Impaired Cardiac Function and Cognitive Brain Aging

Canadian Journal of Cardiology

-

(2017) 1e10

Review

Impaired Cardiac Function and Cognitive Brain Aging Isabelle F. van der Velpen, MSc,a Clyde W. Yancy, MD, MSc,b Farzaneh A. Sorond, MD, PhD,c and Behnam Sabayan, MD, PhDc,d a b

Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

Division of Cardiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA c

Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

d

Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

ABSTRACT

  RESUM E

It is well established that patients with heart failure are at a greater risk for dementia. Recent evidence suggests that the heart-brain link goes beyond advanced heart failure, and even suboptimal cardiac function is associated with brain structural and functional changes leading to cognitive impairment. In this review, we address several pathophysiological mechanisms underlying this association, including hemodynamic stress and cerebral hypoperfusion, neuroinflammation, cardiac arrhythmias, and hypercoagulation. The close link between cardiac function and brain health has numerous clinical and public health implications. Cardiac dysfunction and cognitive impairment are both common in older adults. However, in our current clinical practice,

tabli que les patients atteints d’insuffisance cardiaque sont Il est bien e s à un risque plus e leve  de de mence. Des donne es scientifiques expose centes montrent que le lien entre le cœur et le cerveau ne se limite re e, mais que même la fonction pas à l’insuffisance cardiaque avance e à des changements structurels et sous-optimale du cœur est associe fonctionnels dans le cerveau qui mènent aux troubles cognitifs. Dans sente revue, nous nous penchons sur plusieurs me canismes la pre physiopathologiques qui sous-tendent cette association, à savoir le modynamique et l’hypoperfusion ce re brale, la neurostress he inflammation, les arythmies cardiaques et l’hypercoagulation. Le lien troit entre la fonction cardiaque et la sante  du cerveau a de e

Demographic Trends With the world population aging, chronic conditions such as heart failure and dementia are on the rise.1 About twothirds of older adults live with at least 2 comorbidities, and cardiovascular diseases are among the most prevalent medical conditions.2 Despite the surge in the number of individuals with cardiovascular diseases, mortality from cardiovascular events has dropped significantly in the past decades. In highincome countries, mortality from ischemic heart disease has declined steadily since 1980.3 In the period between 1999 and 2011, the number of hospitalizations for acute cardiovascular events in the United States decreased by about 38% for myocardial infarction and by a lesser degree for heart failure. Similarly, 30-day readmission rates after cardiac events have

also declined about 19% for myocardial infarction, and 1-year mortality has decreased about 23.4%.4 Our success in managing cardiovascular diseases combined with increasing life expectancy is manifested by an increasing number of older individuals with mild to moderate degrees of impaired cardiac function.5 Left ventricular dysfunction and heart failure are now common conditions affecting up to about one-third of older adults.6 Older adults with heart failure are frequently affected by other comorbid conditions. About 60% of patients with heart failure have at least 3 comorbidities at the time of a heart failure diagnosis.7 Among these comorbidities, functional and cognitive impairment are particularly common in this population. These impairments, which are present in 17% of patients at the time of diagnosis, are associated with adverse clinical outcomes and shorter survival.5,7-9 A recent population-based study demonstrated a hazard ratio of 1.21 for all-cause dementia in patients with heart failure.8 Public health policy concerning dementia is a major priority in countries around the world, with an estimated global prevalence of 90.3 million dementia cases by 2040.10 The connection between heart failure and accelerated cognitive decline, which is perhaps

Received for publication April 30, 2017. Accepted July 16, 2017. Corresponding author: Dr Behnam Sabayan, MD, PhD, Department of Neurology, Feinberg School of Medicine, Northwestern University, 676 N St Clair St, Ste 1300, Chicago, Illinois 60611-4296, USA. Tel.: þ1-312-5033936; fax: þ1-312-503-3951. E-mail: [email protected] See page 8 for disclosure information.

http://dx.doi.org/10.1016/j.cjca.2017.07.008 0828-282X/Ó 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

2

Canadian Journal of Cardiology Volume - 2017

these medical conditions are generally evaluated and treated in isolation. Emerging evidence on the significance of the heart-brain link calls for comprehensive cardiovascular risk assessment in patients with cognitive impairment and a neurocognitive workup in patients with impaired cardiac function. A multidisciplinary approach by cardiologists, neurologists, and geriatricians would benefit the diagnostic process and disease management and ultimately improve the quality of life for patients with cardiac and cognitive dysfunction.

percussions cliniques et en sante  publique. La dysnombreuses re quents chez les fonction cardiaque et les troubles cognitifs sont fre es. Toutefois, dans notre pratique clinique actuelle, ces personnes âge tats de sante  sont ge ne ralement e value s et traite  s se pare ment. Des e es scientifiques e mergentes sur l’importance du lien entre le donne valuation exhaustive du risque cœur et le cerveau demandent une e cardiovasculaire chez les patients ayant des troubles cognitifs et un gradation de la bilan neurocognitif chez les patients ayant une de quipe fonction cardiaque. Une approche multidisciplinaire d’une e e de cardiologues, de neurologues et de ge riatres serait utile compose au processus de diagnostic et à la prise en charge de la maladie, puis liorerait la qualite  de vie des patients ayant une ultimement ame dysfonction cardiaque et cognitive.

better called “brain failure,” seems intuitive. Yet, the exact pathophysiological mechanisms underlying this link remain to be elucidated.

microvascular endothelium is involved in many aspects of CBF regulation and is capable of producing a variety of vasoactive substances, including nitric oxide.22,24 Similar to the systemic circulation, the cerebral circulation is subject to age-related endothelial dysfunction.22 Current data indicate that endothelial dysfunction disturbs neurovascular coupling and may in this way contribute to neurodegenerative processes.25 Apart from energy supply to the brain, the neurovascular unit has a significant role in the regulation of neuroinflammation. Data from animal models consistently show that inflammatory processes in the brain are strong drivers of neuronal injury and cell death.26 Disruption of the brain vascular integrity exposes the brain to a wide variety of neurotoxic agents, resulting in neuronal dysfunction and apoptosis. Neuronal injury itself induces as inflammatory response by microglial activation, which goes on to produce proinflammatory cytokines that can further augment synaptic activity and integrity.22

The Brain As a Vascular Organ The brain has about 2% of the body’s weight but consumes 20% of the body’s oxygen and glucose. This high metabolic rate remains relatively constant over a wide array of mental and motor activities.11 To provide the means for such a high metabolic demand, it is estimated that about 15%-20% of cardiac output is distributed to the brain in resting conditions in healthy adults.12 Cardiac output provides a driving force for cerebral blood flow (CBF), a key factor in maintaining neuronal homeostasis and preserving brain structural and functional integrity. Despite changes in cardiac output and systemic arterial pressure, CBF is preserved in a narrow range by cerebral autoregulation.13 Cerebral autoregulation is classically defined as the process that maintains a constant CBF over a wide range of blood pressure variations.14 This model of static hemodynamic control has been increasingly challenged, and focus has shifted toward a more dynamic model of cerebral autoregulation that allows fluctuations in CBF on variations in blood pressure and other physiological stimuli.15-17 Prolonged exposure to cardiovascular risk factors and impaired cardiac function can impair cerebral autoregulation and lead to cerebral hypoperfusion, probably through its adverse effects on the neurovascular unit,18-20 which is the interface between the systemic circulation and the central nervous system. This functional unit consists of a cerebral blood vessel formed by endothelial cells and a complex of neurons and non-neuronal cells such as astrocytes, pericytes, and microglia (Fig. 1).21,22 The neurovascular unit is involved tightly in the regional distribution of blood flow in response to local neural synaptic activityda process termed “neurovascular coupling” or “functional hyperemia.”22,23 The neurovascular unit exercises a profound effect on the blood brain barrier (BBB) microvascular permeability and therefore on nutrient supply, clearance of toxic molecules, and paracrine functions of the endothelial cells. Hence, the integrity of the neurovascular unit and the BBB is crucial for brain homeostasis, regulation of nutrient transport to the brain, and protection of the central nervous system from the neurotoxins circulating in the blood. Disturbances in neurovascular coupling lead to an imbalance between neuronal energy need and CBF, causing neuronal dysfunction and cell death.13 The

Cognitive Impairment and Dementia Degenerative changes in the brain associated with brain aging are reflected by a combination of neurological and functional symptoms, which can collectively be grouped as dementia. This is a clinical syndrome characterized by progressive cognitive dysfunction, which is most pronounced in memory function, processing new information, executive functioning, visuospatial functioning, language, and behavior, altogether impairing a person’s capacity to perform activities of everyday life and live independently.10,27 In mild cognitive impairment (MCI), a person is affected by limited changes in cognitive function, although daily activities can still be performed and managed. Patients with MCI are more likely to experience dementia, but not every MCI case will progress to dementia.27,28 Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60%-80% of all dementia cases. Pathologically it is characterized by beta-amyloid plaques and tau tangles, accompanied by neuronal damage and death. Traditionally, a vascular type of dementia (VaD) accounts for another 10% of dementia cases and was a consequence of neuronal damage after a stroke. However, mounting evidence indicates that neurovascular damage is very common in patients with AD. About 50% of patients with AD have evidence of silent infarcts leading to pathologic conditions.27 The contribution of vascular diseases, in particular cardiac

van der Velpen et al. Impaired Cardiac Function and Brain Aging

3

Figure 1. Neurovascular (NV) unit, consisting of cerebral blood vessel formed by endothelial cells, astrocytes, pericytes, and microglia. Impaired cardiac function has a significant influence on cerebral blood flow (CBF), neuroinflammation, and endothelial dysfunction affecting the function of the neurovascular unit. Endothelial dysfunction with nitric oxide (NO) release and reductions in CBF lead to disturbances in neurovascular coupling and disruption of the blood-brain barrier (BBB). This results in an imbalance between neuronal energy need and blood supply, causing neuronal injury and cell death. Moreover, it exposes the central nervous system to neurotoxic agents in the blood and disrupts the regulation of nutrient transport to the brain. Neuroinflammation, both as a result of neuronal injury and systemic sources, induces activation of microglia. The release of proinflammatory cytokines by microglia further amplifies neurovascular injury. Ultimately, neuronal injury and BBB abnormalities give way to structural changes in the brain.

dysfunction, in cognitive impairment and dementia is remarkable. Several population-based studies have reported a high prevalence of VaD and AD in patients with heart failure.8,29,30 Cermakova et al.29 reported a prevalence of 36% for vascular dementia in a study in patients with both heart failure and dementia. Qiu et al.31 showed that patients with heart failure have about an 80% higher risk of developing AD. It is important to note that the diagnosis of dementia is largely based on clinical judgment and not on pathologic data, increasing the chance of diagnostic bias when a diagnosis of VaD was made based on cardiovascular history. A diagnosis of dementia is based on clinical presentation, combined with an objective cognitive assessment by means of detailed neurocognitive testing.27 A definitive diagnosis of dementia type can only be made postmortem based on pathologic lesions in the brain. There are several brief cognitive screening instruments available, of which the Mini Mental State Examination and Montreal Cognitive Assessment are well known.32 A systematic review on cognitive screening tools in patients with heart failure concluded that the diagnostic accuracy of tests in this population is yet to be determined.33 With progression of the disease, persons with dementia rely heavily on care from family members and caregivers, because their ability to perform activities of daily living

deteriorates.27,34 In the final stages of AD, the patient is bedbound and in need of constant care. Ultimately, dementia is fatal.27 To date, there is no cure available. Treatments to slow the progression of AD are not yet available.27 A promising strategy to reduce the burden of dementia is to identify modifiable risk factors that may help to prevent or delay the onset of dementia.8,10 Impaired Cardiac Function and the Brain Determinants of CBF regulation CBF is maintained by the harmonized interplay between the systemic and cerebrovascular circulations.15,35 The intricate regulation of CBF is determined mainly by mean arterial pressure and cardiac output, arterial blood gases, cerebral metabolism, and the autonomic nervous system.11,15,36 CBF is directly affected by changes in cerebral perfusion pressure, which is the net pressure gradient over the brain defined as the difference between mean systemic arterial pressure and intracranial pressure, under the condition that intracranial pressure exceeds central venous pressure.15 It is important to note that arterial blood gases and blood pressure are interdependent in the regulation of CBF and cannot be viewed separately.15 Cerebral reactivity to carbon dioxide (CO2) is a crucial

4

function of homeostasis, regulating central pH and the respiratory chemoreceptor stimulus.37 CO2 reactivity occurs mainly at the level of pial arteries, although there is some evidence that large cerebral vessels can also be reactive to changes in arterial blood gases.15,38 As an effect of these vasomotor reactions, CBF increases on hypercapnia, whereas hypocapnia induces reduction of CBF through cerebral vasoconstriction.37 The role of the sympathetic nervous system in CBF regulation remains debated. The human cerebrovascular system is innervated extensively with sympathetic nerve fibres.39 It is thought that neurogenic control is an important contributor to cerebral autoregulation and acts as a buffer in the large vessels during a rise in perfusion pressure.15 Nevertheless, whether the sympathetic nervous system has a tonic effect on CBF regulation is unknown.39 CBF can be altered in patients with heart failure in a number of ways. Abnormal hemodynamic responses in heart failure lead to a reduction in cardiac output, compromising CBF.36 Hypocapnia in heart failure is prevalent because of hyperventilation caused by pulmonary edema, altered chemoreflexes and ergoreflexes, and respiratory muscle weakness. Sympathetic nervous system activation and reninangiotensin-aldosterone system (RAAS) activation in heart failure induce sympathetic activity in the brain, potentially resulting in cerebral vasoconstriction. Together, these changes lead to suboptimal cerebral perfusion. Hemodynamic stress: blood pressure regulation Hemodynamic abnormalities are a hallmark of heart failure and many cardiovascular diseases that impair cardiac function. Blood pressure dysregulation can alter cerebrovascular function in a number of ways. Hypertension is a well-known risk factor for cardiovascular and cerebrovascular diseases. Elevated blood pressure over an extended period induces hemodynamic stress on the cerebral blood vessels and damages the endothelium, resulting in increased vascular tone.13 With increasing age, hypertension, as well as other forms of blood pressure dysregulation, can lead to cerebrovascular damage and subsequent cognitive impairment.40 For instance, higher blood pressure variability (BPV) has been linked to a greater risk of cerebrovascular events. Blood pressure values fluctuate during the course of the day but may also vary substantially between measurements taken during visits at the doctor’s officedtermed “visit-to-visit BPV.”41 A growing body of evidence suggests that beat-to-beat variation in systemic hemodynamic parameters can be physiological and might even be protective for brain function and structure.42,43 In contrast, long-lasting and exaggerated fluctuations in blood pressure appear to be influenced by cardiovascular risk factors, arterial stiffness, and end-organ damage such as cardiac dysfunction, and linked to adverse brain outcomes.41,44 Higher visit-to-visit BPV, independent of systolic blood pressure, is related to a higher risk of white matter hyperintensity, stroke and subclinical brain infarctions, microbleeds, and changes in hippocampal volume, all of which have been implicated in the pathophysiology of cognitive impairment.41,45 Indeed, higher visit-to-visit BPV has been associated with worse cognitive performance in older adults.45

Canadian Journal of Cardiology Volume - 2017

Apart from hypertension and BPV, low blood pressure is another hemodynamic feature that is linked to cognitive impairment. Orthostatic hypotension is common in older age and is related to worse cognitive performance, especially in individuals taking antihypertensive medication.13 Available data show that the cerebrovascular system is more effective at compensating for transient hypertension compared with hypotension.43,44,46,47 A recent study showed that blood flow velocity in the middle cerebral artery was less affected by hypertension than by hypotension.48 With the brain possibly being unable to compensate, low systemic blood pressure may lead to a reduced CBF, leaving brain tissue vulnerable to ischemic events.49 In patients with heart failure, blood pressure abnormalities are a common phenomenon. Although hypotension regularly occurs in patients with a reduced ejection fraction and can cause end-organ hypoperfusion as a consequence of reduced cardiac output,18 patients with a preserved ejection fraction frequently exhibit comorbid hypertension.50,51 In both conditions, patients with heart failure are predisposed to cerebrovascular damage. Hemodynamic stress: cardiac output The heart is the generator of blood flow through the systemic and cerebrovascular systems. Evidence from large observational studies shows that reduced cardiac output is linked to cognitive impairment.9,13 In diverse populations of both healthy older adults and older adults with heart failure, lower cardiac output has repeatedly been associated with worse executive functioning, smaller brain volume, increased white matter intensity seen on magnetic resonance imaging, cognitive impairment, and AD, even after correction for the conventional cardiovascular risk factors.9 Reduced cardiac output leads to cerebral hypoperfusion, with subsequent consequences on neuronal function.13 It has been suggested that ab-deposition and neurofibrillary tangles characteristic of AD may also be an expression of the neuronal energy crisis triggered by reduced CBF.13 During acute reductions in cardiac output, such as in the case of orthostatic hypotension, CBF is quickly restored in the larger vessels of the brain.52,53 However, during chronically reduced cardiac output, as is the case in heart failure, cerebral autoregulation is unable to compensate for subtle disruptions in CBF, which exposes neurons to chronic injury.52 The association between suboptimal cardiac output and cerebral perfusion is further strengthened by studies demonstrating that interventions to improve left ventricular function increase CBF and improve cognitive function.49,53 A recent study in healthy subjects demonstrated that the distribution of cardiac output in the brain circulation system changes with age, although total cardiac output remained stable during the adult lifespan.12 Another study showed that although global CBF velocity might be unaffected in early stages of heart failure, these patients experience considerable alteration in their cerebral autoregulation and vasomotor reactivity.18 Reduced perfusion of the brain may lead to reduced oxygen and glucose delivery to brain tissue. It is known that certain regions in the brain are more vulnerable to cerebral hypoxia than others. One of these regions is the hippocampus. A recent study by Suzuki et al.54 demonstrated that reduced

van der Velpen et al. Impaired Cardiac Function and Brain Aging

CBF in the posterior hippocampus was significantly associated with severity of cognitive symptoms in patients with heart failure. The posterior hippocampus plays a major role in cognitive function and its hypoxic-ischemic vulnerability has been demonstrated in patients that have been resuscitated after cardiac arrest. In another recent study by Browndyke et al.,55 postoperative cognitive dysfunction has been linked to perioperative alterations in resting-state brain functional connectivity in the default mode network, especially the posterior cingulate cortex (PCC). This network is centrally involved in global cerebral communication processes. The PCC has a 40% higher metabolic rate than most other brain regions and has been implicated in a number of cognitive processes from autobiographical memory to emotional salience. These results suggest that perioperative reduction in CBF from reduced cardiac output has effects on regions implicated in cognitive function. In summary, cerebral hypoperfusion has been linked to cognitive dysfunction in patients with heart failure and in the general population. In patients with heart failure, baseline CBF and its regulation are altered, largely because of reduced cardiac output. The hippocampus and PCC are critical structures for cognition that seem to be particularly vulnerable to hypoxic insults. Cardiac arrhythmias Atrial fibrillation (AF) is a common condition in heart failure.56 AF is considered a major risk factor for cardioembolic stroke. AF is also associated with an increased risk for cognitive impairment and dementia. Large populationbased studies show that individuals with AF have an increased risk for cognitive impairment and dementia that is amplified in the presence of a recent stroke.9 A meta-analysis on this topic reported a relative risk of 1.34 for cognitive impairment independent of stroke. In patients with AF and a history of stroke, this relative risk increased to 2.7.57 AF is also known to lead to subclinical cerebrovascular events. Subclinical brain infarcts have been associated with a steeper cognitive decline and dementia in older adults.58 A recent study showed that the presence of both subclinical brain infarcts and AF was associated with higher odds of MCI when compared with AF alone.59 The results of this study suggest that the threshold for dementia in patients with AF is decreased through multiple cerebrovascular pathologic conditions.59 In line with these results, another study demonstrated that in patients diagnosed with AD, postmortem neuropathologic lesions were less severe in patients with heart failure and AF.60 These results suggest that in patients with both heart failure and AD, subclinical cerebrovascular lesions decrease the threshold for clinically evident cognitive impairment and dementia. The link between AF and cognitive impairment may not be limited to the higher risk of cerebrovascular events. Several studies have suggested cerebral hypoperfusion as another potential mechanism underlying this link.57,61 Because of rapid contraction of the atria in AF, the ability to fill the ventricles is reduced, leading to a decrease in cardiac output.13 Cerebral hypoperfusion has been demonstrated in individuals with AF.13,62 In a study of patients with heart failure, concomitant AF was associated with decreased blood flow velocity in the middle cerebral artery and worse global

5

cognitive performance and memory compared with patients without AF. In the latter patients, cognition was not associated with cerebral hypoperfusion, which suggests that AF in the presence of heart failure deteriorates cardiac output and subsequently contributes to reductions in CBF to a point of causing neurocognitive dysfunction.63 Inflammation Inflammatory responses are a well-recognized phenomenon in cardiovascular disease. Atherosclerosis, hypertension, and obesity are associated with a chronic proinflammatory state.64,65 In this section, we discuss how tissue hypoxia, renal hypoperfusion, and autonomic imbalance in heart failure contribute to systemic inflammation. Systemic inflammation may contribute to the development of cognitive impairment by induction of neuroinflammation and disruption of neurovascular coupling.26,66 Neuroinflammation has been implicated in the pathophysiology of cognitive decline, although the exact mechanisms remained to be clarified.26,67 Local triggers of inflammation in the brain are capable of inducing neuronal injury. In fact, ab-depositions characteristic of AD seem to be able to invoke an inflammatory response and thus contribute to cognitive impairment.26,67 Besides local inflammation, several studies have shown an association between peripheral systemic inflammation and the development of cognitive impairment.66 Systemic inflammation is a well-established phenomenon in patients with heart failure.68-70 Several factors induce and escalate a proinflammatory state in patients with heart failure. Peripheral tissue hypoxia is one of the mechanisms proposed to induce a proinflammatory state in these patients.71 Tissue hypoxia is a common feature in heart failure and is known to be capable of activating an array of cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-6, and IL-1 in patients with heart failure.68,70 These cytokines have also been implicated in the neuroinflammatory state associated with cognitive decline.66,67 Systemic inflammation, both acute and chronic, involves the production of TNF-a from macrophages, which is a cytokine known to trigger the central innate immune response and in this way activate microglial cells in the brain.66 The proinflammatory state associated with cardiovascular dysfunction is further augmented by activation of the cardiorenal axis. Hypoperfusion of the kidneys is an important feature of heart failure and is a key trigger for the development and progression of the cardiorenal syndrome. Renal hypoperfusion activates the RAAS, which then leads to activation of the sympathetic nervous system and is involved in the release of reactive oxygen species (ROS).72,73 ROS production itself escalates oxidative stress and results in a self-perpetuating inflammatory state with constant release of cytokines such as TNF-a, IL-6, and IL-1. Studies in patients with kidney disease have demonstrated an increased incidence of cerebrovascular events, cognitive impairment, and dementia.74 Apart from the long-term cerebral consequences of kidney impairment, it has been shown that even in acute kidney injury, promotion of systemic inflammation and overproduction/ undersecretion of oxidative agents affects the brain and can cause impaired neurocognitive symptoms.74

6

Moreover, activation of the RAAS triggers the sympathetic nervous system, with subsequent release of norepinephrine.73 Heart failure by nature is characterized by increased sympathetic tone as a compensatory measure to maintain cardiac output, with concurrent effects on heart rate regulation and blood pressure control.72 Meanwhile, parasympathetic function is inhibited, leading to alterations in heart rate and heart rate variability.72 The resulting autonomic imbalance contributes to the progression of heart failure and a vicious cycle of promotion and aggravation of systemic inflammation. Evidence from populations of older individuals with dementia and MCI indicates that these patients commonly have impaired autonomic function.75,76 Decreased activity of the cholinergic nervous system, likely to induce general autonomic dysfunction, has been demonstrated in various dementia types.75 Dysregulation of the autonomic nervous system can lead to blood pressure dysregulation and orthostatic hypotension.75,76 The resulting hypotensive events can cause postural dizziness, falls, and syncope in patients, greatly increasing morbidity, mortality, and institutionalization.75,76 Autonomic dysfunction of cardiovascular origin might explain the impaired parasympathetic function in patients with MCI and dementia. Hypercoagulable state Heart failure has been well recognized as a condition that predisposes one to arterial and venous thrombotic events. As a leading cause of heart failure, ischemic heart disease is tightly connected to a prothrombotic state through platelet activation and aggregation. Venous thromboembolism is a common comorbidity in heart failure, with an incidence of 22% in hospitalized patients without prophylaxis. The concurrent risk of stroke is further increased in the presence of atrial fibrillation, as described earlier.77 When Virchow’s triad of hemodynamic changes, endothelial injury, and hypercoagulability is applied to heart failure, it becomes clear why the risk of thrombosis is increased. Patients with heart failure have characteristic hemodynamic alterations that lead to impaired blood flow and lower flow velocities. This can lead to stasis of blood, which induces formation of thrombi in the left ventricle.77 Endothelial injury in heart failure involves a proinflammatory state and a reduction in vasodilation mediated by a nitric oxide deficiency caused by neurohormonal activation. At sites of atherosclerotic plaque rupture, endothelial injury results in a cascade of platelet activation, which is further maintained by the release of tissue factor and generation of thrombin.77 Ultimately, platelet hyperreactivity, systemic inflammation, elevated levels of procoagulants, and impaired fibrinolysis all mediate hypercoagulability in patients with heart failure.77 Hypercoagulability is a feature present in both heart failure and cognitive impairment. Several studies have demonstrated a hypercoagulable state in patients with dementia.78,79 These patients were found to have elevated concentrations of serum fibrinogen, which has been implicated in the development of neuroinflammation, neurovascular damage, and blood-brain barrier permeability.78,79 In patients with AD, chronic activation of platelets has been demonstrated, resulting in neuronal injury and microinfarcts.26 At a clinical level,

Canadian Journal of Cardiology Volume - 2017

hypercoagulation has profound effects on cardiovascular morbidity and mortality and has been associated with cerebral ischemia, stroke, and vascular dementia.78 In a study of patients with cardiovascular risk factors but no overt disease, hypercoagulability was closely associated with multiple silent lacunar cerebral infarcts.80 This implies that even in patients with subclinical cardiovascular disease, a hypercoagulable state may already contribute to the development of small and large cerebral pathologic conditions, accelerating the rate of cognitive decline. Several studies have explored the effect of antithrombotic medication on cognitive decline and suggested a protective effect.78 A recent systematic review on anticoagulation therapy in patients with AF found a modest protective effect on cognitive function but could not exclude the risk of bias in these results.81 Nevertheless, results suggest that treatment of a hypercoagulable state in patients at risk may reduce the risk of cognitive impairment. Further research is needed to confirm an effect on cognitive function. Cardiovascular Comorbidities in Patients With Cognitive Impairment Comorbid chronic diseases are common in patients with cognitive impairment and dementia.82,83 Patients with dementia on average have 2 to 8 additional comorbidities.83 Cardiovascular diseases are major contributors to these comorbidities. A study in nearly 20,000 patients with dementia demonstrated that 70% of these patients use at least 1 cardioprotective medication.82 Several large cohort studies have investigated the prevalence of traditional cardiovascular risk factors in patients with cognitive impairment, with varying and sometimes conflicting results. Different studies report prevalence numbers for hypertension ranging from 37.1%-52.1% in patients with AD and 51.8%-57.2% in vascular and other types of dementia.84-86 The reported prevalence of diabetes mellitus ranges from 8%-20.6% in patients with AD and 14.8%-21.8% for other types of dementia.84-89 Hypercholesterolemia was present in approximately 10% of patients with AD.84 Within these studies, there were large differences when prevalence of cardiovascular risk factors was compared between patients with different types of dementia and a control population. Prevalence of cardiovascular risk factors was consistently higher in patients with vascular dementia, which may better reflect underlying pathophysiological processes. However, it may also indicate that clinicians are more inclined to classify a dementia diagnosis in a patient with a history of cardiovascular disease as vascular dementia rather than AD.84,87 The clinical presentations of vascular dementia and AD may be similar and share pathophysiological features associated with cardiovascular risk factors.87 Along with cardiovascular risk factors, the burden of cardiovascular diseases is fairly high in patients with dementia. For instance, Cermakova et al.87 reported that in a cohort consisting of about 30,000 patients with dementia, 23% of participants had ischemic heart disease. Heart failure was present in 15% of patients, and atrial fibrillation or flutter was documented in 19% of the population. The prevalence of congestive heart failure can reach up to 30% in patients with dementia, whereas the prevalence in control individuals is reported to be 10%-14%.84,86,87,89

van der Velpen et al. Impaired Cardiac Function and Brain Aging

7

Figure 2. The heart and the brain are both highly vascular organs. Hence, exposure to cardiovascular risk factors such as hypertension (HTN), diabetes mellitus (DM), and hyperlipidemia (HLP) makes both organs susceptible to dysfunction. Apart from shared risk factors, several mechanisms potentially underlie the heart-brain connection. Impaired cardiac function results in global hemodynamic dysregulation causing a hypoperfusion state and activates the renin angiotensin aldosterone system (RAAS). In addition, impaired cardiac function is strongly associated with cardiac arrhythmias and proinflammatory and hypercoagulation states, all of which can affect the brain neurovascular and structural integrity and ultimately accelerate cognitive brain aging. The close ties between the 2 organs warrant a need for a comprehensive heart-brain axis evaluation in patients with cognitive impairment and cardiac dysfunction. BP, blood pressure; MI, myocardial infarction; SVD, small vessel disease.

Despite the variance in reported prevalence, it is clear that cardiovascular comorbidities are abundant in patients with dementia. It is important to note that disease management in patients with cognitive impairment is not optimal. Besides a lack of insight, adherence to a treatment regimen is a great challenge, especially when dealing with multiple comorbidities.88 In most cases, managing these conditions leads to polypharmacy and drug interactions that may further compromise mental and physical functioning in these vulnerable older adults. Underdiagnosis of comorbid conditions in patients with dementia has been described in different populations and for a variety of conditions.83,84,90 It has been reported that patients with dementia are less likely to be diagnosed with ischemic heart disease than are patients without dementia. A large population-based study demonstrated that patients with AD were more likely to experience an ischemic cardiovascular event and be admitted to the hospital but were less likely to undergo revascularization procedures, which could not entirely be explained by contraindications.90 Rattinger et al.91 demonstrated that patients with heart failure and cognitive impairment or dementia were also less likely to receive adequate cardiovascular medication. In those patients who did receive medication, overall adherence was high, which was likely attributable to assistance from caregivers at home or in long-term-care facilities.82,91 Patients with dementia may be less able to express physical complaints, thus complicating the recognition of symptoms, which is necessary for diagnosis and adequate treatment.90 The management of cardiovascular disease and comorbidities is important to prevent deterioration of cardiac function but even more so to maintain quality of life and the

functional independence of the patient. Cardiovascular comorbidities are independent predictors of mortality in patients with dementia. Heart failure and diabetes mellitus were the strongest predictors of mortality in a large Swedish cohort study.87 In summary, cardiovascular comorbidities are common in patients with different types of dementia. However, there are discrepancies between the classification of dementia type and the prevalence of cardiovascular comorbidities. Patients with dementia are at risk of underdiagnosis of cardiovascular disease and may therefore miss out on proper management of these comorbidities, adding to the burden of disease already present in these patients. Heart-Brain Connection and Current Clinical Practice The pathophysiology of cognitive brain aging and impaired cardiac function are interlaced at different levels. Whether from shared cardiovascular risk factors or as a result of hemodynamic instability, cardiac arrhythmias, or hypercoagulable state, the links between cardiac and neurocognitive function are undeniable (Fig. 2). The available evidence for the heart-brain axis is now at a point at which it has surpassed a mere association, and there is reason to assume a causal relationship. Recognition of this link has important implications for clinical practice and public health policy. Studies reviewed in this article show that patients with impaired cardiac function are at risk for cognitive impairment. This effect may be most pronounced in patients with heart failure, but it is important to recognize that patients with subclinical cardiac disorders are

8

also at an increased risk of cognitive decline. There is a clear need to perform comprehensive neurocognitive evaluation for patients with suboptimal cardiac function. An integrative assessment of cerebrovascular function could provide valuable additional information on CBF status.92 If cognitive impairment is diagnosed early, monitoring and treatment of the cardiovascular disorder can also be tailored to cognitive function. It provides the time to arrange care if necessary (eg, aid with medication) and adds to the clinical interpretation of signs and symptoms in the absence of complaints expressed by the patient because of impaired disease insight. Similarly, cardiovascular risk assessment would be valuable in patients with cognitive disorders. As we described in this review, cardiovascular comorbidities are very common in patients with cognitive impairment. Importantly, a larger burden of cardiovascular risk factors has been associated with faster cognitive decline, especially in patients with atherosclerotic and genetic risk factors.93,94 Current clinical practice is based on a single-diseasecentered approach, which in the climate of chronic comorbid conditions may no longer be appropriate. Expansion of the heart-brain axis into the clinician’s office implies a closer collaboration between cardiologists, neurologists, and geriatricians. Early diagnosis of cognitive impairment in patients with cardiovascular disease or cardiovascular disease in patients with cognitive impairment requires an integrated multidisciplinary approach for the management of these conditions. Integrated care is paramount in patients with cognitive impairment to guide patients and their loved ones through progression of the disease and still adequately treat comorbid conditions. An integrated approach to disease as well as socioeconomic and behavioral factors could have far-reaching effects on quality of life, health care costs, and mortality.1 Early detection of comorbid cardiovascular disease in patients in the preclinical phase of dementia could slow progression of the disease, potentially increasing quality of life in these patients.95 Furthermore, the role of modifiable cardiovascular risk factors in the development of cognitive impairment has implications for the prevention of neurocognitive decline in patients with these risk factors or subclinical cardiovascular disease, or both. A multidisciplinary clinical approach calls for effective measures to achieve the goal of early detection and management.

Canadian Journal of Cardiology Volume - 2017 4. Krumholz HM, Normand SL, Wang Y. Trends in hospitalizations and outcomes for acute cardiovascular disease and stroke, 1999-2011. Circulation 2014;130:966-75. 5. Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC. Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail 2007;9:440-9. 6. van Riet EE, Hoes AW, Wagenaar KP, et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail 2016;18:242-52. 7. Murad K, Goff DC Jr, Morgan TM, et al. Burden of comorbidities and functional and cognitive impairments in elderly patients at the initial diagnosis of heart failure and their impact on total mortality: the Cardiovascular Health Study. JACC Heart Fail 2015;3:542-50. 8. Adelborg K, Horvath-Puho E, Ording A, et al. Heart failure and risk of dementia: a Danish nationwide population-based cohort study. Eur J Heart Fail 2017;19:253-60. 9. Marelli A, Miller SP, Marino BS, Jefferson AL, Newburger JW. Brain in congenital heart disease across the lifespan: the cumulative burden of injury. Circulation 2016;133:1951-62. 10. Prince M, Bryce R, Albanese E, et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013;9:63-75.e62. 11. Raichle ME, Gusnard DA. Appraising the brain’s energy budget. Proc Natl Acad Sci U S A 2002;99:10237-9. 12. Xing CY, Tarumi T, Liu J, et al. Distribution of cardiac output to the brain across the adult lifespan. J Cereb Blood Flow Metab 2017;37: 2848-56. 13. de la Torre JC. Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia. Cardiovasc Psychiatry Neurol 2012;2012:367516. 14. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 1959;39:183-238. 15. Willie CK, Tzeng YC, Fisher JA, Ainslie PN. Integrative regulation of human brain blood flow. J Physiol 2014;592:841-59. 16. Tzeng YC, Ainslie PN. Blood pressure regulation IX: cerebral autoregulation under blood pressure challenges. Eur J Appl Physiol 2014;114: 545-59. 17. Tymko MM, Ainslie PN. To regulate, or not to regulate? The devious history of cerebral blood flow control [e-pub ahead of print]. J Physiol doi:10.1113/JP274746, accessed July 10, 2017.

Disclosures The authors have no conflicts of interest to disclose.

18. Erkelens CD, van der Wal HH, de Jong BM, et al. Dynamics of cerebral blood flow in patients with mild non-ischaemic heart failure. Eur J Heart Fail 2017;19:261-8.

References

19. Mankovsky BN, Piolot R, Mankovsky OL, Ziegler D. Impairment of cerebral autoregulation in diabetic patients with cardiovascular autonomic neuropathy and orthostatic hypotension. Diabet Med 2003;20: 119-26.

1. Roberts KC, Rao DP, Bennett TL, Loukine L, Jayaraman GC. Prevalence and patterns of chronic disease multimorbidity and associated determinants in Canada. Health Promot Chronic Dis Prev Can 2015;35: 87-94. 2. van Oostrom SH, Picavet HS, van Gelder BM, et al. Multimorbidity and comorbidity in the Dutch populationddata from general practices. BMC Public Health 2012;12:715. 3. Moran AE, Forouzanfar MH, Roth GA, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study. Circulation 2014;129:1483-92.

20. Pires PW, Dorrance AM. The effects of hypertension on cerebral artery structure and function, and cerebral blood flow. In: Girouard H, ed. Hypertension and the Brain as an End-Organ Target. Cham: Springer International Publishing, 2016:99-134. 21. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013;19:1584-96. 22. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008;57:178-201.

van der Velpen et al. Impaired Cardiac Function and Brain Aging 23. Attwell D, Buchan AM, Charpak S, et al. Glial and neuronal control of brain blood flow. Nature 2010;468:232-43. 24. Toth P, Tarantini S, Csiszar A, Ungvari Z. Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 2017;312:H1-20. 25. Tarantini S, Tran CH, Gordon GR, Ungvari Z, Csiszar A. Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 2017;94:52-8. 26. Heneka MT, Carson MJ, Khoury JE, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015;14:388-405. 27. Alzheimer’s Association. 2017 Alzheimer’s disease facts and figures. Alzheimer’s Dement 2017;13:325-73.

9

41. Parati G, Ochoa JE, Lombardi C, Bilo G. Blood pressure variability: assessment, predictive value, and potential as a therapeutic target. Curr Hypertens Rep 2015;17:537. 42. Krzych LJ, Bochenek A. Blood pressure variability: epidemiological and clinical issues. Cardiol J 2013;20:112-20. 43. Rickards CA, Tzeng YC. Arterial pressure and cerebral blood flow variability: friend or foe? A review. Front Physiol 2014;5:120. 44. Rothwell PM, Howard SC, Dolan E, et al. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010;9:469-80. 45. Sabayan B, Wijsman LW, Foster-Dingley JC, et al. Association of visitto-visit variability in blood pressure with cognitive function in old age: prospective cohort study. BMJ 2013;347:f4600. 46. Tzeng YC, Willie CK, Atkinson G, et al. Cerebrovascular regulation during transient hypotension and hypertension in humans. Hypertension 2010;56:268-73.

28. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement 2011;7: 263-9.

47. Numan T, Bain AR, Hoiland RL, et al. Static autoregulation in humans: a review and reanalysis. Med Eng Phys 2014;36:1487-95.

29. Cermakova P, Lund LH, Fereshtehnejad SM, et al. Heart failure and dementia: survival in relation to types of heart failure and different dementia disorders. Eur J Heart Fail 2015;17:612-9.

48. Brassard P, Ferland-Dutil H, Smirl JD, et al. Evidence for hysteresis in the cerebral pressure-flow relationship in healthy men. Am J Physiol Heart Circ Physiol 2017;312:H701-4.

30. Hjelm C, Brostrom A, Dahl A, et al. Factors associated with increased risk for dementia in individuals age 80 years or older with congestive heart failure. J Cardiovasc Nurs 2014;29:82-90.

49. Sabayan B, van Buchem MA, Sigurdsson S, et al. Cardiac hemodynamics are linked with structural and functional features of brain aging: the age, gene/environment susceptibility (AGES)-Reykjavik study. J Am Heart Assoc 2015;4:e001294.

31. Qiu C, Winblad B, Marengoni A, et al. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med 2006;166:1003-8. 32. Ismail Z, Rajji TK, Shulman KI. Brief cognitive screening instruments: an update. Int J Geriatr Psychiatry 2010;25:111-20. 33. Cameron J, Kure CE, Pressler SJ, et al. Diagnostic accuracy of cognitive screening instruments in heart failure: a systematic review. J Cardiovasc Nurs 2016;31:412-24. 34. Giebel CM, Sutcliffe C, Stolt M, et al. Deterioration of basic activities of daily living and their impact on quality of life across different cognitive stages of dementia: a European study. Int Psychogeriatr 2014;26: 1283-93. 35. Panerai RB. Cerebral autoregulation: from models to clinical applications. Cardiovasc Eng 2008;8:42-59. 36. Brassard P, Gustafsson F. Exercise intolerance in heart failure: did we forget the brain? Can J Cardiol 2016;32:475-84. 37. Ainslie PN, Duffin J. Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation. Am J Physiol 2009;296:R1473-95. 38. Willie CK, Macleod DB, Shaw AD, et al. Regional brain blood flow in man during acute changes in arterial blood gases. J Physiol 2012;590: 3261-75. 39. Brassard P, Tymko MM, Ainslie PN. Sympathetic control of the brain circulation: appreciating the complexities to better understand the controversy [e-pub ahead of print]. Auton Neurosci doi:10.1016/j.autneu. 2017.05.003. 40. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-13.

50. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database. J Am Coll Cardiol 2006;47:76-84. 51. Quiroz R, Doros G, Shaw P, Liang CS, Gauthier DF, Sam F. Comparison of characteristics and outcomes of patients with heart failure preserved ejection fraction versus reduced left ventricular ejection fraction in an urban cohort. Am J Cardiol 2014;113:691-6. 52. Jefferson AL, Beiser AS, Himali JJ, et al. Low cardiac index is associated with incident dementia and Alzheimer disease: the Framingham Heart Study. Circulation 2015;131:1333-9. 53. Meng L, Hou W, Chui J, Han R, Gelb AW. Cardiac output and cerebral blood flow: the integrated regulation of brain perfusion in adult humans. Anesthesiology 2015;123:1198-208. 54. Suzuki H, Matsumoto Y, Ota H, et al. Hippocampal blood flow abnormality associated with depressive symptoms and cognitive impairment in patients with chronic heart failure. Circ J 2016;80:1773-80. 55. Browndyke JN, Berger M, Harshbarger TB, et al. Resting-state functional connectivity and cognition after major cardiac surgery in older adults without preoperative cognitive impairment: preliminary findings. J Am Geriatr Soc 2017;65:e6-12. 56. Kotecha D, Chudasama R, Lane DA, Kirchhof P, Lip GY. Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: a systematic review and meta-analysis of death and adverse outcomes. Int J Cardiol 2016;203:660-6. 57. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 2013;158:338-46.

10

58. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348: 1215-22. 59. Graff-Radford J, Madhavan M, Vemuri P, et al. Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 2016;12: 391-8. 60. Sposato LA, Ruiz Vargas E, Riccio PM, et al. Milder Alzheimer’s disease pathology in heart failure and atrial fibrillation. Alzheimers Dement 2017;13:770-7. 61. Ettorre E, Cicerchia M, De Benedetto G, et al. A possible role of atrial fibrillation as a risk factor for dementia. Arch Gerontol Geriatr 2009;49(suppl 1):71-6. 62. Lavy S, Stern S, Melamed E, et al. Effect of chronic atrial fibrillation on regional cerebral blood flow. Stroke 1980;11:35-8. 63. Alosco ML, Spitznagel MB, Sweet LH, Josephson, et al. Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure. PACE 2015;38:178-86. 64. Siti HN, Kamisah Y, Kamsiah J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul Pharmacol 2015;71:40-56. 65. Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 2004;89:2595-600. 66. Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 2009;73:768-74. 67. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000;21:383-421. 68. Anker SD, von Haehling S. Inflammatory mediators in chronic heart failure: an overview. Heart 2004;90:464-70. 69. Hasper D, Hummel M, Kleber FX, Reindl I, Volk HD. Systemic inflammation in patients with heart failure. Eur Heart J 1998;19:761-5. 70. Candia AM, Villacorta H Jr, Mesquita ET. Immune-inflammatory activation in heart failure. Arq Bras Cardiol 2007;89:183-90, 201-208. 71. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. The New England journal of medicine 2011;364:656-65 [in Portugese]. 72. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res 2014;114:1815-26. 73. Viswanathan G, Gilbert S. The cardiorenal syndrome: making the connection. Int J Nephrol 2010;2011:283137.

Canadian Journal of Cardiology Volume - 2017 79. Bester J, Soma P, Kell DB, Pretorius E. Viscoelastic and ultrastructural characteristics of whole blood and plasma in Alzheimer-type dementia, and the possible role of bacterial lipopolysaccharides (LPS). Oncotarget 2015;6:35284-303. 80. Kario K, Matsuo T, Kobayashi H, Asada R, Matsuo M. ‘Silent’ cerebral infarction is associated with hypercoagulability, endothelial cell damage, and high Lp(a) levels in elderly Japanese. Arterioscler Thromb Vasc Biol 1996;16:734-41. 81. Moffitt P, Lane DA, Park H, O’Connell J, Quinn TJ. Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review. Age Ageing 2016;45:767-75. 82. Cermakova P, Fereshtehnejad S-M, Johnell K, et al. Cardiovascular medication burden in dementia disorders: a nationwide study of 19,743 dementia patients in the Swedish Dementia Registry. Alzheimers Res Ther 2014;6:34. 83. Poblador-Plou B, Calderón-Larrañaga A, Marta-Moreno J, et al. Comorbidity of dementia: a cross-sectional study of primary care older patients. BMC Psychiatry 2014;14. 84. Imfeld P, Brauchli Pernus YB, Jick SS, Meier CR. Epidemiology, comorbidities, and medication use of patients with Alzheimer’s disease or vascular dementia in the UK. J Alzheimers Dis 2013;35:565-73. 85. Sherzai D, Sherzai A, Lui K, et al. The association between diabetes and dementia among elderly individuals: a nationwide inpatient sample analysis. J Geriatr Psychiatry Neurol 2016;29:120-5. 86. Eaker ED, Mickel SF, Chyou PH, Mueller-Rizner NJ, Slusser JP. Alzheimer’s disease or other dementia and medical care utilization. Ann Epidemiol 2002;12:39-45. 87. Cermakova P, Johnell K, Fastbom J, et al. Cardiovascular diseases in w30,000 patients in the Swedish Dementia Registry. J Alzheimers Dis 2015;48:949-58. 88. Bunn F, Goodman C, Malone JR, et al. Managing diabetes in people with dementia: protocol for a realist review. Syst Rev 2016;5:5. 89. Hill JW, Futterman R, Duttagupta S, et al. Alzheimer’s disease and related dementias increase costs of comorbidities in managed Medicare. Neurology 2002;58:62-70. 90. Tolppanen AM, Kettunen R, Ahonen R, Soininen H, Hartikainen S. Incident ischaemic heart disease in persons with Alzheimer’s disease in a Finnish nationwide exposure-matched cohort. Int J Cardiol 2013;170: 195-201.

74. Lu R, Kiernan MC, Murray A, Rosner MH, Ronco C. Kidney-brain crosstalk in the acute and chronic setting. Nat Rev Nephrol 2015;11: 707-19.

91. Rattinger GB, Dutcher SK, Chhabra PT, et al. The effect of dementia on medication use and adherence among Medicare beneficiaries with chronic heart failure. Am J Geriatr Pharmacother 2012;10:69-80.

75. Allan LM, Ballard CG, Allen J, et al. Autonomic dysfunction in dementia. J Neurol Neurosurg Psychiatry 2007;78:671-7.

92. Willie CK, Colino FL, Bailey DM, et al. Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function. J Neurosci Methods 2011;196:221-37.

76. Nicolini P, Ciulla MM, Malfatto G, et al. Autonomic dysfunction in mild cognitive impairment: evidence from power spectral analysis of heart rate variability in a cross-sectional case-control study. PLoS One 2014;9: e96656.

93. Kaffashian S, Dugravot A, Elbaz A, et al. Predicting cognitive decline: a dementia risk score vs. the Framingham vascular risk scores. Neurology 2013;80:1300-6.

77. Kim JH, Shah P, Tantry US, Gurbel PA. Coagulation abnormalities in heart failure: pathophysiology and therapeutic implications. Curr Heart Fail Rep 2016;13:319-28.

94. Viticchi G, Falsetti L, Buratti L, et al. Framingham risk score can predict cognitive decline progression in Alzheimer’s disease. Neurobiol Aging 2015;36:2940-5.

78. Gupta A, Watkins A, Thomas P, et al. Coagulation and inflammatory markers in Alzheimer’s and vascular dementia. Int J Clin Pract 2005;59: 52-7.

95. Blom K, Emmelot-Vonk MH, Koek HL. The influence of vascular risk factors on cognitive decline in patients with dementia: a systematic review. Maturitas 2013;76:113-7.