Consequences of Altered Cardiac Activity on Brain Activity
Many heart diseases can affect brain activity and the most common are atrial fibrillation, arterial hypertension, heart failure, ischemic heart disease, valvular heart disease, pulmonary arterial hypertension, and sudden cardiac arrest. The mechanisms underlying the brain dysfunction and the cognitive impairment can be different depending on the heart disease, but the decreased blood perfusion, silent cerebral infarctions due to cardioembolism, and cerebral white matter hyperintensities are the most commonly involved pathogenetic mechanisms, although also genetics seems to play a role in many diseases. Another important aspect to be considered is the presence of depression, which is common in many heart diseases and can affect not only the quality of life but also the outcome. Considering the importance of brain dysfunction on outcome, it is evident from the literature, how important it is to correctly identify patients who develop this type of problem in order to optimize their treatment and improve their outcome.
KeywordsHeart diseases Brain dysfunction Cognitive impairment Hypoperfusion Cardioembolism
Heart and brain have several connections between them and if it is well known that the functioning of the heart undergoes numerous influences from the brain and the central nervous system, it is equally well demonstrated that the heart functioning can affect the brain activity. In fact, the heart and the brain do not share only the same risk factors, but there are several types of heart disease that potentially affect the brain.
Atrial fibrillation (AF) is one of the most common arrhythmias, with higher incidence and prevalence rates in developed countries . It is estimated that in Europe AF is present in 3.7–4.2% of people aged 60–70 years and in 10–17% of those aged 80 years or older . AF is one of the major causes of stroke, heart failure, sudden death, and cardiovascular morbidity in the world  and it is independently associated with a twofold increased risk of all-cause mortality in women and a 1.5-fold increase in men . It is well demonstrated that the presence of AF can influence the brain activity in many ways. The risk of ischemic stroke is increased if AF is present due to the increased risk of thromboembolism, originating mainly from the left atrial appendage, caused by this arrhythmia , and the CHA2DS2-VASc score is the most effective and clinically used score to estimate the risk of stroke and thromboembolism in AF patients . Oral anticoagulation (OAC) with vitamin K antagonists (VKAs)  or non-VKA oral anticoagulants (NOACs) [8, 9, 10, 11, 12] markedly reduces stroke and mortality in AF patients. Moreover, NOACs seem not only to have better long-term efficacy and safety compared with warfarin, but also to be associated with a lower risk of cerebral ischemic events and new-onset dementia . AF is not only associated with an increased risk of symptomatic stroke, but also TIAs and silent cerebral infarctions . It was indeed demonstrated that patient with paroxysmal and persistent AF had a higher prevalence and number of areas of silent cerebral ischemia than controls in sinus rhythm and this is associated with worse cognitive performance in immediate memory, visual-spatial abilities, language, attention, and delayed memory . Furthermore, AF is associated with a higher risk of cognitive impairment and dementia, independent of ischemic stroke  both in elderly people and in younger one. Regarding younger people, a longer exposure period might lead to changes that produce greater neuronal injury and loss, possibly due to the interaction of degenerative and vascular changes , and they are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation . It was also demonstrated that people with atrial fibrillation treated with long-term warfarin anticoagulation have higher rates of all dementia types compared with patients receiving long-term warfarin for other indications . The brain functions impaired by the presence of AF can vary, such as learning and memory, attention and executive functions, working memory, visuospatial skills , and different subtypes of dementia can be promoted, especially Alzheimer’s disease and vascular dementia . The underlying mechanisms that link AF and cognitive impairment are not well known and many factors seem to play a role. AF decreases blood flow to the brain as well as perfusion of brain tissue compared with sinus rhythm , and this reduction and variation beat-to-beat of cerebral perfusion certainly plays an important role in the development of cognitive impairment . Furthermore, if AF is associated with heart failure, the cognitive deficit is exacerbated possibly through their association in decreasing cerebral perfusion . Other possible mechanisms that explain this fact seems to be cerebral microinfarcts, an important neuropathological predictor of clinical dementia , due to microemboli . In fact, AF leads to a hypercoagulatory state  that could give rise to subclinical cerebral embolism, and transcranial Doppler ultrasonography has detected cerebral microemboli in up to 30% of patients with AF . Also genetic polymorphisms, especially apoE genotype, are related with cognitive impairment in AF . In addition, AF is demonstrated to be associated with increased hippocampal atrophy and smaller brain volume, evaluated with magnetic resonance imaging, and this association is stronger with increasing burden of the arrhythmia, suggesting a cumulative negative effect of AF on the brain independent of cerebral infarcts . Consistently with all these evidences, especially with the ones which underlying the link between reduction in brain perfusion during AF and cognitive decline, the strategy of atrioventricular node ablation and pacing improve left ventricular systolic function, thereby increasing blood pressure and improving cerebral perfusion with an improvement in immediate and delayed verbal memory, abstract mentation, attention, psychomotor speed, as well as in learning . On the other hand, postoperative neurocognitive dysfunction and neuropsychological decline, especially in memory, seem to be related to the procedure of transcatheter AF ablation,  but there are conflicting evidences on that .
Anxiety and depression are more frequent in patient with AF than in general population , especially in patient with persistent AF respect to patient with paroxysmal AF , increasing the perception of severity of symptoms related to AF  and driving to a reduction in health-related quality of life . Catheter ablation is more effective for improving depression, anxiety, and quality of life in patients with AF compared with antiarrhythmic drug therapy .
Arterial hypertension is defined as values ≥140 mmHg of systolic blood pressure (SBP) and/or ≥ 90 mmHg of diastolic blood pressure (DBP). Overall, the prevalence of hypertension appears to be around 30–45% of the general population, with a steep increase with aging. The most common types of brain lesions favored by hypertension are white matter hyperintensities, silent infarcts, and microbleeds. White matter hyperintensities and silent infarcts are associated with an increased risk of stroke, cognitive decline, and dementia . In particular, regarding the risk of stroke, it is well demonstrated since decades that it is increased by the presence of arterial hypertension through many mechanism: a high intraluminal pressure will lead to extensive alteration in endothelium and smooth muscle function in intracerebral arteries that can lead to local thrombi formation and ischemic lesions, to fibrinoid necrosis that can cause lacunar infarcts through focal stenosis and occlusions and to degenerative changes in smooth muscle cells and endothelium that predisposes for intracerebral hemorrhages. Furthermore, hypertension accelerates the arteriosclerotic process, thus increasing the likelihood for cerebral lesions related to stenosis and embolism originating from large extracranial vessels, the aortic arch, and from the heart. Moreover, adaptive structural changes in the resistance vessels, while having the positive effect of reducing the vessel wall tension, have the negative consequence of increasing peripheral vascular resistance that may compromise the collateral circulation and enhance the risk for ischemic events in connection with episodes of hypotension or distal to a stenosis . An antihypertensive stepped-care drug treatment has the capability to dramatically reduce the incidence of total stroke and major cardiovascular events . It is also known for years that hypertension-associated pathogenic processes may cause mild cognitive impairment  and that arterial hypertension, especially the SBP, predict the onset of impaired cognitive performance affecting attention, learning and memory, executive functions, visuospatial skills, psychomotor abilities, and perceptual skills . The underlying mechanisms are not fully known, but a role in cognitive dysfunction is played by the reductions in cerebral blood flow and metabolism driven by long-standing hypertension . Moreover, as mentioned at the beginning of this chapter, cerebral white matter hyperintensities (WMHs), which are believed to be the consequence of small vessel disease, are one of the stronger predictors of dementia and cognitive decline . WMHs are associated both with high SBP and high DBP , and there are evidences that adequate treatment of hypertension may reduce the course of WMHs progression . However, the fact that antihypertensive treatment can reduce the risk of the onset of dementia is not fully proven as there are conflicting evidences . Other factors have been related to the decline of cognitive function due to hypertension, in particular there are evidences on the fact that the role of neuroinflammation in the susceptibility of the brain for neurodegeneration and memory impairment is enhanced in hypertension, and that ACE inhibition can play a protective role . Moreover, genetic probably play a significant role, as it was demonstrated that the interaction between hypertension and the presence of the APOE ε4 allele was associated with steeper cognitive decline over a long period . Finally, recent evidence focuses on the importance of small vessel disease and in particular on the role of hypertension as a contributing factor to worse clinical outcomes, especially cognitive impairment, and neuroradiological presentation in patients with sporadic small vessel disease . Concluding, blood pressure has complex relationships with cognitive functioning and poorly controlled hypertension increase the risk of cognitive dysfunction and perhaps vascular and possibly other types of dementia, affecting also the quality of life of the patients. Therefore, it is important to provide appropriate patient education regarding likely risks associated with hypertension .
Heart Failure (HF) is a clinical syndrome characterized by typical symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles, and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output (HF with reduced ejection fraction) and/or elevated intracardiac pressures (HF with preserved ejection fraction) at rest or during stress and leading to the fact that the metabolic requirements are not met . About 1–2% of the adult population in developed countries is affected by HF, and this percentage increase with the age up to 10% in patients aged over 70 years . It is known for many years that the presence of HF is associated in many patients with brain failure [52, 53], and this correlation is present in all ages, also in pediatric population . There are many evidences supporting that severity of cognitive impairment is associated with the severity of HF, quantified as reduction of ejection fraction (EF) or symptom burden,  and the association between HF and cognitive decline is also found in patient with reduced EF, but without symptoms . Moreover, the brain failure seems to be present equally in patients with HF with reduced EF and in patient with HF with preserved EF . It is possible to recognize two different types of cognitive problem in HF: an acute change in cognition during an acute presentation of HF (delirium) and a chronic decrease of the cognitive abilities in chronic HF. Regarding delirium, it is common in many acute medical conditions, so it is difficult to establish a direct correlation with HF, but it was demonstrated that its presence during hospitalization for HF increases the length of hospital stay, worsens the outcome, and increases the mortality . As for the chronic decrease of the cognitive abilities, it affects many abilities and cognitive domains as deficits in attention, executive functioning, visuospatial functioning, memory, perceptual speed, and language , leading to an increased risk to develop different type of dementia, including vascular dementia  and Alzheimer’s disease . Furthermore, HF is associated with poor level of self-care management, which can also affect the adherence to the therapy . The potential pathophysiological explanations of cognitive impairment in heart failure vary and different factors can coexist in the same patient. The formation of tangle and plaque-like structures and fibrillar deposits (that is, the “hallmark” lesions of Alzheimer’s disease (AD) dementia), which was demonstrated within the myocardium of patients with hypertrophic cardiomyopathy and idiopathic dilated cardiomyopathy, explains the possibility of a common myocardial and cerebral pathology in a subset of patients with HF [60, 62], whereas the systemic inflammatory state recognized in patients with HF may also contribute to cognitive impairment through different cytokine-mediated interactions between neurons and glial cells . The reduction in cerebral blood flow caused by low cardiac output, low systolic blood pressure, and impaired autoregulatory mechanisms are probably also involved in brain changes affecting people with HF . Moreover, as during AF, cardioembolism may play a role in the development of cognitive impairment in HF, as it was seen in HF patients with sinus rhythm. Reduced EF seems to be the most important determinant of thrombus formation and potential embolic cerebral infarction in these patients . At a macroscopic level, it was demonstrated, via magnetic resonance images, that patients with HF have a gray matter loss in the left cingulate, in the right inferior frontal gyrus, in the left middle and superior frontal gyri, in the right middle temporal lobe, in the right and left anterior cingulate, in the right middle frontal gyrus, in the inferior and pre-central frontal gyri, in the right caudate, and in the occipital-parietal regions involving the left precuneus, which are relevant brain regions for cognitive function and that compromise performance on cognitive tasks that require mental effort . The risk for cognitive decline in HF patients appeared to be modifiable with cardiac treatment, as clinical interventions that improve cardiac function can also improve cognitive function  and better treatment adherence predict improved cognition 1 year later . These facts underlie the importance to screen for cognitive impairment in HF patients and, although Mini-Mental State Examination (MMSE) is one of the most widely used, the Montreal Cognitive Assessment (MoCA) seems to be more comprehensive and appears to be the most suitable screening tool for HF as it tests all of the domains most often affected in this disease .
Finally, it should not be forgotten that depression plays an important role in HF. Approximately, 20% of these patients have clinically significant depression and another 35% have minor depression  and is often underdiagnosed . Depression was associated with poorer outcome in HF patients , so it is recommended to screen for it using tool as PHQ-2 and PHQ-9  and treat it using, for example, SSRIs, which are considered to be both efficacious and safe .
Ischemic Heart Disease
Ischemic heart disease (IHD) is the leading cause of death all over the world  and consists of several different conditions, such as myocardial infarction (MI) and angina pectoris (AP), which are the most prevalent ones. IHD is mainly due to the development of atherosclerosis in the coronary arteries, with reduction of blood supply to heart muscle, so it is also known as coronary artery disease (CAD) . The prevalence of IHD is about 20% in people over 65 years old, 7% in those 45–64, and 1.3% in those 18–45, with higher rates among men than women of a given age . The literature on the presence of cognitive dysfunction in IHD patients is mixed in general, the majority of prospective and cross-sectional studies demonstrating a significant association with cognition or dementia, resulting in a 45% increased risk of cognitive impairment or dementia . In fact, cognitive impairment is observed in about 35% of the patients with a previous history of IHD and most of the cognitive domains are affected even if a predominance of impairment in verbal memory learning and executive function was reported . IHD patients had lower cognitive performance and greater degrees of decline compared to people without IHD . Moreover, atherosclerosis extent and severity of angina pectoris were demonstrated to be associated with the severity of cognitive decline . The exact biological mechanism underlying the association between IHD and cognitive impairment or dementia is not still fully known, but many pathways seem to play a role . First of all, the common risk factors for IHD and dementia are the same, like as obesity, type-2 diabetes, smoking, hypertension, physical inactivity, and hypercholesterolemia , but the association between IHD and dementia cannot lay only on this . Moreover, IHD can be associated with other cardiac diseases, like atrial fibrillation and heart failure, which, as explained previously, increase the risk of cognitive impairment and dementia. Vascular insufficiency consequent to IHD could also be involved leading to cerebrovascular changes such as a reduced cerebral blood flow and cerebral hypoperfusion , brain infarctions, and white matter lesions , which are associated with reduced cognitive functioning and risk of dementia . Furthermore, patients with IHD have a loss of gray matter in some specific brain regions that are relevant to cognitive function, and the greater is the extent of coronary stenosis, the greater is the loss . It was also hypothesized, in a single study in adult rat, that the increased production of hydrogen peroxide in the hippocampus could play a role in the myocardial infarction induced cognitive dysfunction. More evidences are needed to support this mechanism . An important aspect to be addressed is the cardiac surgery consequent to IHD: the cerebral dysfunction following cardiac surgery is an important complication and can occur in different ways, classified as stroke, encephalopathy (including delirium), or postoperative cognitive dysfunction (POCD). The etiologies involved are cerebral emboli, hypoperfusion, or inflammation that has largely been attributed to the use of cardiopulmonary bypass . The most important predictors associated with cognitive decline in the postoperative period were demonstrated to be older age, female gender, higher bleeding episodes, and high postsurgery creatinine level . Regarding cardiac treatment, it seems to be able not only to increase cardiac function, but also to have beneficial effects on brain function , though beta-1–selective beta-blocker use was associated with worse incidental learning . As in atrial fibrillation and heart failure, also in IHD patients, the depression is an important aspect to be studied in deep. In fact, somatic symptoms of depression after a myocardial infarction predicted subsequent mortality, whilst depression, anxiety, and type D personality were associated with worse cognitive performance independent of clinical CAD severity and sociodemographic characteristics, especially in younger people [92, 93]. The effective treatment of depression reduces mortality in depressed postmyocardial infarction patients. In conclusion, considering the association of IHD and cognitive dysfunction, it is really important to screen for it and for depression before hospital discharge and during follow-up to improve its recognition and treatment .
Valvular Heart Disease
The risk of cognitive impairment in patients with valvular disease is present mainly when a valve correction is to be performed. In fact, clinically silent brain injury detected with cerebral magnetic resonance imaging (MRI) is well known after various cardiovascular interventions, including surgical valve correction, and they can favor cognitive decline . However, from the 1990s, new techniques for percutaneous valve corrections have been developed, especially for high-risk patients, such as transcatheter aortic valve implantation (TAVI) and MitraClip [96, 97]. Regarding TAVI, it is known to be associated with silent cerebral injury as well as surgical aortic valve replacement (AVR), but the risk of cerebral emboli seems to be inferior respect AVR. However, both AVR and TAVI are associated with a significant improvement of quality of life without a detrimental effect on cognitive function, despite the high intrinsic risk for cognitive deterioration of this population . Also MitraClip procedure causes acute cerebral lesions in the vast majority of patients, but these lesions resolve completely in the follow-up. Nevertheless, the number of lesions may have an impact on cognitive function as patients with more lesions showed a significant decline in their test scores in a single study .
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a rare and debilitating chronic disease of the pulmonary vasculature, characterized by increased blood pressure within the arteries of the lungs, which ultimately leads to right heart failure and death. The most common symptoms are shortness of breath, tiredness, and syncope. PAH is classified in different subgroups depending on its etiology and different mechanisms can be involved, including left heart disease (group WHO II) and chronic arterial obstruction (group WHO IV), the latter which is represented mainly by chronic thromboembolic pulmonary hypertension (CTEPH) . Patients with PAH may suffer from cognitive impairments, depression, and anxiety . In particular, cognitive deficits seem to be related to reduced oxygen delivery and cerebral tissue oxygenation (CTO), which is the strongest predictor of cognitive dysfunction, and disease-targeted medications result in better cognitive function . Moreover, mental disorders, exercise capacity, long-term oxygen therapy, right heart failure, and age play an important role in the quality of life of these patients and advanced practice nursing strategies (such as counseling, psychiatric referrals, psychotherapy, guided imagery, leading support groups, and low-grade resistance training) may help to increase their quality of life . Considering these evidences, it is clear the importance of screening PAH patients to assess their outcomes, and a new questionnaire, called PAH-SYMPACT, was recently proposed for clinical use including also cognitive/emotional impact of PAH . Regarding the subgroup of CTEPH, pulmonary endarterectomy with repeated short periods of circulatory arrest with moderate hypothermia results in a better quality of life and reduced symptoms of depression and anxiety without worsening cognitive function .
Sudden Cardiac Arrest
Sudden cardiac arrest (SCA) affects about 1 person per 1000 inhabitants every year and is one of the leading causes of death in the industrialized countries, with a mean survival to hospital discharge of 5–10% . During a cardiac arrest, the brain can suffer from a temporary limitation in blood supply, which can lead to hypoxic brain injury. Postcardiac arrest brain injury manifests as coma, seizures, myoclonus, and brain death. Among patients surviving to ICU admission but subsequently dying in hospital, brain injury is the cause of death in approximately two thirds after out-of-hospital cardiac arrest and approximately in 25% after in-hospital cardiac arrest. Unlike cardiovascular failure, which cause death in the first three days after the event, brain injury accounts for most of the later deaths [107, 108]. Postcardiac arrest brain injury may be exacerbated by microcirculatory failure, impaired autoregulation, hypotension, hypercarbia, hypoxemia, hyperoxemia, pyrexia, hypoglycemia, hyperglycemia, and seizures . In patients who survive at hospital discharge, one of the main clinical consequences of hypoxic brain injury is cognitive impairment . Cognitive problems affect about half of the survivors of out-of-hospital cardiac arrest . The cognitive domains that were affected most frequently are memory, attention, processing speed, and executive functioning, but also other domains can be affected. Moreover, memory problems were reported most frequently, especially regarding the episodic long-term memory functioning . A possible explanation for this is that the hippocampus, a brain structure important for the storage of information, is very sensitive to decreased cerebral perfusion . Furthermore, memory seems to be affected by global brain ischemia rather than focal brain lesions  and by the global cerebral atrophy seen after out-of-hospital cardiac arrest, which can also explain why so many cognitive domains can be impaired after cardiac arrest . Mild induced hypothermia 32–36 °C is recommended as a neuroprotective strategy for patients who remain comatose after hospital admission  as it can improve outcome after a period of global cerebral hypoxia-ischemia . Cooling suppresses many of the pathways leading to delayed cell death, including apoptosis, and also decreases the cerebral metabolic rate for oxygen by about 6% for each 1 °C reduction in core temperature, and this may reduce the release of excitatory amino acids and free radicals [117, 118]. Hypothermia also blocks the intracellular consequences of excitotoxin exposure (high calcium and glutamate concentrations) and reduces the inflammatory response associated with the postcardiac arrest syndrome [109, 119]. Cognitive function is similar in patients with cardiac arrest receiving targeted temperature management at 33 °C or 36 °C . Cognitive impairment was significantly associated with lower participation, together with the closely related symptoms of fatigue, depression, and restricted mobility. All these predictive variables should be used during follow-up to identify SCA survivors at risk of a less successful recovery that may benefit from further support and rehabilitation . Another important aspect that needs to be considered is the presence of anxiety and depression in SCA survivors, which are present in up to 50% of the patients independently of SCA characteristics [122, 123] and negatively affect the quality of life and the outcomes . All these evidences support the need of comprehensive outcome measurements of SCA survivors: a recent advisory statement from the International Liaison Committee on Resuscitation (COSCA – Core Outcome Set for Cardiac Arrest) suggests that evaluation should include survival, neurological function, and health-related quality of life (HRQoL). In particular, the statement recommends reporting the survival status and modified Rankin Scale (mRS) at hospital discharge, 30 days, or both. mRS is preferred over cerebral performance category (CPC) or other scales because it is a brief, clinician-completed, ordinal hierarchical rating scale used to determine a summary score of global disability after a neurological event or condition; it captures impairment of physical and cognitive abilities; and it can discriminate between levels of mild and moderate disability. Moreover, HRQoL should be measured with ≥1 tools from the HUI3, SF-36v2, or EQ-5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if it is possible .
Brain dysfunction is also fundamental in prognostication: bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory-evoked potentials were identified as the most robust predictors of poor outcome in comatose patients with absent or extensor motor response at ≥72 h from SCA, either treated or not treated with controlled temperature. Early status myoclonus, elevated values of neuron specific enolase at 48–72 h from SCA, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. If the initial assessment is inconclusive, prolonged observation and repeated assessments should be considered .
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