A Correlative Relationship Between Heart Failure and Cognitive Impairment: A Narrative Review

Abstract

Heart failure (HF) is a chronic condition affecting millions of people worldwide. While the cardinal manifestations of HF are related to the cardiovascular system, it has become progressively evident that mild cognitive impairment (MCI) is also a significant complication of the disease. In fact, a significant number of patients with HF may experience MCI, which can manifest as deficits in attention, memory, executive function, and processing speed. The mechanisms responsible for cognitive dysfunction in HF are intricate and multifactorial. Possible factors contributing to this condition include decreased cerebral blood flow, thrombogenicity associated with HF, systemic inflammatory conditions, and proteotoxicity. MCI in HF has significant clinical implications, as it is linked to poorer quality of life, increased morbidity and mortality, and higher healthcare costs. Additionally, MCI can disrupt self-care behaviors, adherence to medication, and decision-making abilities, all of which are crucial for effectively managing HF. However, there is currently no gold standard diagnostic tool and follow-up strategy for MCI in HF patients. There is limited knowledge on the prevention and treatment of MCI. In conclusion, MCI is a common and clinically important complication of HF. Considering the substantial influence of MCI on patient outcomes, it is imperative for healthcare providers to be cognizant of this issue and integrate cognitive screening and management strategies into the care of HF patients.

Graphical Abstract

INTRODUCTION

Heart failure (HF) is a syndrome with various symptoms that come from functional and structural cardiac abnormalities.1 Because HF increases with the aging process, the prevalence rate of HF is gradually rising. The prevalence of HF is reported to be 1–2% in many developed countries, and was 2.24% in Korea in 2018.2 In particular, the prevalence is estimated to exceed 10% in the geriatric population aged 70 years and above.3 So HF has more impact on hospitalization and death as a country moves on to an aging society. Like HF, mild cognitive impairment (MCI) is also an increasing disease with aging.4 MCI is not a fatal disease by itself, but it is receiving attention socially because it could ruin the patient’s independence and dignity, deteriorate to dementia, and cause a huge socio-economic burden.5

Since the function of the heart is blood supply and circulation to each part of the body, cardiac dysfunction could cause abnormalities in various organs, and brain function is no exception. The relationship between HF and MCI has long been suggested, the prevalence of MCI in HF patients was reported to be 30–80%.6 MCI leads to a decrease in quality of life (QOL), reduces compliance with medication, and has been found to be an independent risk factor in HF mortality.7 Therefore, it is important to understand MCI accompanied by HF for proper management of HF.

However, there are many ambiguous parts in this field. Because the evaluation tools for MCI are not unified and the characteristics of the population are different for each study, the prevalence rate varies greatly. MCI is a broad concept and includes detailed domains such as memory, attention, comprehension, reasoning, problem-solving, decision-making, and production of language.8 Mini-Mental State Examination (MMSE) is commonly used but evaluates only overall cognitive functionality, and the prevalence of MCI changes depending on which domains are examined in detail. Changes in the brain parenchyma are also of interest, but few studies have been conducted on this topic.9 There are no effective strategies to prevent or alleviate MCI in HF patients, so future research is needed in this area too.10 This article will review the epidemiology, pathophysiology, risk factors, assessment using functional and imaging tools, prevention, treatment, and future perspectives of MCI in patients with HF.

EPIDEMIOLOGY

MCI is an intermediate state between normal aging processes and dementia.11 Amnesia is the most common symptom, and it can be diagnosed when there is damage to one or more cognitive function domains.12 The prevalence of MCI among those over 65 years old is 10–20%, aging and education level are major risk factors.13 The proportion of deterioration from MCI to dementia is known to be 10–15% per year.14 In Korea, the prevalence of MCI in the population aged 65 years old or older was reported as 24.1% in 2011.15 The trend in MCI prevalence has not been investigated, but it is estimated that MCI is increasing because the prevalence of dementia is gradually rising.16

Several previous reports have shown a higher prevalence of MCI in the group of patients with HF compared to the general population. In a multi-center study in Italy, the prevalence of MCI was 35% among the 1,511 hospitalized HF patients.17 In a cohort of 100 chronic compensated HF patients in Singapore, the prevalence of MCI was 42%.18 When patients hospitalized with acute decompensated HF in the United States were surveyed, the MCI prevalence rate reached 78%.19 More recently, 605 patients with chronic stable HF were surveyed in five European countries and the United States, and the prevalence of cognitive impairment (CI) was reported as 67%.20 According to these studies, it is estimated that the prevalence of MCI in HF patients is 1.5 to 2 times higher than that of the general population group. The reason for the large difference in MCI prevalence between reports is that the cognitive function evaluation methods and the characteristics of the population are not unified. The detailed conditions of each study are shown in Table 1. In previous studies, acute decompensated HF, old age, low education, accompanying comorbidities, and low physical ability were risk factors for MCI, in the population with these factors, MCI prevalence tended to be higher.21

Table 1. Characteristics and prevalence of CI in HF patients.

Published year	Population				HF status		CI status
	Region	Total patients	Female, %	Age, yr	HF status	HFrEF or LVEF, %	Screening tool	MoCA score	Prevalence of CI, %
200516	Italy	1,511	54.0	78.0	A + C	N/A	Hodkinson Abbreviated Mental Test score< 7	N/A	35.0
201817	Singapore	100	15.0	58.7	C	HFrEF 65.0	Abnormal domain in neuropsychological test ≥ 1	21.3	44.0
201818	US	202	54.0	72.0	A	HFrEF 52.5	MoCA < 26	21.7	78.0
202019	Europe & US	605	29.0	66.9	C	LVEF 38.7	MoCA ≤ 26	24.4	66.4

HF = heart failure, CI = cognitive impairment, US = United States, A = acute decompensated heart failure, C = chronic stable heart failure, HFrEF = heart failure reduced ejection fraction, LVEF = left ventricular ejection fraction, MoCA = Montreal cognitive assessment, N/A = not available.

In the HF population, stroke has increased as well as MCI. About 9% of all stroke cases are caused by HF.22 Although atrial fibrillation is a major cause of stroke, the annual risk of stroke in patients with HF with reduced ejection fraction (HFrEF) who do not have atrial fibrillation is also 1.2%, which is greater than that of the general population of the same age.23 In addition to stroke, various structural changes in the brain also increase in HF.24 However, because not all patients with HF are subjected to neuroimaging tests such as brain magnetic resonance imaging (MRI), epidemiologic data on structural changes in the brain in HF patients is insufficient.

PATHOPHYSIOLOGY

Human brain mass accounts for only 2% of its total body weight, but its energy use is up to 20%.25 Since the brain has no energy storage system and totally relies on glucose metabolism, a proper and constant supply of energy through the bloodstream is essential. Therefore, the role of a normal heart pump is important for maintaining brain function, and in fact, 15% of cardiac output is delivered to the brain.25 In patients with HFrEF, cerebral blood flow (CBF) is known to decrease by 14–30%, and it is considered as one of a major mechanism of brain damage, including CI.26

CBF reduction associated with low cardiac output

In patients with HFrEF, systemic hypoperfusion and hypotension resulting from low cardiac output cause CBF reduction.27 The decreased CBF in patients with HFrEF has been confirmed through transcranial doppler measurement and it has been reported that decreased CBF is associated with impaired global cognitive function.28,29,30 Low cardiac output creates a chronic and persistent state of hypoperfusion in the brain, which is vulnerable to watershed infarction and there is also a report that the lower cardiac index raises the risk of dementia.31,32 There are some previous reports of improved cognitive function after cardiac output recovery through medication, left ventricular assist device (LVAD), and heart transplantation, which support that low cardiac output is the main mechanism of brain damage in HF patients.26,33,34 However, the low cardiac output theory cannot fully explain the reason for changes in brain function in patients with HF with preserved ejection fraction (HFpEF).

CBF reduction caused by damage to cerebrovascular autoregulation in HF

Damage to cerebrovascular autoregulation is another cause of CBF reduction.35 Autoregulation means that the cerebral vessel contracts and relaxes according to the physiological situation and regulates CBF. In a healthy state, the cerebrovascular vessel is separated from body circulation by the blood-brain barrier (BBB). The BBB blocks the passage of various toxic substances, but carbon dioxide (CO₂) can pass through the BBB relatively freely.36 Cerebrovascular vessel resistance responds to the pressure of arterial carbon dioxide (PaCO₂) sensitively, and a 1 mmHg PaCO₂ increase outside the normal range makes CBF increase by 3–6%. On the other hand, the response of CBF to hypoxemia is less than that of PaCO₂.37 This physiological response system is called autoregulation. Endothelial dysfunction, vascular smooth cell proliferation, and decreased bioavailability of nitric oxide would be observed in HF patients. These microvascular changes could damage the cerebrovascular autoregulation system, cause abnormal reactivity, and reduce CBF. This CBF reduction process appears in HFpEF as well as HFrEF.38

Once brain tissues are injured by ischemia and hypoxia caused by CBF reduction, various molecular responses make cracks in a tight BBB junction. This process is not clearly defined, but it is known that the hypoxia inducible factor-1 plays a key role.39 Injured BBB loses maintaining intracranial homeostasis environment. Fluids, ions, proteins, and many toxic substances could influx into intracerebral vessels because the permeability of BBB is increased.40 This can lead to brain edema, oxidative damage, and neuronal inflammation, which can result in secondary brain pathology such as Alzheimer’s disease.41

Thrombogenicity in HF

HF is one of the major risk factors for stroke, so HF could be the cause of CI and brain parenchymal changes. It is already well known that atrial fibrillation, myocardial infarction, and valvular heart disease are thrombogenic statuses, and the patent foramen ovale can act as an unexpected channel for the embolus. However, even if there was no coexistence of these risk factors, HF is a thromboembolic condition by itself.42 Blood stasis could be induced in the akinetic ventricular segment and aneurysmal change area of ischemic cardiomyopathy heart, and thrombus production would increase. Prothrombotic features such as platelet hyperactivity and impaired fibrinolysis in HF patients are also linked to increased thrombus formation.43 It has been reported that the annual stroke incidence was 1.0% in HFpEF and 1.2% in HFrEF without atrial fibrillation.24 Compared to the stroke annual incidence rate of the general population in Korea, 0.21%, HF increases the risk of stroke definitely.44 In addition, in a cohort study of acute stroke, HF without atrial fibrillation was reported as an independent risk factor for stroke, and dilated cardiomyopathy or valvular heart disease mainly caused embolic stroke, and patients with ischemic cardiomyopathy were reported to have lacunar infarction predominance.45

Systemic inflammatory reaction associated with HF

HF makes high systemic inflammatory reactions and various cytokines increase in the patient’s bloodstream.46 Circulating inflammatory cytokines induce local brain edema in a loosened BBB state, which is one of the causes of increased CI in patients with HF.40 Various cytokines are expected to be associated with CI. In order for memory to be permanently stored in the brain, a process called “memory consolidation” is required, and the hippocampus is the main organ responsible for it.47 According to previous studies on cytokines and memory consolidation, both the absence and overexpression of cytokines interfere with this process. Interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α) are known to particularly inhibit hippocampal-dependent learning and memory processes.48 Since most of these studies have been conducted on rodent models rather than humans, they cannot be applied directly to models of HF patients. However, a small population study has been reported in HF patients, a relationship was observed in which the higher the level of IL-6, C-reactive protein in the blood, the lower the Montreal Cognitive Assessment (MoCA) score.49 In addition, there was a report that TNF-α, cortisol, IL-6, and total plasma homocysteine were detected as high in HF patients and these increased inflammatory marker levels are associated with grey matter volume loss.50

Proteotoxicity in HF

Proteotoxicity is a phenomenon in which misfolded soluble protein oligomer does not function normally and causes cell death, and is found in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Protein misfolding is also observed in cardiac amyloidosis, where monoclonal light chains or transthyretin make up amyloid fibril, which deposits in the myocardium and creates pathology.51 Misfolded protein is also found in hypertrophic cardiomyopathy and dilated cardiomyopathy myocardium, which is similar to that observed in neurodegenerative disorders. Based on these results, it is speculated that proteotoxicity is a common pathophysiology of HF and CI, but there is insufficient clear evidence.52

The bi-directional relationship between MCI and HF

Due to the bi-directional interaction between cardiac and brain function, a decrease in brain function adversely affects heart function.53 CI makes it difficult for patients to maintain their independence and lowers their QOL. A memory problem lowers drug adherence, and low medication compliance worsens the prognosis of HF and various chronic diseases.54 The HF patients group is likely to have depression and anxiety disorders more than five times compared to the general population.55 Since the co-existence of mood disorders exacerbates the HF prognosis, consideration of mood disorders is needed in the treatment of HF.56 The autonomic nerve system (ANS) regulates cardiac function. ANS dysfunction may increase the incidence of arrhythmia and lead to a worsening HF prognosis.57 So an abnormally high sympathetic tone is one of the main therapeutic targets of HF. Although the process is not clarified fully, a low CBF from HF causes a decrease in brain function, and it is believed to cause ANS dysfunction.58 In addition, organic brain lesions such as stroke are known to increase the level of catecholamine in the blood and sympathetic tone abnormally.59 For these reasons, HF could cause impaired brain function, and impaired brain function can cause deterioration of HF (Fig. 1), constituting a vicious circle.

Fig. 1. The bi-directional relationship between mild cognitive impairment and heart failure.

CO = cardiac output, CBF = cerebral blood flow, ANS = autonomic nerve system, BBB = blood-brain barrier, HF = heart failure.

Various organ dysfunctions due to HF

HF causes dysfunction in various organs, which can also lead to CI. HF can lead to changes in the structure and function of the heart, including atrial enlargement. These changes can create an environment that is conducive to the development of atrial fibrillation. The stretched and enlarged atria are more prone to developing abnormal electrical signals that cause the irregular heartbeat characteristic of atrial fibrillation.60 It is evident that atrial fibrillation is a risk factor for stroke. Even in the absence of an overt stroke, it increases the risk of CI and dementia.61 Renal dysfunction often results from HF, and sometimes, chronic kidney disease (CKD) is accompanied by HF due to shared risk factors. There is a bidirectional relationship between HF and renal dysfunction. HF acts as a cause of renal injury, and the prevalence of HF is high among patients with CKD.62 Renal dysfunction is a risk factor for CI due to shared atherosclerotic risk factors, and the accumulation of uremic toxins.63 Furthermore, hemodialysis has been shown to contribute to cognitive decline, which is believed to be associated with intra-dialytic hemodynamic instability.64 Liver dysfunction is also often observed in patients with HF. It mainly appears in the form of congestive hepatopathy or cardiac cirrhosis in right HF, and also as a result of toxic substances, such as alcohol, that simultaneously damage both the heart and liver.65 It is well known that toxic substances, such as alcohol, adversely affect cognitive function.66 Studies on the relationship between congestive hepatopathy or cardiac cirrhosis resulting from HF and cognitive function are scarce. However, an increase in cognitive dysfunction has been reported in common liver diseases such as nonalcoholic steatohepatitis. The mechanism behind this association includes increased systemic inflammation, dysbiosis of the gut microbiota, and impaired urea cycle function due to decreased liver function.67 When patients with liver cirrhosis experience partial CI, it is referred to as minimal hepatic encephalopathy, and its frequency is estimated to be over 20%.68 Various mechanisms have been suggested for the cause of cognitive decline in liver cirrhosis, with the most prominent one being the abnormal brain metabolism of ammonia and glutamine.69 Because these mechanisms are common features of liver dysfunction, congestive hepatopathy and cardiac cirrhosis have the potential to negatively impact cognitive function. This point requires further investigation. Anemia is not difficult to detect in patients with HF, either due to the medications they are taking or as a secondary consequence of HF.70 Independently of HF, anemia is an overt risk factor for CI, as indicated by a meta-analysis showing a 1.39-fold increase in the incidence of CI.71

DIAGNOSIS & ASSESSMENT

Cognitive function assessment

Establishing an appropriate assessment tool for accurate diagnosis and severity evaluation of CI is required. The diagnosis of CI in HF patients is not much different from the general population. Although there are various neuropsychiatric tests and each has its own strength points, the most widely used tools are MMSE and MoCA.72 Both tests consisted of 30 questions—30 points questionnaire, if someone has 23–26 points or less, who is diagnosed as MCI. The age of patients, education level, and cultural background should be considered in the diagnosis of MCI. Both tests evaluate various cognitive domains such as orientation, memory, language, visuospatial function, and so on, and there are differences in detailed questions. MMSE and MoCA are simple and convenient tests, but there is a limit that diagnostic accuracy is insufficient.73 This is one of the reasons why the reported CI prevalence in HF patients has such a wide range. Other neuropsychiatric tests such as Mini-Cog or Cambridge cognition examination also do not show superior accuracy, so there is no gold standard assessment tool.74 The accuracy of several cognitive assessment tools is summarized in Table 2.75,76 The cognitive function is a comprehensive concept, and it can be divided into several functional subdomains. The five domains, memory, executive functioning, visuospatial perception, attention, and language are generally included in the cognitive function evaluation, and there may be details of each of these domains. MMSE and MoCA are usually used to measure overall cognitive function and to screen the CI, and specific individual tests are required for each domain for the accurate evaluation of cognitive function.77

Table 2. Cognitive function assessment tools commonly used for diagnosing and evaluating mild cognitive impairment.

Variables	No. of questions (total score)	Cut-off for MCIa	Sensitivity, %	Specificity, %	Test time, min
MMSE70	30 (30)	≤ 27	71	74	≤ 10
MoCA70	30 (30)	≤ 26	83	75	≤ 10
Mini-Cog71	2 (5)	≤ 2	55	83	≤ 3
CAMCOG70	59 (107)	≤ 94	77	78	≤ 30

MMSE = Mini-Mental State Examination, MoCA = Montreal Cognitive Assessment, CAMCOG = Cambridge cognition examination, MCI = mild cognitive impairment.

^aThe cut-off value is not an absolute criterion for the diagnosis of MCI, but it is a value that is commonly used in many studies. When determining MCI, it is important to consider not only the assessment test score, but also the patient’s age, gender, education level, and comorbidities.

Neuroimaging study

Neuroimaging study, represented by brain MRI, is essential in evaluating brain function because it can check brain diseases such as infarction and hemorrhages, and structural changes such as white matter hyperintensities (WMH).

White matter changes

WMH is a representative vascular pathologic condition that occurs in the brain’s small vessels such as cerebral perforating arteries. WMH has high signal strength in the T2 weighted image or fluid-attended inversion recovery MRI setting and is presented as a scattering pattern in the periventricular area.71 The pathological process is not yet apparent. The most possible explanation is the damage of BBB and myelin sheath by chronic hypoperfusion. It is believed that plasma protein influx into the brain through abnormal BBB, causes edema, and loss of myelin content creates high signal strength of white matter.78 WMH is associated with CI, depression, anxiety, and gait disturbance, which lowers the patient's independence and QOL.79,80 It is an independent risk factor that increases dementia and stroke by about 3-fold more.81 WMH is often observed in asymptomatic healthy elderly, but HF is an independent factor that increases WHM 2.8 times compared to healthy controls after multivariate adjustment, and the risk of the prevalence increases along the HF durations.82

Gray matter volume (GMV) decrease

Decreased GMV is also a brain MRI finding observed in patients with CI.83 Brain imaging studies in CI patients have reported a decrease in GMV in a specific area, and the hippocampal area is commonly mentioned.84 In patients with HF, it was reported that cognitive function and daily living performance were impaired when GMV decreased, including the hippocampal area.85 It is not yet clear whether HF makes GMV reduction worse. One case-control study reported a negative correlation between serum NT-proBNP levels and GMV in HF patients.86 But in another cohort study, the degree of GMV reduction was not severer than physiological aging, even after tracking HF patients for 3 years.87 According to a recent meta-analysis, the correlation between GMV reduction and cognitive decline in HF patients seems reasonable.88 However, the specific factors of HF that exacerbate GMV reduction are ambiguous and need further research.

Cortical thickness

Various neurodegenerative disorders begin with neural loss and it makes structural changes with cortical thinning.89 Brain imaging studies of MCI, Dementia, and Parkinson’s patients have confirmed a decrease in cortical thickness.90 A similar cortical thickness change is expected in the MCI of HF patients, but there are not enough studies on this. A case-control study published in 2015 compared brain MRI in HF patients of MCI with healthy controls. This study confirmed cortical thinning of the region in autonomic, cognitive, affective, language, and visual function domains.91 Much more research is needed to determine which areas of cortical thinning are more sensitive to hypoperfusion and which areas of cortical thinning can act as a sensitive indicator of cognitive dysfunction.

Lacunar infarction & microbleed

Lacunar infarction is a kind of cerebral small vessel disease, mainly presented as subcortical infarction at perforating arteries. It is usually round or ovoid within 20 mm, and multiple foci can be observed.92 Lacunar infarction is often found as an incidental finding in the elderly because it has a smaller infarction area and is mild in neurological deficits compared to cortical infarction. However, even if the mechanism is unclear, the risk of developing post-stroke CI in lacunar infarction is known to be similar to that of large-territory cerebral infarction.93 The risk of CI is positively correlated with the number and area of lacunar infarcts, when CI occurs, the risk of recurrent infarction or death increases.94 Microbleeds are a manifestation of small cerebral artery bleeding and they are observed as hypointense lesions of about 5 mm in T2 MRI images because of a deposit of hemosiderin.95 Microbleeds are sometimes found incidentally in healthy elderly people, but the frequency increases significantly in patients with brain lesions such as hemorrhages and cerebral infarction. And it is also known to be a risk factor for CI.96 It is currently unknown whether lacunar infarction and microbleeds are associated with cognitive decline in individuals with HF, and additional research is necessary to investigate this potential relationship.

PREVENTION & TREATMENT

The cognitive function problems of HF patients have been described even in the guidelines, but little is known about treatment and prevention methods. There is insufficient research on treatment methods targeted at CI, and most of the currently available data is investigating changes in cognitive function according to standard HF treatment.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i)

SGLT2i are emerging as a key strategy in the treatment of HF. An animal study has reported that SGLT2i alleviates cognitive dysfunction in murine model,97 and in a propensity score matching study, SGLT2i was expected to lower the risk of dementia compared to DPP4i in diabetes mellitus (DM) patients.98 In addition, in a study of patients with HFpEF and DM in 2022, a statistically significant increase in MoCA score was reported in the empagliflozin administration group compared to the metformin and insulin administration groups, raising expectations that SGLT2i will work positively for cognitive function.99 For the background of this action, the anti-oxidative and anti-inflammatory effect of empagliflozin could reduce brain vascular damage,100 and SGLT2i also has an acetylcholinesterase inhibition effect, which is considered to have a more direct mechanism for neuroprotective effect.101

Angiotensin receptor/neprilysin inhibitor (ARNI)

Through the PARADGM-HF study, ARNI has established itself as an essential drug for HFrEF. Since neprilysin, an exclusive target of ARNI, plays a role in removing amyloid beta in the brain, there were concerns that neprilysin inhibitors could theoretically cause the amyloid beta accumulation, leading to cognitive decline and dementia.102 However, in the PARADGM-HF study, the ARNI administration group did not differ in terms of cognitive function compared to the enalapril administration group.103 A PERSPECTIVE trial (NCT02884206) including HFpEF and HF with midrange ejection fraction (HFmrEF) patients is underway. The study’s findings will clarify ARNI’s impact on the cognitive function of patients with HFpEF and HFmrEF.

Angiotensin-converting enzyme inhibitor (ACEi) & angiotensin receptor blocker (ARB)

In a study before the era of ARNI, it has been reported that ACEi causes improvement in cognitive function in patients with HF.104 In hypertensive patients without HF, ACEi and ARB also have a positive effect on cognitive function.105 They are believed to ameliorate atherosclerosis and improve CBF by inhibiting the renin-angiotensin-aldosterone system (RAAS). Various RAAS receptors are expressed in the brain’s neurons, microglia, and astrocytes, so ACEi and ARB will be expected to have direct effects on the brain system. It is also known that the RAAS has crosstalk with dopaminergic and cholinergic pathways.106 However, orthostatic hypotension is a risk factor for CI in elderly patients, so attention should be paid to overdose.107

Mineralocorticoid receptor antagonist (MRA)

The MRA contributes to HF treatment by blocking the RAAS, but its effect on cognitive function is complicated by the aspect of suppressing steroids. Mineralocorticoid receptors, expressed in the limbic system in the brain, are involved in memory. Therefore, there may be concerns that MRA may adversely affect the memory field. In a study of depressive disease patients, mineralocorticoid stimulation showed improvement in memory in the younger age group but the opposite effect in the older group. Many parts of the mechanisms by which mineralocorticoids and MRA operate in cognitive functions are still ambiguous. Studies evaluating the role of MRA on cognitive function in HF patients are insufficient and inconclusive.108

Beta blocker

The effectiveness of beta blockers in the management of cognitive function among patients with HF is still unclear, as only a limited number of studies have explored this area. While there have been concerns regarding the potential exacerbation of psychiatric conditions such as depression and anxiety with beta blocker use, recent research has refuted such claims.109 There have been reports that beta blocker aggravates vascular dementia,110 but there are also large-scale studies that show no association,111 so a well-controlled study is needed in the future.

Device assist therapy

HF treatment using devices could also help improve cognitive function. Although it was a small-scale trial, there is a study that showed improvement in cognitive function in the group of patients whose left ventricular ejection fraction was recovered after cardiac resynchronization therapy implantation.112 Patients who have successfully undergone LVADs also show improvement in cognitive function. It is thought that the rising heart pump function causes better CBF.113

The foregoing points to the possible impact of individual HF treatment on cognitive function. Since the cited studies are not well-controlled designed trials for specified HF patients, the strength of the evidence is weak. As the practical HF treatment is a multifaceted approach that encompasses pharmacotherapy, assistive devices, vascular and arrhythmic procedures, and lifestyle modifications, it is not advisable to avoid specific treatment due to apprehensions about cognitive function.

CLINICAL IMPLICATION OF MCI IN HF MANAGEMENT

Self-care management is a major part of HF treatment, and CI causes problems for patients caring for themselves. They have difficulties understanding education and recommendations on lifestyle habits from doctors, have lower drug adherence, and have trouble keeping hospital appointments.114 In a previous study, 251 chronic HF patients were classified into groups with and without MCI, drug adherence was investigated through the pill count method. The HF without MCI group took the medication more regularly than the MCI accompanied HF group (78% vs. 70%, P = 0.017).115 These self-care problems, at least in part caused by CI, can worsen clinical outcomes. In a study of 720 hospitalized HF patients (mean age 77 years-old), it was reported that the risk of readmission increased 1.9-fold when MCI (Mini-Cog ≤ 2) was accompanied with HF.116 In the FRAGILE-HF study, 1,180 patients with hospitalized HF over the age of 65 were enrolled, the effect on clinical outcome was evaluated by investigating not only cognitive dysfunction but also physical and social weakness. In this study, the prevalence of MCI was 37.1% and the composite outcome, including all-cause death, increased in patients with more vulnerable domain.117 Therefore, recent HF guidelines suggest CI is an obstacle to optimal treatment of HF, but they did not provide standard diagnosis criteria.118

FUTURE PROSPECTIVE & CONCLUSION

It is widely accepted that the prevalence of CI increases in HF patients, and CI makes the prognosis of HF poor. Nonetheless, many parts of this area are unclear and require further investigation.

First, it is not clear which characteristics of HF increase CI. The main mechanism of CI in HF, suggested to date, is considered to be the reduction of CBF. Based on this, more CI is expected to occur in HFrEF than in HFpEF, but the data on this point are inconsistent. Future investigators will need to plan further studies on the possibility that the character of the brain parenchyma and cerebrovascular condition may be related to CI, not the characteristics of HF itself. Next, it is unclear what brain parenchymal changes are specific to CI. There may be changes such as WMH and GMV decrease that have been previously mentioned, but we are not sure whether these neuroimaging findings have a direct link with CI because there is no serial observation data over time. Finally, there is no proven prevention and treatment strategy for CI. Cognitive dysfunction or dementia is an unsolved challenge in the neurology field, too. Rather than a strategy to treat CI, future research capabilities need to be focused on the view of prevention by clarifying in detail the process of CI occurrence in HF. If there is an effective plan suppressing the occurrence of CI, the HF team could screen a high-risk group for CI in HF more actively, and it will lead to long-term outcome improvement.