The Importance of Identifying Early Changes in Cardiac Structure and Function for the Prevention of Cognitive Impairment and Dementia

The connection between the heart and the brain has long been recognized as a fundamental aspect of human physiology. In his 1649 treatise Les Passions de l’ â me, René Descartes described how “animal spirits”, the finest, most fiery particles of the blood, ascend “in the greatest abundance from the heart into the brain and thence through the nerves into the muscles [to] impart motion to all the members”. However, it was not until the late 1970s that cardiac disease was first proposed as a potential mechanism for cognitive loss resulting in vascular dementia [1].

Multiple cardiac pathologies have since been shown to contribute to progressive cognitive decline and dementia in elderly populations, including left ventricular hypertrophy (LVH), a marker of prolonged exposure to hypertension (Fig. 1) [2]. Prevalent in more than two thirds of individuals over age 65 [3], hypertension is a well-established risk factor for both cardiovascular morbidity and cognitive decline [4]. Several major observational studies, including the Framingham and Honolulu-Asia Aging studies have previously demonstrated associations between high blood pressure in midlife and cognitive decline in elderly populations [5–7] and numerous clinical trials have also shown preventive effects for the treatment of hypertension on the incidence of cognitive decline and dementia [8–16]. Specifically, Syst-Eur [14] reported a 55% reduction in the incidence of dementia over 4 years of follow-up, while both PROGRESS [15] and HOPE [16] demonstrated 19% and 41% reductions in the incidence of cognitive decline or dementia among patients with a prior history of stroke, respectively. However, several other trials have shown no significant effects of anti-hypertensive treatment on cognitive outcomes [8–13], highlighting remaining gaps in our understanding of the pathogenic mechanisms underlying the link between hypertension and dementia, particularly within later-life cohorts.

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Fig.1

Cardiovascular risk factors associated with cognitive decline and progression to dementia in elderly populations. Modified from de la Torre (2012) [2].

Although the associations between blood pressure level and control and cognitive function are thought to be mediated primarily by end organ effects of chronic hypertension and resulting sequelae (e.g., chronic hypertension⟶LVH⟶stroke/heart failure⟶white matter hypoperfusion⟶cognitive decline/dementia), there is increasing evidence that early changes in cardiac structure and function, such as LVH, may independently contribute to cognitive decline and impairment [17]. In the current issue of the Journal of Alzheimer’s Disease, Mahinrad and colleagues [18] examined the relationship between LVH and cognitive decline in a cohort of patients (N = 4,233) obtained from the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study [19]. Over a mean follow-up of 3.2 years, they compared those with lower versus higher levels of LVH, as measured using the Sokolow-Lyon index on baseline electrocardiogram, on tasks of domain-specific cognitive function. They showed that those with higher levels of LVH had a steeper decline in cognitive function on all tasks over time compared to those with a lower burden of LVH, independent of adjustment for cardiovascular risk factors and co-morbidities, including hypertension, anti-hypertensive medication use, and recurrent cardiovascular events. The authors interpreted these findings as evidence to support a link between subclinical cardiac changes and cognitive function in elderly adults.

The Mahinrad et al. study is consistent with several prior studies reporting associations between LVH and cognition [20–24], but represents an important incremental contribution to this literature. As prior studies have predominantly evaluated cross-sectional associations between LVH and cognition, with the majority using the Mini-Mental State Examination (MMSE) to index cognitive function [20, 23], specific strengths of the Mahinrad et al. study include the longitudinal design and the use of a comprehensive battery of neuropsychological assessments to evaluate multiple cognitive domains, including selective attention, processing speed, and immediate and delayed memory. Two prior longitudinal studies have previously examined this relationship. However, the findings of one showing a predictive association between LVH and cognitive decline, but not blood pressure, at 5 years of follow-up [24] were again limited by the use of MMSE, which has consistently shown poor sensitivity for the identification of individuals with mild cognitive impairment [25, 26], particularly in individuals over 60 years of age [27], and findings of the other employed a composite indicator of target end organ damage that included LVH in addition to other morbidities and thus did not examine the independent effects of LVH [23]. Mahinrad et al.’s use of multiple domain-specific measures, assessed prospectively over time, thus provides more robust evidence for the impact of LVH on cognitive functioning, specifically for both memory and executive functions. These findings are important to elucidate the cortical networks potentially vulnerable to subclinical cardiac dysfunction and help inform the development of potential therapeutic targets for preventive interventions in individuals at risk of cognitive decline and dementia.

A potential source of bias in longitudinal investigations of associations between early indicators of cardiac dysfunction and downstream clinical outcomes, such as cognitive decline or incident dementia, is the high probability of the occurrence of competing risks that may confound this association. Another strength of the Mahinrad et al. study was their use of analytic strategies to address this source of bias. In addition to carefully considering several potential confounders and adjusting both baseline and longitudinal models for the history of diabetes, vascular disease, body mass index, smoking status, systolic and diastolic blood pressure, total and HDL-cholesterol, antihypertensive and anticoagulant medications, the authors also stratified their analyses by those with and without the occurrence of competing events, including coronary events, stroke, transient ischemic attack, incident atrial fibrillation and hospitalization for heart failure during follow-up and showed no differences in annual change in cognition among those with and without these events. In accounting for this potential bias, Mahinrad et al. demonstrated that observed declines in cognitive function were not mediated by competing cardiovascular events, strengthening their argument for an association between LVH and cognition, independent of cardiovascular comorbidity and incident cardiovascular outcomes.

The findings of Mahinrad and colleagues are timely in the context of emerging awareness of the potential utility of early markers of pathophysiologic changes in cardiac structure or function detectable prior to the onset of manifest cardiovascular disease. Like LVH, preclinical substrates of atrial fibrillation are also common in aging and have previously been associated with other determinants of cardiac health, including hypertension and hyperlipidemia [28]. There is an increasing interest in determining the putative contributions of markers of ventricular and atrial dysfunction to the pathogenesis of cognitive decline and dementia, either independently or mediated by major cardiovascular events, including atrial fibrillation, stroke, and heart failure [29]. An increased understanding of the complex mechanisms underlying these associations will be required for the development of targeted therapies to mitigate the clinical progression of cognitive decline and dementia. The identification of preclinical markers of structural and electrophysiological remodeling of the heart offers a new potential pathway of investigation to elucidate the synergistic and/or independent pathophysiologic effects of cardiovascular risk determinants on the development of cognitive impairment and dementia.