Makoto Sasaki

BACKGROUND: To what extent cerebral small vessel disease (SVD) contributes to functional disability remains unclear. We investigated the longitudinal effect of SVD burden on functional decline. METHODS: In this investigator-initiated, prospective, multicenter, and observational study, patients receiving oral antithrombotic therapy for cerebrovascular or cardiovascular diseases were enrolled from 52 hospitals across Japan (2016–2019) and followed for 24 months. SVD score (range, 0–4) was calculated on baseline magnetic resonance imaging obtained under prespecified conditions. The outcomes were an increase in modified Rankin Scale (mRS) score from baseline to end of follow-up (ΔmRS score ≥1). Logistic regression evaluated the association between ΔmRS score ≥1 and SVD score, adjusting for age, sex, premorbid mRS, vascular risk factors, antithrombotic therapy, magnetic resonance imaging field strength, and bleeding or ischemic events during follow-up. Bleeding and ischemic events were treated as time-dependent covariates. Causal mediation analyses using a 4-way decomposition separated the effects of SVD score ≥3 on ΔmRS score ≥1 into direct and indirect effects (mediated by major bleeding or ischemic events). RESULTS: Of 5378 patients enrolled, 613 were excluded mainly due to the lack of clinical or imaging data. Finally, 4765 patients were analyzed (1573 women; median age, 73 years); ΔmRS score ≥1 was observed in 13.2% of patients with SVD score 0, 16.1% with 1, 20.7% with 2, 28.1% with 3, and 28.2% with 4. SVD score of 3 (adjusted odds ratio, 1.65 [95% CI, 1.27–2.15]) and SVD score of 4 (1.62 [95% CI, 1.19–2.19]) were associated with ΔmRS score ≥1 compared with SVD score of 0. Causal mediation analysis indicated that 73.05% of the total effect of SVD score ≥3 on ΔmRS score ≥1 was attributed to the controlled direct effect (coefficient, 0.497 [95% CI, 0.26–0.73]). CONCLUSIONS: SVD burden was associated with functional decline beyond significant bleeding or ischemic events.

BACKGROUND: Defining the risk of developing major bleeding, especially intracranial hemorrhage (ICH), or ischemic stroke (IS) in patients receiving antithrombotic therapy is crucial. Existing risk prediction tools would inadequately assess the net clinical benefit of antithrombotic therapy. We aimed to develop novel risk scores incorporating covert vascular brain injury to personalize the risk assessment of major bleeding, ICH, and IS in patients receiving antithrombotic therapy. METHODS: The prospective, multicenter, observational study (BAT2 [Bleeding With Antithrombotic Therapy Study-2]) enrolled patients receiving oral antiplatelets or anticoagulants from 52 hospitals across Japan between 2016 and 2019. Multimodal brain magnetic resonance imaging was performed at baseline under prespecified conditions to determine cerebral small vessel disease (white matter hyperintensity, cerebral microbleed, lacune, enlarged perivascular space, and cortical superficial siderosis), nonlacunar infarct, and intracranial artery disease with central reading. Risk scores, collectively termed the BAT2 scores, were developed separately to evaluate the comparative risks of (1) major bleeding, (2) ICH, and (3) IS based on covariates from Cox proportional hazards models and clinical relevance. Model performance was assessed with the Harrell C-index and calibration slope adjusted for optimism via bootstrapping. RESULTS: Of 5378 patients enrolled, 5250 were analyzed (mean age, 71±11 years, 33% women); 93 experienced major bleeding, including 55 had ICH, and 197 had IS during a median follow-up of 2.0 years. Predictors for bleeding included age, underweight, renal impairment, hypertension, cerebral microbleed, lacune, and antithrombotic treatment type. Predictors for ICH further included deep white matter hyperintensity but not renal impairment. For IS, predictors included age, renal impairment, diabetes, atrial fibrillation, lacune, cerebral microbleed, nonlacunar infarct, and intracranial artery disease. Prediction performance showed optimism-adjusted C-index and calibration slope of 0.69 (95% CI, 0.64–0.74) and 0.82 (95% CI, 0.62–1.06) for bleeding, 0.75 (95% CI, 0.67–0.80) and 0.80 (95% CI, 0.56–1.02) for ICH, and 0.64 (95% CI, 0.60–0.68) and 0.92 (95% CI, 0.73–1.18) for IS. CONCLUSIONS: The BAT2 scores may help optimize the balance between risks and benefits of antithrombotic therapy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02889653. URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000023669.

BACKGROUND AND PURPOSE: Post-carotid endarterectomy (CEA) cerebral hyperperfusion (CH) can cause intracerebral hemorrhage and cognitive decline. Alterations in susceptibility in response to acetazolamide (ACZ) on 7T MRI quantitative susceptibility mapping (QSM) detects elevated CBV occurring due to impaired cerebrovascular autoregulation. We explored preoperative relative susceptibility changes on 7T MRI QSM in response to ACZ and their ability to predict CH following CEA. MATERIALS AND METHODS: Sixty-three patients with uni-or bilateral cervical ICA stenosis ≥70% underwent 7T MRI at baseline and at 5, 10, 15, and 20 min after ACZ administration before surgery. The difference between the susceptibility of venous structures and surrounding brain parenchyma at each time point after ACZ administration relative to the difference at baseline (relative susceptibility difference; RSD) on QSM images was calculated in the cerebral hemisphere ipsilateral to surgery. Brain perfusion SPECT was conducted preoperatively and immediately following CEA to detect postoperative CH (≥ 100% rise in CBF postoperatively). RESULTS: In nine patients with postoperative CH, RSD was significantly increased at 5 or 10 min following ACZ administration (p < 0.05) but reduced at 15 and 20 min (p < 0.05). In 54 patients without postoperative CH, RSD at all four time points after ACZ administration was significantly lower than the baseline value (p < 0.05). The area under the receiver operating characteristic curve to predict postoperative CH was significantly greater in RSD₅ (0.981; 95% CI, 0.910–0.999) than in RSD₁₅ (0.872; 95% CI, 0.764–0.943) (p < 0.05) or RSD₂₀ (0.780; 95% CI, 0.658–0.874) (p < 0.01). Sensitivity, specificity, and positive and negative predictive values for RSD₅ at a cutoff near the left upper corner of the curve were 100%, 89%, 60%, and 100%, respectively. Logistic regression analysis revealed that only RSD₅ significantly predicted postoperative CH (95% CI, 455.9–4043.6; p < 0.05). CONCLUSIONS: Changes in susceptibility on preoperative 7T MRI QSM following ACZ administration predict CH following CEA. Patients with increased RSD₅ on pre-CEA 7T MRI QSM following ACZ administration should undergo brain perfusion imaging immediately after surgery. Detection of CH on postoperative brain perfusion imaging warrants intensive blood pressure control. ABBREVIATIONS: CEA= carotid endarterectomy; CH= cerebral hyperperfusion; OEF= oxygen extraction fraction; ACZ= acetazolamide; QSM =quantitative susceptibility mapping; 3D =three-dimensional; RSD=relative susceptibility difference; SD= standard deviation; ROC =receiver operating characteristic.

BACKGROUND: Restenosis after carotid artery stenting (CAS) is associated with the risk of developing ischemic stroke. We aimed to evaluate the inhibitory effect of cilostazol addition on in-stent restenosis (ISR) in patients treated with CAS. METHODS: In a randomized, open-label, blind-end point trial, patients with symptomatic and asymptomatic carotid artery stenosis and scheduled for CAS were randomly assigned to adding cilostazol (50 or 100 mg, twice per day) on other antiplatelets from 3 days before CAS or not adding cilostazol. Concomitant use of other antiplatelets was unrestricted. ISR was diagnosed by a peak systolic velocity of at least 1.75 m/s on duplex ultrasonography. The primary outcome was incidence of ISR within 2 years after CAS. Secondary outcomes included occurrences of cardiovascular events or any death and hemorrhagic events. RESULTS: Participants were recruited from December 2010 to September 2015. Although the sample size was initially set to be 900 (450 in each group), 631 patients (mean age 69.9 years, 558 men, 325 in the cilostazol, and 306 in the noncilostazol group) were included in the primary analysis. Within 2 years’ follow-up, ISR occurred in 31 of 325 patients (cumulative incidence 10.8%) in the cilostazol group and 46 of 306 patients (19.6%) in the noncilostazol group (hazard ratio, 0.64 [95% CI, 0.41–1.0]; P =0.056). In the exploratory analysis, incidence of ISR beyond 30 days after CAS was lower in the cilostazol group than in the noncilostazol group (10.3% versus 19.3%; P =0.040). Incidences of cardiovascular events or any death and hemorrhagic events were similar between the groups (6.2% versus 6.7% and 2.3% versus 1.4%, respectively). CONCLUSIONS: The addition of cilostazol to other antiplatelet agents could contribute to the reduction of ISR in the chronic stage of patients who underwent CAS, the authenticity of which depends on further studies with sufficient statistical power. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01261234.

Obesity and overweight, fundamental components of the metabolic syndrome, predispose individuals to lifestyle-related diseases. The extent to which adopting healthy lifestyles can reduce obesity risk, even in those with a high genetic risk, remains uncertain. Our aim was to assess the extent to which lifestyle modifications can improve outcomes in individuals with a high polygenic score (PGS) for obesity. We quantified the genetic risk of obesity using PGSs. Four datasets from the Tohoku Medical Megabank Community-Based Cohort (TMM CommCohort) were employed in the study. One dataset (n = 9958) was used to select the best model for calculating PGS. The remaining datasets (total n = 69,341) were used in a meta-analysis to validate the model and to evaluate associated risks. The odds ratio (OR) for obesity risk in the intermediate (11th–90th percentiles in the dataset) and high PGS categories (91st–100th) was 2.27 [95% confidence intervals: 2.12–2.44] and 4.83 [4.45–5.25], respectively, compared to that in the low PGS category (1st–10th). Trend analysis showed that an increase in leisure-time physical activity was significantly associated with reduced obesity risk across all genetic risk categories, representing an OR of 0.9 [0.87–0.94] even among individuals in the high PGS category. Similarly, sodium intake displayed a positive association with obesity across all genetic risk categories, yielding an OR of 1.24 [1.17–1.31] in the high PGS category. The risk of obesity was linked to the adoption of healthy lifestyles, even in individuals with high PGS. Our results may provide perspectives for integrating PGSs into preventive medicine.

Quantitative susceptibility mapping (QSM) has been proposed to assess intraplaque hemorrhage (IPH) in the carotid artery. The purpose of this study was to compare the diagnostic accuracy of preoperative QSM with that of the conventional T1-weighed (T1W) three-dimensional (3D)-FSE sequence for detecting IPH in cervical ICA stenosis in patients undergoing carotid endarterectomy (CEA) using histology as the reference standard. Carotid T1W 3D-FSE and QSM images were obtained from 16 patients with cervical ICA stenosis before CEA. Relative signal intensity (RSI) and susceptibility of the ICA were measured on three axial images including the location of most severe stenosis on T1W 3D-FSE and QSM images, respectively. Three transverse sections of carotid plaques excised by CEA, which corresponded with images on MRI, were stained with H&E, antibody against glycophorin A and Prussian blue, and the relative area (RA) of histologic IPH was calculated. The correlation coefficient was significantly greater between susceptibility and RA-histologic IPH (ρ = 0.691) than between RSI and RA-histologic IPH (ρ = 0.413; P = .0259). The areas under the receiver operating characteristic curves for detecting histologic sections consisting primarily of IPH (RA-histologic IPH > 40.7%) tended to be greater for susceptibility (0.964) than for T1WI FSE-RSI (0.811). Marginal homogeneity was observed between susceptibility and histologic sections consisting primarily of IPH (P = .0412) but not between T1W FSE-RSI and histologic sections consisting primarily of IPH (P = .1824). Pre-CEA QSM detects histologic IPH in cervical ICA stenosis more accurately than preoperative T1W 3D-FSE imaging. QSM = quantitative susceptibility mapping; IPH = intraplaque hemorrhage; T1W = T1-weighed; 3D = three-dimensional; CEA = carotid endarterectomy; RSI = relative signal intensity; RA = relative area.

Background and Purpose Plaque composition, but not stenosis degree, may play a key role in the development of recurrent ischemic events in patients with symptomatic, mild (Methods This study included 124 patients with cerebrovascular or retinal ischemic events ipsilateral to mild carotid stenosis. Best medical therapy (BMT) was administered to all participants. CEA or carotid artery stenting (CAS) was implemented at each institution’s discretion. Baseline and 6-, 12-, and 24-month follow-up data were collected. Primary endpoint was ipsilateral ischemic stroke. Secondary endpoints included any stroke, ipsilateral TIA, ipsilateral ocular symptoms, any death, and plaque progression requiring CEA/CAS. Multivariate Cox proportional hazard model was used to evaluate the predictors for each endpoint. Results Of 124 patients, 70 patients (56.5%) had the history of ipsilateral ischemic stroke and 51 (43.5%) had been treated with antiplatelet agents. Mean stenosis degree was 22.4±13.7%. Plaque composition was categorized into fibrous plaque in 22 patients, lipid-rich/necrotic core (LR/NC) in 25, and intraplaque hemorrhage (IPH) in 69. BMT was indicated for 59 patients, while CEA was performed in 63. The incidence of primary endpoint was significantly higher in BMT group than in CEA group (15.1% vs. 1.7%; HR, 0.18; 95%CI, 0.05–0.84; P=0.03). The predictors for ipsilateral ischemic stroke were CEA (HR, 0.18; 95%CI, 0.05–0.84; P=0.03) and IPH (HR, 1.92; 95%CI, 1.26–4.28; P=0.04). The results on secondary endpoints were very similar. Conclusion IPH may highly predict subsequent cerebrovascular events, whereas CEA may reduce these risk during a 2-year follow-up in patients with symptomatic, mild carotid stenosis. Registration This study has been registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (UMIN000023635). Contributors SK, KO, UM, and MS designed the study. DK wrote an original draft. All authors recruited patients. DK, KC, KY, KY, MM, SY, SM, KO, MU, MS, and SK analyzed the imaging data as the members of Central Judgement Committee and contributed to data analysis. SK takes final responsibility for the submitted publication.

Genetic testing is key in modern healthcare, particularly for monogenic disorders such as familial hypercholesterolemia. This Tohoku Medical Megabank Project study explored the impact of first-degree relatives’ dyslipidemia history on individual responses to familial hypercholesterolemia genomic results. Involving 214 participants and using Japan’s 3.5KJPN genome reference panel, the study assessed preferences and intentions regarding familial hypercholesterolemia genetic testing results. The data revealed a significant inclination among participants with a family history of dyslipidemia to share their genetic test results, with more than 80% of participants intending to share positive results with their partners and children and 98.1% acknowledging the usefulness of positive results for personal health management. The study underscores the importance of family health history in genetic-testing perceptions, highlighting the need for family-centered approaches in genetic counseling and healthcare. Notable study limitations include the regional scope and reliance on questionnaire data. The study results emphasize the association between family health history and genetic-testing attitudes and decisions.