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Cardiac Hypertrophy Is Associated With Advanced Brain Aging in the General Population

Background Hypertrophy of the left ventricle (LV) has recently been associated with adverse changes of brain structure in older adults, notably increased burden of white matter hyperintensities (WMHs). Whether greater LV size or mass is also related to WMH burden in middle‐aged adults is currently unclear. In addition, its relation with alterations in cortical thickness (CT) has not been studied to date. Methods and Results Data from 1602 participants of the population‐based SHIP (Study of Health in Pomerania) with LV ejection fraction >40% and no history of myocardial infarction were included (aged 21–82 years; median age, 49 years; 53% women). Participants underwent both echocardiography and magnetic resonance imaging of the head. Imaging markers of brain aging (ie, CT and WMH volume) were determined from magnetic resonance imaging scans. LV mass and diameter were associated with lower global CT and greater WMH volume, while adjusting for age, sex, body height, fat‐free body mass, and intracranial volume. Moreover, thicknesses of the interventricular septum and posterior wall were also associated with lower global CT. These associations could not be explained by cardiovascular risk factors (including hypertension), inflammatory markers, or sociodemographic factors. Regional analyses showed distinct spatial patterns of lower CT in association with LV diameter and posterior wall thickness. Conclusions LV diameter and mass are associated with lower global and regional CT as well as greater WMH burden in the general population. These findings highlight the brain structural underpinnings of the associations of LV hypertrophy with cognitive decline and dementia.

late diastole (E/A) were calculated. Certification examinations for inter-observer variations revealed an agreement of more than 90%.

Cortical Thickness
T1-weighted MRI scans were processed with the image-processing pipeline FreeSurfer version 5.3 which is documented and freely available for download online (http://surfer.nmr.mgh.harvard.edu). The processing includes segmentation of the cerebral cortex, calculation of mean CT of each hemisphere as well as regional CT according the Desikan-Killiany atlas. The Desikan-Killiany atlas comprises 34 gyral-based regions per hemisphere and has been successfully applied in a wide range of imaging studies in the past (28). The underlying method has been shown to give anatomically valid and reliable results (29). The list of all cortical regions can be found in Table S3. Global CT was defined as the mean thickness of left and right hemisphere.
CT but not cortical volume or surface area was considered because it is weaker associated with body size and sex (30), thereby minimizing the nuisance variation shared with structural cardiac measurements. Moreover, CT has been found to be a more sensitive measure of neurodegeneration in Alzheimer's disease (31,32). FreeSurfer also gives an estimate of the total intracranial volume (TIV) of the head which can be used to account for some of the variability of CT between the study participants.

White Matter Hyperintensities
After preprocessing and coregistration of T1-weighted and FLAIR scans WMH lesions were segmented using a support vector machine-based method (33). Quality of segmentations were assessed by visual inspection, and total WMH volumes and counts were determined.
Minimum WMH volume was set to 5 mm 3 . For details we refer to Habes et al. (34).

Inflammatory Markers
Blood samples were taken from the cubital vein of the participants in supine position.
White blood cell count (WBC) was determined using the Sysmex XT 2000, XE 5000 or SE Eschborn, Germany). Concentrations of C-reactive protein (CRP) were determined in serum by nephelometry on the Dimension VISTA (Siemens Healthcare Diagnostics, Eschborn, Germany). Fibrinogen concentrations were measured in citrate plasma according to Clauss using the BCS or the BCS XP system (Siemens Healthcare Diagnostics, Eschborn, Germany).

Socio-Demographic Variables
Living alone was defined as not sharing the home with a partner (neither married nor unmarried). Equalized disposable income was defined as the ratio of the winsorized household income in Euro (ranging from 333.33€ to 5,066.67€) and the square root of the number of household members (35). The number of years of education was calculated as the sum of years of scholastic and occupational education with values ranging from 8 (e.g. completed lower secondary school and no professional qualification) to 17 (university degree) years. Standardized regression coefficients with 95% confidence intervals are given. Results are adjusted for age, sex, body height, fat-free body mass, total intracranial volume, and the interaction of sex with age (base model). In addition, associations with echocardiographic parameters were also adjusted for all cardiovascular risk factors, inflammatory markers, and socio-demographic variables (extended model). Standardized regression coefficients with 95% confidence intervals are given. Results are adjusted for age, sex, body height, fat-free body mass, total intracranial volume, and the interaction of sex with age (base model). In addition, associations with echocardiographic parameters were also adjusted for all cardiovascular risk factors, inflammatory markers, and socio-demographic variables (extended model).  After regressing both outcomes on the control variables of the base model there were six and three cases, respectively, with unusually residual values (marked with red) which were excluded from the analyses. Solid lines represent the best fits by restricted cubic splines with five knots located at the 5%, 27.5%, 50%, 72.5%, and 95% quantiles.

Figure S3. Sensitivity analyses of associations of global cortical thickness with structural and functional echocardiographic parameters.
Regression coefficients of left ventricular diameter during diastole (LVD, A) and systole (LVS, B), interventricular septal thickness during systole (IVSS, C), posterior wall thickness during diastole (PWD, D) and left ventricular mass (LVM, E) did not change significantly when additionally controlling for waist circumference, diabetes, hypertension, systolic and diastolic blood pressure, C-reactive protein, white blood cell count, fibrinogen, smoking status, living alone, equivalised disposable income, or years of education both individually and all together (Z-tests, |z|<0.94). Continuous control variables were modelled with restricted cubic splines with 5 knots. Significance levels: * p<.05, ** p<.01, *** p<.001 Figure S4. Sensitivity analyses of associations of white matter hyperintensity volume with echocardiographic parameters.
Regression coefficients of left ventricular diameter during diastole (LVD, a) left ventricular mass (LVM, b), and ratio of peak velocity blood flow in early diastole to peak velocity flow in late diastole (E/A, c) did not change significantly when additionally controlling for waist circumference, diabetes, hypertension, systolic and diastolic blood pressure, C-reactive protein, white blood cell count, fibrinogen, smoking status, living alone, equivalised disposable income, or years of education both individually and all together (Z-tests, |z|<0.51. Continuous control variables were modelled with restricted cubic splines with 5 knots. Significance levels: * p<.05, ** p<.01, *** p<.001 Figure S5. Associations of regional cortical thickness with structural and functional echocardiographic parameters (base model).
Analyses were adjusted for age, sex, body height, fat-free mass, total intracranial volume, and the interaction of sex with age. Labels are shown for those regions where associations remained significant after correction for multiple testing (Benjamini-Hochberg method, FDR ≤ 5%). For the abbreviations see Table S3. Figure S6. Associations of regional cortical thickness with structural and functional echocardiographic parameters (extended model).
In addition to the control variables of the base model, analyses were adjusted for cardiovascular risk factors (waist circumference, diabetes, hypertension, systolic and diastolic blood pressure, smoking), inflammatory markers (white blood cell count, fibrinogen, and Creactive protein), and socio-demographic variables (living alone, equivalised disposable income, and years of education). Labels are shown for those regions where associations remained significant after correction for multiple testing (Benjamini-Hochberg method, FDR ≤ 5%). For the abbreviations see Table S3.