Background Choline and betaine have been suggested to play a pivotal role in neurotransmitter synthesis, cell membrane integrity, and methyl-group metabolism, exerting neuroprotective effects in patients with various neurological disorders. However, population-based evidence on choline and betaine with subsequent cardiovascular events after stroke is rare. Objectives We aimed to prospectively investigate the relationships of circulating choline and betaine with cardiovascular events and recurrent stroke in patients with ischemic stroke. Methods We performed a nested case-control study within the China Antihypertensive Trial in Acute Ischemic Stroke. A total of 323 cardiovascular events (including 264 recurrent strokes) and 323 controls (free of recurrent cardiovascular events) matched for age (±1 y), sex, and treatment group were included. The primary endpoint was a composite of cardiovascular events after ischemic stroke. Plasma choline and betaine were measured at baseline by ultra-high-performance LC-MS/MS. Conditional logistic regression models were applied, and discrimination, reclassification, and calibration of models with choline pathway metabolites were evaluated. Results Plasma choline and betaine were inversely associated with cardiovascular events and recurrent stroke after ischemic stroke. Specifically, in fully adjusted models, each additional SD of choline and betaine was associated with 35% (95% CI: 20%–48%) and 30% (95% CI: 14%–43%) decreased risks of subsequent cardiovascular events, respectively, and 34% (95% CI: 16%–48%) and 29% (95% CI: 12%–43%) decreased risks of recurrent stroke, respectively. In addition, both choline and betaine offered substantial risk discrimination and reclassification improvement for cardiovascular events and recurrent stroke beyond traditional risk factors, as evidenced by an increase in C statistics, the net reclassification index, and integrated discrimination improvement. Conclusions Plasma choline pathway metabolites, including choline and betaine, were associated with decreased risks of cardiovascular events and recurrent stroke and provided incremental value in risk discrimination and stratification in patients with ischemic stroke. This nested case-control study was based on the China Antihypertensive Trial in Acute Ischemic Stroke, which is registered at clinicaltrials.gov as NCT01840072.
Background: DPP4 (dipeptidyl peptidase-4) inhibitors have been proven to promote neuronal regeneration, reverse the development of cognitive deficits. However, the association of circulating soluble form (sDPP4 [soluble DPP4]) with poststroke cognitive impairment (PSCI) is unclear. We aimed to investigate the association between plasma sDPP4 levels and PSCI in patients with ischemic stroke. Methods: A total of 600 noncardioembolic stroke patients were included based on a preplanned ancillary study from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Montreal Cognitive Assessment to evaluate cognitive function at 3 months follow-up after ischemic stroke. Binary logistic regression analyses were performed to investigate the association of plasma sDPP4 levels with subsequent PSCI. We further calculated integrated discrimination improvement and category-free net reclassification improvement to investigate the incremental prognostic effect of plasma sDPP4 beyond the basic model with conventional risk factors. Results: Plasma sDPP4 was inversely associated with PSCI after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartile of sDPP4 was 0.49 (0.29–0.81; P for trend=0.011). Each 1-SD increase of logarithm-transformed plasma sDPP4 concentration was associated with 17% (odds ratio, 0.83 [95% CI, 0.70–0.99]) lower risk of PSCI. Adding plasma sDPP4 to the basic model notably improved risk reclassification for PSCI, as shown by a category-free net reclassification improvement of 19.10% (95% CI, 2.52%–35.68%; P =0.03) and integrated discrimination improvement of 0.79% (95% CI, 0.13%–1.46%; P =0.02). Conclusions: Higher plasma sDPP4 levels were associated with decreased risk of cognitive impairment after noncardioembolic ischemic stroke.
Background and purpose Choline pathway nutrients, including choline and betaine, are reported to exert antidepressant effects. However, there is little population‐based evidence on the relationships between circulating choline and betaine and poststroke depression (PSD). We aimed to prospectively explore the associations between plasma choline and betaine and depression after ischemic stroke. Methods This study was based on the China Antihypertensive Trial in Acute Ischemic Stroke. A total of 612 participants with plasma choline and betaine concentrations were included in the analysis. The study outcome was depression 3 months after ischemic stroke. Logistic regression models were performed to estimate the relationships between plasma choline and betaine and the risk of PSD. Risk reclassification and calibration of models with choline or betaine were analyzed. Results Patients with PSD had lower choline and betaine levels than those without PSD (p < 0.05). Compared with tertile 1, the multivariable‐adjusted odds ratios (95% CIs) for tertile 3 of choline and betaine were 0.54 (0.35–0.83) and 0.59 (0.38–0.92), respectively. Per 1 SD increase in choline or betaine was associated with a 25% (95% CI 9%–37%) or an 19% (95% CI 3%–32%) decreased risk of PSD, respectively. Furthermore, the addition of choline or betaine to the established risk factors model improved the risk reclassification for PSD, as shown by an increase in the net reclassification index and integrated discrimination improvement (all p < 0.05). Conclusions Patients with elevated levels of choline and betaine had a lower risk of depression after acute ischemic stroke, suggesting the protective significance of choline pathway nutrients for PSD.
Background: Clinically significant changes in neurological deficits frequently occur after stroke onset, reflecting further neurological injury, or neurological improvement. However, the NIH stroke scale (NIHSS) score is only evaluated once in most studies only, usually at stroke onset. Utilizing repeated measures of NIHSS scores to identify different trajectories of neurological function may be more informative, and provide more useful predictive information. We determined the association of neurological function trajectories with long-term clinical outcomes after ischemic stroke. Methods: A total of 4025 participants with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke were included. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. A group-based trajectory model was used to identify distinct neurological function trajectories, as measured by NIHSS at admission, 14 days or hospital discharge, and 3 months. Study outcomes were cardiovascular events, recurrent stroke, and all-cause mortality during 3–24 months after ischemic stroke onset. Cox proportional hazards models were used to examine associations of neurological function trajectories with outcomes. Results: We identified 3 distinct subgroups of NIHSS trajectories: persistent severe (persistent high NIHSS scores during the 3-month follow-up), moderate (NIHSS scores started at around 5 and gradually reduced), and mild (NIHSS scores always below 2). The three trajectory groups had different clinical profiles, and different risk of stroke outcomes at 24-month follow-up. Compared to the mild trajectory group, patients in the persistent severe trajectory group had a higher risk of cardiovascular events (multivariable-adjusted hazard ratios (95% CIs) 1.77 (1.10–2.86)), recurrent stroke (1.82 (1.10–3.00)) and all-cause mortality (5.64 (3.37–9.43)) Those with moderate trajectory had an intermediate risk; 1.45 (1.03–2.04) for cardiovascular events and 1.52 (1.06–2.19) for recurrent stroke. Conclusions: Longitudinal neurological function trajectories derived from repeated NIHSS measurements during the first 3 months after stroke, provide additional predictive information and are associated with long-term clinical outcomes. The trajectories characterized by persistent severe and moderate neurological impairment were associated with increased risk of subsequent cardiovascular events.
BackgroundThe homeostatic chemokines CCL19 and CCL21 are involved in carotid plaque vulnerability and post‐ischemic neuroinflammatory responses. This study aimed to examine the prognostic values of CCL19 and CCL21 in ischemic stroke.MethodsPlasma CCL19 and CCL21 were measured in 4483 ischemic stroke patients from two independent cohorts of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) and IIPAIS (Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke), and participants were followed up at 3 months after stroke. The primary outcome was the composite outcome of death or major disability. The associations of CCL19 and CCL21 levels with the primary outcome were examined.ResultsIn CATIS, multivariable‐adjusted odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 compared with the lowest quartiles were 2.06 and 2.62, respectively. In IIPAIS, odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 were 2.81 and 2.78 compared with the lowest quartiles, respectively. In the pooled analysis of the two cohorts, odds ratios of the primary outcome associated with the highest quartiles of CCL19 and CCL21 were 2.24 and 2.66, respectively. Similar findings were observed in the analysis with major disability, death, and the composite outcome of death or cardiovascular events as the secondary study outcomes. Adding CCL19 and CCL21 to conventional risk factors significantly improved risk reclassification and discrimination for adverse outcomes.ConclusionsBoth CCL19 and CCL21 levels were independently associated with adverse outcomes within 3 months after ischemic stroke and should be further investigated for risk stratification and potential therapeutic targets of ischemic stroke.
Background and ObjectivesRecent studies have suggested that plasma soluble dipeptidyl peptidase-4 (sDPP4) have important physiological effects, which may influence the prognosis of ischemic stroke. Our study aimed to examine the relationship between plasma sDDP4 levels and long-term clinical outcomes among acute ischemic stroke patients.MethodsSecondary analysis was conducted among 3,564 participants (2,270 men and 1,294 women) from the China Antihypertensive Trial in Acute Ischemic Stroke with baseline measurement of plasma sDPP4 levels. We evaluated the associations between plasma sDPP4 levels and 2-year clinical outcomes using logistic regression and Cox regression models. We further investigated the predictive utility of sDPP4 by calculating net reclassification index (NRI) and integrated discrimination improvement (IDI).ResultsThe highest plasma sDPP4 quartile was associated with lower risk of cardiovascular events (HR 0.62, 95% CI 0.45-0.87), recurrent stroke (HR 0.70, 95% CI 0.49-0.99), all-cause mortality (HR 0.62, 95% CI 0.44-0.87), stroke-specific mortality (HR 0.65, 95% CI 0.44-0.94) and poor functional outcomes (OR 0.66, 95% CI 0.53-0.82) at 2 years compared with the lowest sDPP4 category in multivariable models. The addition of plasma sDPP4 to conventional risk factors model significantly improved risk prediction of all outcomes.DiscussionIn this study, we found that higher plasma sDPP4 levels in acute ischemic stroke patients were associated with decreased risks of cardiovascular events, recurrent stroke, all-cause mortality, and poor functional outcomes after ischemic stroke. These findings suggest that plasma sDPP4 may be a potential prognostic marker for initial risk stratification in patients with acute ischemic stroke.
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