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Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

ABSTRACT: Background:Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies. Key hypotheses/aims:(1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions. Design:Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case-control study enrolling patients aged 18-49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient-control pairs enrolled by the end of 2018. Summary:SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019.

SUBMITTER: Putaala J

PROVIDER: S-EPMC6453214 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

Putaala Jukka J Martinez-Majander Nicolas N Saeed Sahrai S Yesilot Nilufer N Jäkälä Pekka P Nerg Ossi O Tsivgoulis Georgios G Numminen Heikki H Gordin Daniel D von Sarnowski Bettina B Waje-Andreassen Ulrike U Ylikotila Pauli P Roine Risto O RO Zedde Marialuisa M Huhtakangas Juha J Fonseca Catarina C Redfors Petra P de Leeuw Frank-Erik FE Pezzini Alessandro A Kõrv Janika J Schneider Siim S Tanislav Christian C Enzinger Christian C Jatuzis Dalius D Siegerink Bob B Martínez-Sánchez Patricia P Grau Armin J AJ Palm Frederick F Groop Per-Henrik PH Lanthier Sylvain S Ten Cate Hugo H Pussinen Pirkko P Paju Susanna S Sinisalo Juha J Lehto Mika M Lindgren Arne A Ferro José J Kittner Steven S Fazekas Franz F Gerdts Eva E Tatlisumak Turgut T

European stroke journal 20170404 2

<h4>Background</h4>Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies.<h4>Key hypotheses/aims</h4>(1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-a ...[more]

PMID: 31008307

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Project description:BackgroundThe prevalence of stroke in young adults is increasing. We investigated the monogenic basis of young adult cryptogenic stroke patients.MethodsThis multicenter study enrolled cryptogenic stroke patients under 55 years old, and individuals with nonstroke diseases were included as controls. Targeted next-generation sequencing (NGS) was applied with a custom-designed gene panel that included 551 genes. Rare variants were classified into 2 groups: pathogenic variants and variants of unknown significance.ResultsA total of 153 individuals, including 30 (21 males, 70%; mean age 36.1±10.2 years) in the disease group and 123 (59 males, 48.0%; mean age 40.4±13.1 years) in the control group, were recruited. In the disease group, 32 rare variants were identified. Among these individuals, 18 pathogenic variants in 16 patients were detected, with a 53.3% (16/30) diagnostic yield of monogenic causes for cryptogenic stroke. None of these mutations were observed in the control group. Among the mutant genes, the most prevalent were Notch receptor 3 (NOTCH3), protein kinase AMP-activated noncatalytic subunit gamma 2 (PRKAG2), and ryanodine receptor 2 (RYR2). Genes associated with cardiogenic diseases showed the highest mutation frequency (10/18, 55.6%) followed by genes associated with small-vessel diseases (SVDs) and coagulation disorders. None of the patients with mutations had evident abnormalities in the heart or other systems checked by routine tests. For the imaging phenotype-genotype association analysis, infarctions in both the anterior and posterior cerebral circulation were only observed in patients with genes related to cardiogenic disease.ConclusionsIn this study, pathogenic variants were identified in nearly half of the young-onset cryptogenic stroke patients, with genes related to cardiogenic diseases being the most frequently mutated. This may have implications for future clinical decision-making, including the development of finer and more sensitive examinations.

Project description:Acute Ischemic Stroke (AIS) in the young is increasing in prevalence and the largest subtype within this cohort is cryptogenic. To curb this trend, new ways of defining cryptogenic stroke and associated risk factors are needed. We aimed to gain insights into the presence or absence of cardiovascular risk factors in cases of cryptogenic stroke. We conducted a retrospective cohort study of patients aged 18-49 who presented to an urban tertiary care center with AIS. We manually collected predefined demographic, clinical, laboratory and radiological variables. Clinical risk phenotypes were determined using these variables through multivariate analysis of patients with the small and large vessel disease subtypes (vascular phenotype) and cardioembolic subtype (cardiac phenotype). The resultant phenotype models were applied to cases deemed cryptogenic. Within the 449 patients who met criteria, patients with small and large vessel disease (vascular phenotype) had higher rates of hypertension, intracranial atherosclerosis, and diabetes mellitus, and higher admission glucose, HbA1c, admission blood pressure, and cholesterol compared to the patients with cardioembolic AIS. The cardioembolic subgroup (cardiac phenotype) had significantly higher rates of congestive heart failure (CHF), rheumatic heart disease, atrial fibrillation, clotting disorders, left ventricular hypertrophy, larger left atrial sizes, lower ejection fractions, and higher B-type natriuretic peptide and troponin levels. Adjusted multivariate analysis produced six variables independently associated with the vascular phenotype (age, male sex, hemoglobin A1c, ejection fraction (EF), low-density lipoprotein (LDL) cholesterol, and family history of AIS) and five independently associated with the cardiac phenotype (age, female sex, decreased EF, CHF, and absence of intracranial atherosclerosis). Applying these models to cryptogenic stroke cases yielded that 51.5% fit the vascular phenotype and 3.1% fit the cardiac phenotype. In our cohort, half of young patients with cryptogenic stroke fit the risk factor phenotype of small and large vessel strokes.

Dataset Information

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

Publications

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

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