Hemodynamic Instability in Heart Failure Intensifies Age-Dependent Cognitive Decline

INTRODUCTION

“The relation between heart disease and dementia deserves joint research by cardiologists and psychiatrists” [1]. So ends the last sentence of an anonymous editorial published in The Lancet in 1977, a pioneering proposal in one of the most prestigious medical journals on the planet. The editorial refers to the role of the heart in the development of acquired dementia. It is fair to say that very few publications were recorded in the Cumulated Index Medicus for 1976, concerning dementia although the concept of this disorder was first documented by Egyptian “psychiatrists” in 2000 BC.

Unfortunately, as it is common in medicine, the Lancet editorial fell mostly on deaf ears or complacent minds despite the prestige of the journal and the intriguing observation. It is perplexing how the entire field of medicine (except for one Lancet editor) could ignore for centuries the obvious pathologic blowback that either organ can inflict on the other in view of their direct vascular and electrical connection.

Not until about the mid-1990s [2] did some relevant research begin to trickle down regarding the clinical association between cognitive impairment and cardiovascular pathology, but to this day, this link remains mostly ignored by practicing cardiologist and psychiatrists. For example, there is an appreciable paucity of articles published in prestigious clinical cardiology and psychiatric journals dealing with the issue of heart disease and cognitive impairment. This practice is similarly followed at major cardiology or psychiatric conferences [3] despite credible evidence that cardiovascular pathology reflected by heart failure poses as an independent risk factor for cognitive impairment in the elderly (Fig. 1) [4, 5]. The inability to recognize or test for cognitive decline following hospitalization and discharge for heart failure may be the major contributor to the highest rate in readmissions observed after hospitalization for any cardiac condition [5]. This is a failure that promotes poorer quality-of-life for the discharged patient who may not be able to cognitively cope with discharge instructions, thereupon increasing chances of hospital readmission while raising mortality and morbidity.

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Fig. 1

Heart parts associated with heart failure and sequential development of chronic brain hypoperfusion leading to cognitive impairment, a presumed precursor of Alzheimer’s disease. Heart failure reduces ejection fraction and cardiac output due to left ventricular dysfunction and inadequate pumping of blood to organs and tissues. See text for details.

This indifference in medical care extends into most randomized clinical trials evaluating heart failure medications on elderly populations. These trials rarely examine the post hoc outcome of such treatments on cognitive function as a secondary endpoint [6].

On the brighter side, the cavalier attitude shown by practicing cardiologists relevant to the topic of cardiovascular pathology and cognitive impairment is currently the subject of intense research from other specialists including neuroradiologists, neuropathologists, epidemiologists, neurologists, and especially neuroscientists of all branches who have stepped up to meet the heart-brain interactions and bring hope to those at high risk of neurodegenerative disease.

Considerable evidence has shown that when the heart of an elderly person does not pump out adequate blood to the body, systolic heart failure can be expected to develop. Likewise, when the cardiac myocardium has difficulty relaxing, diastolic heart failure is the common outcome. Either or both conditions can substantially raise the risk of cognitive impairment in the elderly individual due to the intensification of chronic brain hypoperfusion (CBH) [7, 8] (Fig. 2).

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Fig. 2

Sketch shows the common outcome in elderly diastolic heart failure when the left ventricle has difficulty relaxing due to a thickened and stiffened myocardium, a process that will increase afterload and weaken cardiac output. Conversely, when the left ventricle of the heart has a thin and weak myocardium due mainly to myocyte loss during aging, systolic heart failure and diminished cardiac output can be expected to develop. In either case of diastolic or systolic heart failure, the heart will not pump out adequate blood to the body but for different pathologic reasons (see text). Moreover, either or both conditions can substantially raise the risk of cognitive impairment in the elderly due to the intensification of chronic brain hypoperfusion generated by lowered cardiac output.

Has anything useful been learned from the collective research done since 1977? The answer is unquestionably positive.

Currently, it is apparent that key age-related defects in parts of the left atrium and left ventricle can significantly contribute to the hemodynamic changes leading to heart failure [9]. Although the molecular nuts and bolts of this process have yet to be clarified, this review will present the known and presumed pathways leading to cognitive decline originating mainly from the wear and tear of heart parts that normally function like a labyrinthian “Aeternitas Mega 4 Watch”, although the latter will work with considerable less atrophy over time.

Apart from identifying some major cardiac structures that worsen age-dependent cognitive decline [10, 11], specific measures involving the prevention of cognitive deterioration and malignant cardiogenic events will be examined below in the context of the evidence available.

The concept proposed here is that hemodynamic instability initiated from specific cardiac structural and functional abnormalities commonly observed in elderly people with heart failure, pose an important risk in the rise of progressive cognitive deterioration in this population group. It is reasonable to infer from the collective evidence that surgical or medical intervention of such cardiac defects may alleviate or delay symptomatic heart failure and also slow down or prevent the onset of severe cognitive impairment that can be generated in the absence of such treatments.

The purpose of this brief review is two-fold: 1) to call attention how some key heart parts can structurally and functionally deteriorate during aging to a point where heart failure is initiated; 2) to examine why the development of heart failure induces cognitive impairment and how this pathologic process can be targeted for treatment.

The complexity of physiological factors involved in heart failure will not be fully covered here but the reader is referred to the excellent review on this topic by Sinescu and Axente [12].

HEART FAILURE SYNOPSIS

Heart failure is a clinical syndrome characterized by a host of early symptoms (dyspnea, fatigue, disorientation, confusion) induced by progressive abnormalities of structural, functional, or both, worn out heart parts that contribute to lower the ability of the left ventricle to provide the body with adequate blood for its metabolic needs [13, 14].

About 40 million people are affected by heart failure around the world although heart failure is only one cardiac abnormality out of numerous that can lead to cognitive decline.

It is estimated that 30% to 80% of patients with heart failure reveal cognitive impairment to some degree and most of these are past the age of 65 [3].

Evidence indicates that some forms of heart failure may be accessible to treatment that can significantly delay dementia onset [15, 16].

Heart failure prevalence increases with age as the myocardium stiffens and left ventricular relaxation is prolonged, conditions that often lead to a reduction in diastolic and systolic function [17, 18].

The most common causes of heart failure are hypertension and coronary artery disease, either or both which typically affect the aging population and are also the most widespread phenotypic risk factors to Alzheimer’s disease (AD) [7, 19].

Treatment of heart failure is initially directed toward three goals: 1) prevention or control of hypertension, 2) improvement of heart’s pumping action, and 3) healthier lifestyle changes [20]. Interventions limiting structural damage to heart parts may be helpful if physiological remodeling has already begun or when risk factors to early heart failure are detected [21 –23].

There is good evidence that dedicated heart failure clinics established in community hospitals show a benefit in reducing heart failure hospitalization and all-cause mortality [23]. There is no data regarding these heart failure clinics as impacting the prevalence of cognitive decline when patient follow-up is recorded but such data has not been adequately investigated [20].

Treatment outlook is substantially more beneficial to the patient when the underlying causes of heart failure are first detected and managed since it limits the speed of the presenting symptoms from worsening.

Unfortunately, observational studies suggest that 3 of 4 patients undergoing evaluation by a cardiologist are never recognized to have treatable or manageable cognitive impairment, a finding reinforced by the lack of routine screening for cognitive impairment using heart failure guidelines [24].

The upshot of this outcome is a missed opportunity to provide good medical practice and confirms the casualness noted in the introduction concerning the disposition of expert cardiology examinations in diagnosing and prognosing heart failure while ignoring cognitive impairment as a possible co-morbid condition [21, 25].

ESSENTIAL PARTS OF THE HEART AND COGNITIVE FUNCTION

Broken down, the essential parts of the human heart consist of 4 chambers, 4 valves, vessels, muscular wall, and conduction system. These heart parts help pump out about 7,500 liters of blood via 100,000 beats daily in a healthy adult.

To stay healthy, the brain requires 20% of all oxygen and 25% of all glucose produced in the body. This allows the heart to normally supply the brain with 4–8 L/min of all blood pumped out of the left ventricle (cardiac output) or over 50% of the blood volume in the left ventricle at every heart beat (ejection fraction) [26]. In this context, when the required oxygen and glucose concentration is not supplied to the brain, brain cells become the most vulnerable cells in the body [27]. This is due to their absolute dependence on these two nutrients as their sole energy substrate and consequently enjoy a privileged slice of the glucose pie that surpasses that of any other body organ [28]. This privilege for craving glucose by brain cells has its drawback in that as cardiac output is diminished, the first body tissue to express a noxious hit is the brain.

Thus, the primary function of the cardiovascular system is to deliver nutrients to cells and organs in the body according to their metabolic need and to remove waste products, like CO₂, from body cells via the circulation.

Although fuzzy logic (defined here as imprecision or uncertainty) dominates much of cardiac dysfunctional mechanisms, there is a consensus that structural and functional deterioration of the cardiovascular system is most likely the main target of the aging process. This understanding is suspected because the heart is the most physically active organ in the body and the most vulnerable to aging-related breakdown. It is now axiomatic that cardiac function declines with aging.

The energy provided by blood from the heart to all organs is, at all times, the core of the complex physiological system that keeps the body alive. And yet, emphasizing the extreme sensitivity of brain cells to cardiac-induced CBH, most organs, except the brain, do not pay a crippling price when ejection fraction falls below 50% [29].

It follows that when cardiovascular disease or cerebral hemodynamic changes interfere with an aging heart’s blood pumping ability, vulnerable brain cells associated with cognitive regulatory sites can aggravate cognitive dysfunction anywhere from mild to vastly severe outcomes [25].

TARGETING BRAIN HYPOPERFUSION

Cerebral blood flow (CBF) insufficiency, now commonly called brain hypoperfusion, is more pronounced and prevalent during aging [30] due to two identifiable factors: 1) normal age-dependent CBF decline, which is estimated to drop at 0.50% per year or 20% from age 20–60 [11 , 31]; and 2) vascular risk factors to AD, adding an extra burden to CBF decline [32, 33].

Brain hypoperfusion is not brain ischemia. The latter is normally a sudden, event limiting significant blood flow to some region of the brain due to an intravascular blood clot. Brain hypoperfusion is a slow, progressive process that often takes years to become symptomatic [34 –37]. Both age-dependent CBF decline and vascular risk factors to AD are commonly manifested during aging although the physiopathologic cause for each process differs considerably in their relative dependence on cardiac output [38]. Both age-dependent CBF decline and lowering CBF due to vascular factors can be considered contributors to brain hypoperfusion.

Since currently little can be done to slow-down aging and its associated CBF decline, our efforts are better served by trying to combat the vascular risk factors that can place a critical burden on age-dependent CBF decline [39].

Therapeutic targets for age-dependent CBF decline would thus aim at countering the CBH drop either by artificially boosting CBF or by medically managing vascular risk factors to AD as soon as they are detected during advanced aging. Such risk factors as hypertension, atherosclerosis, type 2 diabetes, high body mass index, and cholesterolemia, are some of the modifiable AD risk factors known to participate in worsening CBF [40].

By contrast, despite some claims to the contrary, boosting CBF pharmacologically on a day-to-day basis has been tried in assorted clinical studies without much success. Moreover, there is no evidence that any drug clinically tested so far has shown any benefit in improving mild cognitive impairment (MCI) [41].

Addressing cognitive precursors of AD, such as subjective memory complaints or MCI, could provide an effective window of treatment opportunity in slowing or preventing further cognitive deterioration.

For example, we first advanced the notion in 1997 that a number of risk factors ostensibly considered independent in their association with AD, included hypertension, type 2 diabetes, history of traumatic brain injury, heart disease, and other disparate conditions, were in fact, vascular risk factors capable of accelerating AD onset [42]. We proposed then that these factors could escalate to AD onset by virtue of further reducing normal age-dependent CBF to noxious brain hypoperfusion levels [42].

Our proposal was supported at the start of the 21st century by human epidemiological studies [43] and further confirmed in a prospective, population-based study in 2001 [44]. Currently, the role of vascular risk factors in accelerating cognitive impairment and AD in the elderly has broad agreement among researchers in the field [45 –49].

By the same token, specific pathological abnormalities that develop in the aging heart parts (reviewed below) have also been implicated in cognitive dysfunction, very likely by contributing to the physiopathological pathways that result in heart failure (Fig. 1). Evidence strongly points to heart failure as a major risk factor to AD [46 , 51].

HEART FAILURE AND COGNITION

Currently, many longitudinal studies have linked heart failure during advanced aging with cognitive impairment and this association appears dependent on reduced cerebral perfusion [10 , 52–55]. Moreover, the capacity for cerebrovascular reactivity and autoregulation appears significantly impaired in heart failure, features that parallel and worsen CBH [56].

There is wide agreement that aging is the main driver of cardiovascular abnormalities that manifestly provoke hemodynamic facilitators of cognitive impairment [27 , 57].

Heart failure is a clinical syndrome characterized by an assortment of early symptoms (dyspnea, fatigue, disorientation, confusion) induced by progressive structural and functional abnormalities of one or several heart parts. The wear-and-tear of time in these heart parts contribute to lessen the ability of the left ventricle to provide adequate blood flow to the body at a rate commensurate with its needs. This process typically results in CBH which eventually leads to cognitive deterioration in the elderly (Fig. 1) [58].

In this scenario, left ventricular ejection fraction is reduced below the normal level of 50% at each heartbeat, primarily due to aortic stiffness and reduced distensibility [59 –61].

In a second scenario, ejection fraction during heart failure is preserved (>50%) but cognitive impairment still results in the same manner as in the first scenario [62]. How to explain this?

Heart failure with preserved ejection fraction is now the subject of intense research and considerable speculation surrounds its vascular physiology, especially its ambiguous outcome to cognitive impairment.

The concept that reduced ejection fraction correlates with systolic dysfunction while preserved ejection fraction reflects diastolic dysfunction has been challenged as being the primary drivers of reduced or preserved ejection fraction, and it is questionable whether it should be considered as a useful marker of ventricular contractility [63]. If this conclusion is valid, it would support the appropriateness of using reduced ejection fraction as a diagnostic criterion linked to cognitive disability in heart failure patients.

On the other hand, preservation of ejection fraction in heart failure would still lead to cognitive impairment by its pathohemodynamic action, but this process would unfold independent of aortic stiffness, unlike reduced ejection fraction. We suspect instead carotid intima-media thickness in older adults with heart failure would present the main obstacle to preserved ejection fraction. The likely reason may be the known association of cognitive impairment with heart failure, regardless whether ejection fraction is preserved or not [64, 65].

To this end, we propose that cognitive impairment with preserved ejection fraction diminishes CBF at the common carotid level by carotid intima-media thickness, not at the aortic level where stiffness and reduced distensibility initially lower forward blood flow through an increase in aortic pulse wave velocity (PWV) [66].

Accordingly, the hemodynamic outcome of reduced or preserved ejection fraction in heart failure can be regarded as basically similar in depressing laminar capillary blood flow, an action that can limit high energy nutrients from normally supplying brain cell metabolism. Maintaining brain capillary laminar flow is vital for the indispensable delivery of oxygen and glucose to nerve cells that are in constant need of these and other nutrients for their neurometabolic energy survival (for review, see [67]).

Despite the many controversies related to the pathology of heart failure, the present concept of this disease continues to be that its prevalence increases with age as the aorta stiffens and the left ventricular myocardium gets larger, weaker, and is unable to pump enough blood to the body.

Chronic insufficiency of blood flow pumped from the heart to the brain is empirically responsible for cognitive impairment in the elderly. This conclusion finds support by research showing the effects of CBH in the aging brain particularly on cardiomyocyte loss, aortic stiffness, isolated systolic hypertension, diastolic dysfunction, and low cardiac output [68].

Any of these acquired risk factors to AD can independently promote heart failure (reflected by an ejection fraction <50%), impaired cerebrovascular reactivity (reflected by aortic stiffening) and decreased arterial compliance (reflected by high carotid intima-media thickness and aortic stiffness) [69, 70].

The most common causes of heart failure include hypertension and coronary artery disease which not only target the aging population but are also the most common phenotypic risk factors to AD due to their CBF lowering effects [19 , 72].

Treatment of heart failure is initially directed toward prevention of hypertension and myocardial infarction, or, toward limiting structural damage to heart parts if physiological remodeling is already present.

Consequently, it is evident that properly treating the pathology impacting the heart parts may not only mitigate heart failure but provide a secondary benefit in delaying the advent of subjective memory complaints or MCI in the aged population by modifying the likely pathways to AD.

HEART TRANSPLANT FOR MEMORY RECOVERY FROM HEART FAILURE

A last resort that may provide end-stage heart patients with an unanticipated grace period from severe cognitive decline and death is heart transplantation. Very little, if anything, is known about potential recovery from MCI or severe cognitive dysfunction following a heart transplant. One brief study previously reported brain hypoperfusion, memory deficits, and related hypometabolism could be reversed post-transplant in human patients [73]. If confirmed, these findings would indicate that neurons associated with memory loss seen in heart failure are not all irreversibly damaged but can be ‘rescued’ with CBF restoration as we have shown experimentally in rodents [74].

Neuronal rescue in cognitive decline during heart failure is an area of research that could provide groundbreaking evidence in the treatment of cardiac disease and dementia.

AGE AND HEART DISEASE

Heart parts affecting somatic function are evident during aging but are not exclusive of old age since their malfunction can occur at any age.

Curiously, if assorted cardiac abnormalities can occur at any age, why is it that cardiomyopathy resulting in cognitive impairment and eventual dementia is primarily seen in the elderly population (>60 y/o) whereas no definitive cognitive deficits in the presence of aortic stiffness or heart failure are commonly detected in young subjects [75]? This puzzling paradox will be examined in more detail below, notwithstanding that a search of the literature disclosed no mention of this issue.

CARDIAC HEMODYNAMICS AND COGNITIVE FUNCTION

It has been known for decades that CBF is directly tied to heart failure but the precise biodynamic ‘nuts and bolts’ process remains elusive [76, 77].

Notwithstanding the complexity of the problem, it can be argued with some confidence that abnormalities of the micro- and macrovascular brain hemodynamics play an integral role in age-related cognitive decline and neurodegeneration [78 –85].

Here, we present evidence that one trajectory to heart failure and cognitive impairment is via brain hypoperfusion. For example, substantial evidence has been reported that one of the predominant hemodynamic mechanisms involved in declining cognitive function affecting the elderly is associated with lowered CBF and evidence indicates a direct effect on the emergence of heart failure [85 –98].

Currently, general agreement holds that CBH arising from a variety of cardiovascular abnormalities, will result in cognitive deficits during aging, the severity and cognitive domains affected being dependent on the source of CBH [85 , 100].

In that context, we have previously proposed a model of late-onset AD where three essential factors slowly converge en route to the progressive dawning of cognitive impairment: 1) geriatric age (>65); 2) age-dependent CBF decline; and 3) presence of multifactorial vascular risk factors to AD that accelerate age-dependent CBF decline [85, 96].

The first factor considers that reaching a geriatric age can become a principal inducer of brain hemodynamic alterations [100, 101]; the second factor involves a physiologically normal but potentially insidious process that lowers CBF in proportion to increased aging, thus from age 20, age-dependent CBF declines at a rate of 0.4–0.5% /year or about 20% by age 60 [11, 28]; the third factor adds a further burden (or final straw) that pushes age-dependent CBF decline to an even lower perfusion level where vulnerable brain cells can no longer cope with their dwindled energy supply, giving way to progressive neurodegeneration followed by cognitive decline [85, 101]. We have described this hemodynamic ‘point of no return’ as ‘critically-attained threshold of cerebral hypoperfusion’ (CATCH) [32, 102]. CATCH is a watershed event because it involves a turning point that determines whether many of the brain cells will perish from insufficient energy supply or survive the stress of CBH [85].

CATCH describes how normal age-dependent CBF decline is accelerated by the presence of vascular risk factors to AD. Stated another way, if normal CBF decline drops about 16–20% from age 20–60 [11 , 103–105], the beginning of CATCH would drive the rate of age-dependent CBF fall to a level much greater than 20% during a 40-year period [85]. The outcome would accelerate and boost the degree of cognitive impairment [106]. The mechanobiology of CATCH in precipitating cognitive deterioration remains unclear but could hinge on the quality and pathogenicity of each vascular risk factor acquired during a lifetime as well as the relative health and genomics of the individual affected. This is a pioneering area of unexplored brain research to which a young investigator could engage in and contribute significant findings to our understanding of dementia.

All in all, the collective evidence indicates the important role arterial stiffening plays during aging in worsening age-related CBF to a level where CATCH becomes pivotal and cognitive loss is accelerated [101].

Since there are obvious degrees of severity of arterial stiffening based on a host of independent factors, the exact speed of cognitive decline galloping towards AD onset, is difficult to predict. The reason follows Heisenberg’s principle: in this case, the more one measures the causative factors involved in arterial stiffening, the less predictable the acceleration of cognitive decline will become.

Nevertheless, the general equation involving aging  +  severity of arterial stiffening  +  rate of CBF decline  =  start of cognitive impairment , would seem to be more reliable to predict AD onset than using a prognosis where arterial stiffening is minimal or absent [102].

The link between CBH and cognitive impairment may thus depend, to a large extent, on the many identified vascular risk factors to AD, all of which are reported to lower CBF to some degree (for review, see [58]). The main hemodynamic consequences of these vascular risk factors to AD is to diminish normal CBF, starting around midlife (and possibly before), initially imperiling a healthier course to old age [107 –110].

The core of these heterogenous, age-dependent, hemodynamic risk factors appears to be cardiovascular disease. For instance, research studies show a 14–19% reduction of CBF in heart failure patients when compared to matched, normal controls [111, 112]. This drop in CBF results from low ejection fraction engendered by left ventricular systolic dysfunction. Systolic dysfunction in old age is known to be associated with reduced CBF [111].

ATRIAL DEFICITS AND COGNITIVE FUNCTION

Atrial fibrillation (AF) is the most common cardiac arrhythmia seen worldwide in clinical practice [113]. The causal association between AF and ischemic stroke has been well documented in the literature [114]. This association has boosted research into the risk of post-stroke cognitive decline during aging, although a segment of the population with AF but without signs of thromboembolic stroke, still show an increased risk of cognitive deterioration [35].

This paradoxical finding suggests that AF expression without overt evidence of stroke can independently lower cardiac ejection fraction which would act to diminish CBF supply longitudinally in the elderly individual and promote or intensify the risk of cognitive decline.

Atrial ablation studies seem to support this conclusion of AF showing a significant zero rate of AF after ablation but poorer contraction of the left ventricle due to the “stunned” post-ablation myocardium in the left atrium [115]. This outlook could negatively affect cardiac output or ejection fraction during atrial recovery from ablation. The stunned post-ablation atrium, however, recovers spontaneously after 3 weeks of normal sinus rhythm [115].

Three types of AF have been described. Paroxysmal AF episodes occur occasionally and will stop spontaneously after a few hours or a few days with return to normal sinus rhythm [116]. Persistent AF, if left alone, will continue until treatment is applied, such as anti-arrhythmic therapy although these agents may not control AF for days, weeks or ever.

Electrical cardioversion (EC) has a dependable success rate ranging between 90–95% in reversing an episode of paroxysmal or persistent AF to normal sinus rhythm [117, 118]. Permanent AF does not generally respond to electrical cardioversion or to most antiarrhythmics but, like persistent AF, may be amenable to minimally invasive catheter ablation. In this procedure, an ablation catheter is threaded into the left atrium and small, thermal, radiowave or electric lesions are made at the active foci that give rise to the AF aberrant signals [119 –121]. Scar tissue formed from the tiny-spot ablation lesions prevent the AF aberrant signals from crossing the scar area.

Recent meta-analyses of over 260,000 cases has reported AF is associated with an increased risk of cognitive decline and incident dementia [122 –124] (Fig. 1). Although the causes for this association are multifactorial and not fully understood, we surmise the trajectory from AF to cognitive decline and dementia could reasonably involve the development of CBH followed by heart failure [86] (Fig. 1). This proposal finds support in elderly people with reduced cardiac output [125, 126] or lowered ejection fraction, the implication being that CBH is a key promoter linking the comorbid AF:heart failure connection [127, 128] (Fig. 1).

Left atrial dysfunction can influence cognitive behavior in other ways. In a sample of older adults undergoing neuropsychological and echocardiographic measures of left atrial size, it was reported that enlargement of atrial volume was associated with cognitive impairment in older adults [129]. The underlying causes of left atrial enlargement are many, including systolic hypertension, type 2 diabetes, smoking, obesity, coronary artery disease, and heart failure, conditions commonly posing a high risk to cognitive impairment in the older patient [130, 131]. Mechanically, increased atrial size affects microstructural and functional remodeling, specifically, interstitial fibrosis and myocyte hypertrophy [132].

Left atrial enlargement increases with age and can result from systolic and diastolic dysfunction causing brain hemodynamic changes [129]. These hemodynamic changes can result in cardiovascular events, such as stroke, coronary heart disease, and heart failure [133]. Left atrial enlargement has, therefore, multivariate causes and is commonly linked with mitral valve regurgitation. This process is mainly due to the enhanced volume created by the chronic backflow of ventricular blood which stretches and enlarges atrial cardiomyocytes [134].

Aside from AF and its deleterious effects on cardiac output, ejection fraction, and thrombogenesis, cognitive impairment emerging from atrial dysfunction is also vulnerable to inflammatory pathways but it is still an open question whether AF is the cause of atrial inflammation or a consequence of inflammation [128]. Leukocyte infiltration accompanied by a host of inflammatory cytokines, including tumor necrosis factor-α, IL-6, nuclear factor κ-light-chain-enhancer of activated B cells, and the pro-oxidant myeloperoxidase, have been found increased in atrial tissue of patients with valvular disease [126].

It is evident from the informative snippets provided above that the atrium looms as a powerful, muscular chamber transacting with complex cardiac processes and indirectly managing detrimental brain hemodynamics and pernicious inflammations that can jeopardize left ventricular function. The atrium’s main role is to modulate left ventricular filling with oxygenated blood and contribute to the heart’s performance despite a multitude of cardiac insults that can culminate during old age in total cardiac breakdown, heart failure, and cognitive deterioration [135].

The upshot of atrial dysfunction in diverse pathological machinations during advanced aging is the frequent emergence of heart failure and the initiation of cognitive decline, conditions that are amenable to interventions by knowing their causation when detected early.

RANOLAZINE IN ATRIAL FIBRILLATION

One drug that seems to stand out in hypertrophic obstructive cardiomyopathy (HOCM) from the rest is ranolazine, an FDA approved antianginal agent with interesting biomolecular actions. In patients treated with chemotherapy for cancer, ranolazine caused cardiac relaxation and significantly reduced diastolic dysfunction induced by cancer chemotherapy, a plus not matched by other cardiovascular drugs [136].

The main mechanism of action of ranolazine is as an inhibitor of late sodium entry into cardiomyocytes, an action that reduces downstream toxicity of cytosolic calcium overload in ischemic myocytes while improving coronary blood flow, a negative consequence of HOCM [137]. Ranolazine given at medically indicated doses does not lower heart rate or blood pressure.

It is reported that ranolazine increases coronary venous levels of adenosine in vivo and in the endothelial cells of cardiomyocytes, in vitro [138]. Adenosine is well recognized as a cardioprotective substance in ischemic heart disease, especially in aging hearts [139]. In a rodent model of heart failure, ranolazine downregulated caspase-9 expression and upregulated pAKT and Bcl-2 expression in cardiomyocytes, thus improving cardiac function in this model [140].

Future trials of ranolazine may uncover other benefits offered by this remarkable agent, particularly in the prevention of persistent and permanent AF [141]. Currently, experimental studies indicate ranolazine plays a role in molecular signaling pathways that prevent AF via improved mitochondrial function, by reduced oxidative stress, and by decreased atrial myocytic apoptosis [142]. Off-label use of ranolazine by some European cardiologists have privately advised patients with persistent and permanent AF to start a trial of oral ranolazine in an attempt to control their arrhythmic episodes when other interventions have failed.

Improved cardiac technology and discoveries in pharmacology, surgical interventions, and lifestyle changes have significantly helped extend life expectancy in modern societies [143]. This trend could offer more hope to elderly patients; health in reducing the prevalence of cognitive impairment by examining potential and modifiable risk factors to cardiac impairment.

MITRAL AND AORTIC VALVES

The left ventricular heart valves tend to degenerate with aging, a process aided by accumulating calcium deposits in the aortic valve cusps and mitral annulus [144]. The calcium deposits will affect ejection fraction and extracardiac hemodynamics [144]. When calcific deposits in the aortic valve become severe enough, aortic stenosis will result. The outlook for aortic stenosis will depend on whether the left ventricle can overcome the valvular and hemodynamic afterload by increasing the pressure of its ejection fraction during systole. Failure to achieve this compensation will result in brain energy needs from being met, essentially adding to reduced cardiac output and CBH as precursors of cognitive decline [145].

Mitral annular calcification producing mitral stenosis can affect left ventricular pressure and aortic pressure during the cardiac cycle. Mitral valve calcification is associated with mitral valve stenosis and regurgitation.

Mitral valve regurgitation occurs from many cardiac diseases including structural support of the mitral leaflets, especially the posterior cusp, following rupture of the chordae tendinae, which then allows the leaflet to bulge upward into the atrium at each ventricular contraction. The mitral valve is like a one-way door and when it swings back, dire consequences can follow (Fig. 3). The backward flow of blood allows ventricular blood to push back (regurgitate) into the atrium which can increase its volume with time.

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Fig. 3

Sketch of ventricular blood flowing backward from left ventricle to left atrium due to inefficient mitral valve unable to close tightly. The most common cause of mitral valve inefficiency is mitral valve prolapse. The consequences of moderate-severe mitral valve prolapse are multiple, including mitral valve regurgitation, promotion of myocardial ventricular hypertrophy, coronary artery disease, lowered ejection fraction, heart failure, and reduction of systolic pressure, conditions that diminish blood pumping of oxygen and vital nutrients to meet organ needs. These events tend to develop slowly and progressively in the elderly. Severe mitral valve regurgitation is associated with chronic brain hypoperfusion, a presumed pathogenic precursor of cognitive impairment and Alzheimer’s disease. RV, right ventricle.

Aside from acquired disease and structural defects, genetic susceptibility can also be responsible for mitral valve prolapse and regurgitation [146].

Mild mitral regurgitation requires only observation (Fig. 3). However, untreated, symptomatic mitral regurgitation can lead to mitral valve prolapse, ventricular hypertrophy, and heart failure due to volume overload.

Volume overload has attendant consequences on pulmonary congestion and hypoxia, key features of heart failure and cognitive deterioration.

Surgical repair of mitral valve regurgitation is the optimal treatment when compared to mitral valve replacement and there are claims that it attains better cure rate of symptoms, provides improved heart function, and has better survival rate [147].

More recently, a minimally invasive transcatheter mitral valve repair (TMVR) technique has been used that is reported to spare significant damage to memory and executive function in selected patients [148]. The procedure uses a robotic, steerable guide catheter with two arms and two grippers to deliver the guide catheter and clip into the left atrium where the surgeon positions the clip to repair the valve defect [149]. Reported sparing of memory and executive function using TMVR could result from reducing the incidence of heart failure, a common outcome following conventional mitral regurgitation surgical repair [150, 151]. TMVR has essentially replaced open heart mitral valve repair or replacement as the preferred treatment due to its minimal invasiveness, lower risk of incisional infection, reduced blood loss, and a shorter hospital stay [152, 153]. The tradeoff for mitral valve surgical is cognitive decline.

A systematic review and meta-analysis indicate cognitive decline can follow several months after conventional mitral valve surgical repair with elderly individuals being the most vulnerable to this procedure [154]. Microembolism and stroke are ostensibly the suspected culprits of cognitive impairment after mitral valve repair [154].

HYPERTENSION: TO TREAT OR NOT

With respect to cognitive function, it can be concluded from multiple studies of blood pressure in the elderly that both hypertension and hypotension are associated with cognitive decline [155 –157]. This paradox is difficult to frame from a clinical viewpoint because chronic systolic hypertension in the aged increases the risk of stroke, heart failure, cognitive impairment, coronary artery disease, renal failure, and heart attack, while hypotension poses a risk to cognitive impairment, heart failure, arrhythmia, aortic stenosis, syncope, and cardiovascular disease [158, 159].

Another problem is how to define the threshold for diagnosing and managing systolic hypertension in an elderly person as recommended by two diverse cardiology guidelines: 130–139 mm Hg; or above 140 mm Hg [160]?

To complicate matters even more, the list of pathological conditions associated with hypertension and hypotension listed above can be considered as independent variables interacting with the cerebral physiology (e.g., blood pressure, blood flow) or mental state (e.g., cognitive function) or both. The question of high blood pressure being protective [161] or harmful [162] in late-life, therefore, remains unresolved.

With millions of elderly patients confronting cognitive impairment amidst a multitude of cardiovascular disease risk factors, the propagation of more Heart Failure Clinics and the creation of Heart-Brain Clinics would likely help resolve these issues [163, 164].

VENTRICULAR HYPERTROPHY AND COGNITIVE FUNCTION

Left ventricular hypertrophy occurs when the ventricle cannot relax sufficiently to allow normal filling with blood during diastole due to thickening of its muscular wall. At an elderly age, ventricular wall thickening will commonly stiffen the ventricular myocardium and weaken the overworked muscles which then compensate by working harder but pumping less blood to the body due to aortic stiffening, cardiac overload from systolic hypertension, and from aortic stenosis (Fig. 2). Many cardiac related disorders are known to cause ventricular hypertrophy, including AF, type 2 diabetes, smoking, valvular defects, and the most common of all, systolic hypertension [165]. It can be said with some confidence that these heart conditions are primary risks to heart failure and progressive cognitive decline [166].

Echocardiography is considered the gold-standard, non-invasive tool to determine enlargement of left ventricular mass and its severity in the prognosis of its influence as a harbinger of morbidity and mortality.

Ventricular hypertrophy occurs commonly in the elderly and stems from hypertension which develops morphologically from enlargement of cardiomyocytes in the cardiac wall.

The bioenergetic metabolism of the aged heart muscle also appears to be abnormal in its ability to use mitochondrial ATP [167]. This suggests that cardiac muscle in the aged has a greater chance of structural and functional impairment that can lead to additional pathophysiological consequences due to impoverished energy supply to myocytes.

For example, the left ventricular myocardium in late life can become so excessively thick and stiff that pumping of blood becomes very difficult, generally leading to brain hypoperfusion, heart failure, and cognitive dysfunction [168]. Co-morbid culprits of ventricular wall thickness are diverse but commonly include heart attacks, genetic mutations, hypertrophic cardiomyopathy, and dilated cardiomyopathy [169]. These conditions tend to unfold in older people and particularly when heart failure is already present [170].

Ventricular wall thickening can vary in different places of the wall (Fig. 3). For example, the septal region that divides the right and left ventricles is often the most common area to hypertrophy. This action diminishes ventricular stroke volume by partly obstructing the outlet tract of blood flow to the aorta, a condition known as HOCM [171]. HOCM brings on its own set of problems aside from lowering blood flow pumped into a stiff aorta, among them, promoting non-laminar flow (a risk for brain microemboli) mitral regurgitation, aortic stenosis, and disruption of the cardiac electrical conduction system [170].

Treatments to delay or prevent severe HOCM from turning into end-stage heart failure, include surgical or alcohol septal ablation, where physically reducing the septal muscle from bulging into the left ventricular outflow tract is performed to increase cardiac output. Surgical myectomy to remove excess septal muscle will also lessen the effects of mitral regurgitation, discussed above. Implanting a defibrillator to prevent sudden cardiac death from ventricular fibrillation can be an effective prophylactic option [170].

Pharmacological therapy for HOCM aims primarily to limit heart failure as well as arrhythmias, anginal symptoms, and improvement of outlet tract when septal ablation is contraindicated. Medicines for HOCM include beta adrenergic blockers to control hypertension and ventricular or supraventricular arrhythmias. Other agents include calcium channel blockers to improve left ventricular filling time, antiarrhythmics to prevent AF, and a variety of drugs with possible limiting effects on improving outlet tract obstruction but none so far described is evidence based [165].

ARTERIAL STIFFENING

Arterial stiffness is generally considered a major risk factor for heart failure and its source has been linked to conditions that alter the hemodynamics of pulsatile flow on the arterial wall, such as hypertension, type 2 diabetes, hyperlipidemia, and atherosclerosis [172].

High aortic stiffness is also associated with poorer cognitive function among nondemented individuals in cross-sectional [173] and longitudinal studies [174 –176].

Aortic stiffness causes an increase in afterload which is compensated by left ventricular hypertrophy. A consistent finding in aged hearts is the progressive loss and hypertrophy of myocytes in the atrial and ventricular walls [165]. Increased arterial stiffness is also associated with lower diastolic blood pressure and reduced coronary perfusion [174].

Atrial and ventricular myocytes form the atrial and ventricular walls of the heart. Cardiomyocytes are concerned with the contractile function of the heart and since most of them are terminally differentiated postmitotically, their loss following injury or disease provides them with very limited regenerative activity. Loss of cardiomyocytes during advanced aging leads to hypertrophy of the remaining myocytes creating enlargement in the diameter of the left ventricle that can lower cardiac output and limit significant plasticity of the heart [177].

Age-associated myocyte loss contributes to altering the contractile properties of the heart that can predispose to heart failure. In myocardial cell death, the ratio of myocytes to fibroblasts is altered in favor of the latter as myocytes die off and fibroblasts continue to divide and produce collagen, resulting in a weaker ventricle whose contraction and ejection fraction lessen [178].

Arterial stiffness commonly occurs during biological aging when large, conductance arteries, such as the aorta and the common carotid arteries reveal reduced capacity to cushion an increase in pulsatile blood flow pumped out to the brain during each heartbeat [179] (Fig. 4).

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Fig. 4

MRI showing regions where cerebrovascular damage in the elderly most commonly occur during arterial stiffness: 1) corpus callosum, 2) internal capsule, 3) corona radiata, 4) superior longitudinal fasciculus. These vulnerable regions to arterial stiffness are associated with lowered cerebral perfusion and cognitive impairment. From Badji et al., [165].

The process of cushioning the aortic pulsatile flow is called the Windkessel effect. Windkessel acts to lower fluctuations in pulsatile flow at each cardiac contraction in order to supply a smooth, laminar blood flow to peripheral vessels, including the carotid arteries and distal brain microvessels [165] (Fig. 5).

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Fig. 5

Comparison of young versus old aortic walls (inset) at the origin of the ascending aorta. Note the old aorta shows an increased lumen diameter and increased thickening of the wall compared to the young aorta. Young aortic wall contains a moderate quantity of elastin and muscle fibers (vascular smooth muscle cells). and, by comparison, a minor concentration of collagen fibers, whereas old aorta contains a significant reduction of elastin ((yellow) fibers, expanded muscle (red) fibers and an excess of collagen fibers (black) creating aortic stiffness and reduced compliance to ventricular ejection fraction. Aortic stiffness can alter cerebral hemodynamics affecting pulsatile pressure as blood flow travels from the heart to the peripheral vessels. This action can convert normal laminar blood flow to disturbed or turbulent flow thus impeding energy delivery of glucose and oxygen transport from capillaries across the blood-brain barrier to neural tissue.

This process lowers the workload of the heart and reduces large fluctuations in blood pressure throughout each cardiac cycle, thereby supplying a consistent flow of blood to the peripheral vasculature [165 , 181] (Fig. 5). However, arterial buffering of pulsatile flow becomes less efficient as we age [180]. Diminished dampening of pulsatile flow gradually opens a Pandora’s box of health afflictions including hypertension, atherosclerosis, CBH, carotid intima media thickening, and heart failure, all active promoters of cognitive impairment [118, 165].

Arterial stiffness peripheral to the aorta depends on the degree of distensibility or absence of it, as blood rushes past the wall of the artery. The distensibility or compliance of peripheral arteries rely on the health of three elements that bear the pressure of pulsatile blood flow originating from the aortic ejection of blood: elastin, collagen, and vascular smooth muscle cells [182, 183] (Fig. 5).

The main role of elastin fibers in preserving arterial compliance is to permit expansion and resilient recoil (rebound elasticity) from the pressure exerted by systolic blood flow pounding on the stretched arterial wall. When “elastin fatigue” arises from aging, elastin failure begins and is gradually replaced by collagen, the degree of arterial stiffening worsens [184] (Fig. 6). This occurs because of countless repeated cycles (about a billion cycles in a normal lifetime) of arterial distension and recoil, commonly the wear and tear of any body tissue over time, leading to the fragmentation of elastin fibers. Age also contributes to changes in the compounds desmosine and isodesmosine, which are critical in cross-linking the polypeptide chains of elastin to form stable elastic fibers [185, 186]. It has been reported that release of these amino acid-derived compounds may reflect elastin degradation in cardiovascular disease, including contributions from hypertension, atherosclerosis, and arteriosclerosis [187].

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Fig. 6

Left parasternal long axis view showing the composite of major heart parts that commonly contribute to heart failure during aging. Aging itself does not cause heart failure, but it does increase the risk for age-associated changes in cardiovascular structure and function. Cardiac structure and function changes occur mainly via the heart parts depicted here which often converge to reduce the heart’s ability to pump out enough blood to meet metabolic organ demand, including brain. The pathophysiologic process leading to heart failure can begin with cardiac muscle in the atrium and left ventricle unable to efficiently contract and push blood into the outlet tract and aorta. Blood flow must first pass through the mitral and aortic valves at sufficient pressure and quantities while confronting possible reduced contractility from myocardium, deficient heart valves, enlargement of left ventricle, and aortic stiffening, all which can diminish cardiac output, and functional viability. Heart failure is considered a major risk factor to mild cognitive impairment and consequent onset of Alzheimer’s disease. See text for details. LVOT, left ventricular outlet tract; pulmo, pulmonary; RV, right ventricle.

Many reasons have been proposed to explain aortic stiffening, including aging-related decrease in the elastin content of the aortic media, as well as a relative overgrowth of collagen content that appears to replace elastin loss [188]. Aging contributes to elastin decay, fragmentation, and loss of vessel elasticity allowing a shift of its load bearing function to collagen fibers which can then increase stiffness to the arterial vessel [180, 189].

In contrast to elastin, collagen fibers in arteries are 100–1,000 times stiffer than elastin and act mainly to provide tensile strength to the outer vessel wall and prevent vessel failure at high pressures [190 –192]. Unlike elastin, collagen concentration increases during aging in all three layers of the arterial wall, adding increased hardening to central aorta and peripheral arteries [193]. Normal collagen concentration is recognized as the reinforcing element in arterial walls contributing to the function, integrity, and strength of arteries (Fig. 5).

The third element to bear pulsatile pressure blood flow in arteries are the smooth muscle cells that circle the vascular lumen of vessels, except capillaries.

Due to their circular orientation around the medial layer of arterials, vascular smooth muscle cells play an important role in vascular homeostasis by regulating the luminal diameter of blood vessels where dynamic vasodilation or vasoconstriction result in response to stimuli received from a wide range of vasoactive signaling substances, including hormones, neurotransmitters, and metabolites.

Vascular smooth muscle cells are consequently not only critical in the regulation of blood flow and specific organ demand but also of major significance in cardiovascular disease [194 –196]. There is evidence that smooth muscle vessel contraction contributes in part to the genesis of essential hypertension and to increased vascular resistance but the exact physiological mechanisms involved have not been clarified. Some evidence suggests that hypertension not only provokes but also follows aortic stiffness and even accelerates and worsens such stiffness once present [180 , 198].

Elastin and collagen respectively provide the strength and elasticity of the arterial medial wall. The vascular smooth muscle cells are oriented in a circle around the vascular lumen of arteries forming numerous layers in the medium layer. They play an important role in the pathogenesis of vascular diseases by their ability to vasodilate and vasoconstrict in the redistribution of blood flow to body areas where they are needed (Fig. 5).

Medical interventions used currently to treat aortic stiffening during advancing years focus on lifestyle changes, including cessation of smoking, lowering obesity, maintaining a healthy diet (e.g., Mediterranean diet), and following a program of physical activity tailor-made to the individual’s age, health status, and exercise potential. Pharmacologically, blockers of renin-angiotensin-aldosterone system and hormone replacement therapy have been used with modest success [199, 200].

Other drugs that independently may lessen arterial stiffness have been tried in clinical trials and include antihypertensives such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers, diuretics, and many more, but very limited success has been reported from their primary use [200].

With significant arterial stiffening during aging, flow may turn from laminar to pulsatile or disturbed, substantially diminishing the supply of energy nutrients from entering the blood-brain barrier to meet neurometabolic cell demand [201] (Fig. 5). The dynamics and potential pathology of laminar versus disturbed brain blood flow arriving at the capillary level were reviewed in detail by us elsewhere [11, 201].

There are two main points to be made here relative to arterial stiffening during aging. First is whether arterial stiffening has a significant association with cognitive decline. There is now overwhelming evidence from longitudinal clinical studies, although not all are in unanimous agreement [202], the viewpoint that arterial stiffness during advancing years is not only associated with cognitive dysfunction but can serve as a sensitive predictor of impending cognitive decline [182 , 202–204] (Fig. 1).

The second point to be made is whether treatment of arterial stiffening or reduced compliance will lower the incidence of cognitive impairment in the elderly. The strategy would follow a specific line of thinking. Since systolic hypertension is a high risk to both heart disease and arterial stiffening, and the risk appears compounded by older age, it is reasonable to employ antihypertensive agents to delay, to some degree, cognitive meltdown. Also, increased arterial stiffness is associated with lower diastolic blood pressure and reduced coronary perfusion, so agents targeting these potentially fatal conditions need to be considered or applied when appropriate [165].

However, there is mixed evidence from clinical studies that using antihypertensive therapy to slow down cognitive decline may not be clinically helpful and could be counterproductive [205 –207].

PATHOLOGY OF PULSE WAVE VELOCITY

In systolic hypertension, arterial walls of large conduit arteries are found to be stiffer and thicker when compared to normotensive matched controls [208]. Arterial stiffness will increase PWV, defined as the rate at which the pressure waves from systolic contraction propagate along the arterial tree, according to the relative arterial wall elasticity.

A non-invasive and relatively accurate marker to gauge arterial stiffness is to measure PWV. Large arteries (aorta, common carotids, iliac) propagate a pressure wave that ends where arteriolar resistance vessels begin. At that level, the pressure waveform generates waves that reflect backward.

Higher rates of the waves’ reflection emanating from higher PWV are inversely associated with a stiffer and less distensible artery [209]. When a higher PWV reaches resistant brain arterioles, the reflected wave will arrive at the aorta during systole rather than diastole. This shift results in cardiovascular deficits including raising systolic pressure, elevating left ventricular afterload and increasing myocardial oxygen demand [210].

The PWV is significantly higher during aging due to increased stiffening in the large arteries, particularly the aorta [180, 211]. Poor vessel wall elasticity is reflected by high PWV [212, 213].

Moreover, the strongest predictor of cognitive loss in elders with arterial stiffness is reported to be a significant increase PWV [214].

Evidence for these abnormal mechanisms arises from studies of pulsatile arterial hemodynamics, as highlighted by the role played by PWV and wave reflections as independent factors in cardiovascular disease risk during hypertension [210]. Resistance arterioles (200–300μm) are characterized by the presence of a myogenic tone able to protect the capillary bed against anomalous high blood pressure and to control the local tissue blood flow. Several types of alteration of resistance vessels are characteristic of chronic hypertension: reduced lumen diameter in relation to exaggerated vasoconstriction, hypertrophy of the vascular wall resulting in decreased lumen size, and increased wall-to-lumen ratio, as well as rarefaction of microvessels in arterioles and capillaries [215].

Through modification in the timing of pulse wave reflections, it is also possible to reduce the disproportionate increase in systolic blood pressure and its associated cardiovascular disease risk [179].

CONCLUSIONS

This review attempts to show the important dependence between the construct of cognitive impairment and the aging left side parts of the heart, involving the atrium, the left ventricular chamber, its valves, the myocardium, the outlet tract, and the proximal aorta (Fig. 6).

What do these heart parts have in common? In a nutshell, they all reflect three key interactive actions: 1) structural/functional changes from advanced aging; 2) abnormal brain hypoperfusion; and 3) cognitive function.

If the three interactive actions are examined chronologically so as to appreciate how they ultimately converge, it is plain that aging is the fundamental driver of wear and tear in altering structure and function of the heart parts mentioned above which in turn aggravate age-dependent brain hypoperfusion [85]. The cognitive pathology that often results from this sequence of events is explained by substantive evidence indicating that aging reduces CBF from worn-out heart parts which in turn trigger cognitive deterioration.

The credibility for this conclusion lies in the fact that the cognitive pathology resulting from these three events is unlikely to occur if their sequence is permuted [85]. Knowing this, essential clues to more realistic research solutions in AD prevention can be considered,

Society is in the midst of a socio-economic drumfire by the pharmaceutical industry that aims to hatch a delusional silver bullet for AD, or at least, a spent, silver-cartridge that can somehow meet the approval of the FDA, a callous approach that has closed many alternative research doors at the expense of ignoring conceivably preventive measures (no money there) that could manage this disease as a chronic disorder.

Currently, prevention or slowing down progressive cognitive impairment is feasible and realistic, even when the wear and tear of heart parts can lean toward the initial consequences of heart failure. The trick relies in those health care professionals, particularly cardiologists and primary care physicians, to take an active role in recognizing and applying the appropriate management and interventions needed to salvage the salvageable. Can it be done?