© 2002 European Society of Cardiology
Chronic heart failure and cognitive impairment: co-existence of conditions or true association?
Department of Medicine for the Elderly, Glasgow Royal Infirmary 84 Castle Street, Glasgow, UK
Academic Section of Geriatric Medicine, Glasgow Royal Infirmary 84 Castle Street, Glasgow, UK
Chronic heart failure (C.H.F.) and cognitive impairment (C.I.) are both common problems in old age. They are both associated with significant mortality, impaired quality of life and disability. Common also to both conditions is the heavy economic burden they incur and the increasing proportion of Health and Social Service resources that they consume.
The prevalence of C.H.F. is estimated to be 10% in those over the age of 75 years [1] rising to 15–20% over the age of 80. The prevalence of dementia is estimated at 8% in the over 65s [2]. In addition many patients who have cognitive impairment do not fulfill the diagnostic criteria for dementia: cognitive impairment no dementia (C.I.N.D.) is twice as common as dementia, occurring in 17% of the population over the age of 65 years [3]. Approximately 20% of all cases of dementia are predominantly vascular in aetiology [4]. Many of the remainder have a vascular component. A vascular aetiology is particularly likely in the very elderly, over the age of 80 years. Given that this is the most rapidly expanding sector of the population, our ability to manage these conditions effectively in this age group is becoming increasingly important.
While such common conditions as C.H.F. and C.I. may occur by chance within the same individuals there is some evidence to suggest that C.H.F. is independently associated with cognitive impairment. To date, only two studies have examined this area. The first was a small observational study of 57 consecutive heart failure admissions, mean age 77 years [5]. The Mini Mental State Examination (M.M.S.E.), a screening test for cognitive impairment, was administered to all subjects. M.M.S.E. score of <24 (cut-off below which the probability of dementia is high) was found in 53% of participants. Older age and ejection fraction <30% were significant correlates of a lower M.M.S.E. score. The second study was a cross sectional community based study of 1075 patients over the age of 65 years [6]. Again the M.M.S.E. was used and a score of <24 was found in 56.8% of patients with C.H.F. compared to only 20% of those without C.H.F. This association was independent of gender, age, educational level, geriatric depression score, diabetes, hypertension, alcohol consumption, smoking or presence of atrial fibrillation. There are as yet no published longitudinal studies following the natural history of cognitive change in C.H.F., although studies are ongoing.
What then are the mechanisms by which C.H.F. might affect cognition? It is likely that impairment of cerebral circulation plays an important role. Low grade ischaemia of the deep white matter may be particularly important. Leukoaraiosis, a C.T. brain appearance of white matter low attenuation occurs in 70% of patients with vascular dementia [7], compared to <4% of healthy elderly people [8]. It is associated with disability, gait disorders and cognitive impairment. Neuropathologically there is vascular remodelling with lipohyalinosis and narrowing of the penetrating arterioles. Subsequently there is hypoperfusion and ischaemia of white matter with resultant diffuse loss of myelin [9]. Age, congestive heart failure and systolic blood pressure of <130 are all predictors of leukoaraiosis [10]. In some series hypertension is also associated with leukoaraiosis. It is possible that the initial vascular remodelling is in response to raised mean arterial blood pressure. The ultrastructural changes do protect the brain against high perfusion pressure. However, the ability of the vessels to dilate at low pressure is also impaired. This then shifts both the upper and lower limits for cerebral blood flow auto-regulation. It is possible that with progressive heart failure as mean arterial pressure falls cerebral hypoperfusion of deep white matter results.
Silent cerebral infarction is another potential way by which C.H.F. may impair cognition: it is frequently detected by brain C.T. and most commonly occurs in the basal ganglia and occipital lobes. The presence of congestive heart failure is an independent risk factor for silent cerebral infarction. Patients with CHF clearly often have multiple vascular risk factors and are, therefore, at risk of the full spectrum of stroke disorders: lacunar infarcts, cortical infarcts and multi-infarct state can all result in cognitive decline [11].
Atrial fibrillation is frequently present in patients with CHF: the Rotterdam study has shown that atrial fibrillation is associated with both Alzheimer's disease and vascular dementia; and that this association cannot simply be accounted for by the occurrence of stroke [12]. Case control studies of cognitive function in patients with AF have also shown consistently poorer performances in neuropsychological testing [13]. However, in patients with CHF the association of cognitive impairment was independent of the presence of AF; while it may be a contributory factor it is not the sole explanation.
CHF is associated with a hypercoagulable state: patients with CHF have elevated levels of thrombin/antithrombin complexes; beta-thromboglobulin; and D-dimers [14]. Elevated fibrinogen levels have been reported in patients with lacunar infarcts and in leukoaraiosis [15]; white matter ischaemia is also associated with increased fibrinogen and factor VIIc levels [16]. Abnormalities of thrombosis and haemostasis may be important in the pathogenesis of ischaemic damage.
In CHF there is abnormal vascular endothelial function: this is characterised by increased vasoconstriction and a reduced vasodilator response to exercise. Underlying this is up regulation of vascular ACE which inactivates bradykinin (a potent vasodilator which mediates its effect by release of nitric oxide, prostacyclin or endothelial derived hyper-polarisation factor) and produces angiotensin II [17]. Tissue ACE is also important in the modulation of a number of neurotransmitters including encephalins, endorphins, neurotensin, substance P and kinins. It may be that changes in the levels of these substances may influence cognition [18]. This also provides a potential target for therapy: ACE inhibitors increase the levels of the above neurotransmitters and through their effect on kinins raise concentrations of excitatory aminoacids, nitric oxide, prostaglandins, noradrenaline, and acetylcholine. This may be the mechanism for the improvement of memory and cognition suggested in studies of A.C.E. inhibitors in younger patients with hypertension. These trials are limited by the fact that A.C.E. inhibitors were usually compared with an alternative drug which may have had adverse effects on the above. There are few data on the effects of A.C.E. inhibitors on cognition in older patients.
Cerebrovascular reactivity has recently been assessed in patients with CHF using transcranial Doppler to compare CO2 reactivity in heart failure patients with age-matched and normal controls [19]. Reactivity was found to be impaired in all grades of heart failure compared to controls and in NYHA IV as compared to NYHA II and III patients. There was a significant relationship between cerebrovascular reactivity and left ventricular ejection fraction. It was postulated that patients with CHF compensate for the reduction in cardiac output by lowering cerebrovascular resistance through arteriolar dilatation. This however, renders them potentially unable to compensate for the additional effects of vasodilating or diuretic drugs. Impaired cerebrovascular reactivity may contribute to declining cognitive function.
Can impaired cognition in heart failure patients be improved? The only data currently available are from highly selected groups undergoing cardiac transplantation. Two studies have yielded conflicting results: one suggested improvement in cognitive function following transplant [20] whereas the other was unable to demonstrate any change in cognition despite greatly improved physical health [21]. Similarly there has been controversy over whether or not pacemaker implantation, which improves cerebral blood flow, improves cognition in elderly patients with bradycardia or heart block [22,23]. Overall results have been disappointing.
The theory that cognitive impairment in CHF might be prevented or attenuated is very attractive but remains untested. One current study, PEP-CHF, a randomised controlled trial of Perindopril in patients over 70 years with CHF and preserved systolic function does have a substudy of cognitive function [24]. This should provide very useful information on the natural history of cognitive change in a population of older patients with CHF and on the effects of ACE inhibition in this group.
Finally, hard endpoints such as mortality or days of hospitalisation are easy to record. Quality of life, disability and cognitive impairment are much more complex and time consuming to measure. Nonetheless, we would suggest that to our population of ageing, elderly heart failure patients who have multiple co-morbidities, these are the elements which matter. The whole field of cognitive impairment in patients with CHF is, we feel, worthy of further study and offers exciting opportunities for collaborative research between different specialities.
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