Heart failure and cognitive dysfunction.

International Journal of Cardiology 178 (2015) 12–23

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Heart failure and cognitive dysfunction James Ampadu a, John E. Morley b,c,⁎ a b c

PGY-2, Department of Internal Medicine, Saint Louis University Hospital, St. Louis, MO, United States Division of Geriatric Medicine, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States Division of Endocrinology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States

a r t i c l e

i n f o

Article history: Received 7 October 2014 Accepted 20 October 2014 Available online 22 October 2014 Keywords: Heart failure Cognitive impairment Dementia Delirium Dementia screening

a b s t r a c t It has been estimated that 5.1 million Americans suffer from heart failure. Cognitive impairment has been described as a consequence of heart failure in numerous studies spanning the last three decades. This systematic review helps differentiate “cognitive impairment” into mild cognitive impairment, dementia, and delirium. We evaluate the prevalence, pathophysiology, treatment modalities, and possible outcomes previously described with these associations in heart failure. This review also assesses the utility of the different screening modalities and their efficacy as they pertain to recognizing cognitive impairment. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction It has been estimated that 5.1 million Americans suffer from heart failure [1]. Cognitive impairment has been described as a consequence of heart failure in numerous studies spanning the last three decades. In 1997, Zuccalà et al. accredited cognitive impairment with a fivefold increase in mortality in heart failure patients [2]. The prevalence of cognitive impairment in heart failure has varied from study to study, ranging from 25 to 75%. Influencing factors in some studies have included recently hospitalized heart failure patients and patients with advanced left systolic dysfunction [3]. In this systematic review, we will closer analyze and discuss this variance in heart failure as we further distinguish cognitive impairment into mild cognitive impairment, dementia, and delirium. The pathophysiology of heart failure and cognition impairment is still under investigation. Previously described mechanisms that will be discussed in this review include chronic or intermittent cerebral hypoperfusion and/or microemboli from possible left ventricular thrombi formation [4]. A few studies have evaluated the extent of brain changes in heart failure patients in comparison to non-heart failure patients. Alosco et al. [5] described an association between cerebral hypoperfusion defined by transcranial Doppler sonography of the middle cerebral artery and greater white matter hyperintensities seen on brain MRI. Almeida et al. [6] also studied brain changes over a 2 year span in heart failure patients and concluded with subtle regional gray matter

⁎ Corresponding author at: Division of Geriatric Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, United States. E-mail address: [email protected] (J.E. Morley).

http://dx.doi.org/10.1016/j.ijcard.2014.10.087 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

loss. While the exact mechanisms remain unclear, the evidence of cognitive impairment has been well established. Cognitive impairment has been defined by different screening modalities throughout our systematic review. Special areas of interest that have been assessed include memory, executive functioning, attention, language, psychomotor speed, and visuospatial ability. The Mini Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were the two most common screening tests utilized for cognitive impairment in our review. Cameron et al. [7] compared the agreeability between these tests and found “subtle, clinically relevant” cognitive deficits that were greater captured with the MoCA than MMSE. We will discuss the benefits and limitations of each screening modality, as well as their use throughout the literature in demonstrating the association between heart failure and cognition. The management of heart failure can be very demanding on a patient. It requires strict adherence to medications, diet, symptom recognition, and follow-up. If these requirements are not met, most of which on a daily basis, decompensation, hospital admission, and mortality are likely to increase. It was estimated that the annual cost of heart failure exceeded $35 billion, a large portion attributed to hospital readmissions [8]. A study of 149 heart failure subjects, evaluated three domains of cognition comprising attention, executive functioning, and language. These areas were scored and linked to adherence in each subject. Adherence was specific to adherence to medications, appointments, and dietary regimens. Results showed that reduced performance in each cognitive domain corresponded to worse overall adherence [9]. This review was established to investigate the impact of cognition, consisting of mild cognitive impairment, dementia, and delirium, on the management of heart failure and different treatment modalities

J. Ampadu, J.E. Morley / International Journal of Cardiology 178 (2015) 12–23

that have been utilized to slow the degree and alter the effects of the impairment. 2. Methods A systematic review of PubMed database was performed for studies published between 1985 and 2014 using the following phrases: “heart failure and cognitive impairment”, “heart failure and delirium”, “heart failure and dementia”. The “Heart failure and cognition” search resulted in 591 articles, further filtered to 110 articles used in this review. The “Heart failure and delirium” search resulted in 127 articles, further filtered to 9 articles. The “Heart failure and dementia” search resulted 684 articles, further filtered into 29 articles. Articles were excluded by relevance, redundancy, and year of publication.

3. Prevalence With the prevalence of heart failure expected to double over the next 40 years, it has been estimated that subclinical cognitive impairment may affect as many as 1 million patients in the US [2]. Throughout the literature, the prevalence of cognitive impairment in heart failure has varied from study to study, ranging from 25–75%. In 2012, Gure et al. [10] studied 6189 heart failure subjects older than 67 years of age. The study, accounting for age, education level, net worth, and prior stroke, resulted in prevalence of mild cognitive impairment in 24% and 15% for dementia. In 2007, a prospective three-month study by Debette et al. [11] evaluated cognition in eighty-three hospitalized patients for CHF decompensation with LVEF b45%. 61% of these patients were found to have cognitive impairment and 31% were found to have “overt cognitive impairment” defined by MMSE scores. This variance has been accredited to sample size, selection bias, definition of cognitive impairment, and seemingly most influential, age and degree of heart failure [12]. Zuccalà et al. [3] found a relationship between left ventricular ejection fraction b30% and Mini Mental Status Examination scores b24. In a study by Harkness et al. [13] patients with NYHA classes III– IV (91%) were more likely to have MoCA score b 26 than NYHA classes I–II (52%). Trojano et al. [14] compared cognitive function of 515 hospitalized elderly patients, categorizing them into 149 NYHA class II, 159 NYHA class III–IV, and 207 non-CHF patients. Cognitive impairment was defined by abnormal performance on at least three neuropsychological tests consisting of cognitive domains, such as attention, verbal attainment, visual–spatial intelligence, and verbal and visuospatial memory. Cognitive impairment was seen in 57.9% of the NYHA classes III–IV group, 43% of the NYHA class II group, and 34.4% of the non-CHF group. These studies suggest that the degree of heart failure is related to the prevalence of cognitive impairment. The degree of left ventricular dysfunction also correlates to the severity of cognitive decline. Mild cognitive impairment, evident with deficits in attention, executive functioning, visuospatial functioning, memory, perceptual speed, and language, has been described in over 75% of heart failure patients [15]. Even with subclinical cognitive impairment, there has been an independent association with increased 1-month mortality and 1-year mortality among heart failure patients [16]. For this reason, it is very important to recognize the risk factors for MCI in heart failure patients. Most studies analyzing the effects of heart failure on cognition focus on mild cognitive impairment as an endpoint. One should be mindful that MCI serves as a bridge from a normal cognitive state to dementia. This is supported by the previously described screening modalities, used to demarcate the severity of cognitive impairment, i.e. MoCA, SLUMS and RCS. In addition, screening options for specific dementias have progressed with the advances in imaging from flurodeoxyglucose PET scans measuring the cerebral glucose metabolism and B-amyloid burden, as well as to MRI imaging revealing volume loss, i.e. hippocampal shrinkage, and areas of infarct [17]. Individuals with evidence of amnestic MCI are at an increase risk of dementia than the general population. The annual rate of progression from multi domain MCI, amnestic MCI, and nonamnestic MCI to non-specific dementia are 12.2%, 11.7%, and 4.1%, respectively [18]. This progression is important to recognize, as severe cognitive impairment has been associated with higher mortality in

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CHF patients. For this reason, it should not come as a surprise that these disease states share common pathologic processes, as well as risk factors and preventive measures. Cerebral hypoperfusion, reducing delivery of glucose, the brain's energy substrate, could damage or destroy neurons leading to impairment and consequential dementia. This is why it is not uncommon to find severe cognitive impairment more prevalent in NYHA class IV than NYHA class II [19]. In 2009, transthoracic echocardiograms in Alzheimer's dementia (AD) patients were compared to the control with results suggesting that AD patients have worsened transmitral flow efficacy of diastolic filling [20]. Hjelm et al. [21] found a higher prevalence of all types of dementia in CHF patients compared to the control, 40% vs 30%, including vascular dementia in CHF subjects 16% vs 6% non-CHF subjects. Diabetes was an associated risk factor specifically seen in vascular dementia. Other dementia risk factors in CHF included depression, increased homocysteine levels, and hypertension. In 2003, Qui et al. [22] evaluated the effects of systolic and diastolic blood pressures on the development of dementia within a 6-year period. The study consisted of 1270 dementia-free subjects, aged 75–101 years old. Subjects with a systolic blood pressure (SBP) N 180 mm Hg had an adjusted relative risk of 1.5 for Alzheimer's disease and 1.6 for dementia. Subjects with a diastolic blood pressure (DBP) b65 mm Hg had an adjusted relative risk of 1.7 for Alzheimer's disease and 1.5 for dementia. No associations with Alzheimer's disease and incident dementia were seen with low SBP and high DBP. In 2006, again Qui et al. [23] found an additive effect of heart failure and low DBP on the risk of developing dementia. Hawkins et al. [24] assessed predominately overweight and obese males, demonstrating a relationship between area of cognitive impairment and body mass index. Poorer attention and executive functioning were associated with higher BMI, p = 0.01, p = 0.04 respectively. Formiga et al. [25] utilized the Barthel Index as a surrogate for functional status in hospitalized decompensated heart failure patients, finding among other variables, an independent association between poorer preadmission functional status and cognitive impairment, as well as shortterm mortality. While the true prevalence of cognitive impairment in CHF remains debatable, given its many confounding factors, the expectant rise alongside heart failure is not.

4. Role of imaging Due to the advancement in neuroimaging, structural brain abnormalities have been strongly associated with congestive heart failure patients. It has been described that CHF patients have more severe white matter hyperintensities (WMHs) when compared to healthy non-cardiac and cardiac controls. Pathologic findings in white matter hyperintensities include myelin pallor, tissue refraction, (defined by loss of myelin and axons) and mild gliosis [26]. White matter hyperintensities, themselves are associated with decline in global cognition. The presence of WMH also places patients at risk for developing depression, anxiety, cerebrovascular events, dementia, and ultimately mortality [27]. These lesions are frequently seen in small vessel disease. They are thought to be a result of chronic hypoperfusion of the white matter, creating a disruption in blood–brain-barrier, and subsequent leakage of plasma into the white matter [26]. In CHF patients, reduced ejection fraction and cardiac output, eventually leading to cerebral hypoxia and ischemic brain damage, have been proposed as the two mechanisms leading to these radiographic abnormalities [27]. Cerebral autoregulation, measured by the vasodilatory response to carbon dioxide, has been found to be impaired in CHF patients and associated with poor ejection fraction and NYHA class. In NYHA class III–IV patients, cerebral blood flow was reduced by 30%, when captured by single-photon emission computed tomography. Moreover, low systolic blood pressure has been described as an independent predictor of cognitive impairment in heart failure patients [28]. As mean arterial pressure decreases beyond 80% of baseline or 60 mm Hg, cerebral blood flow declines [29].

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Poor cerebral autoregulation in older persons is worsened by heart failure evidenced by hypoperfusion, creating an environment of local ischemia and release of vasodilators such as endothelin nitric oxide, prostacyclin, epoxygenases, and also vasoconstrictors, thromboxane A2, endothelin-1, and 20-hydroxyeicosatetraenoic acids [30]. All these mediators are proposed to contribute to the development of Alzheimer's dementia likely secondarily to protein misfolding, specifically of betaamyloid (Abeta), and subsequent impaired clearance of Abeta and phosphorylated tau proteins. From a cellular level, the hypoperfused state leads to oxidative and endoplasmic reticulum stress resulting in little ATP production. This shortage of ATP/energy results in ineffective posttranslation processing, consisting of impaired protein synthesis, assembly, transport, and folding. In addition, it has been hypothesized that the defect in protein processing, protein cleavage abnormalities, and improper degradation of oxidized proteins, can lead to the production of Abeta peptides through the proteolytic enzyme, BACE-1. The downregulation of BACE-2, enzyme that cleaves the beta-amyloid precursor to prevent Abeta production, has its role as well [30]. Alves and Busatto [31] found that the regional cerebral blood flow deficits in CHF patients by single photon emission computed tomography were similar to the regional deficits in glucose metabolism seen on positron emission tomography in AD patients and more importantly, similar amyloid deposition were present in these patients. Given the increased propensity for CHF patients to have multiple cortical/subcortical infarcts and small vessel disease leading to lacunar infarcts, it has been postulated that cerebral microembolic events are also plausible mechanisms. CHF is the second leading cardiac cause for stoke, increasing the risk two- to threefold. For every 5% decline in left ventricular ejection fraction, the stroke risk increases by 18%. This is due to the increase in end-diastolic volume and subsequent intracardiac stasis leading to thrombus formation [29]. As MRI has become more utilized, brain atrophy has become more commonly described among CHF patients. Often correlated with disease duration and cognitive decline, it has been hypothesized that brain atrophy is encompassed in the cardiac cachexia syndrome that occurs in fat, muscle, and bone tissues commonly seen in end-stage heart failure. In a study comparing 20 CHF patients and 20 age-matched controls, cortical brain atrophy was present in 50% of CHF vs 5% control [29]. Alosco et al. [27] examined the cerebral blood flow and white matter hyperintensities in CHF patients as well as the relationship between cognitive impairment and white matter hyperintensities. TCD ultrasonography was utilized to assess cerebral blood flow and the middle cerebral artery was chosen as a surrogate. Study concluded with the association of lower cerebral perfusion and greater volume of white matter hyperintensities. Furthermore, greater WMHs were independently associated with reduced global cognition, demonstrated by lower scores on Mini Mental Status Examinations. Beer et al. [32] had similar findings in a study comparing CHF and non-CHF patients without clinically significant cognitive impairment. A moderate association was found between cognitive scores, determined by the CAMCOG test, and deep matter white hyperintensities along with left medial temporal atrophy in CHF patients. A previous study by Vogels et al. [33] in 2007, correlated specific cognitive impairments and location of lesion, associating medial temporal atrophy with cognitive dysfunction including memory impairment and executive functioning. This contrasted to white matter hyperintensities, as they were associated with mood disorders including depression and anxiety. Almeida et al. [34] devised a study to evaluate if there were not just white matter changes in heart failure patient, but gray matter changes as well. This study compared CHF, ischemic heart disease, and healthy control subjects, analyzing cerebral gray matter loss and mood changes over a two-year span. Similar changes in total gray matter volume were noted across all groups. However, depression and anxiety were greater in the CHF patients. This was accredited to the subtle pattern of gray matter loss in that subgroup. Gray matter loss in CHF patients was noted in “the right and left thalamus, left caudate, left and right posterior

cingulate, left and right parahippocampal gyri, left superior and middle temporal gyri, and right inferior parietal lobule [34].” These areas of the brain regulate emotion. 5. Associations with heart failure and cognitive decline Heart failure causes cognitive decline both through a variety of direct mechanisms and also indirectly due to a number of conditions associated with heart failure (Fig. 1). Approximately 20% of persons with congestive heart failure have clinically significant depression and another 35% have minor depression [35,36]. Depression is a common cause of cognitive impairment [37,38] and has been shown to be a determining factor in producing memory impairment in heart failure [39]. In patients with heart failure, the combination of depression with a decrease in global cerebral blood flow velocity resulted in increased deficits in attention and executive function [40]. Anticholinergic burden of medications and polypharmacy are both associated with increased cognitive dysfunction [41–46]: Inappropriate drug use was found to be common in heart failure in European Union nursing home residents [47]. Non-centrally active angiotensin-converting enzyme inhibitors are associated with a greater risk of dementia and functional disability [48]. Vasodilation, which increases the use of cerebral hypoperfusion are more commonly used in heart failure patients with dementia, than other heart failure drugs [49]. Surprisingly, the use of digoxin in heart failure improved cognition, presumably related to an increase in cardiac output [50]. Cachexia and protein energy undernutrition are common concomitants of end-stage heart failure [51–53]. Low serum albumin in heart failure is independently associated with poor cognition [54]. Protein energy undernutrition is well recognized to cause cognitive impairment [55,56]. Anemia in heart failure patients is also associated with cognitive impairment [54,57]. Diabetes mellitus is a common condition leading to cardiomyopathy, ischemic heart disease and heart failure [58]. Both hyper- and hypoglycemia can lead to cognitive decline [59–63]. In addition, hypertriglyceridemia is associated with poor cognitive function [64,65], possibly by impairing the ability of leptin to cross the blood brain barrier [66,67]. In males with heart failure, testosterone levels are commonly low [68,69]. Low bioavailable testosterone is a strong determinant of cognitive function, mild cognitive impairment and Alzheimer's disease [70–72]. In an animal model of Alzheimer's disease, low testosterone is associated with cognitive impairment and this can be reversed with testosterone replacement [73] in hypogonadal males [74–76]. Finally, among the indirect causes it must be recognized that diffuse atherosclerosis leads to vascular infarcts in the central nervous system. These are commonly associated with memory impairment as seen in mild cognitive impairment and may eventually lead to vascular dementia and/or Alzheimer's disease [77–79]. 5.1. Hypoxia and the blood brain barrier The major cause of cognitive impairment in heart failure appears to be low grade hypoxia that leads to disruption of the tight junctions of the blood brain barrier (BBB) (Fig. 2) [80]. The tight junction of the BBB consists of a number of membrane-associated proteins, such as occluding, Claudine and junctional association molecules that bind the endothelial cells tightly together. The development and maintenance of these junctional proteins is dependent on a variety of proteins produced by astrocytes and pericytes. Hypoxia results in the release of hypoxia inducible factor-1 (HIF-1) [81,82]. In the presence of hypoxia, HIF-1 translocates from the cytoplasm to the nucleus where it binds to hypoxia-responsive elements resulting in the expression of a variety of genes involved in the adaptation to hypoxia. These include the glucose transporter-1 leading to alterations in neuronal glucose uptake and pro-survival factors such as erythropoietin. It also activates prodeath genes, e.g., BNIP3 and p53 [83].


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(APP=amyloid precursor protein; HIF-1 = hypoxia inducible factor-1; IL-1 = interleukin 1; IL-6 = Interleukin-6; TNFα-factor-1 = tumor necrosis factorα-1; BNP = brain naturetic peptide; ANP = Atrial naturetic peptide)

Fig. 1. The potential factors involved in the pathogenesis of cognitive dysfunction in heart failure. (APP = amyloid precursor protein; HIF-1 = hypoxia inducible factor-1; IL-1 = interleukin 1; IL-6 = interleukin-6; TNF-α-1 = tumor necrosis factor-α-1; BNP = brain naturetic peptide; ANP = atrial naturetic peptide).

In astrocytes HIF-1 leads to the production of vascular endothelial factor-1 (VEGF-1). VEGF-1 in excess results in increased BBB permeability by disrupting the tight junction [84]. Astrocytes also secrete basic fibroblast growth factor that increases BBB permeability to albumin and reduces accludin permeability [85]. Pericytes produce angiopoietin-1 which destabilizes claudine [86]. This leads to influx of fluid, albumin and other protein influx from the blood into the neurons. It also results in immune cell infiltration. Aquaporin-4 receptors are molecular pumps that regulate fluid flow between the interstitial fluid of the brain and the cerebrospinal fluid [87]. This movement of water plays a major role in the clearance of molecular waste. Alterations in peripheral fluid status lead to changes in the aquaporin-4 receptors [88–90]. These changes can lead to swelling of astrocytes and microglia [91]. This leads to neuroinflammation and alterations in cholinergic function in the brain; finally resulting in edema, oxidative damage and neuronal dysfunction.

Oxidative damage results in local cytokine production in the brain leading to an increase in amyloid precursor protein (APP) and amyloidbeta protein with a reduction in memory and a further increase in free radical production [92,93]. In animal models of heart failure there is an increase in APP [94]. 5.2. Cytokines Inflammatory cytokines, produced by both the heart and extra cardiac sources, are elevated in heart failure [95,96]. A small study of patients with NYHA II or III heart failure found that higher levels of IL-6 and CRP were associated with poorer performance on the MoCA [97]. There was no association with TNF-α. Inflammatory markers were lower in those on angiotensin converting enzyme inhibitors. Peripheral administration of inflammatory cytokines modifies cognitive processes in both animals

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(HIF-1 = hypoxia-inducible factor 1; bFGF = basic fibroblast growth factor; ANG-1 = angiopoietin-1, VEGF = vascular endothelial growth factor)

Fig. 2. Simplistic view of how hypoxia disrupts the blood brain barrier. (HIF-1 = hypoxia-inducible factor 1; bFGF = basic fibroblast growth factor; ANG-1 = angiopoietin-1, VEGF = vascular endothelial growth factor).

and humans [98,99]. IL-1, IL-6 and TNF-α modulate cognition by altering synaptic plasticity and neurogenesis as well as directly inhibiting the neurotransmitter cascades involved in learning and memory [100]. For example, interleukin-1β decreases glutamate release, decreases brain derived nerve factor and activates the p38-mitogenactivated protein kinase and CREB within the hippocampus, providing a mechanism by which it can interfere with memory consolidation [101,102]. Peripheral cytokines affect the central nervous system either by activating peripheral vagal afferents which project to the amygdala and the hippocampus through the nucleus tractus solitaries [103–106]. This mechanism then activates the release of brain derived cytokines from glia or astrocytes. In addition, IL-1 can directly enter the brain through the blood brain barrier at the posterior division of the system and possibly other sites [107]. It has been shown that this peripheral IL-1 has direct effects on cognitive processes [108]. Finally, cytokines stimulate the activity of cyclooxygenase 2 (COX-2) at the blood brain barrier [109,110]. The COX-2 enzyme then produces prostaglandin E2, which then can bind to EP3 receptors in the brain. Cytokines reduce the production of VEGF and BDNF which are important for neural plasticity [111]. Finally, cytokines increase corticotrophin releasing factor resulting in activation of the hypothalamic–pituitary–adrenal axis [110]. Elevated corticosteroids suppress neurogenesis [112]. A simplified version of how

increased cytokines in heart failure can lead to memory dysfunction is provided in Fig. 3.

5.3. Homocysteine Elevated homocysteine levels are common in heart failure, probably associated with the cardio-renal syndrome [113,114]. Elevated homocysteine in persons with symptomatic heart disease is associated with worse cognitive function [115]. This is associated with white matter lesions, lacunar infarcts and brain atrophy [116,117]. Mice with hyperhomocysteinemia have cognitive impairment [118, 119]. In cultured astrocytes, homocysteine resulted in induction of reactive oxygen species, which led to alteration in the actin cytoskeleton of astrocytes but not co-cultured neurons [120]. Hyperhomocysteine in rodents increases DNA damage and reduces the activity of antioxidant defenses [121]. There is evidence that hyperhomocysteinemia inhibits basic fibroblast growth factor in the dentate gyrus of the hippocampus resulting in inhibition of neurogenesis [122]. In a transgenic mouse model of Alzheimer's disease (Tg2576) hyperhomocysteinemia increased amyloidosis [123]. In many cases folate replacement may ameliorate the effects of hyperhomocysteinemia. Overall, there is a suggestion that elevated homocysteinemia levels may play a role in the cognitive dysfunction of heart disease.


PGE2 = prostaglandin E2; IL = interleukin; TNF = tumor-necrosis factor; CRF = corticotrophin releasing factor; BBB = blood brain barrier; VEGF = vascular endothelial factor; BDNF = brain derived neurotrophic factor

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Table 1 A mnemonic for the major causes of cognitive dysfunction in heart failure. Hypoxia Emotional (depression) Atrial fibrillation (look for anticholinergic medications) Renal → homocysteinemia, hyponatremia Triglycerides and hyper/hypoglycemia BNP → hyponatremia Rhythm disturbances (atrial fibrillation) Anemia Inflammation (cytokine elevation) Nutritional problems (cachexia/low folate)

6. Screening for MCI

Fig. 3. A simplified version of how inflammatory cytokines can cause cognitive defects in heart failure. PGE2 = prostaglandin E2; IL = interleukin; TNF = tumor-necrosis factor; CRF = corticotrophin releasing factor; BBB = blood brain barrier; VEGF = vascular endothelial factor; BDNF = brain derived neurotrophic factor.

5.4. Brain naturetic peptide (BNP) Persons with cardiovascular disease and elevated BNP are more likely to have cognitive dysfunction, especially in their ability to form concepts [124]. In a study of persons 75 years and older, followed for 5 years, elevated BNP levels were a predictor of dementia [125]. Elevated BNP levels after brain injury are associated with hyponatremia [126,127]. Other mechanisms of hyponatremia in heart failure include elevated arginine vasopressin, increased angiotensin II stimulating thirst, alter renal handling of salt and diuretics [128]. Mild hyponatremia is associated with impaired cognition [129,130].

5.5. Atrial fibrillation Atrial fibrillation, including paroxysmal atrial fibrillation, have been shown to be strongly related to cognitive and functional decline independent of whether or not the person has had a stroke [131–135]. Atrial fibrillation is associated with reduced brain volume [136] and hippocampal atrophy [137]. The cognitive impairment due to atrial fibrillation is not only due to micro-emboli, but also secondary to a reduction in ventricular rate response and a decline in cerebral perfusion [138]. In summary, many secondary effects of heart failure can cause mild cognitive impairment. The synergy of these factors leads to the cognitive impairment so commonly observed in heart failure. Table 1 provides a simple mnemonic to summarize the major causes of cognitive deterioration in heart failure.

Identifying risk factors for mild cognitive impairment are only valuable if there are tools available to identify the subclinical cognitive impairment. A prospective study of 282 hospitalized heart failure patients by Dodson et al. [139] compared the Mini Mental Status Examination (MMSE) and the physicians' documentation of cognitive impairment at time of discharge. The Mini Mental Status Examination is a 30-point scale consisting of 11 domains assessing orientation, shortterm memory, attention, and visual spatial skills. In this study, scores between 21–24 were deemed “mild cognitive impairment” and scores b20 were deemed “moderate to severe impairment.” The MMSE classified 132/282 patients as having cognitive impairment, 25.2% as “mild cognitive impairment” and 21.6% as “moderate-severe cognitive impairment.” Comparing these patients with the documentation of physicians, documentation was less common, only 30/132. It was demonstrated that physicians missed more mild cognitive impairment cases, only documenting 11%. The study concluded showing that patients whose cognitive impairment was not documented were more likely to experience 6-month mortality and hospital readmission. Another screening modality, the Montreal Cognitive Assessment (MoCA) is a brief exam to screen for mild cognitive impairment. As the MMSE, the MoCA is also a 30-point test. It assesses cognitive domains of memory, language, and conceptual thinking [140]. When comparing these two screening modalities head-to-head, the MoCA has shown higher sensitivity in several studies. Luis et al. [141] found the MoCA test, with cutoff score of 26, producing a sensitivity of 97% and specificity of 35%. When using a lower cutoff score of 23, sensitivity was 96% with an increase in specificity of 95%. Interestingly, the MMSE when using scoring 24 or below was deemed “insensitive” to cognitive impairment. Nasreddine et al. [42] echoed those findings using a cutoff score of 26 for mild cognitive impairment, revealing a MMSE sensitivity of 18% while MoCA sensitivity was 90%. Smith et al. [143] showed similar results comparing cutoff scores of 26, the MMSE showed a poor sensitivity of 17% while MoCA had sensitivity of 83%. Lowest MoCA scores in heart failure patients have been accredited to short-term memory, delayed recall, and visuospatial/executive domains [144]. A newer, shorter screening modality able to be performed in 3 min is the Mini-cog. This test, not influenced by education and language, utilizes the clock drawing and three-item recall. Borson et al. [145] compared the Mini-cog to the MMSE. The Mini-cog was administered in less than half the time of the MMSE and demonstrated a sensitivity of 99% for dementia, but is not useful for MCI. The Saint Louis University Mental Status (SLUMS) Examination has been shown to be at least equivalent to the MoCA, and perhaps better for the diagnosis of MCI [146–149]. It takes approximately 6.5 min to perform, which is faster than the MoCA or MMSE. However, this is too long for a busy clinical service. For this reason, we developed the Rapid Cognitive Screen (RCS) (Table 2) [150]. The RCS takes 2.5 min to perform. It has reasonable sensitivity and specificity for detecting MCI. It performs at a superior level compared to the Mini-cog. Either the SLUMS, MoCA or RCS is screening modalities that can be employed in

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Table 2 The international version of the Rapid Cognitive Screen (RCS). (0–5 = dementia; 6–7 = MCI; 8–10 = normal) Recall: Five objects — apple, pen, tie, house, car. [Recall objects after clock drawing; 5 points.] Clock drawing: Draw with time at 10 min to eleven o'clock. [4 points] Insight: Jill was a very successful stockbroker. She made a lot of money on the stock market. She then met Jack, a devastatingly handsome man. She married him and had three children. They lived in Berlin. She then stopped work and stayed at home to bring up her children. When they were teenagers, she went back to work. She and Jack lived happily ever after. What country did they live in? [1 point]

all settings of patient care including the outpatient setting. They can help to improve patient compliance and recognize potentially treatable cognitive problems. 7. Consequences of MCI The responsibilities of heart failure patients are plentiful, especially when it comes to self-care management. The care of these patients requires numerous modifications and adjustments that are often made daily. In order to recognize worsening symptoms, adhere to medication regimens, keep scheduled doctor's appointments, and comply with dietary restrictions, memory and executive functioning need to be intact. In a study evaluating heart failure patients by Callegari et al. [151], 26% had cognitive impairments in one cognitive function and 30% had impairments in four or more cognitive functions. It is no surprise that the detection of cognitive impairment, even when mild, means a poorer prognosis in heart failure (HF). Self-reported impairments in instrumental activities of daily living (IADL) have been commonly described in heart failure patients. Alosco et al. [152] assessed the degree of cognitive impairment as it pertains to IADLs. The study concluded that cognitive function is an independent predictor of self-reported IADLs. Specifically, the poorer cognitive performance, measured by tests including the MMSE, correlated with reduced independence, due to greater difficulty, in medication adherence and driving. In addition, a study consisting of 251 veterans with congestive heart failure found cognitive impairment in 58% of subjects. The greatest deficits in cognition were noted in verbal learning, immediate memory, and delayed verbal memory. These deficits were significantly associated with poorer medication adherence [153]. Moreover, HF patients with a MoCA score b26 in contrast to a MoCA score N26 were found to have significantly lower self care management [154]. McLennan et al. [155] went further and concluded that cognitively impaired heart failure patients are more likely to experience an unplanned hospitalization and/or death within 5 years. In 2003, Zuccalà et al. [156] compared heart failure patients with and without cognitive impairment and the in-hospital and outof-hospital one-year mortality rates. In-hospital one-year mortality occurred in 18% of the cognitively impaired group compared to only 3% of the control group. Out-of-hospital one-year mortality occurred at higher rates across the board, 27% of the cognitively impaired group and 15% of the control group. The study concluded with an almost fivefold increase in mortality among cognitively impaired heart failure patients. Rogers et al. [157] found that memory loss and confusion are specific barriers to communication with their physicians. Given these prognostications associated with cognitive decline in heart failure, treating the rate of decline seems to be a valuable area for further investigation and more specifically, of benefit in reducing the mortality rate associated with the cognitive decline. 8. Treatment of cognitive dysfunction As most facets of heart failure are dependent on preventive strategies, the attempts in slowing the progression of cognitive decline in

heart failure also adopt that design. Previously, the pathophysiology behind cognitive impairment was discussed. These areas of prevention are specifically promising in ceasing the decline and moreover, reducing hospitalizations and mortality in heart failure patients. Hoth et al. [158] investigated the influence of poor left ventricular ejection fraction on cognitive impairment by introducing these patients to cardiac resynchronization therapy (CRT) for 3 months and evaluating several cognitive domains. The study concluded that CRT produced significant increases in executive functioning and visuospatial functioning after 3 months in patients with improved LVEF. Furthermore, with improved LVEF, there was less global cognitive decline. Keeping with the theme of improving LVEF, Zimpfer et al. [159] demonstrated improvement in neurocognition after implantation of a ventricular assist device in severe heart failure patients. Gruhn et al. [160] illustrated a significant improvement in cerebral blood flow after heart transplantation, proposing a mechanism for cognitive improvements, as cerebral hypoperfusion has been postulated as a contributing cause in the cognitive decline. In 2013, Kozdağ et al. [161] focused on the manipulations of cardiac output and cognitive improvements by utilizing enhanced external counterpulsation (EECP) and its effects on preload and afterload. When compared to the control, the EECP treatment group showed significant improvements in cognitive domains including spontaneous naming, attention, and executive functioning. Tanne et al. [162] were interested in the effects of exercise training programs on the cognition of NYHA class III heart failure patients. Subjects who completed the exercise-training program were found to have improvements in attention and psychomotor speed. Cognitive improvements have even been recognized directly after participation in aerobic exercise within cardiac rehabilitation programs [163]. Dietary changes, i.e. avoidance of high sodium intake, have been suggested as a means to alter extent of cognitive decline [164]. In the hospitalsetting, potential reversible causes have been correlated with improved cognition in heart failure as well. Prior to discharge, the normalization of glucose, potassium, and hemoglobin were seen to better cognition in CHF [165]. Hyperglycemia is a known cause of cognitive dysfunction [166,167]. Few studies have demonstrated cognitive improvements in heart failure with the use of ACE-inhibitors, thought to be secondary to increased cerebral perfusion by its effect on the rennin-angiotensinaldosterone axis and by lowering blood viscosity [168–170]. There is evidence in animals that ACE inhibitors may have direct effects on the central nervous system [171]. It is important to recognize that there are a number of reversible causes of cognitive impairment such as hypothyroidism, vitamin B12 deficiency, sleep apnea (often associated with right sided heart failure), anticholinergic drugs, depression, infections, hearing and visual disturbances and space occupying lesions [172, 173]. These causes should not be neglected in persons with heart failure. Interventions as simple as antihypertensive drug use seemed to decrease this risk of dementia due to heart failure, possibly by reducing pulse pressure [174]. The drug class demonstrating greatest risk reduction was diuretics [23]. 9. Delirium In view of the previously explained alterations in hemodynamics in CHF patients, it is not unreasonable to assume that this group will be prone to acute, reversible cognitive states as well as suffering progressive declines. Mathillas et al. [175] demonstrated that congestive heart failure alone was an independent risk factor for delirium superimposed on dementia. Uthamalingam et al. [176] found 115 delirious patients out of a total 883 patients, using the Confusion Assessment Method, admitted in the hospital for acute decompensated heart failure. This study found increased in-hospital all-cause mortality in delirious patients (11% vs 6% non-delirious patients). In addition, delirious patients had an increased 30-day and 90-day rehospitalization rate for acute decompensated heart failure as well as increase in nursing home placement upon discharge. Strikingly, delirium was also associated with an increased


all-cause mortality 90-days post discharge. In the post-anesthesiacare unit (PACU), congestive heart failure was again found to be an independent risk factor for post-operative delirium resulting in higher in-hospital mortality and longer PACU and hospital course [177]. These studies demonstrate the prevalence of delirium in CHF and moreover, the importance in recognition of delirium as it plays a crucial role in prognosis and hospital readmissions. Many risk factors can predispose heart failure patients to delirium. Other than heart failure exacerbations themselves leading to poor cerebral perfusion and pulmonary compromise, electrolyte abnormalities such as hyponatremia, azotemia, and hypo-hyperkalemia as well as poor adherence to therapies and polypharmacy with subsequent adverse drug events (ADE) are common findings in CHF [178,179]. ADEs have been associated with delirium on admission to hospital, odds ratio 4.6, with a stronger association to delirium after admission, odds ratio 22.2 [179]. Chan et al. [180] dissected hospital admissions in the elderly as it pertained to adverse drug effects. Study concluded with ADE from single drug accounting for 46% of admissions and multiple drugs for 25% admissions. Of these medications, the most common class of ADEs were cardiovascular medications with falls and postural hypotension accounting for 24.1%, heart failure 16.9%, and delirium 14.5%. Beta blockers, nondihydropyridine calcium channel blockers, digoxin, and anti-arrhythmic medications like amiodarone have all been associated with neuropsychiatric disorders including delirium [181]. Two ADE categories that were classified as severe and preventable were noncompliance and omission of indicated therapy. Strategies implemented to reduce risk of adverse drug events and consequential delirium include frequent medication reconciliation, reducing the number of prescribers, and prescribing new medications sparingly with appropriate monitoring and follow-up [182]. Delirium should not only be assessed in CHF patients due to its associated increased hospital mortality and adverse events but as it pertains to dementia as well. The presence of delirium has been associated with an increased risk for dementia and cognitive declines compared to patients with no history of delirium [183]. Patients diagnosed with delirium in the hospital have also been shown to exhibit delirium after discharge [184]. The recovery period after delirium can be a long one, affecting quality of life and functional ability. This makes prevention of delirium, along with recognition and correction of reversible causes, the cornerstone in reducing hospital admissions, costs, morbidity, and mortality in CHF patients. 10. Conclusion Varying degrees of cognitive declines continue to be recognized in heart failure patients. These variations can be subtle to severe and/or reversible to progressive. Cognitive declines noted in heart failure often include declines in memory, executive functioning, attention, language, psychomotor speed, and visuospatial ability. The abilities to adhere to medication regimens, keep scheduled appointments, recognize symptoms of an exacerbation, and perform IADLs are all compromised once cognition is impaired. When these declines are identified, the risk of poor outcomes, hospital readmission, and death all increase. In addition, mortality increases when cognitive impairment goes without notice. Common screening modalities, which help to delineate cognitive impairment, have varying levels of efficacy and utility, noted by sensitivities/ specificities and time to administer the exams. There have been associations to cognitive impairment in heart failure, which should also prompt a physician into screening for cognitive impairment, elevated BNP, atrial fibrillation, and elevated homocysteine. With advances in neuroimaging, several characteristic findings such as white matter hyperintensities, gray matter, and brain atrophy can demonstrate evidence of cognitive impairment and postulated mechanisms of the impairment. Mechanisms described throughout the literature are thought to be secondary to chronic hypoperfusion, leading to poor cerebral perfusion and small vessel disease with lacunar infarcts and microemboli, all associated with worsening

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LVEF and cardiac output. This is why the literature addresses treatment options with the focus of improving the cardiac output and LVEF. With the poor reserve of heart failure patients, numerous insults can lead to impairment. For this reason, this review emphasizes the prevention of reversible causes and resolution of delirious states as delirium is associated with poor outcomes, such as increased risk of dementia unspecified, Alzheimer's dementia, hospital readmissions, and mortality. Correction of all electrolytes/anemia/metabolic deficits, avoidance of polypharmacy, and awareness of medication side effect profiles are among the supported interventions to avoid these risks associated with delirium. Heart failure has many associated complications. The awareness of cognitive impairment as a common complication of heart failure should be the responsibility of all physicians with appropriate periodic screening, as heart failure increases in prevalence with cognitive impairment hand in hand. Conflict of interest statement The authors declare they have no conflicts of interest regarding the writing of this article. Acknowledgments No grant funds were received. References [1] A.S. Go, D. Mozaffarian, V.L. Roger, E.J. Benjamin, J.D. Berry, W.B. Borden, D.M. Bravata, S. Dai, E.S. Ford, C.S. Fox, S. Franco, H.J. Fullerton, C. Gillespie, S.M. Hailpern, J.A. Heit, V.J. Howard, M.D. Huffman, B.M. Kissela, S.J. Kittner, D.T. Lackland, J.H. Lichtman, L.D. Lisabeth, D. Magid, G.M. Marcus, A. Marelli, D.B. Matchar, D.K. McGuire, E.R. Mohler, C.S. Moy, M.E. Mussolino, G. Nichol, N.P. Paynter, P.J. Schreiner, P.D. Sorlie, J. Stein, T.N. Turan, S.S. Virani, N.D. Wong, D. Woo, M.B. Turner, American Heart Association Statistics Committee and Stroke Statistics Subcommittee, Heart disease and stroke statistics—2013 update: a report from the American Heart Association, Circulation 127 (2013) 143–152. [2] G. Zuccalà, E. Marzetti, M. Cesari, M.R. Lo Monaco, L. Antonica, A. Cocchi, P. Carbonin, R. Bernabei, Correlates of cognitive impairment among patients with heart failure: results of a multicenter survey, Am. J. Med. 118 (2005) 496–502. [3] G. Zuccalà, C. Cattel, E. Manes-Gravina, M.G. Di Niro, A. Cocchi, R. Bernabei, Left ventricular dysfunction: a clue to cognitive impairment in older patients with heart failure, J. Neurol. Neurosurg. Psychiatry 63 (1997) 509–512. [4] R. Schmidt, F. Fazekas, H. Offenbacher, J. Dusleag, H. Lechner, Brain magnetic resonance imaging and neuropsychologic evaluation of patients with idiopathic dilated cardiomyopathy, Stroke 22 (1991) 195–199. [5] M.L. Alosco, A.M. Brickman, M.B. Spitznagel, S.L. Garcia, A. Narkhede, E.Y. Griffith, N. Raz, R. Cohen, L.H. Sweet, L.H. Colbert, R. Josephson, J. Hughes, J. Rosneck, J. Gunstad, Cerebral perfusion is associated with white matter hyperintensities in older adults with heart failure, Congest. Heart Fail. 19 (2013) E29–E34. [6] O.P. Almeida, G.J. Garrido, C. Beer, N.T. Lautenschlager, L. Arnolda, L. Flicker, Cognitive and brain changes associated with ischaemic heart disease and heart failure, Eur. Heart J. 33 (2012) 1769–1776. [7] J. Cameron, L. Worrall-Carter, K. Page, S. Stewart, C.F. Ski, Screening for mild cognitive impairment in patients with heart failure: Montreal cognitive assessment versus mini mental state exam, Eur. J. Cardiovasc. Nurs. 12 (2013) 252–260. [8] S.I. Chaudhry, G. McAvay, S. Chen, H. Whitson, A.B. Newman, H.M. Krumholz, T.M. Gill, Risk factors for hospital admission among older persons with newly diagnosed heart failure: findings from the Cardiovascular Health Study, J. Am. Coll. Cardiol. 61 (2013) 635–642. [9] M.L. Alosco, M.B. Spitznagel, M. van Dulmen, N. Raz, R. Cohen, L.H. Sweet, L.H. Colbert, R. Josephson, J. Hughes, J. Rosneck, J. Gunstad, Cognitive function and treatment adherence in older adults with heart failure, Psychosom. Med. 74 (2012) 965–973. [10] T.R. Gure, C.S. Blaum, K.M. Langa, The prevalence of cognitive impairment in older adults with heart failure, J. Am. Geriatr. Soc. 60 (2012) 1724–1729. [11] S. Debette, C. Bauters, D. Leys, N. Lamblin, F. Pasquier, P. de Groote, Prevalence and determinants of cognitive impairment in chronic heart failure patients, Congest. Heart Fail. 13 (2007) 205–208. [12] J.A. Dodson, S.I. Chaudhry, Geriatric conditions in heart failure, Curr. Cardiovasc. Risk Rep. 6 (2012) 404–410. [13] K. Harkness, C. Demers, G.A. Heckman, R.S. McKelvie, Screening for cognitive deficits using the Montreal Cognitive Assessment Tool in outpatients ≥ 65 years of age with heart failure, Am. J. Cardiol. 107 (2011) 1203–1207. [14] L. Trojano, R. Antonelli Incalzi, D. Acanfora, C. Picone, P. Mecocci, F. Rengo, Cognitive impairment: a key feature of congestive heart failure in the elderly, J. Neurol. 250 (2003) 1456–1463. [15] M.L. Alosco, M.B. Spitznagel, N. Raz, R. Cohen, L.H. Sweet, L.H. Colbert, R. Josephson, M. van Dulmen, J. Hughes, J. Rosneck, J. Gunstad, Obesity interacts with cerebral

20

[16] [17]

[18] [19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29] [30]

[31] [32]

[33]

[34]

[35]

[36]

[37] [38] [39]

[40]

[41] [42]

J. Ampadu, J.E. Morley / International Journal of Cardiology 178 (2015) 12–23 hypoperfusion to exacerbate cognitive impairment in older adults with heart failure, Cerebrovasc. Dis. Extra 2 (2012) 88–98. J.A. Dodson, S.I. Chaudhry, Geriatric conditions in heart failure, Curr. Cardiovasc. Risk Rep. 6 (2012) 404–410. E.M. Reiman, J.B.S. Langbaum, P.N. Tariot, Alzheimer's prevention initiative: a proposal to evaluate presymptomatic treatments as quickly as possible, Biomark. Med 4 (1) (Feb 2010) 3–14. T.F. Hughes, B.E. Snitz, M. Ganguli, Should mild cognitive impairment be subtyped? Curr. Opin. Psychiatry 24 (3) (2011) 237–242. M. Huijts, R.J. van Oostenbrugge, A. Duits, T. Burkard, S. Muzzarelli, M.T. Maeder, R. Schindler, M.E. Pfisterer, H.P. Brunner-La Rocca, TIME-CHF investigators. Cognitive impairment in heart failure: results from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) randomized trial, Eur. J. Heart Fail. 15 (6) (Jun 2013) 699–707. M. Belohlavek, P. Jiamsripong, A.M. Calleja, E.M. McMahon, C.L. Maarouf, T.A. Kokjohn, T.L. Chaffin, L.J. Vedders, Z. Garami, T.G. Beach, M.N. Sabbagh, A.E. Roher, Patients with Alzheimer disease have altered transmitral flow: echocardiographic analysis of the vortex formation time, J. Ultrasound Med. 28 (11) (Nov 2009) 1493–1500. C. Hjelm, A. Broström, A. Dahl, B. Johansson, M. Fredrikson, A. Strömberg, Factors associated with increased risk for dementia in individuals age 80 years or older with congestive heart failure, J. Cardiovasc. Nurs. 29 (1) (Jan-Feb 2014) 82–90. Chengxuan Qiu, Eva von Strauss, Johan Fastbom, Bengt Winblad, Laura Fratiglioni, Low blood pressure and risk of dementia in the Kungsholmen project—a 6-year follow up study, Arch. Neurol. 60 (2) (2003) 223–228. C. Qiu, B. Winblad, A. Marengoni, I. Klarin, J. Fastbom, L. Fratiglioni, Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study, Arch. Intern. Med. 166 (9) (May 8 2006) 1003–1008. M.A. Hawkins, J. Gunstad, M. Dolansky, J.D. Redle, R. Josephson, S.M. Moore, J.W. Hughes, Greater body mass index is associated with poorer cognitive functioning in male heart failure patients, J. Card. Fail. 20 (2014) 199–206. F. Formiga, D. Chivite, A. Conde, F. Ruiz-Laiglesia, A.G. Franco, C.P. Bocanegra, L. Manzano, M.M. Pérez-Barquero, RICA Investigators, Basal functional status predicts three-month mortality after a heart failure hospitalization in elderly patients — the prospective RICA study, Int. J. Cardiol. 172 (2014) 127–131. S. Debette, H.S. Markus, The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis, BMJ 341 (2010) c3666. M.L. Alosco, A.M. Brickman, M.B. Spitznagel, S.L. Garcia, A. Narkhede, E.Y. Griffith, N. Raz, R. Cohen, L.H. Sweet, L.H. Colbert, R. Josephson, J. Hughes, J. Rosneck, J. Gunstad, Cerebral perfusion is associated with white matter hyperintensities in older adults with heart failure, Congest. Heart Fail. 19 (2013) E29–E34. E. Dardiotis, G. Giamouzis, D. Mastrogiannis, C. Vogiatzi, J. Skoularigis, F. Triposkiadis, G.M. Hadjigeorgiou, Cognitive impairment in heart failure, Cardiol. Res. Pract. (June 6 2012), http://dx.doi.org/10.1155/2012/595 821 (Epub). C.A. Sila, Cognitive impairment in chronic heart failure, Clev. Clin. J. Med. 74 (Suppl. 1) (2007) S132–S137. J.C. De la Torre, Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia, Cardiovasc. Psychiatry Neurol. 2012 (2012) 367516. T.C. Alves, G.F. Busatto, Regional cerebral blood flow reductions, heart failure and Alzheimer's disease, Neurol. Res. 28 (6) (Sep 2006) 579–587. C. Beer, E. Ebenezer, S. Fenner, N.T. Lautenschlager, L. Arnolda, L. Flicker, O.P. Almeida, Contributors to cognitive impairment in congestive heart failure: a pilot case–control study, Int. Med. J. 39 (2009) 600–605. R.L. Vogels, J.M. Oosterman, B. van Harten, A.A. Gouw, J.M. Schroeder-Tanka, P. Scheltens, W.M. van der Flier, H.C. Weinstein, Neuroimaging and correlates of cognitive function among patients with heart failure, Dement. Geriatr. Cogn. Disord. 24 (2007) 418–423. O.P. Almeida, G.J. Garrido, C. Etherton-Beer, N.T. Lautenschlager, L. Arnolda, H. Alfonso, L. Flicker, Brain and mood changes over 2 years in healthy controls and adults with heart failure and ischaemic heart disease, Congest. Heart Fail. 19 (2013) E29–E34. T. Rutledge, V.A. Reis, S.E. Linke, B.H. Greenberg, P.J. Mills, Depression in heart failure: a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes, J. Am. Coll. Cardiol. 48 (2006) 1527–1537. J.K. Rustad, T.A. Stern, K.A. Hebert, D.L. Musselman, Diagnosis and treatment of depression in patients with congestive heart failure: a review of the literature, Prim. Care Companion C.N.S. Disord. 15 (2013) (Aug 15. pii: PCC.13r01511. Epub ahead of print). J.E. Morley, Depression in nursing home residents, J. Am. Med. Dir. Assoc. 11 (2010) 301–303. M. Thakur, D.G. Blazer, Depression in long-term care, J. Am. Med. Dir. Assoc. 9 (2008) 82–87. O. Hanon, J.S. Vidal, P. de Groote, M. Galinier, R. Isnard, D. Logeart, M. Komajda, Prevalence of memory disorders in ambulatory patients aged ≥70 years with chronic heart failure (from the EFICARE study), Am. J. Cardiol. 113 (2014) 1205–1210. M.L. Alosco, M.B. Spitznagel, N. Raz, R. Cohen, L.H. Sweet, S. Garcia, R. Josephson, M. van Dulmen, J. Hughes, J. Rosneck, J. Gunstad, The interactive effects of cerebral perfusion and depression on cognitive function in older adults with heart failure, Psychosom. Med. 75 (2013) 632–639. T. West, M.C. Pruchnicki, K. Porter, R. Emptage, Evaluation of anticholinergic burden of medications in older adults, J. Am. Pharm. Assoc. 53 (2003) 496–504. S.P. Fitzgerald, N.G. Bean, An analysis of the interactions between individual comorbidities and their treatments—implications for guidelines and polypharmacy, J. Am. Med. Dir. Assoc. 11 (2010) 475–484.

[43] J.E. Morley, Anticholinergic medications and cognition, J. Am. Med. Dir. Assoc. 12 (2011) 543-543 (e1). [44] E. Lowry, R.J. Woodman, R.L. Soiza, A.A. Mangoni, Associations between the anticholinergic risk scale score and physical function: potential implications for adverse outcomes in older hospitalized patients, J. Am. Med. Dir. Assoc. 12 (2011) 565–572. [45] M.O. Little, A. Morley, Reducing polypharmacy: evidence from a simple quality improvement initiative, J. Am. Med. Dir. Assoc. 14 (2013) 152–156. [46] M.T. Beier, Updated 2012 Beers criteria: what's noteworthy and cautionary? J. Am. Med. Dir. Assoc. 13 (2012) 768–769. [47] G. Colloca, M. Tosato, D.L. Vetrano, E. Topinkova, D. Fialova, J. Gindin, H.G. van der Roest, F. Landi, R. Liperoti, R. Bernabei, G. Onder, SHELTER project, Inappropriate drugs in elderly patients with severe cognitive impairment: results from the shelter study, PLoS One 7 (10) (2012) e46669. [48] K.M. Sink, X. Leng, J. Williamson, S.B. Kritchevsky, K. Yaffe, L. Kuller, S. Yasar, H. Atkinson, M. Robbins, B. Psaty, D.C. Goff Jr., Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study, Arch. Intern. Med. 169 (2009) 1195–1202. [49] G.B. Rattinger, S.K. Dutcher, P.T. Chhabra, C.S. Franey, L. Simoni-Wastila, S.S. Gottlieb, B. Stuart, I.H. Zuckerman, The effect of dementia on medication use and adherence among Medicare beneficiaries with chronic heart failure, Am. J. Geriatr. Pharmacother. 10 (2012) 69–80. [50] A. Laudisio, E. Marzetti, F. Pagano, A. Cocchi, R. Bernabei, G. Zuccalá, Digoxin and cognitive performance in patients with heart failure: a cohort, pharmacoepidemiological survey, Drugs Aging 26 (2009) 103–112. [51] J. Farkas, S. von Haehling, I.K. Kalantar-Zadeh, J.E. Morley, S.D. Anker, M. Lainscak, Cachexia as a major public health problem: frequent, costly, and deadly, J. Cachex. Sarcopenia Muscle 4 (2013) 173–178. [52] J.M. Argilés, S.D. Anker, W.J. Evans, J.E. Morley, K.C. Fearon, F. Strasser, M. Muscaritoli, V.E. Baracos, Consensus on cachexia definitions, J. Am. Med. Dir. Assoc. 11 (2010) 229–230. [53] W.J. Evans, J.E. Morley, J. Argilés, C. Bales, V. Baracos, D. Guttridge, A. Jatoi, K. Kalantar-Zadeh, H. Lochs, G. Mantovani, D. Marks, W.E. Mitch, M. Muscaritoli, A. Najand, P. Ponikowski, F. Rossi Fanelli, M. Schambelan, A. Schols, M. Schuster, D. Thomas, R. Wolfe, S.D. Anker, Cachexia: a new definition, Clin. Nutr. 27 (2008) 793–799. [54] G. Zuccala, E. Marzetti, M. Cesari, M.R. Lo Monaco, L. Antonica, A. Cocchi, P. Carbonin, R. Bernabei, Correlates of cognitive impairment among patients with heart failure: results of a multicenter survey, Am. J. Med. 118 (2005) 496–502. [55] J.E. Morley, Weight loss in older persons: new therapeutic approaches, Curr. Pharm. Des. 13 (2007) 3637–3647. [56] J.E. Morley, Undernutrition: a major problem in nursing homes, J. Am. Med. Dir. Assoc. 12 (2011) 243–246. [57] D. Del Sindaco, G. Pulignano, A. Di Lenarda, L. Tarantini, G. Cioffi, S. Tolone, M.D. Tinti, L. Monzo, G. Barbati, G. Minardi, Role of a multidisciplinary program in improving outcomes in cognitively impaired heart failure older patients, Monaldi Arch. Chest Dis. 78 (2012) 20–28. [58] J.M. Pappachan, G.I. Varughese, R. Sriraman, G. Arunagirinathan, Diabetic cardiomyopathy: pathophysiology, diagnostic evaluation and management, World J. Diabetes 4 (2013) 177–189. [59] J.P. Ryan, D.F. Fine, C. Rosano, Type 2 diabetes and cognitive impairment: contributions from neuroimaging, J. Geriatr. Psychiatry Neurol. 27 (2014) 47–55. [60] A. Sinclair, J.E. Morley, How to manage diabetes mellitus in older persons in the 21st century: applying these principles to long term diabetes care, J. Am. Med. Dir. Assoc. 14 (2013) 777–780. [61] L.H. Mallery, T. Ransom, B. Steeves, B. Cook, P. Dunbar, P. Moorhouse, Evidenceinformed guidelines for treating frail older adults with type 2 diabetes: from the Diabetes Care Program of Nova Scotia (DCPNS) and the Palliative and Therapeutic Harmonization (PATH) program, J. Am. Med. Dir. Assoc. 14 (2013) 801–808. [62] A. Sinclair, J.E. Morley, L. Rodriguez-Mañas, G. Paolisso, T. Bayer, A. Zeyfang, I. Bourdel-Marchasson, U. Vischer, J. Woo, I. Chapman, T. Dunning, G. Meneilly, J. Rodriguez-Saldana, L.M. Gutierrez Robledo, T. Cukierman-Yaffe, R. Gadsby, G. Schernthaner, K. Lorig, Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and the International Task Force of Experts in Diabetes, J. Am. Med. Dir. Assoc. 13 (2012) 497–502. [63] J.F. Flood, A.D. Mooradian, J.E. Morley, Characteristics of learning and memory in streptozocin-induced diabetic mice, Diabetes 39 (1990) 1391–1398. [64] J.E. Morley, Cognition and nutrition, Curr. Opin. Clin. Nutr. Metab. Care 17 (2014) 1–4. [65] S.A. Farr, K.A. Yamada, D.A. Butterfield, H.M. Abdul, L. Xu, N.E. Miller, W.A. Banks, J.E. Morley, Obesity and hypertriglyceridemia produce cognitive impairment, Endocrinology 149 (2008) 2628–2636. [66] W.A. Banks, S.A. Farr, J.E. Morley, The effects of high fat diets on the blood–brain barrier transport of leptin: failure or adaptation? Physiol. Behav. 88 (2006) 244–248. [67] S.A. Farr, W.A. Banks, J.E. Morley, Effects of leptin on memory processing, Peptides 27 (2006) 1420–1425. [68] E.A. Jankowska, B. Biel, J. Majda, A. Szklarska, M. Lopuszanska, M. Medras, S.D. Anker, W. Banasiak, P.A. Poole-Wilson, P. Ponikowski, Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival, Circulation 114 (2006) 1829–1837. [69] A. Florvaag, V. Oberle, M. Fritzenwanger, D. Kretschmar, S. Betge, B. Goebel, D. Barz, M. Ferrari, H.R. Figulla, M. Franz, C. Jung, Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells, Aging Male 15 (2012) 180–186.

J. Ampadu, J.E. Morley / International Journal of Cardiology 178 (2015) 12–23 [70] J.E. Morley, F. Kaiser, W.J. Raum, H.M. Perry III, J.F. Flood, J. Jensen, A.J. Silver, E. Roberts, Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone, Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 7537–7542. [71] L.W. Chu, S. Tam, R.L. Wong, P.Y. Yik, Y. Song, B.M. Cheung, J.E. Morley, K.S. Lam, Bioavailable testosterone predicts a lower risk of Alzheimer's disease in older men, J. Alzheimers Dis. 21 (2010) 1335–1345. [72] L.W. Chu, S. Tam, P.W. Lee, R.L. Wong, P.Y. Yik, W. Tsui, Y. Song, B.M. Cheung, J.E. Morley, K.S. Lam, Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men, Clin. Endocrinol. (Oxf) 68 (2008) 589–598. [73] J.F. Flood, S.A. Farr, F.E. Kaiser, M. La Regina, J.E. Morley, Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory, Physiol. Behav. 57 (1995) 669–673. [74] M.M. Cherrier, A.M. Matsumoto, J.K. Amory, S. Asthana, W. Bremner, E.R. Peskind, M.A. Raskind, S. Craft, Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment, Neurology 64 (2005) 2063–2068. [75] M.M. Cherrier, Testosterone effects on cognition in health and disease, Front. Horm. Res. 37 (2009) 150–162. [76] M.M. Cherrier, A.M. Matsumoto, J.K. Amory, M. Johnson, S. Craft, E.R. Peskind, M.A. Raskind, Characterization of verbal and spatial memory changes in from moderate to supraphysiological increases in serum testosterone in healthy older men, Psychoneuroendocrinology 32 (2007) 72–79. [77] J.E. Morley, Alzheimer's disease: future treatments, J. Am. Med. Dir. Assoc. 12 (2011) 1–7. [78] H. Villars, S. Oustric, S. Andrieu, J.P. Baeyens, R. Bernabei, H. Brodaty, K. BrummelSmith, C. Celafu, N. Chappell, J. Fitten, G. Frisoni, L. Froelich, O. Guerin, G. Gold, I. Holmerova, S. Iliffe, A. Lukas, R. Melis, J.E. Morley, H. Nies, F. Nourhashemi, J. Petermans, J. Ribera Casado, L. Rubenstein, A. Salva, C. Sieber, A. Sinclair, R. Schindler, E. Stephan, R.Y. Wong, B. Vellas, The primary care physician and Alzheimer's disease: an international position paper, J. Nutr. Health Aging 14 (2010) 110–120. [79] S. Joshi, J.E. Morley, Cognitive impairment, Med. Clin. North Am. 90 (2006) 769–787. [80] S. Engelhardt, S. Patkar, O.O. Ogunshola, Cell-specific blood–brain barrier regulation in health and disease: a focus on hypoxia, Br. J. Pharmacol. 171 (2014) 1210–1230. [81] O.O. Ogunshola, A. Al-Ahmad, HIF-1 at the blood–brain barrier: a mediator of permeability? High. Alt. Med. Biol. 13 (2012) 153–161. [82] S. Engelhardt, A.J. Al-Ahmad, M. Gassmann, O.O. Ogunshola, Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism, J. Cell. Physiol. (Dec 25 2013), http://dx.doi.org/10.1002/jcp.24544 (Epub ahead of print). [83] N. Singh, G. Sharma, V. Mishra, R. Raghubir, Hypoxia inducible factor-1: its potential role in cerebral ischemia, Cell. Mol. Neurobiol. 32 (2012) 491–507. [84] W. Chen, V. Jadhav, J. Tang, J.H. Zhang, HIF-1 alpha inhibition ameliorates neonatal brain damage after hypoxic–ischemic injury, Acta Neurochir. Suppl. 102 (2008) 395–399. [85] Y.L. Wang, Y.N. Hui, B. Guo, J.X. Ma, Strengthening tight junctions of retinal microvascular endothelial cells by pericytes under normoxia and hypoxia involving angiopoietin-1 signal way, Eye 21 (2007) 1501–1510. [86] B. Reuss, R. Dono, K. Unsicker, Functions of fibroblast growth factor (FGF)-2 and FGF-5 in astroglial differentiation and blood–brain barrier permeability: evidence from mouse mutants, J. Neurosci. 23 (2003) 6404–6412. [87] C. Iacovetta, E. Rudloff, R. Kirby, The role of aquaporin 4 in the brain, Vet. Clin. Pathol. 41 (2012) 32–44. [88] N. Saito, H. Ikegami, K. Shimada, Effect of water deprivation on aquaporin 4 (AQP4) mRNA expression in chickens (Gallus domesticus), Brain Res. Mol. Brain Res. 141 (2005) 193–197. [89] F. Umenishi, A.S. Verkman, M.A. Gropper, Quantitative analysis of aquaporin mRNA expression in rat tissues by RNase protection assay, DNA Cell Biol. 6 (1996) 475–480. [90] B.J. Kolber, M. Key, C. Yanfang, M. Morris, C. Krane, Aquaporin 4 mRNA expression in mouse brain is induced in response to dehydration, FASEB J. 17 (2003) 4–5. [91] A. Sfera, C. Osorio, Water for thought: is there a role for aquaporin channels in delirium? Front. Psychiatry (2014) 5 (May). [92] J.E. Morley, S.A. Farr, The role of amyloid-beta in the regulation of memory, Biochem. Pharmacol. 88 (2014) 479–485. [93] J.E. Morley, S.A. Farr, V.B. Kumar, H.J. Armbrecht, The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer's disease, Curr. Pharm. Des. 18 (2012) 1123–1130. [94] X. Hong, L. Bu, Y. Wang, J. Xue, J. Wu, Y. Huang, J. Liu, H. Suo, L. Yang, Y. Shi, Y. Lou, Z. Sun, G. Zhu, T. Behnisch, M. Yu, J. Jia, W. Hai, H. Meng, S. Liang, F. Huang, Y. Zou, J. Ge, Increases in the risk of cognitive impairment and alterations of cerebral β-amyloid metabolism in mouse model of heart failure, PLoS One 8 (2013) e63829, http://dx. doi.org/10.1371/journal.pone.0063829. [95] S.D. Anker, S. von Haehling, Inflammatory mediators in chronic heart failure: an overview, Heart 90 (2004) 464–470. [96] P. Aukrust, L. Gullestad, T. Ueland, J.K. Damas, A. Yndestad, Inflammatory and antiinflammatory cytokines in chronic heart failure: potential therapeutic implication, Ann. Med. 37 (2005) 74–85. [97] P. Athilingam, J. Moynihan, L. Chen, R. D'Aoust, M. Groer, K. Kip, Elevated levels of interleukin 6 and C-reactive protein association with cognitive impairment in heart failure, Congest. Heart Fail. 19 (2013) 92–98. [98] C.J. Wilson, C.E. Finch, H.J. Cohen, Cytokines and cognition—the case for a head-totoe inflammatory paradigm, J. Am. Geriatr. Soc. 50 (2002) 2041–4056.

21

[99] M. Bianchi, P. Sacerdote, A.E. Panerai, Cytokines and cognitive function in mice, Biol. Signals Recept. 7 (1998) 45–54. [100] J. McAfoose, B.T. Baune BT, Evidence for a cytokine model of cognitive function, Neurosci. Biobehav. Rev. 33 (2009) 355–366. [101] P. Gonzalez, I. Machado, A. Vilcaes, C. Caruso, G.A. Roth, H. Schioth, M. Lsaga, T. Scimonelli, Molecular mechanisms involved in interleukin 1-beta (IL-1β)-induced memory impairment. Modulation by alpha-melanocyte-stimulating hormone (α-MSH), Brain Behav. Immun. 34 (2013) 141–150. [102] D. Srinivasan, J.H. Yen, D.J. Joseph, W. Friedman, Cell type-specific interleukin1beta signaling in the CNS, J. Neurosci. 24 (2004) 6482–6488. [103] L.P. Kapcala, J.R. He, Y. Gao, J.O. Pieper, L.J. DeTolla, Subdiaphragmatic vagotomy inhibits intra-abdominal interleukin-1 beta stimulation of adrenocorticotropin secretion, Brain Res. 728 (1996) 247–254. [104] B. Sousa-Pinto, M. Ferreira-Pinto, M. Santos, A.F. Leite-Moreira, Central nervous system circuits modified in heart failure: pathophysiology and therapeutic implications, Heart Fail. Rev. (February 27, 2014), http://dx.doi.org/10.1007/s10741014-9427-x (Epublished). [105] J.F. Flood, M.O. Merbaum, J.E. Morley, The memory enhancing effects of cholecystokinin octapeptide are dependent on an intact stria terminalis, Neurobiol. Learn. Mem. 64 (1995) 139–145. [106] J.F. Flood, J.S. Garland, J.E. Morley, Evidence that cholecystokinin-enhanced retention is mediated by changes in opioid activity in the amygdala, Brain Res. 585 (1992) 94–104. [107] W.A. Banks, S.A. Farr, J.E. Morley, Entry of blood-borne cytokines into the central nervous system: effects on cognitive processes, Neuroimmunomodulation 10 (2002–2003) 319–327. [108] W.A. Banks, S.A. Farr, M.E. La Scola, J.E. Morley, Intravenous human interleukinalpha impairs memory processing in mice: dependence on blood–brain barrier transport into posterior division of the septum, J. Pharmacol. Exp. Ther. 299 (2001) 536–541. [109] Z.H. Zhang, Y. Yu, S.G. Wei, Y. Nakamura, K. Nakamura, R.B. Felder, EP(3) receptors mediate PGE(2)-induced hypothalamic paraventricular nucleus excitation and sympathetic activation, Am. J. Physiol. Heart Circ. Physiol. 301 (2011) H1559–H1569. [110] A. Ericsson, C. Arias, P.E. Sawchenko, Evidence for an intramedullary prostaglandindependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1, J. Neurosci. 17 (1997) 7166–7179. [111] R. Yirmiya, I. Goshen, Immune modulation of learning, memory, neural plasticity and neurogenesis, Brain Behav. Immun. 25 (2011) 181–213. [112] D. Tanokashira, T. Morita, K. Hayashi, T. Mayanagi, K. Fukumoto, Y. Kubota, T. Yamashita, K. Sobue, Glucocorticoid suppresses dendritic spine development mediated by down-regulation of caldesmon expression, J. Neurosci. 32 (2012) 14583–14591. [113] E. Okuyan, A. Uslu, M.A. Cakar, I. Sahin, I. Onür, A. Enhos, H.I. Biter, S. Cetin, M.H. Dinçkal, Homocysteine levels in patients with heart failure with preserved ejection fraction, Cardiology 117 (2010) 21–27. [114] R.S. Schofield, T.R. Wessel, T.C. Walker, T.S. Cleeton, J.A. Hill, J.M. Aranda Jr., Hyperhomocysteinemia in patients with heart failure referred for cardiac transplantation: preliminary observations, Clin. Cardiol. 26 (2003) 407–410. [115] R.P. Kloppenborg, P.J. Nederkoorn, Y. van der Graaf, M.I. Geerlings, Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMART-MR study, Atherosclerosis 216 (2011) 461–466. [116] R.P. Kloppenborg, P.J. Nederkoorn, A.M. Grool, K.L. Vincken, W.P. Mali, M. Vermeulen, Y. van der Graaf, M.I. Geerlings, SMART Study Group, Cerebral smallvessel disease and progression of brain atrophy: the SMART-MR study, Neurology 79 (2012) 2029–2036. [117] C. Dufouil, A. Alpérovitch, V. Ducros, C. Tzourio, Homocysteine, white matter hyperintensities, and cognition in healthy elderly people, Ann. Neurol. 53 (2003) 214–221. [118] B.C. Rhodehouse, M.A. Erickson, W.A. Banks, S.E. Bearden, Hyperhomocysteinemic mice show cognitive impairment without features of Alzheimer's disease phenotype, J. Alzheimers Dis. 35 (2013) 59–66. [119] L. Gao, X.N. Zeng, H.M. Guo, X.M. Wu, H.J. Chen, R.K. Di, Y. Wu, Cognitive and neurochemical alterations in hyperhomocysteinemic rat, Neurol. Sci. 33 (2012) 39–43. [120] S.O. Loureiro, L. Romão, T. Alves, A. Fonseca, L. Heimfarth, V. Moura Neto, A.T. Wyse, R. Pessoa-Pureur, Homocysteine induces cytoskeletal remodeling and production of reactive oxygen species in cultured cortical astrocytes, Brain Res. 1355 (2010) 151–164. [121] C. Matté, V. Mackedanz, F.M. Stefanello, E.B. Scherer, A.C. Andreazza, C. Zanotto, A.M. Moro, S.C. Garcia, C.A. Gonçalves, B. Erdtmann, M. Salvador, A.T. Wyse, Chronic hyperhomocysteinemia alters antioxidant defenses and increases DNA damage in brain and blood of rats: protective effect of folic acid, Neurochem. Int. 54 (2009) 7–13. [122] L.G. Rabaneda, M. Carrasco, M.A. López-Toledano, M. Murillo-Carretero, F.A. Ruiz, C. Estrada, C. Castro, Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression, FASEB J. 22 (2008) 3823–3835. [123] J.M. Zhuo, D. Praticò, Normalization of hyperhomocysteinemia improves cognitive deficits and ameliorates brain amyloidosis of a transgenic mouse model of Alzheimer's disease, FASEB J. 24 (2010) 3895–3902. [124] J. Gunstad, A. Poppas, S. Smeal, R.H. Paul, D.F. Tate, A.L. Jefferson, D.E. Forman, R.A. Cohen, Relation of brain natriuretic peptide levels to cognitive dysfunction in adults N55 years of age with cardiovascular disease, Am. J. Cardiol. 98 (2006) 538–540.

22


[125] T. Kerola, T. Nieminen, S. Hartikainen, R. Sulkava, O. Vuolteenaho, R. Kettunen, B-type natriuretic peptide as a predictor of declining cognitive function and dementia—a cohort study of an elderly general population with a 5-year follow-up, Ann. Med. 42 (2010) 207–215. [126] D.C. Lu, D.K. Binder, B. Chien, A. Maisel, G.T. Manley, Cerebral salt wasting and elevated brain natriuretic peptide levels after traumatic brain injury: 2 case reports, Surg. Neurol. 69 (2008) 226–229. [127] T. Nakamura, K. Sakamoto, T. Yamano, M. Kikkawa, K. Zen, T. Hikosaka, T. Kubota, A. Azuma, T. Nishimura, Increased plasma brain natriuretic peptide level as a guide for silent myocardial ischemia in patients with non-obstructive hypertrophic cardiomyopathy, J. Am. Coll. Cardiol. 39 (2002) 1657–1663. [128] G.T. Jao, J.R. Chiong, Hyponatremia in acute decompensated heart failure: mechanisms, prognosis, and treatment options, Clin. Cardiol. 33 (2010) 666–671. [129] R. Gunathilake, C. Oldmeadow, M. McEvoy, B. Kelly, K. Inder, P. Schofield, J. Attia, Mild hyponatremia is associated with impaired cognition and falls in community-dwelling older persons, J. Am. Geriatr. Soc. 61 (2013) 1838–1839. [130] B. Renneboog, W. Musch, X. Vandemergel, M.U. Manto, G. Decaux, Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits, Am. J. Med. 119 (71) (2006) e1–e8. [131] S. Kalantarian, T.A. Stern, M. Mansour, J.N. Ruskin, Cognitive impairment associated with atrial fibrillation: a meta-analysis, Ann. Intern. Med. 158 (5 Pt 1) (2013) 338–346. [132] J. Ball, M.J. Carrington, S. Stewart, SAFETY investigators, Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart 99 (2013) 542–547. [133] R. Peters, N. Beckett, Atrial fibrillation is associated with an increased risk of cognitive and functional decline, Evid. Based Med. 18 (2013) e16, http://dx.doi.org/10. 1136/eb-2012-100809. [134] I. Marzona, M. O'Donnell, K. Teo, P. Gao, C. Anderson, J. Bosch, S. Yusuf, Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies, CMAJ 184 (2012) E329–E336. [135] M.W. Rich, Atrial fibrillation in long term care, J. Am. Med. Dir. Assoc. 13 (2012) 688–691. [136] H. Stefansdottir, S.O. Arnar, T. Aspelund, S. Sigurdsson, M.K. Jonsdottir, H. Hjaltason, L.J. Launer, V. Gudnason, Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts, Stroke 44 (2013) 1020–1025. [137] S. Knecht, C. Oelschläger, T. Duning, H. Lohmann, J. Albers, C. Stehling, W. Heindel, G. Breithardt, K. Berger, E.B. Ringelstein, P. Kirchhof, H. Wersching, Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy, Eur. Heart J. 29 (2008) 2125–2132. [138] F. Cacciatore, G. Testa, A. Langellotto, G. Galizia, D. Della-Morte, G. Gargiulo, A. Vevilacqua, M.T. Del Genio, V. Canonico, F. Rengo, P. Abete, Role of ventricular rate response on dementia in cognitively impaired elderly subjects with atrial fibrillation: a 10-year study, Dement. Geriatr. Cogn. Disord. 34 (2012) 143–148. [139] J.A. Dodson, T.T. Truong, V.R. Towle, G. Kerins, S.I. Chaudhry, Cognitive impairment in older adults with heart failure: prevalence, documentation, and impact on outcomes, Am. J. Med. 126 (2013) 120–126. [140] J.A. Dodson, S.I. Chaudhry, Geriatric conditions in heart failure, Curr. Cardiovasc. Risk Rep. (Oct. 6 2012) 404–410. [141] C.A. Luis, A.P. Keegan, M. Mullan, Cross validation of the Montreal Cognitive Assessment in community dwelling older adults residing in the Southeastern US, Int. J. Geriatr. Psychiatry 24 (2009) 197–201. [142] Z.S. Nasreddine, N.A. Phillips, V. Bédirian, S. Charbonneau, V. Whitehead, et al., The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment, J. Am. Geriatr. Soc. 53 (2005) 695–699. [143] T. Smith, N. Gildeh, C. Holmes, The Montreal Cognitive Assessment: validity and utility in a memory clinic setting, Can. J. Psychiatry 52 (2007) 329–332. [144] P. Athilingam, K.B. King, S.W. Burgin, M. Ackerman, L.A. Cushman, L. Chen, Montreal Cognitive Assessment and Mini-Mental Status Examination compared as cognitive screening tools in heart failure, Heart Lung 40 (2011) 521–529. [145] S. Borson, J. Scanlan, M. Brush, P. Vitaliano, A. Dokmak, The Mini-cog: a cognitive ‘vital signs’ measure for dementia screening in multi-lingual elderly, Int. J. Geriatr. Psychiatry 15 (2000) 1021–1027. [146] S.H. Tariq, N. Tumosa, J.T. Chibnall, M.H. Perry III, J.E. Morley, Comparison of the Saint Louis University mental status examination and the mini-mental state examination for detecting dementia and mild neurocognitive disorder—a pilot study, Am. J. Geriatr. Psychiatry 14 (2006) 900–910. [147] D.M. Cruz-Oliver, T.K. Malmstrom, C.M. Allen, N. Tumosa, J.E. Morley, The Veterans Affairs Saint Louis University mental status exam (SLUMS exam) and the minimental status exam as predictors of mortality and institutionalization, J. Nutr. Health Aging 16 (2012) 636–641. [148] D.M. Cruz-Oliver, J.E. Morley, Early detection of cognitive impairment: do screening tests help? J. Am. Med. Dir. Assoc. 11 (2010) 1–6. [149] L. Feliciano, S.M. Horning, K.J. Klebe, S.L. Anderson, R.E. Cornwell, H.P. Davis, Utility of the SLUMS as a cognitive screening tool among a nonveteran sample of older adults, Am. J. Geriatr. Psychiatry 21 (2013) 623–630. [150] J.E. Morley, Mild cognitive impairment—a treatable condition, J. Am. Med. Dir. Assoc. 15 (2014) 1–5. [151] S. Callegari, G. Majani, A. Giardini, A. Pierobon, C. Opasich, F. Cobelli, L. Tavazzi, Relationship between cognitive impairment and clinical status in chronic heart failure patients, Monaldi Arch. Chest Dis. 58 (2002) 19–25. [152] M.L. Alosco, M.B. Spitznagel, R. Cohen MB, L.H. Sweet, L.H. Colbert, R. Josephson, D. Waechter, J. Hughes, J. Rosneck, J. Gunstad, Cognitive impairment is independently

[153]

[154]

[155]

[156]

[157]

[158]

[159]

[160]

[161]

[162]

[163]

[164]

[165]

[166]

[167] [168]

[169] [170]

[171] [172] [173] [174] [175]

[176]

[177]

[178]

[179]

associated with reduced instrumental activities of daily living in persons with heart failure, J. Cardiovasc. Nurs. 27 (2012) 44–50. L.A. Hawkins, S. Kilian, A. Firek, T.M. Kashner, C.J. Firek, H. Silvet, Cognitive impairment and medication adherence in outpatients with heart failure, Heart Lung 41 (2012) 572–582. K. Harkness, G.A. Heckman, N. Akhtar-Danesh, C. Demers, E. Gunn, R.S. McKelvie, Cognitive function and self-care management in older patients with heart failure, Eur. J. Cardiovasc. Nurs. 13 (2014) 277–284. S.N. McLennan, S.A. Pearson, J. Cameron, S. Stewart, Prognostic importance of cognitive impairment in chronic heart failure patients: does specialist management make a difference? Eur. J. Heart Fail. 8 (2006) 494–501. G. Zuccalà, C. Pedone, M. Cesari, G. Onder, M. Pahor, E. Marzetti, M.R. Lo Monaco, A. Cocchi, P. Carbonin, R. Bernabei, The effects of cognitive impairment on mortality among hospitalized patients with heart failure, Am. J. Med. 115 (2003) 97–103. A.E. Rogers, J.M. Addington-Hall, A.J. Abery, A.S. McCoy, C. Bulpitt, A.J. Coats, J.S. Gibbs, Knowledge and communication difficulties for patients with chronic heart failure: qualitative study, BMJ 321 (7261) (2000) 605–607. K.F. Hoth, A. Poppas, K.E. Ellison, et al., Link between change in cognition and left ventricular function following cardiac resynchronization therapy, J. Cardiopulm. Rehabil. Prev. 30 (6) (2010) 401–408. D. Zimpfer, G. Wieselthaler, M. Czerny, R. Fakin, D. Haider, P. Zrunek, W. Roethy, H. Schima, E. Wolner, M. Grimm, Neurocognitive function in patients with ventricular assist devices: a comparison of pulsatile and continuous blood flow devices, ASAIO J. 52 (1) (Jan–Feb 2006) 24–27. N. Gruhn, F.S. Larsen, S. Boesgaard, G.M. Knudsen, S.A. Mortensen, G. Thomsen, J. Aldershvile, Cerebral blood flow in patients with chronic heart failure before and after transplantation, Stroke 32 (11) (Nov 2001) 2530–2533. G. Kozdağ, P. Işeri, G. Gökçe, G. Ertaş, F. Aygün, A. Kutlu, K. Hebert, D. Ural, Treatment with enhanced external counterpulsation improves cognitive functions in chronic heart failure patients, Turk. Kardiyol. Dern. Ars. 41 (5) (Jul 2013) 418–428. D. Tanne, D. Freimark, A. Poreh, O. Merzeliak, B. Bruck, Y. Schwammenthal, E. Schwammenthal, M. Motro, Y. Adler, Cognitive functions in severe congestive heart failure before and after an exercise training program, Int. J. Cardiol. 103 (2) (Aug 18 2005) 145–149 (Epub 2005 Jan 12). S. Carles Jr., D. Curnier, A. Pathak, J. Roncalli, M. Bousquet, J.L. Garcia, M. Galinier, J.M. Senard, Effects of short-term exercise and exercise training on cognitive function among patients with cardiac disease, J. Cardiopulm. Rehabil. Prev. 27 (6) (Nov–Dec 2007) 395–399. M.L. Alosco, M.B. Spitznagel, N. Raz, R. Cohen, L.H. Sweet, L.H. Colbert, R. Josephson, M. van Dulmen, J. Hughes, J. Rosneck, J. Gunstad, Dietary habits moderate the association between heart failure and cognitive impairment, J. Nutr. Gerontol. Geriatr. 32 (2) (2013) 106–121. G. Zuccalà, E. Marzetti, M. Cesari, M.R. Lo Monaco, L. Antonica, A. Cocchi, P. Carbonin, R. Bernabei, Correlates of cognitive impairment among patients with heart failure: results of a multicenter survey, Am. J. Med. 118 (5) (May 2005) 496–502. A. Sinclair, J.E. Morley, L. Rodriguez-Manas, et al., Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and the International Task Force of Experts in Diabetes, J. Am. Med. Dir. Assoc. 13 (2012) 497–502. J.F. Flood, A.D. Mooradian, J.E. Morley, Characteristics of learning and memory in streptozocin-induced diabetic mice, Diabetes 39 (1990) 1391–1398. V. Turchetti, M.A. Bellini, L. Boschi, et al., Haemorheological and endothelialdependent alterations in heart failure after ACE inhibitor, calcium antagonist and beta blocker, Clin. Hemorheol. Microcirc. 27 (2002) 209–218. O.P. Almeida, S. Tamai, Clinical treatment reverses attentional deficits in congestive heart failure, BMC Geriatr. 1 (2001) 2. G. Zuccala, G. Onder, E. Marzetti, et al., Use of angiotensin-converting enzyme inhibitors and variations in cognitive performance among patients with heart failure, Eur. Heart J. 26 (2005) 226–233. J.F. Flood, J.E. Morley, Dose–response differences in the ability of Ramipril to improve retention in diabetic mice, Eur. J. Pharmacol. 240 (2–3) (1993) 311–314. J.E. Morley, Mild cognitive impairment—a treatable condition, J. Am. Med. Dir. Assoc. 15 (2014) 1–5. J.E. Morley, Alzheimer's disease: future treatments, J. Am. Med. Dir. Assoc. 12 (2011) 1–7. A. Sanford, J.E. Morley, Are the new guidelines for cholesterol and hypertension age friendly? J. Am. Med. Dir. Assoc. 15 (2014) 373–375. J. Mathillas, B. Olofsson, H. Lövheim, Y. Gustafson, Thirty-day prevalence of delirium among very old people: a population-based study of very old people living at home and in institutions, Arch. Gerontol. Geriatr. 57 (3) (Nov–Dec 2013) 298–304. S. Uthamalingam, G.S. Gurm, M. Daley, J. Flynn, R. Capodilupo, Usefulness of acute delirium as a predictor of adverse outcomes in patients N65 years of age with acute decompensated heart failure, Am. J. Cardiol. 108 (3) (Aug 1 2011) 402–408. D. Parente, C. Luís, D. Veiga, H. Silva, F. Abelha, Congestive heart failure as a determinant of postoperative delirium, Rev. Port. Cardiol. 32 (9) (Sep 2013) 665–671. A. Cherubini, D.T. Lowenthal, E. Paran, P. Mecocci, L.S. Williams, U. Senin, Hypertension and cognitive function in the elderly, Dis. Mon. 56 (3) (Mar 2010) 106–147. R.Y. Lin, L.C. Heacock, G.A. Bhargave, J.F. Fogel, Clinical associations of delirium in hospitalized adult patients and the role of on admission presentation, Int. J. Geriatr. Psychiatry 25 (10) (Oct 2010) 1022–1029.

J. Ampadu, J.E. Morley / International Journal of Cardiology 178 (2015) 12–23 [180] M. Chan, F. Nicklason, J.H. Vial, Adverse drug events as a cause of hospital admission in the elderly, Int. Med. J. 31 (4) (May–Jun 2001) 199–205. [181] S. Keller, W.H. Frishman, Neuropsychiatric effects of cardiovascular drug therapy, Cardiol. Rev. 11 (2003) 73–93. [182] R.W. Pretorius, G. Gataric, S.K. Swedlund, J.R. Miller, Reducing the risk of adverse drug events in older adults, Am. Fam. Physician 87 (5) (Mar 1 2013) 331–336.

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[183] A. Banerjee, E. Wesley Ely, P.P. Pandharipande, J.L. Vincent, E. Abraham, F.A. Moore, P.M. Kachanek, M.P. Fink, Agitation and delirium, Textbook of critical care, 6th editionElsevier Saunders, 2011. [184] K. Shadvar, F. Baastani, A. Mahmoodpoor, E. Bilehjani, Evaluation of the prevalence and risk factors of delirium in cardiac surgery ICU, J. Cardiovasc. Thorac Res. 5 (4) (2013) 157–161.

Cognitive dysfunction in older adults hospitalized for acute heart failure.

COPD is associated with cognitive dysfunction and poor physical fitness in heart failure.

Decreased physical activity predicts cognitive dysfunction and reduced cerebral blood flow in heart failure.

Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure.

Cognitive dysfunction mediates the effects of poor physical fitness on decreased functional independence in heart failure.

Usefulness of cognitive dysfunction in heart failure to predict cardiovascular risk at 180 days.

Diastolic dysfunction in congestive heart failure.

Cognitive impairment in heart failure patients.

Psychopathology and cognitive dysfunction five years after open-heart surgery.

Obesity and cognitive dysfunction in heart failure: the role of hypertension, type 2 diabetes, and physical fitness.

Cognitive and psycholologic considerations in pediatric heart failure.

[Renal dysfunction in heart failure and hypervolumenia : Importance of congestion and backward failure].

Therapeutic implications of diastolic dysfunction in heart failure.

Therapeutic implications of diastolic dysfunction in heart failure.

Redox-sensitive mechanisms underlying vascular dysfunction in heart failure.

Dopamine vs nesiritide for acute heart failure with renal dysfunction.

Left ventricular diastolic dysfunction in patients with congestive heart failure.

Renal Dysfunction in Korean Acute Heart Failure Patients.

Cognitive status in patients hospitalized with acute decompensated heart failure.

Cognitive impairment in heart failure patients: role of atrial fibrillation.

Can cognitive behaviour therapy be beneficial for heart failure patients?

Cognitive impairment in heart failure: towards a consensus on screening.

Characterization of diastolic dysfunction heart failure following an acute hospitalization for heart failure in an urban, underserved population.

Diabetes, dysglycemia and cognitive dysfunction.