CHA2DS2-VASc score, cerebral small vessel disease, and frailty in older patients with atrial fibrillation

The CHA2DS2-VASc score is a validated predictor of ischemic stroke in atrial fibrillation (AF) patients. However, data are limited on whether the CHA2DS2-VASc score is associated with subclinical brain structural changes or physical frailty among older AF patients. We assessed the relationship between CHA2DS2-VASc scores and brain structural changes or physical frailty in AF patients without history of stroke. Overall, 117 patients completed a comprehensive geriatric assessment for physical frailty. In brain magnetic resonance imaging sub-study (n = 49), brain volume and white matter hyperintensity lesion burden were automatically quantified using the LESIONQUANT software program. Patients with high risk of CHA2DS2-VASc scores (≥ 2 in men or ≥ 3 in women) tended to be older and had more comorbidities, higher frailty index, and slower gait speed. Total white matter hyperintensity lesion burden was higher in those with high risk of CHA2DS2-VASc score than in those with intermediate risk (score of 1 in men or 2 in women) of CHA2DS2-VASc score (1.67 [interquartile range: 0.70–3.45] vs. 0.64 [0.19–1.44], p = 0.036). Cognitive function was associated with brain volume, but gait speed was related with white matter hyperintensity lesion burden. In conclusion, we showed a positive relationship between CHA2DS2-VASc scores, white matter hyperintensity lesion burden, and physical frailty in older AF patients. Subclinical brain changes associated with high CHA2DS2-VASc scores may predict physical frailty risk.


Scientific Reports
| (2020) 10:18765 | https://doi.org/10.1038/s41598-020-75256-6 www.nature.com/scientificreports/ scales 14 . Although SVD is a major contributor to dementia, the relationship between AF and the CHA 2 DS 2 -VASc score and physical or cognitive function remains inconclusive, especially in patients without stroke history 15,16 . A state of decreased physiologic reserve and increased vulnerability is known to be associated with increased risk of adverse health-related outcomes 17 . The comprehensive geriatric assessment (CGA) is widely used with a multidimensional interdisciplinary diagnostic approach for determining frail older adults' medical, psychological, and functional capacity 18 . In our previous study, we identified that the CHA 2 DS 2 -VASc score is positively associated with frailty status and that frailty assessment can be used to predict mortality in older AF patients and provides additional prognostic value, along with the CHA 2 DS 2 -VASc and HAS-BLED scores. However, studies on the underlying mechanism linking frailty and the CHA 2 DS 2 -VASc score in AF patients are limited.
Brain WMH lesions lead to cognitive decline and are correlated with frailty in older adults 19,20 . Patients with higher CHA 2 DS 2 -VASc score are considered to have a higher burden of subclinical WMH lesions, which may affect physical frailty in older AF patients. Therefore, we aimed to evaluate the relationship between CHA 2 DS 2 -VASc scores, brain WMH lesions, and frailty. To obtain evidence for the mechanisms underlying the higher incidence of physical frailty in the high risk of CHA 2 DS 2 -VASc score group, the correlation between CHA 2 DS 2 -VASc scores, subclinical brain structural parameter (volume or WMH lesion), and frailty was evaluated in a sub-study of patients without stroke or transient ischemic attack who underwent brain MRI.

Results
Participants' characteristics. Of the 133 participants recruited, 117 were included in the analysis.
We analysed brain variables (volume of brain structures and WMH lesion burden and anatomical distribution) according to the CHA 2 DS 2 -VASc score groups. With regard to the brain structure volume, only the hippocampus volumes were larger in the intermediate risk of CHA 2 DS 2 -VASc score group than in the high risk of CHA 2 DS 2 -VASc score group. After adjustment for the intracranial volume (ICV), all brain structural volumes were not statistically different between the groups. The total WMH lesion volume adjusted with the ICV and lesion burden were significantly higher in the high risk of CHA 2 DS 2 -VASc score group ( Supplementary Fig. 1). With respect to the anatomical distribution of the WMH lesions, the area of the deep white matter WMH lesion was especially larger in the high risk of CHA 2 DS 2 -VASc score group (Table 2).
Relationship between brain image parameters and cognitive function or physical frailty. Compared with the lower mini-mental state examination (MMSE) score (≤ 24) group (n = 14), the higher MMSE score (> 24) group (n = 35) had larger whole brain, thalamus, cortical grey matter, cerebral white matter, and hippocampi volumes. After adjusting for the ICV, cerebral white matter volume was larger in the higher MMSE score group (p = 0.037). However, the WMH lesion burden or lesion anatomical distribution was not statistically different between the higher and lower MMSE score groups (Supplementary Table 1). Participants who had a faster gait speed (≥ 1.2 m/s, n = 12) had larger whole brain, cortical grey matter, cerebral white matter, and hippocampi volumes than did participants who had a slower gait speed (< 1.2 m/s, n = 36); however, this statistical significance disappeared when the result was adjusted for the ICV. The slower gait speed group had a larger WMH lesion volume (p = 0.012) and lesion volume adjusted for ICV (p = 0.006), and higher lesion burden (p = 0.006). For the WMH lesion anatomical distribution, the slower gait speed group had larger lesion volumes in the periventricular area (p = 0.011) (Supplementary Table 2).

Discussion
Patients with high risk of CHA 2 DS 2 -VASc score tended to be more frail and slower and showed poor physical performance when compared with those with intermediate risk of CHA 2 DS 2 -VASc score. Further, the intermediate risk of CHA 2 DS 2 -VASc score group had a lower cerebral SVD burden. Slow gait speed was also correlated with higher WMH lesion burden, and cognitive function was associated with brain volumes. Regarding the lesion anatomical distribution, the WMH lesion volume was significantly larger in the deep white matter among those www.nature.com/scientificreports/ with high risk of CHA 2 DS 2 -VASc score. A higher WMH lesion burden in the periventricular area was associated with slow gait speed (Fig. 1). Frailty and AF are two related conditions in older individuals and are known to affect each other 21 . As one of the roles played by AF in the onset and progression of frailty, we identified that WMH lesions are highly prevalent in older adults with AF and that the WMH lesion burden is related to cardiovascular risk factors, including a higher CHA 2 DS 2 -VASc score and slow gait speed. Also, the trend of higher WMH lesion burden in higher CHA 2 DS 2 -VASc score group was more prominent in slow gait speed group (gait speed < 1.2 m/s, right column) than the fast gait speed group (gait speed ≥ 1.2 m/s, left column) (Fig. 2). Although its detailed histopathological correlates still need to be investigated, the results of this study indicate that cerebral SVD may be attributable to pathophysiology similar to that of stroke in AF patients and that cerebral SVD leads to physical frailty.

Figure 1.
Relationship between the CHA 2 DS 2 -VASc score, brain white matter hyperintensity lesion, brain volume, and frailty. The CHA 2 DS 2 -VASc score, physical frailty, and white matter hyperintensity lesion/brain volume have a significant ( +) interrelationship.

Figure 2.
Relationship between the CHA 2 DS 2 -VASc score and brain white matter hyperintensity according to gait speed. The trend of higher white matter hyperintensity lesion burden in higher CHA 2 DS 2 -VASc score group was more prominent in slow gait speed group (right column) than the fast gait speed group (left column). www.nature.com/scientificreports/ Visual assessment of WMH lesions is subject to significant interobserver variability, while volumetric measurements can provide more reliable and objective results 14,[22][23][24] . LESIONQUANT provides accurate and reliable segmentation of multiple sclerosis lesions in contrast to manual segmentation performed by experts 25 . This automated segmentation approach also provides volumetric tracking for the identification of longitudinal trends of lesion evolution. Thus, this method can be used for further prospective longitudinal studies to assess progression of WMH lesions over time according to the CHA 2 DS 2 -VASc score or other risk factors.
Our study has some limitations. First, the findings may have limited generalisability because the study participants were relatively robust than the general older AF population owing to the exclusion of patients with symptomatic stroke and TIA and patients who could not understand the questionnaire or provided informed consent. Among them, the patients who participated in the MRI sub-study were physically stronger and functionally independent in contrast to those who were only evaluated with the CGA (Supplementary Table 3). Second, the small sample size and selection of a relatively robust population may be attributable for only the association between a lower MMSE score and small brain volume being discernible and not that with a higher WMH lesion burden. Third, we were unable to collect data on the progression of WMH lesions or occurrence of stroke, TIA, or dementia. Moreover, because of the cross-sectional design, causal relationships could not be identified. Fourth, though we recruited older AF patients and most of them (n = 110, 94%) were recommended for anticoagulation (CHA 2 DS 2 -VASc score ≥ 2), only 55.6% of the participant received anticoagulation. Difference between the cutoff value of CHA 2 DS 2 -VASc score defined in this study and recommended to anticoagulation could affect as an unmeasured confounding factor. Therefore, additional prospective study is warranted to identify correlation between anticoagulation use and WMH severity or progression in older AF patients. Despite these limitations, our results highlight the potential of SVD to be a marker or a result of aging, frailty, cardiovascular risk factors, or multimorbidity.
In conclusion, this work provides further evidence of a cross-sectional relationship between CHA 2 DS 2 -VASc scores, WMH, and frailty in older non-valvular AF patients. Cerebral SVD seemed to be more prevalent and severe among those with high risk of CHA 2 DS 2 -VASc score, which was related with slow gait speed. Further research with a longitudinal design would strengthen the evidence for the causal relationship between CHA 2 DS 2 -VASc score, cerebral SVD, and frailty in older AF population.

Methods
Participants. This was a prospective observational cohort study conducted at Seoul National University Bundang Hospital. Non-valvular AF patients aged ≥ 65 years were recruited from September 2015 to November 2017. The exclusion criteria were as follows: (1) heart failure in New York Heart Association classification IV, (2) unresolved malignancy, and (3) cognitive decline with inability to understand the questionnaire or provide informed consent. This prospective cohort was evaluated using three consecutive CGAs at 6-month intervals. Among the patients who participated in prospective cohort, brain MRI was additionally performed for those who consented to the sub-study. The patients who had diagnosis of symptomatic stroke or transient ischemic attack were excluded for the sub-study. Data on baseline clinicodemographic characteristics were retrieved from electronic health records (EHR).
This study was approved by the institutional review board of Seoul National University Bundang Hospital (IRB No. B-1506/304-309). Informed consent was obtained from all patients, including from those in the sub-study group, prior to enrolment. All methods were performed in accordance with relevant guidelines and regulations.
Brain MRI protocol. MR  . The scan parameters of sagittal 3D T1-weighted imaging and sagittal 3D FLAIR imaging were based on the recommended scanner settings by NEUROQUANT and LESIONQUANT, respectively (CorTechs Labs, San Diego, CA). WMH lesions were assessed via LESIONQUANT, which offers automated quantification of WMH lesion volume, lesion burden, and counts, and anatomical lesion distribution 21 . Volume of the brain structures was measured using NEUROQUANT 26 . The burden of WMH lesions was represented with counts (number), volumes (cm 3 ), % ICV, and lesion burden.

CGA and CHA 2 DS 2 -VASc and HAS-BLED scores.
The CGA protocol included four domains (i.e., medical, functional, psychological, and nutrition) as previously described 27 . Comorbidity was described using the Charlson comorbidity index. Functional status was assessed using activities of daily living (ADL) and instrumental ADL (IADL). The timed up and go (TUGT) time, gait speed, and grip strength were also measured to assess physical function. Gait speed was measured using an automated laser-gated chronometer attached to the wall. Handgrip strength (kg) was measured using a Jamar Plus + Digital Hand Dynamometer (Sammons Preston, Bolingbrook, IL, USA), and the maximum value of two measurements of the dominant hand was used for the analysis. Psychological status was assessed using the Korean version of the mini-mental state examination (MMSE-KC) for cognitive function and the short form of the Korea Geriatric Depression Scale for depressive www.nature.com/scientificreports/ symptoms. Nutritional status was evaluated using the Mini Nutritional Assessment. We adopted cut-off values of MMSE score (≤ 24) and gait speed (< 1.2 m/s) from previous research based on the association of mild cognitive impairment and survival in older adults with the phenotype of cognitive or physical frailty 28,29 . The frailty index was calculated based on CGA 30 . ADL, IADL, TUGT time, MMSE-KC, and albumin level were used. The frailty index is a continuous variable that ranges between 0 and 1; higher scores suggest increased frailty. The CHA 2 DS 2 -VASc and HAS-BLED scores were calculated based on the EHR. The use of anticoagulants or antiplatelet agents was also reviewed. We defined high risk CHA 2 DS 2 -VASc score as ≥ 2 in men or ≥ 3 in women and intermediate risk CHA 2 DS 2 -VASc score as 1 in men or 2 in women based on a previous study 31 . To assess baseline bleeding risk, the patients were evaluated for the HAS-BLED score, with > 3 defined as an elevated risk of bleeding 32 .
Statistical analysis. Data were reported as means with standard deviation or medians with IQR for continuous variables and counts with percentages for categorical variables. We used the chi-square test, Fisher's exact test, independent t-test, or Mann-Whitney U test to evaluate the associations between the CHA 2 DS 2 -VASc score, CGA variables, and brain MRI parameters. All statistical analyses were performed using SPSS version 21.0 (IBM, Armonk, NY, USA), and two-tailed p < 0.05 was considered significant.