|
 
 |
| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 7
| Issue : 1 | Page : 5-12 |
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Exercise and the brain in cardiovascular disease: A narrative review
Jenna L Taylor
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| Date of Submission | 05-Oct-2022 |
| Date of Acceptance | 09-Nov-2022 |
| Date of Web Publication | 26-Dec-2022 |
Correspondence Address:
Dr. Jenna L Taylor
Department of Cardiovascular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_50_22
Patients with cardiovascular diseases (CVDs) (including heart failure) are at increased risk of cognitive impairment and dementia. Vascular risk factors contribute to cognitive decline through cerebral small vessel diseases, pathological brain changes, and hypoperfusion. Habitual exercise and increased cardiorespiratory fitness are associated with higher cognitive function, greater cerebral blood flow, and attenuation of the decline in gray matter volume and white matter integrity. Furthermore, moderate-vigorous exercise training has been shown to improve cognitive function in healthy middle-aged and older adults. Cardiac rehabilitation (CR) is a class 1A recommendation for patients with CVD, which involves exercise training and intensive risk factor modification. This article reviews the current evidence for the effect of exercise-based CR on cognitive function, cerebrovascular function, and brain structure in patients with CVDs. Overall, exercise-based CR appears to improve global cognitive function and attention-psychomotor functions but not language processes. Furthermore, the effect of exercise-based CR on executive function and memory is less clear and there is limited research into the effect of exercise-based CR on cerebrovascular function and brain structure.
Keywords: Cardiac rehabilitation, cerebral blood flow, cerebrovascular function, cognitive function, coronary artery disease, dementia, heart failure
How to cite this article:
Taylor JL. Exercise and the brain in cardiovascular disease: A narrative review. Heart Mind 2023;7:5-12 |
| Introduction | |  |
Mild cognitive impairment (MCI) is a term used to characterize individuals that fall between the cognitive changes of normal aging and dementia.[1] Individuals with MCI demonstrate deficits in one or more cognitive domains (than expected for age and educational background) but are able to maintain independence and most of their daily activities. In contrast, individuals with dementia have deficits in more than one cognitive domain and affect their ability to perform usual activities and live in an autonomous manner.[2] The two most common types of dementia are vascular dementia and the neurodegenerative condition of Alzheimer's disease. Beta-amyloid protein deposition in plaques and tau deposition in neurofibrillary tangles are hallmark features of Alzheimer's disease, which contribute to neuronal injury.[3] While vascular dementia and Alzheimer's disease have distinct pathology, they frequently coexist and can simultaneously contribute to cognitive impairment.[3]
There are approximately 47 million people worldwide living with dementia-related diseases, and this number is expected to triple by 2050.[4] It has been reported that 30% of Alzheimer's disease cases are attributable to modifiable risk factors such as hypertension, obesity, diabetes, and physical inactivity.[5] While the incidence of dementia increases with age, adults with cardiovascular disease (CVD) have a higher risk of cognitive impairment.[6],[7] Moreover, cognitive decline is accelerated following a cardiovascular event or onset of heart failure (HF).[8],[9] Globally, CVD affects over 400 million people[10] and 120 million people in the United States alone.[11] Due to advances in the management of CVD, patients may continue to live with the disease for decades.[12] As a result, the impact of CVD on the aging brain and cognitive impairment is of increasing importance. While normal aging is associated with reductions in cognitive function,[13] brain volume,[14] cerebral blood flow (CBF),[15],[16] and cerebrovascular function,[15],[16] the age-related decline is further exacerbated by the presence of CVD.
| Effect of Cardiovascular Disease on Brain Health | | |
There is substantial evidence that CVD (including HF) increases the risk of cognitive impairment.[6],[7],[17],[18] Pooled meta-analyses have estimated the increased risk at 45% in coronary heart disease (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.21–1.74, P < 0.001)[6] and 62% in HF (1.62, 95% CI: 1.48–1.79, P < 0.0001). The Women's Health Initiative Study showed that the risk of cognitive impairment was greatest for postmenopausal women with a previous myocardial infarction (hazard ratio [HR]: 2.10, 95% CI: 1.40–3.15) than any CVD (HR: 1.29, 95% CI: 1.00–1.67).[18] The Swedish Twin Study found that CVD also increases the risk of Alzheimer's disease in adults with genotype predisposition (apolipoprotein E4 allele carriers) (HR: 2.39, 95% CI: 1.15–4.96),[19] and therefore, the increased risk of cognitive decline with CVD is not isolated to vascular-related dementias.
A summary of potential mechanisms that may contribute to cognitive impairment in CVD is outlined in [Figure 1]. Risk factors for CVD (including hypertension, increased adiposity, hyperlipidemia, and diabetes mellitus) are known to exert adverse effects on vascular function.[20] Hypertension and obesity are associated with overstimulation of the sympathetic nervous system,[21],[22] which can result in excessive vascular resistance, arterial stiffness, and adverse cerebrovascular remodeling.[23] Excess fat tissue also releases adipokines that have detrimental effects on the vasculature through inflammatory pathways.[24] Inflammation and oxidative stress damage the endothelial cell layer,[20] which, through release of nitric oxide, plays an important role in vascular function[25],[26] and maintaining the integrity of the blood-brain barrier.[27] Moreover, CVD risk factors contribute to cerebral vessel diseases that result in pathological brain changes associated with cognitive impairment, even at subclinical stages of CVD.[28] The two most common forms of cerebral vessel diseases are: (1) arteriosclerosis (also referred to as arterial stiffening or hypertensive small vessel disease), which is characterized by the loss of smooth muscle cells, narrowing of the lumen, and thickening of the vessel wall, and (2) cerebral amyloid angiopathy, which is characterized by the progressive accumulation of beta-amyloid protein in the walls of the cerebral arteries, arterioles, capillaries, and veins.[29] These cerebral small vessel diseases result in pathological brain changes (manifesting as white matter hyperintensities, lacunar infarcts, microbleeds, and macroscopic hemorrhage) from vascular damage that causes ischemia, inflammation, vessel rupture, and disruption of the blood-brain barrier and neural connectivity pathways.[29],[30] Furthermore, arterial stiffening and increased pulse pressure can increase microvascular pulsatility and hemodynamic stress within the perivascular spaces of the brain, resulting in microstructural damage, white matter hyperintensities, and impairments in beta-amyloid clearance.[31] Associations between ischemic heart disease and cerebral microbleeds suggest that systemic cardiovascular lesions and cerebral small vessel disease are interrelated processes.[30],[32]{Figure 1}
Lower cerebral perfusion has been shown to increase the risk of dementia.[33] Adequate CBF and the structural and functional integrity of cerebral blood vessels are imperative to normal brain functioning, and represent an early physiological marker of neurocognitive disorders that proceed with physical signs and symptoms.[34] CVD risk factors can cause alterations in vascular structure and tone that modify cerebral hemodynamics and lead to chronic reductions in CBF.[35] The functional ability of the cerebral vessels to dilate or constrict allows for adequate regulation of CBF in response to neural, chemical, and perfusion changes within the body.[36],[37] Reduced function of cerebral vessels can therefore cause hypoperfusion, and subsequently reduce oxygen and glucose to the brain.[38] Impaired cardiac function can also contribute to cerebral hypoperfusion and cognitive impairment by reducing cardiac output and systemic perfusion.[39] A linear relationship exists between cardiac output and CBF,[40],[41] with the extent of CBF reduction in patients with HF correlating with disease severity.[42] Moreover, improvement in left ventricular ejection fraction with cardiac resynchronization therapy has been shown to increase CBF.[43] Although in contrast, Hammond et al.[9] found no difference in cognitive decline for HF patients with reduced ejection fraction compared to HF patients with preserved ejection fraction. Mechanisms for cognitive decline in HF with preserved ejection fraction are likely related to diastolic dysfunction, obesity, vascular impairment, and chronic neurohormonal activation.[44]
Surgical interventions for coronary artery disease (CAD) have been proposed to increase the risk of cognitive decline due to microembolism, intraoperative hypotension, hypoxia, and/or inflammatory processes.[45] However, recent evidence suggests that patients undergoing coronary artery bypass graft surgery (CABG) do not have a greater degree of cognitive decline than other patients with CAD. Sweet et al.[46] found a similar degree of decline on neurocognitive tests for both CABG and percutaneous coronary intervention (PCI) groups compared with healthy controls over 3 weeks, 4 months, and 12 months. Furthermore, an expert review concluded that “the extent of pre-existing cerebrovascular and systemic vascular disease” have a greater effect than procedural variables on neurocognitive function in the short and long term.[47]
| Exercise and Brain Health | | |
It is well established that exercise training is an effective way to improve CVD risk factors,[48] peripheral vascular function and inflammation,[49],[50] and cardiorespiratory fitness.[51] There is also accumulating evidence that moderate-vigorous exercise training improves cognitive function in middle-aged and older adults[52],[53] in areas of attention-processing speed, executive function, and memory. Higher cardiorespiratory fitness, as peak oxygen uptake (peak VO2), has been associated with higher cognitive function,[54] as well as attenuation of gray matter volume decline in regions coupled with cognitive function.[20],[55] Lifelong habitual aerobic exercise and peak VO2 have also been associated with better white matter integrity.[56] In healthy populations, studies have shown that maintaining or increasing peak VO2 over time can reduce dementia incidence and mortality,[57] as well as improve CBF and cerebrovascular function.[54],[58],[59]
Several mechanisms have been proposed for the benefits of exercise in preventing cognitive decline. Davenport et al.[60] and Barnes et al.[20] have published excellent review papers that explore the evidence and mechanisms, particularly relating to CBF physiology and cerebrovascular function. Although resting CBF declines with age, habitual exercisers with higher cardiorespiratory fitness have been shown to have higher resting CBF levels than their sedentary age-matched counterparts.[59] Proposed mechanisms for the effect of exercise on increasing resting CBF are improvements in vascular function (through shear-stress mediated vasodilatory pathways) as well as exercise-induced increases in the recruitment and/or new growth of capillaries (i.e., angiogenesis).[60] The vascular function of the cerebral vessels can be measured with carbon dioxide (CO2) changes within the arterial blood (termed cerebrovascular reactivity), where normal function involves a vasodilatory response to increased CBF with increased CO2 (i.e., hypercapnia). Similar to resting CBF, cerebrovascular reactivity decreases with age;[16] however, higher cardiorespiratory fitness and habitual exercise have been associated with greater cerebrovascular reactivity.[61],[62] Moreover, several studies have shown that aerobic exercise training can improve cerebrovascular reactivity.[63],[64],[65]
Higher levels of cardiorespiratory fitness have also been positively associated with volumes of gray matter and white matter in older adults, specifically the attenuation of the age-related atrophy in the frontal, temporal, and parietal regions.[55],[66] Individual differences in the susceptibility of cognitive impairment as well as discontinuity between cognitive outcomes and neuropathology (e.g., β-amyloid burden and neurofibrillary tangles of tau) have led to a concept that greater brain volumes may provide a greater “brain reserve” or threshold against the clinical manifestations of cognitive impairment.[20],[67] Moreover, “cognitive reserve” is proposed as an active form of reserve whereby cognitively normal adults tolerate a higher level of neuropathology through preexisting cognitive processes or compensatory approaches.[68] Exercise and stimulating environments can contribute to brain reserve with the formation of new neurons (i.e., neurogenesis) through the upregulation of neurotrophic growth factors, such as brain-derived neurotrophic factor and insulin-like growth factor, which contribute to improvements in brain structure and function (neuroplasticity).[69],[70] Exercise-induced improvements in metabolic function (i.e., insulin sensitivity and mitochondrial efficiency) may also improve cerebral oxygen extraction and utilization.[24],[71]
| Effect of Exercise-based Cardiac Rehabilitation on Brain Health | | |
Cardiac rehabilitation (CR) is internationally recognized as a class 1A recommendation for patients following a cardiovascular-related event or procedure, which provides exercise training and intensive CVD risk factor modification.[72],[73] Previous reviews investigating the effect of CR on cognitive function[45],[74] (total studies included = 9) have found promising but limited evidence for exercise-based CR on cognitive function. A literature search of MEDLINE and Scopus was performed using the search term “cardiac rehabilitation” in combination with either “cognitive function/s,” “cognitive performance,” “memory,” “cerebral,” “cerebrovascular function,” “Gray matter,” or “Hyperintensities.” The literature search was also repeated using the terms “heart failure” and “exercise” in place of “cardiac rehabilitation.” Studies were excluded if they involved adjunct cognitive training,[75],[76] assessed associations rather than changes in the brain-related outcome,[77],[78] or provided insufficient details on assessment of the brain-related outcome. This search identified five additional studies that have assessed changes in brain-related outcomes with exercise training in patients with CVD,[79],[80],[81],[82],[83],[84] bringing the total number of included studies to 14. Only one study involved exercise training that was not part of a CR program in patients with HF.[81]
Thirteen of 14 studies involved a measure of cognitive function. A summary of selective cognitive outcomes from the available studies is outlined in [Table 1]. Nine studies assessed global function[79],[80],[81],[82],[85],[87],[88],[91],[93] with six studies finding a significant improvement following CR with the Montreal Cognitive Assessment (MoCA),[81],[91] Mini-Mental State Examination (MMSE),[79] Modified MMSE (3MS),[87] NIH Toolbox Fluid Composite score,[80] and Functional Independence Measure.[93] Three studies found no improvement in global function with MoCA[85] or MMSE.[85],[88]{Table 1}
Eight studies assessed attention-psychomotor function[80],[85],[86],[87],[88],[89],[90],[92] with seven studies reporting a significant improvement following CR with Trail-making Test A (TMT-A) and Digit Symbol Coding Test (DSC),[85],[86],[90] DSC but not TMT-A,[88],[89] pattern comparison test,[80] and the grooved pegboard.[87] Only one study found no improvement in attention-psychomotor function using DSC.[92]
Executive function was measured in eight studies with four studies finding a significant improvement using TMT-B,[89] TMT-B and Stroop Test,[85] Frontal Assessment Battery (FAB),[79] or Dimensional Change Card Sort Test,[80] and four studies showing no significant change in executive function using FAB[87] and/or TMT-B.[87],[88],[90],[92]
Five studies assessed verbal memory, with three studies finding a significant improvement[87],[88],[90] using verbal learning tests and two studies finding no significant change.[80],[92] Five studies assessed visuospatial working memory, with three studies showing a significant improvement using the list sorting test,[80] Benton Revised Visual Retention Test,[89] or Brief Visuospatial Memory Test (BVMT)[87] and two studies showing no change using the Rey-Osterrieth Complex Figure[82] or BVMT.[90] Visuospatial working memory may also be considered an executive function given that some elements of working memory require higher-level control.
All five studies assessing language found no significant improvements following CR using Boston Naming Test[87],[88] and/or verbal fluency tests.[85],[86],[87],[88],[90] While language processing has been shown to be the critical component of verbal fluency tests, they may also in part reflect executive functioning processes.[94]
Two studies found no improvement in any cognitive domain with exercise-based CR,[92] and these studies also found no significant improvements in peak VO2.[82],[92] In contrast, the majority of studies did achieve significant improvements in exercise capacity as peak VO2,[90],[92] peak metabolic equivalents (METs),[86],[87] submaximal METs,[80] 6-min walk test distance,[79],[85],[91] or 2-min step test.[88] Furthermore, several studies reported significant correlations between changes in exercise capacity and changes in cognitive domains, including changes in submaximal METs and working memory,[80] changes in peak METs and verbal memory,[87] and changes in peak METs and attention-executive function.[86]
Three studies assessed changes in resting CBF velocity using transcranial Doppler ultrasound,[85],[87] and one study assessed changes in cerebrovascular reactivity.[85] In patients with HF, Tanne et al.[85] found no change in resting middle cerebral artery velocity (MCAv) or MCAv cerebrovascular reactivity following 18 weeks of exercise-based CR or no-exercise control. Stanek et al.[87] found a significant improvement in resting anterior cerebral artery velocity (ACAv) but not MCAv following 12 weeks of exercise-based CR in patients with coronary artery disease. Furthermore, Stanek et al.[87] found that higher ACAv and MCAv at baseline were associated with greater improvements in visuospatial working memory. In patients with left ventricular assist devices, Smith et al.[84] found a reduction in resting posterior cerebral artery velocity (PCAv) following 12 weeks of exercise training; however, patients had higher PCAv during exercise compared with before training. The studies by Tanne et al.[85] and Stanek et al.[87] demonstrated significant improvements in exercise capacity with 6-min walk test and peak treadmill METs, respectively; however, none of these studies directly measured changes in cardiorespiratory fitness as peak VO2.
Finally, only one study has measured the effect of exercise-based CR on brain structure.[82] Using magnetic resonance imaging, Anazodo et al.[82] found significant bilateral improvements in gray matter volume within the frontal lobe, middle temporal gyrus, and supplementary motor area during CR, which were areas that showed significant atrophy compared with healthy controls at baseline. In the same study, Anazodo et al.[83] found significant improvements in regional gray matter CBF bilaterally within the anterior cingulate by ~30%, but no significant change in global CBF.
Limitations
A common limitation within the available studies is the lack of a true control group. Accordingly, it cannot be determined whether improvements in cognition following a cardiac-related event would occur naturally without exercise-based CR, or could be from learned practice effects related to the cognitive tests. This is challenging since CR is a class 1A recommendation for patients with CVD, and therefore, it would be unethical to allocate patients to a group that does not receive exercise-based CR. Within the available studies, attempts were made to include a control condition or account for practice effects. Tanne et al.[85] compared their exercise group with controls that could not complete the exercise training intervention, although this may introduce confounding bias relating to factors that influence exercise capabilities or dropout. Fujiyoshi et al.[79] compared patients with monthly CR attendance over 6 months to patients who attended less than once per month as a control group, and found significantly greater improvements in global cognition and executive function for patients with a greater frequency of CR (monthly group). Stanek et al.[87] compared their improvements in cognition with practice effects, finding improvements in attention-processing speed and verbal memory exceeded those of practice effects but improvements in global and executive function were similar to practice effects. Only six of the 14 studies reported the intensity of the exercise training; therefore, it is difficult to determine whether exercise intensity during CR influences improvements in cognitive function and cerebrovascular function. Given that high-intensity interval training (HIIT) has been shown to double improvements in peak VO2 and vascular function compared with moderate-intensity exercise,[95],[96],[97] this may provide a greater stimulus for improving cerebrovascular and cognitive functions. HIIT is feasible and safe in CR settings.[98],[99] One of the studies that did not find a significant improvement in peak VO2 involved mainly home-based training (4 sessions per week), with only one supervised training session per week.[92] While fidelity of the training protocol was measured during supervised sessions, poor adherence to the training prescription during home-based sessions may have contributed to the lack of improvements in peak VO2 and cognitive outcomes. Given the increased use of telehealth for CVD patients and CR programs, monitoring and reporting of adherence to home-based training (in terms of attendance, intensity, and duration), should be considered a vital component for assessing the effectiveness of exercise interventions.[100] The use of mobile-health applications may improve the ability of clinicians and researchers to monitor adherence to exercise interventions during home-based exercise.
| Conclusion | | |
The available evidence suggests that exercise-based CR improves global cognitive function and attention-psychomotor functions but not language processes. The effect on executive function and memory is less clear. Furthermore, given the lack of true control groups, it cannot be determined whether these improvements in cognitive function are influenced by learning effects or would have occurred naturally following a cardiac event. Although, several studies have shown significant correlations between improvements in cognitive function and improvements in exercise capacity. Finally, there is very limited research assessing the effect of exercise-based CR on cerebrovascular function and brain structure. Further well-designed studies are warranted to elucidate the effect of exercise training during and following CR on cognitive function and cerebrovascular outcomes, and determine the optimal exercise prescription for improving brain health in patients with CVD.
Ethical statement
The ethical statement is not applicable for this article.
Financial support and sponsorship
JLT is supported in part by the National Institute on Aging (1R21AG073726).
Conflicts of interest
There are no conflicts of interest.
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