Reduced Heart Rate Recovery Is Associated with Poorer Cognitive Function in Older Adults with Cardiovascular Disease

Cardiovascular disease (CVD) in older adults has been associated with varying degrees of cognitive dysfunction. Several mechanisms may explain this association, including impaired cardiovascular reactivity to autonomic nervous system (ANS) signaling. Reduced heart rate recovery following a stress test may be considered an indication of impaired ANS function (i.e., reduced parasympathetic activity). Participants were 47 older adults (53–83 years) who underwent a treadmill stress test and were administered a comprehensive neuropsychological battery upon entry to phase II cardiac rehabilitation. Reduced parasympathetic activity was associated with impaired cognitive performance on a measure of global cognitive function and on tasks of speeded executive function and confrontation naming. These relationships suggest that changes in autonomic function may be mechanistically related to the impaired cognitive function prevalent in CVD patients.


Introduction
Cardiovascular disease (CVD) is associated with varying degrees of cognitive impairment, ranging from minimal difficulties ("brain at risk stage") to dementia [1][2][3][4] and is associated with cognitive decline above and beyond the normal aging process [5]. Impaired cognitive function is observed in persons with CVD, even in the absence of major cardiac events [6]. Older adults with CVD frequently report experiencing significant cognitive dysfunction in everyday life and men with CVD demonstrate a reduction in cognitive function equivalent to approximately four to five years of additional age [7,8]. These findings are in addition to the known associated between CVD and severe neurological conditions like stroke and Alzheimer's disease [9,10].
Several pathophysiological mechanisms associated with CVD contribute to the observed cognitive dysfunction in this population. For example, systemic hypoperfusion is common and associated with reduced cognitive test performance [11][12][13]. Similarly, CVD is associated with development of white matter disease [14], pathological changes to blood vessels [15], and inflammatory processes [16], each of which are known to adversely impact cognitive function. Recent work implicates disrupted autonomic nervous system (ANS) signaling as another potential mechanism for the cognitive impairment, as both blood pressure variability (e.g., standard deviation of systolic blood pressure) and heart rate variability have been linked to neurocognitive outcome in persons with CVD [17][18][19].
Such findings suggest that other, more easily obtained ANS indices may also be associated with reduced cognitive function and provide insight into potential mechanisms. One such ANS index is heart rate recovery, which may be operationally defined as the change from peak HR following 2 Cardiovascular Psychiatry and Neurology maximal exercise (typically during treadmill stress testing) to that measured after two minutes of recovery [18]. This commonly used ANS index is sensitive to parasympathetic activity, as the return to resting HR following exercise termination is predominately accomplished via vagus nerve activity [19][20][21].
To help clarify the association between HR recovery and cognitive function, we assessed a sample of both men and women (age range 53-83 years) with a wide range of CVD conditions using a comprehensive neuropsychological test battery and a treadmill stress test. We hypothesized that ANS dysfunction would be associated with poorer cognitive function, such that greater HR recovery would correspond to better cognitive function.

Participants.
The study sample included 47 (32 men, 15 female) older adults enrolled in a prospective study of the neurocognitive consequences of CVD. All participants were referred by their cardiologists for enrollment into a large cardiac rehabilitation program; information regarding the type of CVD event or condition diagnosis which prompted referral to cardiac rehabilitation can be found in Table 1. The mean time interval between the CVD event or condition diagnosis and the stress test is 36.3 days (minimum = 8, maximum = 147; median = 34). Participants in the study sample had a wide range of CVD conditions, including arrhythmia, atrial fibrillation, coronary artery bypass graft (CABG), valve surgery, cardiac arrest, myocardial infarction, heart failure, and hypertension; see Table 1.
The exclusion criteria in the current student included (1) current signs of dementia (as defined by a score lower than 24 on the Mini Mental Status Exam (MMSE)) [23], (2) history of a major neurological disorder such as Alzheimer's disease, Parkinson's disease, seizures, large vessel stroke, or loss of consciousness >10 minutes, and (3) history of major psychiatric disorder such as schizophrenia, bipolar illness, or substance abuse. In addition, no participants with new onset or chronic atrial arrhythmia were included in the study sample. Participants were not selected based on concerns regarding possible cognitive dysfunction. Participants averaged 67.87 ± 8.92 years of age and 14.07 ± 2.61 years of education. All participants were Caucasian.
On the basis of medical chart review, clinically relevant conditions (i.e., arrhythmia, atrial fibrillation, coronary artery bypass graft (CABG), cardiac arrest, type II diabetes, myocardial infarction, heart failure, high cholesterol, hypertension, and β-blocker usage) were coded as either present or absent; see Table 1.

Exercise Stress Testing.
Resting HR, peak HR, exercise capacity, and HR recovery values for each participant were obtained using a treadmill exercise test. The treadmill exercise test was conducted according to a modified ramp protocol using a Quinton Medtrack ST55 treadmill (Quinton Cardiology, Deerfield, WI). More specifically, the exercise protocol was characterized by an increase in mill elevation every 60 seconds that approximates a relative increase in workload of 15% holding speed constant, as well as an increase in speed every 3 minutes that also reflects an approximate relative increase in workload of 15% from the previous stage. The test was terminated if the patient showed clinical signs of cardiovascular, neurological, or musculoskeletal decompensation, or at the patient's request; such practice is consistent with American College of Cardiology/American Heart Association and American College of Sports Medicine published guidelines for exercise stress testing [24][25][26]. Exercise capacity was estimated in metabolic equivalents (METS) at this peak volition or symptom limited end point [24].
In the present study, HR recovery was operationally defined as the difference in beats per minute (bpm) between peak HR (i.e., HR at exercise termination) and HR two minutes after exercise termination [20,21,27]. Although HR recovery has also been computed from HR one minute after exercise termination, HR recovery at 2 minutes predicted mortality better than other indices in a large study of male patients completing treadmill tests and coronary angiography [28], and, in another study, only HR recovery at 2 minutes predicted the presence of coronary artery disease [29]. In a validation study including 2,193 men, the average drop in HR at 2 minutes was 31.7 ± 13.1, and a reduction in HR of less than 22 bpm within 2 minutes following peak exercise was considered "abnormal" [28].

Neuropsychological Tests.
All participants completed a neuropsychological test battery comprised of tasks commonly used during clinical neuropsychological evaluation; see Table 1. The following four domains were assessed.
2.3. Procedure. All procedures were approved by the Institutional Review Board of the associated university prior to study onset. All participants provided written informed consent prior to study participation. Exercise stress testing was completed upon entry into cardiac rehabilitation. All neuropsychological instruments were individually administered by trained research team members. Neuropsychological testing was completed within 14 days of the exercise stress test.

Data Analysis.
In preliminary analyses, descriptive data regarding participant demographic characteristics, clinical conditions, cardiovascular indices, and neuropsychological test performance were generated. The primary analyses consisted of a series of partial correlations between HR recovery and the neuropsychological test performance variables. Control variables included those factors with known importance for HRR and/or cognitive function in older adults with CVD, specifically sex, age, years of education, β-blocker usage, and exercise capacity (as measured by METS at peak HR). Finally, in order to evaluate the relative strength of the findings, effect size values (i.e., Cohen's d) were calculated for all partial correlations. Previous research has documented a relationship depression and HR recovery in a very similar sample of phase II cardiac rehabilitation patients [21]. All participants in the present study completed the Beck Depression Inventory (BDI) [37] as part of the cardiac rehabilitation program. However, BDI total score was not significantly correlated with any of the neuropsychological test performance variables. In the absence of such correlation, the primary analyses were not adjusted for BDI scores.

Results
Participant demographic characteristics, clinical conditions, cardiovascular indices, reasons for referral to cardiac rehabilitation, and neuropsychological test performance are presented in Table 1. Of note, HR recovery values ranged from 0 bpm to 67 bpm (M = 31.7, SD = 15.2).
Partial correlations and Cohen's d effect sizes between HR recovery and the neuropsychological test performance variables are presented in Table 2. After adjusting for relevant variables (i.e., sex, age, years of education, β-blocker usage, and exercise capacity), HR recovery was significantly correlated with 3MS total score (r = .42, P = .006), BNT shortform total score (r = .40, P = .008), and TMT-B time to completion (r = −.33, P = .03). Associations for 3MS and BNT short form indicate large effect sizes (Cohen's d values of .93 and .87, resp.), while the association for TMT-B indicates a medium effect (Cohen's d = .70). The correlations between HR recovery and both TMT-A time to completion (r = −.28, P = .08) and grooved pegboard time to completion (r = −.28, P = .08) approached statistical significance and were consistent with a medium effect size (Cohen's d = .58 for both measures).

Discussion
The results of the present study indicate that greater heart rate recovery two minutes after exercise termination is associated with better performance in multiple cognitive domains, including global cognitive function, speeded executive function, and language. Several aspects of these findings warrant brief discussion.
The current findings extend previous research [38] and demonstrate that the relationships between ANS-mediated cardiovascular functioning and cognitive tasks are independent of cardiovascular fitness (as measured by exercise capacity). Although the specific mechanisms underlying these associations are currently unknown, we offer several candidate explanations. One likely explanation involves the effects of ANS dysregulation on vascular processes. Endothelial dysfunction and impaired cardiovascular reactivity to ANS signaling are common in CVD patients [39][40][41][42][43][44] and have been suggested as a contributor to cognitive dysfunction in other studies [45]. An additional explanation implicates the inflammatory cytokines of the vagus nerve; more specifically, both slowed HR recovery and cognitive dysfunction may be a reflection of an underlying dysregulation of the cholinergic anti-inflammatory pathway [46]. Another possibility is that poorer HR recovery and cognitive function reflect structural brain changes such as white matter disease or reduced integrity of white matter pathways. For example, the anterior cingulate cortex is important for both ANS functioning and frontal lobe-mediated functions (e.g., attention/executive function/psychomotor speed) [47,48] and damage in this region could well affect both indices. Future neuroimaging studies utilizing standard imaging and diffusion tensor imaging technology [49] will help to clarify this possibility.
Identifying a relationship between a measure of cardiac function and measures of global cognitive function and speeded executive function is consistent with past studies [50,51]. However, finding an association between HR recovery and language function is less common. One possibility is that HR recovery is an underlying marker for neurodegenerative conditions with known language impairment, such as Alzheimer's disease. CVD has long been known as a risk factor for Alzheimer's disease [52,53]. Persons with Alzheimer's disease exhibiting autonomic cardiac dysfunction [54], manifesting as a relatively hypersympathetic and hypo-parasympathetic state [55]. Thus, it may be possible that indices of ANS function (e.g., HR recovery, HR variability) may prove to be proximal predictors of Alzheimer's disease [56].
The current findings are limited in several ways. First, due to the cross-sectional design of the present study, it is not clear whether the association between HR recovery and cognitive function simply represents a cooccurrence or reflects a casual relationship. Future studies with a longitudinal design may clarify this issue. Longitudinal investigations may also examine whether improvements in HR recovery correspond with the cognitive improvements found in CVD patients in cardiac rehabilitation [57][58][59]. Second, the present study examined cognitive functioning within a diverse group of CVD conditions and did not attempt to Cardiovascular Psychiatry and Neurology 5 make any differentiation among them. Although the medium to large effect sizes suggest the findings are robust, replication and extension of the current findings in larger samples with more narrowly defined CVD patient samples are needed. Similarly, future studies should also examine the association between HR recovery and cognitive function in older adults without CVD to help clarify possible mechanisms for this pattern.
In brief summary, the current study extends past work to show that HR recovery following a treadmill stress test (an index of autonomic nervous system function) is related to multiple cognitive domains, including global cognitive functioning, speeded executive function, and language abilities. Further work is needed to clarify possible mechanisms for these findings and to explore potential for therapeutic improvement.