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Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

ABSTRACT: Collagen type IV alpha1 (COL4A1) and alpha2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases, including cerebral microbleeds, porencephaly, and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown, and there is a lack of effective treatment.Using Col4a1 and Col4a2 mutant mouse models, we investigated the genetic complexity and cellular mechanisms underlying the disease. We found that Col4a1 mutations cause abnormal vascular development, which triggers small-vessel disease, recurrent hemorrhagic strokes, and age-related macroangiopathy. We showed that allelic heterogeneity, genetic context, and environmental factors such as intense exercise or anticoagulant medication modulated disease severity and contributed to phenotypic heterogeneity. We found that intracellular accumulation of mutant collagen in vascular endothelial cells and pericytes was a key triggering factor of ICH. Finally, we showed that treatment of mutant mice with a US Food and Drug Administration-approved chemical chaperone resulted in a decreased collagen intracellular accumulation and a significant reduction in ICH severity.Our data are the first to show therapeutic prevention in vivo of ICH resulting from Col4a1 mutation and imply that a mechanism-based therapy promoting protein folding might also prevent ICH in patients with COL4A1 and COL4A2 mutations.

SUBMITTER: Jeanne M

PROVIDER: S-EPMC4497509 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

Jeanne Marion M Jorgensen Jeff J Gould Douglas B DB

Circulation 20150309 18

<h4>Background</h4>Collagen type IV alpha1 (COL4A1) and alpha2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases, including cerebral microbleeds, porencephaly, and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown, and there is a lack of effective treatment.<h4>Methods and results</h4>Using Col4a1 and Col4a2 mutant mouse models, we ...[more]

PMID: 25753534

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Project description:ImportanceLimited evidence is available concerning optimal seizure prophylaxis after spontaneous intracerebral hemorrhage (sICH).ObjectiveTo evaluate which of 4 seizure prophylaxis strategies provides the greatest net benefit for patients with sICH.Design, setting, and participantsThis decision analysis used models to simulate the following 4 common scenarios: (1) a 60-year-old man with low risk of early (≤7 days after stroke) (10%) and late (3.6% or 9.8%) seizures and average risk of short- (9%) and long-term (30%) adverse drug reaction (ADR); (2) an 80-year-old woman with low risk of early (10%) and late (3.6% or 9.8%) seizures and high short- (24%) and long-term (80%) ADR risks; (3) a 55-year-old man with high risk of early (19%) and late (34.8% or 46.2%) seizures and low short- (9%) and long-term (30%) ADR risks; and (4) a 45-year-old woman with high risk of early (19%) and late (34.8% or 46.2%) seizures and high short- (18%) and long-term (60%) ADR risks.InterventionsThe following 4 antiseizure drug strategies were included: (1) conservative, consisting of short-term (7-day) secondary early-seizure prophylaxis with long-term therapy after late seizure; (2) moderate, consisting of long-term secondary early-seizure prophylaxis or late-seizure therapy; (3) aggressive, consisting of long-term primary prophylaxis; and (4) risk guided, consisting of short-term secondary early-seizure prophylaxis among low-risk patients (2HELPS2B score, 0), short-term primary prophylaxis among patients at higher risk (2HELPS2B score, ≥1), and long-term secondary therapy for late seizure.Main outcomes and measuresQuality-adjusted life-years (QALYs).ResultsFor scenario 1, the risk-guided strategy (8.13 QALYs) was preferred over the conservative (8.08 QALYs), moderate (8.07 QALYs), and aggressive (7.88 QALYs) strategies. For scenario 2, the conservative strategy (2.18 QALYs) was preferred over the risk-guided (2.17 QALYs), moderate (2.09 QALYs), and aggressive (1.15 QALYs) strategies. For scenario 3, the aggressive strategy (9.21 QALYs) was preferred over the risk-guided (8.98 QALYs), moderate (8.93 QALYs), and conservative (8.77 QALYs) strategies. For scenario 4, the risk-guided strategy (11.53 QALYs) was preferred over the conservative (11.23 QALYs), moderate (10.93 QALYs), and aggressive (8.08 QALYs) strategies. Sensitivity analyses suggested that short-term strategies (conservative and risk guided) are preferred under most scenarios, and the risk-guided strategy performs comparably to or better than alternative strategies in most settings.Conclusions and relevanceThis decision analytical model suggests that short-term (7-day) prophylaxis dominates longer-term therapy after sICH. Use of the 2HELPS2B score to guide clinical decisions for initiation of short-term primary vs secondary early-seizure prophylaxis should be considered for all patients after sICH.

Project description:PurposeWe develop a new risk score to predict patients with stroke-associated pneumonia (SAP) who have an acute intracranial hemorrhage (ICH).MethodWe applied logistic regression to develop a new risk score called ICH-LR2S2. It was derived from examining a dataset of 70,540 ICH patients between 2015 and 2018 from the Chinese Stroke Center Alliance (CSCA). During the training of ICH-LR2S2, patients were randomly divided into two groups - 80% for the training set and 20% for model validation. A prospective test set was developed using 12,523 patients recruited in 2019. To further verify its effectiveness, we tested ICH-LR2S2 on an external dataset of 24,860 patients from the China National Stroke Registration Management System II (CNSR II). The performance of ICH-LR2S2 was measured by the area under the receiver operating characteristic curve (AUROC).ResultsThe incidence of SAP in the dataset was 25.52%. A 24-point ICH-LR2S2 was developed from independent predictors, including age, modified Rankin Scale, fasting blood glucose, National Institutes of Health Stroke Scale admission score, Glasgow Coma Scale score, C-reactive protein, dysphagia, Chronic Obstructive Pulmonary Disease, and current smoking. The results showed that ICH-LR2S2 achieved an AUC = 0.749 [95% CI 0.739-0.759], which outperforms the best baseline ICH-APS (AUC = 0.704) [95% CI 0.694-0.714]. Compared with the previous ICH risk scores, ICH-LR2S2 incorporates fasting blood glucose and C-reactive protein, improving its discriminative ability. Machine learning methods such as XGboost (AUC = 0.772) [95% CI 0.762-0.782] can further improve our prediction performance. It also performed well when further validated by the external independent cohort of patients (n = 24,860), ICH-LR2S2 AUC = 0.784 [95% CI 0.774-0.794].ConclusionICH-LR2S2 accurately distinguishes SAP patients based on easily available clinical features. It can help identify high-risk patients in the early stages of diseases.

Project description:BackgroundGiven an ageing population the incidence of both patients suffering from intracerebral hemorrhage (ICH) and those requiring oral anticoagulation will increase. Up to now there are no results from randomized trials available whether or not, and when, ICH survivors should resume OAC. This review summarizes the most important observational studies, and initiated ongoing trials, to help guiding physicians in daily routine decision making.FindingsSeveral large observational studies and meta-analyses verified that OAC resumption was associated with a significant reduction of thromboembolic complications and mortality without leading to increased rates of recurrent ICH. OAC resumption seemed further associated with improved functional recovery and favorable long-term outcome. Given the general bleeding risk reduction in patients using Non-vitamin K antagonist oral anticoagulants (NOAC) compared to Vitamin-K-antagonist (VKA), NOAC use should also be preferred after ICH, although specific comparative studies are pending. Patients with lobar ICH need special attention as these patients showed increased ICH recurrence rates, why decision making should include extended diagnostic work-up evaluating cerebral microbleed burden, cortical subarachnoid hemorrhage and superficial siderosis. Further, patients with mechanical heart valves need specific consideration as restarting VKA may be unsafe until two weeks, whereas optimal balancing of hemorrhagic with thromboembolic complications may allow earlier re-initiation one week after ICH. In patients with atrial fibrillation, resumption generally should take place between 4 and 8?weeks after ICH depending on a patient's individual risk profile. Left atrial appendage occlusion (LAAO) might represent an alternative strategy in high-risk patients. Ongoing clinical trials will clarify whether OAC resumption versus LAAO versus no antithrombotic therapy may represent the best possible secondary stroke prevention in ICH survivors with atrial fibrillation.ConclusionsAccording to observational data OAC resumption after ICH seems beneficial and safe. Ongoing clinical trials will create evidence regarding treatment effects of pharmaceutical resumption and interventional alternatives. Yet, individual decision making weighing the patient's individual thromboembolic versus hemorrhagic risks remains essential.

Dataset Information

Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

Publications

Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

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