathlessness and angina, all of which cause discomfort and disability. Especially in patients with HF, quality of life is compromised by these physical complications of chronic illness and emotional distress resulting from poor prognosis [19,20].

2.3. Data analysis
Data were analysed using the Review Manager 4.2 software (Cochrane Collaboration). Mean scores and standardised deviations were extracted from the reviewed articles. Standardised mean difference (SMD) was calculated for proportions (fixed-effect model) using the Mantel-Haenszel method. To increase the homogeneity of the calculated results, the cognitive measures that were most commonly used to describe impairment in general cognitive functioning received priority. SMD was calculated for Mini-mental state examination (MMSE) scores, memory scores, Trail Making Test (TMT) A scores and depression-index scores. To adjust for heterogeneity among the neuropsychological methods that the studies had used to measure memory, a hierarchical approach was used in which total memory scores had precedence over delayed-memory scores, which subsequently had precedence over immediate-recall scores. The studies that presented data for prevalence of cognitive impairment in HF patients and control subjects were used to calculate odds ratios (OR).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Outcomes
 5. Discussion
 6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
 References
 
The search generated a list of fifty-seven studies that investigated cognitive impairment in HF patients. An additional six articles were identified for the review by scanning the reference lists of these studies. Only twenty-two of these sixty-three articles met the Inclusion criteria.

3.1. Methodology
No randomised controlled trials were identified in the literature. The majority (n=22 studies) were categorised as case-control studies. Eight cohort studies [21-30] and twenty-six cross-sectional studies [18,31-41], including fourteen descriptive studies with correlational design [11,42-53] were found. The latter group of uncontrolled studies was excluded because of statistical weakness and increased risk of sampling bias. Four studies[54-57] did not provide raw data for analysis. Three studies published data that had already been analysed in previous publications [43,58,59]. Characteristics of the studies that were ultimately included in the review are summarised in Table 1 (See Appendix A).

3.2. Sample characteristics
Total sample sizes including control groups ranged from 17 patients [60,61] to 13,635 (1583 patients, 12,052 controls) [62]. In four studies, the control groups consisted of healthy participants, both matched and unmatched [63-66]. Patients with other cardiac diagnoses were used as controls in six studies [9,67-71]. In six studies, patient groups were differentiated according to New York Heart Association (NYHA) functional class, MMSE or left ventricular ejection fraction (LVEF) [9,11,60,72-74]. In five studies, patients served as their own controls after cardiac transplant [64,75-78]. Two studies [62,79] used hospitalised patients with other diagnoses as controls.

Mean ages in these studies ranged from 38 (±4.7) to 83 years (±5.4). Overall, the groups that were investigated in the studies were heterogeneous and consisted primarily of hospitalised patients whose clinical state of HF was either sub-acute or stable.

In the transplant studies, data were analysed retrospectively, with the exception of Strauss and colleagues, [70] who prospectively compared post-cardiac transplant patients with post-CABG patients. Three [64,75,78] of the five transplant-study articles reported times of data collection. The data-collection methods that were reported in the remaining seventeen studies were either prospective, concerning consecutive patients prior to or during the intervention phase of a clinical trial, or cross-sectional over periods ranging from 4 months to more than 3 years.

3.3. Neuropsychological measures
All of the reports used standardised neuropsychological tests to determine cognitive outcomes. The MMSE was used as a screening measure for global cognitive performance in nine studies [9,61,64,67-69,73,77,80] and it was the sole neuropsychological component in two of these articles [69,73]. Ekman and colleagues [73] dichotomised the MMSE score, using a median value of 28 as a cut-off at baseline to examine correlated variables in a HF population. The other authors used comparisons between means of MMSE or a cut-off score of 24 as indication of cognitive impairment.

Two authors [62,79] used the Hodkinson Abbreviated Mental Test (AMT). This ten-item general cognitive screening test is comparative to the MMSE, and it was not designed to assess specific domains. Although these general screening tests for cognitive function offer the benefits of brevity and ease of administration, the single scores that they produce can mask mild impairments in specific cognitive domains.

The cognitive areas that were the most commonly assessed in the reviewed studies were memory, attention, problem solving and motor speed. Immediate reproduction and delayed recall of verbal (word lists), visual (figures) and auditory stimuli (short stories, sounds) were the most commonly applied methods of assessing memory. A number of the test batteries used recognition, semantic clustering and learning curves assessed by verbal-learning tests in addition to recall. Fourteen studies assessed simple and complex attention. Executive functions (planning, tactual performance, problem solving) were registered in eleven articles [61,63,65,68,70,72,74-78]. These functions were most commonly assessed indirectly, using the TMT A/B or similar neurological tests. Motor speed, dexterity and reaction times were registered with both computerised and manual tests in thirteen studies [61,63-66,68,70,72,74-78]. Pre-morbid intelligence was fully assessed in only eight studies, and it was partially assessed in two studies; the Wechsler Adult Intelligence Scale (WAIS) and National Adult Reading Test (NART) were the primary means of assessment.

The prevalence of anxiety and depression among HF patients is high, [81,82] and these conditions affect scores on neuropsychological tests negatively. Eleven studies [9,64,66-72,76,77] obtained results from mood and anxiety questionnaires and related these outcomes to cognitive function. The most commonly applied instruments are self-report rating inventories, measuring characteristic attitudes of depression. The Geriatric depression scales (GDS) was used in three studies [9,67,69], the Beck's Depression Inventory (BDI) in two studies [70,77] and the Minnesota Multiphasic Personality Inventory (MMPI) in another two [75,76]. The remaining four articles used less common scales for objective measurement of mood and anxiety, like the Rand's Mental Health Inventory (MHI) [72] and the Hospital anxiety and depression questionnaire (HAD) [71].

3.4. Neuro-physiological and neuro-anatomical measures
The only studies to perform brain imaging were conducted by Schmidt [66] and by Alves and colleagues [61]. Although this method can provide valuable information on pathophysiological mechanisms involved in neuro-cognitive functioning, no systematic visualisation of cerebral structures in HF patients had been performed, even in the cross-sectional studies that were excluded from this review. In two of the studies, [64,70] electroencephalography (EEG), auditory and visually evoked potentials were used in conjunction with standardised neuropsychological tests.

3.5. Cardiovascular parameters
All but six of the twenty-two reviewed studies reported parameters of cardiovascular function. The most common measures were LVEF, NYHA functional class, systolic and diastolic blood pressures.


   4. Outcomes
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Outcomes
5. Discussion
 6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
 References
 
Results of memory scores were suitable for analysis in thirteen studies, as described in Fig. 1. The pooled sample in a total of 863 patients and 753 controls shows a SMD of – 0.43 in favour of the controls and patients who had received transplants, as compared to the HF patients. Only three [65,74,78] of the studies that are presented contained references to standardised normative data for these tests. Because the remaining studies did not provide this information the prevalence and severity data were not interpretable.


Figure 01
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  		Fig. 1 Memory scores.

 
Data on MMSE mean scores and standard deviations were available in six of nine studies that used the MMSE for global cognitive screening. Fig. 2 indicates that HF is associated with a significant decrease in MMSE scores with a SMD of – 0.32 (n=822 patients and 1578 controls). Cacciatore and colleagues [69] reported the most dramatic finding in this group of studies; they found a two-fold increase in the risk of cognitive impairment among patients with HF (OR: 1.96; 95% confidence interval 1.07-3.58; p<0.028). This association was independent of age, education, gender, depression, alcohol consumption, smoking, atrial fibrillation, blood pressure and heart rate. Neither this study nor the Italian population study performed by Zuccala and colleagues provided raw data from the MMSE scores that could be used for pooled analysis.


Figure 02
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  		Fig. 2 MMSE scores.

 
The TMT A, which measures attention, perceptual speed, cognitive flexibility and visual memory was used in nine articles. Data were suitable for pooled analysis in eight of these studies (total number of subjects=466 patients and 469 healthy control subjects or transplant patients who served as their own controls). Results are shown in Fig. 3. Overall, the performance of the HF patients in these studies on psychomotor tasks was worse than that of the control subjects.


Figure 03
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  		Fig. 3 Trail Making Test A (TMTA) scores.

 
Data on other cognitive domains that were frequently assessed were not suitable for pooled analysis.

The reported prevalence of cognitive impairment in HF patients ranged from 25% [71] to 74% [78]. Odds ratios were calculated when data for prevalence of cognitive impairment were available in the HF and control groups. Results are shown in Fig. 4. The scores on neuropsychological tests used to calculate the OR were as follows: the MMSE in the studies conducted by Cacciatore, Almeida and Trojano; the Hodkinson mental test in the study by Zuccala and Corsonello; the Rey Auditory Verbal Learning Test in the study by Roman; and global-memory scores from the articles by Strauss and Grubb. The pooled OR was calculated as 1.62 (95% confidence interval: 1.48-1.79). The risk of cognitive impairment (i.e., global cognitive and memory deterioration) in this pooled sample of 2937 HF patients and 14,848 control subjects was therefore 1.62 times greater for HF patients than it was for control subjects.


Figure 04
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  		Fig. 4 Cognitive dysfunction.

 
The prevalence of depression in hospitalised elderly patients with HF is estimated to be approximately 36%, as compared to 25% in patients without heart disease [81]. Major depression has been reported to be a strong predictor of second myocardial infarction, and it is a risk factor for increased mortality, particularly for HF patients [83]. Although depressed mood may produce deterioration in cognitive performance in general, it was assessed in only eleven of the twenty-two studies reviewed. Nine studies [9,66,67,69,71,72,75-77] found that depression was more prevalent among HF patients as compared to control subjects. Only Strauss and colleagues [70] described no differences in mood and anxiety. Five studies [9,69,71,72,76] conducted correlation analyses between depression scores and cognitive performance to examine potential effects on neuropsychological test outcomes. In their logistic-regression analysis, Trojano and colleagues [9] found that depression was an independent correlate of abnormal performance on at least three neuropsychological tests, with an OR of 2.36 (95% CI, 1.54-3.66). In contrast, the results of Grimm and colleagues [64] could not confirm this relation. In the remaining four articles, cognitive outcomes were corrected for depression scores. The most frequently reported symptoms were depressed mood and feelings of incapacity, fatigue and weakness during work and other activities. Results of pooled analysis are shown in Fig. 5. A pooled SMD of 0.48 (95% CI, 0.39-0.57, Z=10.13, p<0.00001) was calculated for depression scores in 1081 patients in favour of 1713 control subjects.


Figure 05
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  		Fig. 5 Depression scores.

 
4.1. Neuro-physiological and neuro-anatomical measures
Schmidt and colleagues compared the MRI brain scans and neuropsychological performance of twenty neurologically asymptomatic patients (mean age=40±7.8 years) who were suffering from idiopathic dilated cardiomyopathy to those of twenty age-matched control subjects. The patients exhibited a significantly higher rate of cerebral infarcts (20% versus 0%, p<0.05) and cortical and ventricular atrophy than controls. Furthermore, patients with abnormal MRI findings had significantly poorer cognitive performance on learning tasks, verbal memory and reaction times than did the healthy control participants, who were matched for age and education. Alves and colleagues [61] detected a higher incidence of regional cerebral blood flow reductions, bilaterally in the cuneus and the posterior cortical areas of the brain among HF patients than among control subjects, but they found no significant differences between the white-matter hyper-intensities on the MRI brain scans of ten HF patients and those of fourteen control subjects.

Strauss and colleagues [70] reported that 55% of the forty heart-transplant candidates had abnormal EEG findings, but they did not relate these findings to the results of their neuropsychological outcomes.

4.2. Cardiovascular parameters
Cacciatore and colleagues [69] analysed systolic and diastolic blood pressure in patients, stratified by NYHA-class and MMSE score and adjusted for age and education. Their study showed that systolic blood-pressure reduction was negatively associated with HF only among cognitively impaired patients (MMSE<24). Diastolic blood pressure variables could not predict cognitive impairment. Zuccala and colleagues [62] also found a significant negative association between systolic blood pressure and the prevalence of cognitive impairment among older HF patients (MMSE<24). Systolic blood-pressure levels below 130 mm Hg predicted lower MMSE scores, but only among patients with HF. These results are confirmed in the recent population-based cohort study by Qui and colleagues [80]. No consistent association between other cardiovascular risk factors and cognitive impairment could be proven in the reviewed studies. Only Nussbaum [60] and Almeida [68] found that low LVEF was a significant predicting risk factor for worse scores on neuropsychological tests. In contrast, five authors [63,65,72,73,76] were unable to confirm this association.

4.3. Reversibility of cognitive impairment linked to severity of illness
Most of the studies that related the severity of cardiac failure to neuropsychological performance suggest that cognitive deficits become more prominent with increasing severity of illness. In contrast to Schall and colleagues, [78] who found that cardiac transplantation fails to improve postoperative cognitive skills significantly, four authors [64,75-77] reported significant improvement in the cognitive functioning (e.g., memory) of patients who had received transplants. Deshields and colleagues [77] reported that this improvement was independent of significant decreases in depression and anxiety. Although the samples were limited, reversibility of cognitive impairment is suggested by these results.


   5. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Outcomes
 5. Discussion
6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
 References
 
The results of this review indicate that HF is associated with a pattern of generalised cognitive impairment that includes primarily memory, attention, mental flexibility and global cognitive deficits. Pooled analysis shows diminished neuropsychological performance, as expressed by significant differences in SMD rates for MMSE scores, memory scores and psychomotor speed/attention when comparing HF patients to control subjects. The data also suggest that depression is more prevalent among HF patients. Although some results are contradictory, depressed mood and anxiety are independently correlated with deterioration in cognitive performance in this patient sample. The systematic neuropsychologic assessment in HF patients is therefore fundamental to disclose conditions potentially favoring the onset of cognitive impairment such as depression.

The variability of the prevalence rates for cognitive impairment that are reported in the reviewed studies can probably be explained by both differences in characteristics of the samples of predominantly younger patients awaiting cardiac transplantation or the older patients hospitalised for HF and the differences in the range and specificity of the instruments used to assess cognitive impairment. The heterogeneity of samples, including patients and control subjects who had prior histories of stroke and brain injury, poses an additional limitation on the samples in most of the studies. Moreover, the applicability of identical cut-off scores for some of the neuropsychological measures among older individuals has been the subject of debate, and the influence of age differences on test results therefore remains. In the Italian population studies [9,62,67,69,79], cognitive performance was frequently assessed among older hospitalised patients shortly after admission. In the sub-acute stage of heart disease, such environmental and disease-related factors as dyspnoea and pain are known to lower scores on neuropsychological tests [84], and they could therefore partially explain the high prevalence of cognitive impairment among these patients. On the other hand, the global neuropsychological screening methods that were used are known to underestimate mental dysfunction, due to their non-specific sensitivity to disturbances in various cognitive domains. The differences in the breadth and specificity of the instruments used to assess cognitive impairment and their influence on the results is best illustrated by the study from Almeida and Tamai [68]. They reported that 54% of the HF population in their study had MMSE scores<24 and 74% had total Cambridge Cognition Examination (CAMCOG) scores of<80, which is used as a cut-off score for cognitive impairment. This in contrast to the older control participants, that had prevalence rates for impairment of 33% and 30% respectively. One explanation for the discrepancy between the prevalence of cognitive impairment in the same patient sample can be found in the characteristics of the test and their validated cut-off scores. The CAMCOG is a standardised, more extensive cognitive battery for the diagnosis of mental disorders in the elderly. It covers more domains than the MMSE and evaluates eleven subscales including orientation, language, memory, learning, attention, praxis, abstract thinking and perception. The sensitivity and specificity of CAMCOG are higher than the MMSE for the DSM-III diagnoses of dementia, since it manifests a smoother gradient of cognitive assessment, while MMSE tends to manifest polarized results [85]. As a result the prevalence of cognitive impairment may be underestimated in studies that used the MMSE, or a comparable test like the AMT, as the only neuropsychological measure, when compared to studies using more comprehensive neuropsychological instruments.

A number [9,62,67-69,72-74] of the reviewed studies that investigated cognitive function in relation to cardiovascular disease and cardiac surgery did not present analyses according to etiologic groups. Conclusions based on information from single diagnostic groups or aggregate categories of heterogeneous diagnoses are difficult to evaluate. They might reflect cognitive disorders after CABG surgery in an ischemic cardiomyopathy subgroup that can be related to cardio-embolic complications of surgery. A meta-analysis of 176 studies involving 205,717 post-CABG patients identified an elevated frequency of non-fatal stroke among postoperative patients [86]. In addition, patients whose cognitive function declines immediately after surgery (approximately 50% of patients who undergo CABG) are at increased risk for long-term cognitive decline and a reduced level of overall cognitive functioning [87]. Most of the reviewed studies did not take these high rates of prevalence into account in either the analysis or the pathophysiological assumptions concerning the subgroups that were investigated.

5.1. Pathophysiologic considerations
Practically all of the reviewed studies discuss two important pathophysiological hypotheses; cerebral hypo-perfusion and multiple cardiogenic emboli. Because they may occur together, it may be difficult to determine which of these conditions causes impaired cognition in patients with HF. The cerebral effects of chronic reductions in cardiac output, as observed in chronic HF patients, remains poorly understood. It is important to note that this cerebral malfunction has proven reversible after correction of cardiac output in heart-transplant patients. This suggests that the cause of ‘cardiogenic dementia’ is treatable for some patients. Recent evidence supports the hypothesis that, in addition to HF subjects, chronic hypotension or excessive antihypertensive treatment also pose an increased risk of developing dementia [80,88]. Besides cerebral hypo-perfusion, cardiogenic embolism is an important factor. Arrhythmias, valvulopathies and heart-wall disorders are potential sources of cerebral emboli, but it is unlikely to be the sole explanation for cerebral malfunction.

Ischemic heart disease and hypertension are the main causes of HF. Other cardiovascular risk factors (e.g., atrial fibrillation and diabetes mellitus) that contribute to the development of HF are also associated with lower scores on cognitive tests. Indeed, coronary artery disease, atrial fibrillation, hypertension and diabetes have all been reported to be associated with impairment in such specific cognitive domains as verbal learning, abstract thinking and attention [89,90]. In patients with chronic HF, however, the association of cognitive impairment has been shown to be independent of the presence of atrial fibrillation and hypertension; while it may be a contributing factor, it is not the sole explanation. On the other hand, these vascular risk factors are known to be related to cerebral white-matter lesions and an increased risk of dementia [91]. Data derived from the Rotterdam study indicate that these lesions are independently associated with a history of stroke or myocardial infarction, and they tend to be associated with lower scores on cognitive tests.

In our opinion, when describing the neuropsychological effects of cardiovascular disease on the brain, no conclusion can be drawn about the pathophysiological mechanisms without further assessing cerebral function in relation to structural abnormalities. Vascular damage (e.g., white-matter lesions) caused by cardiovascular risk factors could eventually be the cause of mental deterioration in patients with HF, rather than HF itself. Without adequate radiological visualisation of the brain, this remains a tentative association. Only two studies [61,66] used magnetic resonance scanning of the brain. These scans revealed that HF patients with idiopathic and ischemic cardiomyopathy demonstrated significantly worse cognitive test performance than did control subjects. Schmidt observed that performance was most impaired in patients who suffered from morphologic cerebral abnormalities (primarily cerebral infarcts and atrophy) [66].

It is important to note that various biochemical and physiological perturbations, often side effects of medicines used to treat cardiovascular disease, can affect the brain globally, often affecting the most complex intellectual functions first [92]. This is further demonstrated by another factor that is associated with cognitive dysfunction and dementia, the apolipoprotein E (APOE) epsilon4 allele; this factor has been a topic of increasing attention. Recent studies indicate that the risk of substantial decline in cognitive function among the elderly may be modified by gene-environment interactions between APOE genotype and cardiovascular risk factors [93,94].

Eventually not the heart, but a common pathophysiological pathway that affects the microcirculation in both the heart and the brain could be responsible for the observed mental deficits. Heart-failure patients, therefore, might be generally more susceptible than control subjects are to vascular damage caused by such cardiovascular risk factors as hypertension, diabetes and smoking.

The identification of a treatable cause for cognitive impairment could have major implications and allows the development of an appropriate treatment regime. As previously described, significant improvement in cognitive function among patients who have received heart transplants has frequently been reported. In addition, the implantation of pacemakers has had positive effects on both the cardiac and verbal-cognitive functioning of elderly bradycardic patients [95]. More recently, Zuccala and colleagues observed that the use of ACE inhibitors among HF patients is associated with improving cognition (OR=1.57; 95% CI, 1.18-2.08); this result has also emerged in multivariable regression modelling, independent of blood-pressure levels at baseline or discharge[54]. Mental deficits may therefore be at least partially reversible following clinical treatment.


   6. Implications for future research
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Outcomes
 5. Discussion
 6. Implications for future...
7. Conclusion
 Appendix A. Supplementary data
 References
 
The research conducted to date has largely been limited to male transplant candidates and elderly hospitalised populations that include primarily women or population-based HF cohorts. Future research should make more use of broad neuropsychological assessment data and adequate neuro-imaging from representative populations of HF patients, including outpatients. To direct future research and clinical practice, studies are needed that investigate cognitive function using extensive batteries that include executive functions in HF, in order to categorise profile, prevalence and severity in the various etiological subgroups, with respect to underlying pathophysiological mechanisms. Most clinical neuropsychological tests measure memory, language, intelligence and perceptual abilities, and they were not designed to identify substantial deficits in executive functions. As an important subset of cognitive functions, executive functions enable humans to develop and carry out plans, solve problems, function in social structures, adapt to unexpected circumstances, form analogies and enable reasoning; they also ensure that memories can be retrieved. Deficits in executive functions can have devastating effects on medical self-management and quality of life. Neuropsychological tests that are designed to assess this important cognitive domain are under-valued in the reviewed studies.


   7. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Outcomes
 5. Discussion
 6. Implications for future...
 7. Conclusion
Appendix A. Supplementary data
 References
 
Preserving cognitive function and quality of life within the growing population of elderly HF patients requires an awareness of this cerebrovascular complication in the early stages of heart disease. Although systematic data on cognitive status in HF patients is becoming increasingly available, it is clear that there is need for prospective studies and experimental models to clarify the pathogenesis of this condition further, with special attention to cerebral morphologic abnormalities in the various etiologic subgroups of HF patients. Neuropsychology should be used to specify a cognitive profile; the assessment of executive functions is indispensable in this regard.


   Appendix A. Supplementary data
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Outcomes
 5. Discussion
 6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
References
 
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ejheart.2006.11.001.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Outcomes
 5. Discussion
 6. Implications for future...
 7. Conclusion
 Appendix A. Supplementary data
 References
 

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