Our Efforts for Ideal Stroke Prevention and Treatment in Japan

In the present short review for the Sherman Award, Dr Yamaguchi introduces studies at the National Cerebral and Cardiovascular Center, Osaka, which included development of intravenous thrombolysis using low-dose alteplase that was officially approved in Japan, long-term dual antiplatelet therapy using cilostazol together with aspirin or clopidogrel, and others. He also discusses efforts to ensure the passage of the “Stroke and Cardiovascular Disease Control Act,” the aims of which are better primary prevention, better acute treatment, rehabilitation, and secondary prevention of stroke for people living in Japan.

Regulation of Serotonin 1A Receptor SUMOylation by SENP2 and PIASxα

Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety. As such, understanding the regulation of 5-HT1ARs will inform the development of better treatment approaches. We previously demonstrated 5-HT1ARs are SUMOylated by SUMO1 in the rat brain. Agonist stimulation increased SUMOylation and was further enhanced when combined with 17β-estradiol-3-benzoate (EB), which are treatments that cause the transient and prolonged desensitization of 5-HT1AR signaling, respectively. In the current study, we identified the protein inhibitor of activated STAT (PIAS)xα as the enzyme that facilitates SUMOylation, and SENP2 as the protein that catalyzes the deSUMOylation of 5-HT1ARs. We demonstrated that PIASxα significantly increased in the membrane fraction of rats co-treated with EB and an agonist, compared to either the EB-treated or vehicle-treated groups. The acute treatment with an agonist alone shifted the location of SENP2 from the membrane to the cytoplasmic fraction, but it has little effect on PIASxα. Hence, two separate mechanisms regulate SUMOylation and the activity of 5-HT1ARs by an agonist and EB. The effects of EB on 5-HT1AR SUMOylation and signaling may be related to the higher incidence of mood disorders in women during times with large fluctuations in estrogens. Targeting the SUMOylation of 5-HT1ARs could have important clinical relevance for the therapy for several neuropsychiatric disorders in which 5-HT1ARs are implicated.

Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression

Background Acute changes in glomerular filtration rate (GFR) can occur following initiation of interventions targeting progression of chronic kidney disease (CKD). These acute changes complicate the interpretation of long-term treatment effects. Methods To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression enrolling 56,413 participants with at least one estimated GFR measurement by 6 months following randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable meta-regression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. Results The mean acute effect across all studies was -0.21 mL/min per 1.73m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 mL/min per 1.73m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. Conclusion The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Premorbid frailty predicts short and long term outcomes of reperfusion treatment in acute stroke

Background: Frailty is the most important short and long term predictor of disability in the elderly and thus might influence the clinical outcome of acute treatment of stroke. Objective: to evaluate whether frailty predicts short- and long term all-cause mortality and neurological recovery in elderly patients who underwent reperfusion acute treatment of stroke. Methods: the study included consecutive patients older than 65 years who underwent reperfusion treatment in a single stroke Unit from 2015 to 2016. Predictors of stroke outcomes were assessed including demographics, baseline NIHSS, time to needle, treatment and medical complications. Premorbid Frailty was assessed with a comprehensive geriatric assessment (CGA) including functional, nutritional, cognitive, social and comorbidities status. At three and twelve months, all-cause death and clinical recovery (using modified Ranking scale, mRS) were evaluated. Results: One-hundred and two patients who underwent acute reperfusion treatment for stroke entered the study (mean age 77.5, 65- 94 years). Frailty was diagnosed in 32 out of 70 patients and associated with older age (p=0.001) but no differences in baseline NIHSS score, vascular risk profile or treatment management strategy. Frailty status was associated with worse improvement at 24 hours and higher in-hospital mortality. At follow-up, frail patients showed poorer survival at 3 (25% vs 3%, p=0.008) and 12 (38% vs 7%, p=0.001) months. Frailty was the best predictor of neurological recovery at one year follow-up (mRS 3.2 + 1.9 vs 1.9 + 1.9). Discussion: frailty is an important predictor of efficacy of acute treatment of stroke beyond classical predictors of stroke outcomes. Larger longitudinal studies are thus warranted in order to evaluate the risk-benefit of reperfusion treatment in the growing elderly frail population.