Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome

NCT ID: NCT01934725

Last Updated: 2025-05-16

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Total Enrollment: 1200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2031-12-31

Brief Summary

BACKGROUND: In industrialized countries a considerable and increasing proportion of strokes occur at younger ages. Stroke at young age causes marked disability at worst and thus long-standing socioeconomic consequences and exposes survivors for 4-fold risk of premature death compared with background population. Up to 50% of young patients with ischemic stroke remain without definitive etiology for their disease despite extensive modern diagnostic work-up (i.e. cryptogenic stroke). The group of cryptogenic strokes includes those with patent foramen ovale (PFO) or other abnormalities in the atrial septum in the heart as the only or concomitant finding. Population prevalence of PFO is high, 25%, and the mechanisms how PFO would be associated causally with ischemic stroke remain to be clarified. Moreover, there are only scarce data on clinical outcome, long-term risk of new vascular events, and prevention of such events in these patients.

DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO) is an international prospective multicenter case-control study of young adults (age 18-49) presenting with an imaging-positive first-ever ischemic stroke of undetermined etiology (aim N=2000). Patients are included after standardized diagnostic procedures (brain MRI, imaging of intracranial and extracranial vessels, cardiac imaging, and screening for coagulopathies) and age- and sex-matched to healthy controls in a 1:1 fashion. Up to 45 study sites worldwide will be needed to recruit the planned participant population during a 3-year period. Neurovascular imaging and echocardiography studies, and ECGs will be read centrally.

AIMS: SECRETO involves five principal fields of investigation: (1) Stroke triggers and clinical risk factors; (2) Long-term prognosis (new vascular events, functional and psychosocial outcomes); (3) Abnormalities of thrombosis and hemostasis; (4) Biomarkers of e.g. inflammation, atherogenesis, endothelial function, thrombosis, platelet activation, and hemodynamic stress to characterize postulated cryptogenic stroke mechanisms; and (5) genetic study, including genome-wide association and candidate gene studies as well as next-generation sequencing approach. All analyses consider cardiac functional and interatrial structural properties as a possible mediator. Furthermore, SECRETO Family Study (substudy) aims at collecting extensive family history of thrombotic events from informative patients being screened for SECRETO main study and collect genetic samples from all consenting family members for whole-genome sequencing.

SIGNIFICANCE: SECRETO will provide novel information on clinical and subclinical risk factors, both transient and chronic, predisposing to cryptogenic ischemic stroke in young adults. This study also reveals long-term prognosis of this understudied patient population and may discover new genetic background underlying the disease mechanism and provide potential targets for drug development.

Conditions

Brain Infarction; Ischemic Stroke; Thrombosis; Foramen Ovale, Patent

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

Patients w/ cryptogenic ischemic stroke

Patients aged 15 to 49 years with unexplained first-ever ischemic stroke

No interventions assigned to this group

Stroke-free control subjects

Stroke-free subjects age- and gender-matched to patients

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

1. Age 18 to 49 at stroke onset

2. Patient hospitalized due to first-ever imaging-positive ischemic stroke of undetermined etiology after complete timely diagnostic testing.

1. Age 18 to 49 years

2. Absence of prior ischemic stroke as ascertained using the Questionnaire for Verifying Stroke-Free Status

Exclusion Criterion:

1. Informed consent not obtained

Exclusion Criteria

1. Baseline mandatory tests not obtained in the first week following stroke onset, including:

• Brain MRI
• Routine blood tests, including complete blood count, CRP, fasting glucose, creatinine, aPTT, INR, total cholesterol, LDL-cholesterol, HDL-cholesterol, HbA1C, hemoglobin electrophoresis in individuals of African origin

2. Other baseline mandatory tests not obtained within the first two weeks following stroke onset, including:

• Imaging of cervicocephalic arteries by CTA, MRA, or DSA
• Transesophageal (highly recommended) or transthoracic echocardiography
• 24-hour Holter monitoring or continuous in-hospital ECG monitoring with automated arrhythmia detection for at least 24 hours
• Screening for thrombophilia, including antiphospholipid antibodies and other coagulopathies (any abnormal finding must be retested at mandatory 3-month follow-up visit >12 weeks from initial testing or >4 weeks after cessation of anticoagulation at any later time point); mandatory tests include anticardiolipin antibodies, lupus anticoagulant, anti-β2-glycoprotein antibodies, factor V mutation (or aPC resistency ruled out), factor II mutation, homocysteine, antithrombin III, protein C, and protein S

3. No evidence of current brain ischemia

4. Current stroke due to cerebral venous thrombosis or as a complication of subarachnoid hemorrhage, angiography, or cardiac surgery

5. Patient otherwise not eligible for the study or adherent for follow-up (eg nonresident) or has concurrent disease affecting outcome (eg multiple sclerosis, cancer)

6. Informed consent not obtained from the patient or a proxy.

CONTROL SUBJECTS:

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 49 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Finnish Medical Foundation

NETWORK

Sponsor Role: collaborator

Academy of Finland

OTHER

Sponsor Role: collaborator

Hospital District of Helsinki and Uusimaa

OTHER

Sponsor Role: collaborator

Hospital District of Southwestern Finland

OTHER

Sponsor Role: collaborator

Pirkanmaa Hospital District

UNKNOWN

Sponsor Role: collaborator

Hospital District of North Ostrobothnia

UNKNOWN

Sponsor Role: collaborator

Northern Savo Hospital District

OTHER

Sponsor Role: collaborator

Sahlgrenska University Hospital

OTHER

Sponsor Role: collaborator

Sigrid Jusélius Foundation

OTHER

Sponsor Role: collaborator

SECRETO Study Consortium

OTHER

Sponsor Role: lead

Responsible Party

Jukka Putaala

Associate Prof., MD, PhD, MSc

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jukka Putaala, A/Prof.

Role: PRINCIPAL_INVESTIGATOR

Helsinki University Central Hospital

Steven Kittner, Prof.

Role: PRINCIPAL_INVESTIGATOR

University of Maryland Hospital

Locations

Tartu University Hospital

Tartu, , Estonia

Helsinki University Central Hospital

Helsinki, , Finland

Kuopio University Hospital

Kuopio, , Finland

Oulu University Hospital

Oulu, , Finland

Tampere University Hospital

Tampere, , Finland

Turku University Central Hospital

Turku, , Finland

Ernst-Moritz-Arndt University Medicine

Greifswald, , Germany

"Attikon" Hospital, University of Athens, School of Medicine

Athens, , Greece

University of Brescia

Brescia, , Italy

Arcispedale S. Maria Nuova

Reggio Emilia, , Italy

Vilnius University Hospital Santariskiu klinikos

Vilnius, , Lithuania

Radboud University Nijmegen Medical Centre

Nijmegen, , Netherlands

Haukeland University Hospital

Bergen, , Norway

Hospital Santa Maria

Lisbon, , Portugal

Torrecárdenas University Hospital

Almería, , Spain

Sahlgrenska University Hospital

Gothenburg, , Sweden

Istanbul University Istanbul Faculty of Medecine

Istanbul, , Turkey (Türkiye)

Peterborough City Hospital

Peterborough, , United Kingdom

Royal Stoke University Hospital

Stoke-on-Trent, , United Kingdom

Countries

Estonia; Finland; Germany; Greece; Italy; Lithuania; Netherlands; Norway; Portugal; Spain; Sweden; Turkey (Türkiye); United Kingdom

References

Putaala J, Martinez-Majander N, Leppert M, Tulkki L, Pirinen J, Tolppanen H, Sarkanen T, Virtanen M, Jaakonmaki N, Jakala P, Hedman M, Redfors P, Bech-Hanssen O, Junttola U, Huhtakangas J, Ylikotila P, Lautamaki R, Schminke U, von Sarnowski B, Busch R, Yesilot N, Sezgin M, Waje-Andreassen U, Saeed S, Fonseca AC, Paula A, Amaya Pascasio L, Martinez-Sanchez P, Korv J, Muda P, Ferdinand P, Oxley C, Zakarkaite D, Ryliskiene K, Pezzini A, Lombardi CM, Licenik R, Zedde M, Grimaldi T, Tsivgoulis G, Sinisalo J, Gerdts E, Tatlisumak T; SECRETO Study Group. Burden of Modifiable Risk Factors in Young-Onset Cryptogenic Ischemic Stroke by High-Risk Patent Foramen Ovale. Stroke. 2025 Jun;56(6):1428-1440. doi: 10.1161/STROKEAHA.124.049855. Epub 2025 Apr 17.

Reference Type: DERIVED

PMID: 40242852 (View on PubMed)

Kutal S, Tulkki LJ, Sarkanen T, Redfors P, Jood K, Nordanstig A, Yesilot N, Sezgin M, Ylikotila P, Zedde M, Junttola U, Fromm A, Ryliskiene K, Licenik R, Ferdinand P, Jatuzis D, Korv L, Korv J, Pezzini A, Sinisalo J, Lehto M, Gerdts E, Autere J, Fonseca AC, Waje-Andreassen U, Von Sarnowski B, Sairanen T, Tatlisumak T, Huhtakangas J, Jakala P, Putaala J, Martinez-Majander N. Association Between Self-Perceived Stress and Cryptogenic Ischemic Stroke in Young Adults: A Case-Control Study. Neurology. 2025 Mar 25;104(6):e213369. doi: 10.1212/WNL.0000000000213369. Epub 2025 Mar 5.

Reference Type: DERIVED

PMID: 40043226 (View on PubMed)

Sindre RB, Gerdts E, Putaala J, Grymyr LMD, Midtbo H, Almeida AG, Bech-Hanssen O, Busch R, Eilertsen RK, Fonseca AC, Hedman M, Huhtakangas J, Jakala P, Lautamaki R, Lehto M, Martinez-Majander N, Redfors P, Sarkanen T, von Sarnowski B, Sinisalo J, Virtanen M, Waje-Andreassen U, Yesilot N, Ylikotila P, Cramariuc D. Association of Left Atrial Stiffness With Risk of Cryptogenic Ischemic Stroke in Young Adults. JACC Adv. 2024 Mar 14;3(4):100903. doi: 10.1016/j.jacadv.2024.100903. eCollection 2024 Apr.

Reference Type: DERIVED

PMID: 38939654 (View on PubMed)

Zedde M, Grisendi I, Assenza F, Napoli M, Moratti C, Bonacini L, Di Cecco G, D'Aniello S, Pavone C, Merlino G, Putaala J, Valzania F, Pascarella R. The Prepetrous Segment of the Internal Carotid Artery as a Neglected Site of Symptomatic Atherosclerosis: A Single-Center Series. J Clin Med. 2024 Mar 15;13(6):1696. doi: 10.3390/jcm13061696.

Reference Type: DERIVED

PMID: 38541922 (View on PubMed)

Tulkki L, Martinez-Majander N, Haapalahti P, Tolppanen H, Sinisalo J, Repo O, Sarkanen T, Numminen H, Ryodi E, Ylikotila P, Roine RO, Lautamaki R, Saraste A, Miettinen T, Autere J, Jakala P, Hedman M, Huhtakangas J, Junttola U, Putaala J, Pirinen J; SECRETO Study Group. 24-hour ambulatory blood pressure and cryptogenic ischemic stroke in young adults. Ann Med. 2023 Dec;55(1):2203513. doi: 10.1080/07853890.2023.2203513.

Reference Type: DERIVED

PMID: 37086083 (View on PubMed)

Kuusisto JK, Poyhonen PAK, Pirinen J, Lehmonen LJ, Raty HP, Martinez-Majander N, Putaala J, Sinisalo J, Jarvinen V. Revisiting left atrial volumetry by magnetic resonance imaging: the role of atrial shape and 3D angle between left ventricular and left atrial axis. BMC Med Imaging. 2021 Nov 9;21(1):167. doi: 10.1186/s12880-021-00701-5.

Reference Type: DERIVED

PMID: 34753444 (View on PubMed)

Poyhonen P, Kuusisto J, Pirinen J, Raty H, Lehmonen L, Paakkanen R, Martinez-Majander N, Gerdts E, Putaala J, Sinisalo J, Jarvinen V. Right atrium and cryptogenic ischaemic stroke in the young: a case-control study. Open Heart. 2021 May;8(1):e001596. doi: 10.1136/openhrt-2021-001596.

Reference Type: DERIVED

PMID: 34006504 (View on PubMed)

Poyhonen P, Kuusisto J, Jarvinen V, Pirinen J, Raty H, Lehmonen L, Paakkanen R, Martinez-Majander N, Putaala J, Sinisalo J. Left ventricular non-compaction as a potential source for cryptogenic ischemic stroke in the young: A case-control study. PLoS One. 2020 Aug 14;15(8):e0237228. doi: 10.1371/journal.pone.0237228. eCollection 2020.

Reference Type: DERIVED

PMID: 32797064 (View on PubMed)

Pirinen J, Jarvinen V, Martinez-Majander N, Sinisalo J, Poyhonen P, Putaala J. Left Atrial Dynamics Is Altered in Young Adults With Cryptogenic Ischemic Stroke: A Case-Control Study Utilizing Advanced Echocardiography. J Am Heart Assoc. 2020 Apr 7;9(7):e014578. doi: 10.1161/JAHA.119.014578. Epub 2020 Mar 25.

Reference Type: DERIVED

PMID: 32208831 (View on PubMed)

Martinez Majander N, Sinisalo J, Sundararajan S, Strbian D, Putaala J. Cryptic Loss of Consciousness in a 36-Year-Old Woman. Stroke. 2015 Jul;46(7):e164-6. doi: 10.1161/STROKEAHA.115.009405. Epub 2015 May 12. No abstract available.

Reference Type: DERIVED

PMID: 25967578 (View on PubMed)

Related Links

http://www.secretostudy.net

Study website

Other Identifiers

SECRETO

Identifier Type: -

Identifier Source: org_study_id