Associations Between Cardiac Function and Brain Health in Diverse Middle-Aged Adults

Background Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations. Objectives The objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults. Methods A cross-sectional study was conducted in participants of the Dallas Heart Study phase 2 (N = 1,919; 46% Black participants). Left ventricular (LV) mass, LV ejection fraction, LV concentricity, and peak systolic strain (LV Ecc) were assessed by cardiac magnetic resonance imaging. White matter hyperintensities (WMH) volume was measured by fluid attenuated inversion recovery magnetic resonance imaging. The Montreal Cognitive Assessment was used to measure cognitive functioning. Associations between cardiac and brain measures were determined using multivariable linear regression after adjusting for cardiovascular risk factors, education level, and physical activity. Results LV ejection fraction was associated with total Montreal Cognitive Assessment score (β = 0.06 [95% CI: 0.003-0.12], P = 0.042) and LV Ecc was associated with WMH volume (β = 0.08 [95% CI: 0.01-0.14], P = 0.025) in the overall cohort without significant interaction by race/ethnicity. Higher LV mass and concentricity were associated with larger WMH volume in the overall cohort (β = 0.13 [95% CI: 0.03-0.23], P = 0.008 and 0.10 [95% CI: 0.03-0.17], P = 0.005). These associations were more predominant in Black than White participants (β = 0.17 [95% CI: 0.04-0.30] vs β = −0.009 [95% CI: −0.16 to 0.14], P = 0.036 and β = 0.22 [95% CI: 0.13-0.32] vs β = −0.11 [95% CI: −0.21 to −0.01], P < 0.0001, for LV mass and concentricity, respectively). Conclusions Subclinical cardiac dysfunction indicated by LVEF was associated with lower cognitive function. Moreover, LV mass and concentric remodeling were associated with higher WMH burden, particularly among Black individuals.

2][3] It was estimated that patients with congestive heart failure experienced 2-to 4-fold higher risk of cognitive impairment than age-matched controls. 4,5is association between cardiac and brain function was observed not only in patients with overt heart failure but also in community-dwelling older adults without overt cardiovascular disease. 6,7][6][7][8] In addition, recent studies have demonstrated a paradoxically lower brain amyloid burden among Black individuals based on positron emission tomography imaging when compared to White individuals despite having a higher prevalence of the apolipoprotein E4 allele (ApoE-ε4) and prevalence of dementia. 9,10These finding suggested a complex pathophysiologic mechanisms of dementia that is not explained by brain amyloid alone, which may contribute to racial/ ethnic disparities in prevalence of dementia.
There are few studies that have investigated the association between cardiac and brain structure and CARDIAC MAGNETIC RESONANCE IMAGING.cMRI was performed on a 3-T MRI system (Achieva, Philips Medical Systems). 12Left ventricular (LV) images were acquired using prospective electrocardiography gating and turbo field echo sequencing.LV mass, LV end-diastolic volume, LV end-systolic volume, left atrial volume (LA), LV ejection fraction (LVEF), cardiac output, heart rate, blood pressure (BP), and stroke volume were calculated as previously described. 13LV concentricity was defined as LV mass/LV end-diastolic volume (EDV) 0.67 as previously described. 14Peak systolic strain (LV E cc )

Giacona et al
Cardiac and Brain Health in Middle-Aged Adults was assessed using the myocardial tissue tagging method in 6 LV wall segments using harmonic phase imaging software offline (HARP, Diagnosoft Virtue 5.04, Diagnosoft) as previously described. 15NTREAL COGNITIVE ASSESSMENT.The total MoCA score is a 30-point screening tool for the assessment of cognitive function 16 that includes assessment of attention, orientation, language, verbal memory, visuospatial, and executive function. 17The MoCA was administered by trained personnel in DHS-2 as previously described. 16AIN MRI.A 3-T MRI unit (Achieva, Philips Medical Systems) was used for the DHS brain MRI protocol, with acquisition of 2-dimensional fluid-attenuated inversion recovery images and 3-dimensional magnetization prepared rapid acquisition with gradient echo images as previously detailed. 189][20] Measurements of white matter hyperintensities (WMH), and total cranial volumes were extracted as previously described.
No functional MRI was available or processed for this study.Restricted cubic splines of each association between cardiac and brain variables were also constructed Giacona et al Cardiac and Brain Health in Middle-Aged Adults using model 3. Statistical significance was indicated when P value is <0.05.

INTERACTION WITH RACE AND ETHNICITY AND
ApoE4 CARRIER STATUS.Association between LVEF and MoCA was not modified by race and ethnicity (Table 4), but LV E cc was inversely associated with MoCA in Black but not in non-Black individuals (b ¼ À0.43 [95% CI: À0.75 to À0.12], P for interaction ¼ 0.009, Table 4).LV E cc was positively associated with WMH volume (b ¼ 0.08 [95% CI: 0.01-0.14],P ¼ 0.025) (Table 3) in the overall cohort without significant interactions by race/ethnicity (Table 5).In contrast, associations of higher LV mass and concentricity with higher WMH volume were modified by race/ethnicity, with stronger associations observed in Black individuals (b ¼ 0.78 [95% CI: 0.46-1.11]and b ¼ 0.31 [95% CI: 0.02-0.60],P for interaction <0.05 for both) (Table 5).These findings remain unaltered when atrial fibrillation was added as a covariate in model 2 (Supplemental Tables 3   and 4).Additionally, relationships between LVEF, LV mass, concentricity, and LV E cc with MoCA score and WMH were not modified by ApoE-ε4 allele carrier status (Supplemental Tables 5 and 6).These findings remained the same when atrial fibrillation was added as a covariate in model 2 (Supplemental Tables 7 and 8).

DISCUSSION
The main findings from our study are 3-fold.First, in this multiethnic cohort of predominantly middleaged adults without preexisting cardiovascular disease or stroke, lower LVEF was associated with lower cognitive function.Second, lower LVEF, higher LV mass and concentricity, and higher LV E cc were associated with larger WMH volume, a marker of small vessel cerebrovascular disease and brain aging. 21,22Third, the magnitude of association between abnormal LV structure and WMH was stronger in Black than in non-Black adults.
Cardiac and Brain Health in Middle-Aged Adults which is commonly identified in older adults with hypertension, diabetes, stroke, or dementia. 22In our study, although the association between abnormal cardiac structure and WMH remained significant after adjustment for BP and other cardiovascular risk factors, it is possible that cumulative effects of persistent hypertension promote both LV hypertrophy and hypertensive related brain injury that is not otherwise captured by BP assessment at a single time point.Alternatively, hypotension may likewise contribute to WMH. 23,24 Though, it is difficult to assess in our study because cognitive testing, brain, and cardiac MRI were done during an in-person visit in hemodynamically stable patients who were largely asymptomatic.Moreover, atrial fibrillation is a known risk factor for cognitive impairment and dementia.[27] However, when history of atrial fibrillation was incorporated into the models in our study, the observed relationship between cardiac structure/ function with WMH and cognitive function remain the same.
Several population studies have demonstrated an association between cardiac function and brain function but almost all studies have focused on the association during late life.Analysis from the Framingham Heart Study Offspring Cohort showed a U-shape relationship between LVEF and cognitive function. 1Both lowest and highest quintiles of LVEF were associated with impaired cognitive function.In contrast, higher cardiac index was shown to be associated with higher cognitive function. 6Higher LV mass was also shown to predict cognitive impairment and dementia in the MESA (Multi-Ethnic Study of Atherosclerosis). 28kewise, higher global longitudinal strain was associated with lower cognitive performance in Vanderbilt Memory and Aging Project. 2 However, these studies were limited to older cohorts with a mean age above 60 years.Other non-U.S.cohorts of older adults from Iceland and the United Kingdom have shown conflicting evidence regarding the relationship between LVEF and brain function, but the proportion of ethnic minorities was very small among those studies. 7,8w studies have investigated the relationship between cardiac structure and cognitive function.
Analysis from the Coronary Artery Risk Development in Young Adults reported that higher LV mass index associated with lower cognitive function during midlife. 29Our study extended the findings and demonstrated stronger associations between an increase in LV mass, concentricity, or LV E cc and an increase in WMH in Black vs non-Black participants.This is an important finding as it may explain mechanisms underlying an accelerated brain aging beginning from midlife among Black adults when compared to other racial/ethnic groups as evidenced by increased WMH shown in a recent study. 21In addition, an increasing number of studies have showed a paradoxically lower amyloid brain deposit among Black individuals as evidenced by positron emission tomography scan despite having higher prevalence of ApoE-ε4 alleles when compared to White individuals. 9,10Thus, other factors are likely responsible for the racial/ethnic disparities in the prevalence of dementia and Alzheimer disease in this population.Our finding suggests a potential role for optimal cardiovascular health to preserve brain function in this racial/ethnic subgroup which is disproportionately affected by Alzheimer disease. 30 the other hand, ApoE-ε4 allele carrier status did not modify the relationship between LV function/ structure and MoCA or brain structure.Our findings are in contrast with the results from the Vanderbilt Memory and Aging project which showed that lower cardiac output was associated with poorer cognitive performances in ApoE-ε4 allele carriers but not among noncarriers. 31Although factors underlying these divergent results are unknown, the mean age of our cohort is on average more than 20 years younger and more ethnically diverse than previous studies.Moreover, statistical power for subgroup analyses was limited.Thus, additional studies are needed to determine whether ApoE status influences associations between the cardiac and brain axes and whether this differs by race/ethnicity.
The strengths of our study include the use of a highly accurate technique of cMRI in determining cardiac structure and function as well as myocardial strain, which is shown to be a more sensitive marker for LV contractility 32 and predictor of cardiovascular prognosis than LVEF alone, 33,34       Cardiac and Brain Health in Middle-Aged Adults function, especially in middle-aged individuals.Moreover, previous studies have not examined the potential role of race/ethnicity in modifying the association between cardiac structure and function and cognitive function in diverse middle-aged populations.Accordingly, we performed a crosssectional study in the young to middle-aged multiethnic population enrolled in the DHS-2 (Dallas Heart Study phase 2) to determine associations between cardiac function and brain structure and function, after adjusting for traditional vascular risk factors as well as physical activity.METHODS Studies were conducted in participants enrolled in DHS-2 between 2007 and 2009 (NCT00344903) after informed consent was obtained.The study was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center.Details regarding DHS-2 selection criteria, study design, and methods have been described elsewhere. 11The Dallas Heart Study is a multiethnic, population-based probability sample of Dallas County.DHS-2 participants underwent cognitive testing, brain magnetic resonance imaging (MRI) and cardiac magnetic resonance imaging (cMRI), and physical activity assessment during 1 visit.Race was self-reported by study participants, and race categories were defined by investigators based on the US Office of Management and Budget's Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity.As shown in Figure 1, a total of 2,052 participants underwent cMRI; in which, 128 participants with prior history of cardiovascular disease or stroke and 5 participants without reporting race/ethnicity were excluded.Therefore, 1,919 participants were included in our current analysis.Of those, 1,635 participants underwent cognitive function testing with the Montreal Cognitive Assessment (MoCA) and 1,878 participants completed brain MRI.
Center, Dallas, Texas, USA; g Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; and the h Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.*Drs Giacona and Chia contributed equally to this work.

FIGURE 2
FIGURE 2 Association Between Cardiac and Brain Structure and Function

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A C C : A D V A N C E S , V O L . 3 , N O . 2 , 2 0 2 4 Giacona et al F E B R U A R Y 2 0 2 4 : 1 0 0 7 7 Cardiac and Brain Health in Middle-Aged Adults CENTRAL ILLUSTRATION Associations Between Cardiac Function and Brain Health in Diverse Middle-Aged Adults: The Dallas Heart Study-2 Giacona JM, et al.JACC Adv.2024;3(2):100777.
Giacona et alJ A C C : A D V A N C E S , V O L . 3 , N O . 2 , 2 0 2 4 Cardiac and Brain Health in Middle-Aged Adults F E B R U A R Y 2 0 2 4 : 1 0 0 7 7 7 ASSOCIATION BETWEEN CARDIAC STRUCTURE/ FUNCTION AND BRAIN STRUCTURE.Lower LVEF was associated with higher WMH volume after adjustment for cardiovascular risk factors and physical activity (b ¼ À0.08 [95% CI: À0.14 to À0.01], P ¼ 0.024) (Table Mechanisms linking cardiac structure and function with WMH and cognitive function are unknown.Although lower cerebral blood flow may be responsible for the associations between cardiac performance and brain structure and function, cerebral autoregulation normally maintains cerebral blood flow at a constant level under normal physiological conditions.Mechanisms underlying higher WMH associated with LV hypertrophy or hypertrophic cardiac remodeling are also unknown.WMH are thought to represent microvascular disease, in a multiethnic population without overt cardiovascular disease.Our study is limited by the use of MoCA alone as the tool for assessment of cognitive function.The cross-sectional design also limits the ability to determine causal effects.Racial/ethnic data were collected by self-reported only which may be the result of multiple factors including social determinants of health or genetic variation and should not be used to imply underlying genetic effects alone.35Nevertheless, our data suggest a link between subclinical abnormalities in cardiac structure and function with a higher burden of WMH after adjusting for physical activity, particularly among Black participants, the population at the highest risk for ADRD.Future studies are needed to determine if strategies to maintain normal cardiac structure and function during midlife offers protection against cognitive decline in late life.CONCLUSIONSSubclinical cardiac dysfunction was associated with lower cognitive function.Moreover, increased LV mass, concentric remodeling, and higher LV E cc were associated with higher burden of WMH, particularly among Black individuals.FUNDING SUPPORT AND AUTHOR DISCLOSURESThe Dallas Heart Study was funded by the Donald W. Reynolds Foundation and was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1TR001105.Dr Vongpatanasin is supported by the UT Southwestern O'Brien Kidney Center, the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research: R01 AG057571.All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.ADDRESS FOR CORRESPONDENCE: Dr Wanpen Vongpatanasin, Hypertension Section, Cardiology Division, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, H4.130, Dallas, Texas 75390-8586, USA.E-mail: wanpen.vongpatanasin@utsouthwestern.edu.R E F E R E N C E S 1. Jefferson AL, Himali JJ, Au R, et al.Relation of left ventricular ejection fraction to cognitive aging (from the Framingham Heart Study).Am J Cardiol.2011;108(9):1346-1351.2. Kresge HA, Khan OA, Wagener MA, et al.Subclinical compromise in cardiac strain relates to lower cognitive performances in older adults.J Am Heart Assoc.2018;7(4):e007562.

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Jefferson AL, Himali JJ, Beiser AS, et al.Cardiac index is associated with brain aging: the Framingham Heart Study.Circulation.2010;122(7): 690-697.PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Subclinical cardiac dysfunction was associated with lower cognitive function.Additionally, subclinical cardiac remodeling was associated with subclinical brain injury.These findings highlight the importance of maintaining optimal cardiovascular health to aid in maintaining brain health.TRANSLATIONAL OUTLOOK: Further studies are needed to determine if strategies to maintain normal cardiac structure and function during midlife offers protection against cognitive decline in late life.

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Table 1 .
Of those 1,919 participants, the mean age was 49.8 AE 10.7 years, and the mean body mass index was To determine if the relationship between cardiovascular variables and cognitive function was dependent on genetic predisposition to Alzheimer disease, we further stratified participants by the ApoE-ε4 allele carrier status and self-identified race (Black participants vs non-Black participants).ticipants (Table 1).LVEF was significantly lower in Black than non-Black individuals, while peak systolic strain was not significantly different between the 2 groups.Higher proportion of diabetes, current smoking, and ApoE-ε4 carrier, as well as lower proportion of antihypertensive drug use and education above college were identified among Black than non-Black participants (Table 1).ASSOCIATION BETWEEN CARDIAC STRUCTURE/ FUNCTION AND COGNITIVE FUNCTION.Higher LVEF was associated with higher total MoCA score after adjustment for cardiovascular risk factors, education, and time spent in moderate-to-vigorous physical activity (b ¼ 0.06 [95% CI: 0.003-0.12],P ¼ 0.042 (Table 2, Figure 2A, and Central Illustration).There were no associations between cardiac output, LV mass, LV concentricity index, LA volume, or LV E cc with total MoCA score.These findings remained the same when atrial fibrillation was added as a covariate in model 2 (Supplemental Table 1).

TABLE 1
Baseline Characteristics of the Cohort aValues are mean AE SD or %. a Indicates statistical significance.BMI ¼ body mass index; eGFR ¼ estimated glomerular filtration rate; MVPA ¼ moderate-to-vigorous physical activity.

TABLE 4
Association Between Cardiac Structure/Function and Montreal Cognitive Assessment Stratified by Race and Ethnicity (Adjusted Covariates: Age, sex, BSA, SBP, antihypertensive, diabetes, smoking, eGFR, and education levels, and MVPA.a b and 95% CI values are presented as standardized b. b indicates statistical significance.BSA ¼ body surface area; EDV ¼ end-diastolic volume; ESV ¼ end-systolic volume; HR ¼ heart rate; LAV ¼ left atrial volume; LV ¼ left ventricle; LVEF ¼ left ventricular ejection fraction; LVH ¼ left ventricular hypertrophy; MVPA ¼ moderate-to-vigorous physical activity.

TABLE 5
Association Between Cardiac Structure/Function and White Matter Hyperintensity Volume Normalized to Total Cranial Volume Stratified by Race and Ethnicity (Adjusted for Model 3 Covariates) : Age, sex, BSA, SBP, antihypertensive, diabetes, smoking, eGFR, and education levels, and MVPA.a b and 95% CI values are presented as standardized b.