Left Atrial Strain and Cryptogenic Stroke

NCT07224178 | Recruiting

• 1 other identifier: STUDY25010088
• Study Type: observational
• Target: 900
• Locations: 1 country
• Sites: 1

Brief Summary

Cryptogenic stroke is a type of stroke in which the cause of the blood clot cannot be identified, leaving many patients without a clear treatment plan and at high risk for another stroke. Current medical guidelines recommend blood-thinning medication (anticoagulation) only when atrial fibrillation (AF) -an irregular heart rhythm- can be documented. However, AF may occur silently and remain undetected. Long term implantable (placed invasively under the skin) devices may be needed to capture these episodes. AF is known to develop from disease of the left atrium, the upper chamber of the heart that receives blood from the lungs. When the left atrium does not contract normally, blood flow may slow down, increasing the risk of clot formation. Nowadays, the left atrial (LA) function can be quantified precisely using a noninvasive ultrasound technique called strain imaging. This study aims to determine whether reduced LA function is associated with cryptogenic stroke and its recurrence even when AF is not observed. If such an association is confirmed, LA strain could serve as a new biomarker to identify patients at risk, earlier than the development of overt AF, enhance preventive measures to reduce recurrent strokes. Because echocardiographic strain imaging is safe, cost-effective, and widely available, it may become an important tool for improving care in this high-risk population.

Conditions

Ischemic Stroke, Cryptogenic; Ischemic Stroke, Embolic; Recurrent Ischemic Stroke; Hemorrhagic Stroke; Embolic Stroke of Undetermined Source

Keywords

stroke; embolic stroke of undetermined source; speckle-tracking echocardiography; left atrial cardiomyopathy; left atrial strain; recurrent ischemic stroke; new-onset atrial fibrillation

Outcome Measures

Primary Outcomes (1)

• Correlation between left atrial strain (percent deformation) and the rate of cryptogenic stroke

  Quantitative left atrial (LA) strain (% deformation), measured by speckle-tracking echocardiography from transthoracic echocardiograms obtained during stroke workup, will be compared with the rate of cryptogenic stroke.

  Baseline

Secondary Outcomes (3)

• Prediction of recurrent cryptogenic stroke by left atrial strain (percent deformation)

  Up to 1 year from date of index transthoracic echocardiography.

• Incidence of cardiovascular and cerebrovascular mortality among patients with impaired LA strain (percent deformation)

  Up to 1 year from date of index transthoracic echocardiography.

• Incidence of newly detected atrial fibrillation among patients with impaired LA strain

  Up to 1 year from date of index transthoracic echocardiography.

Study Arms (2)

Cryptogenic Stroke Cohort

Subjects in sinus rhythm who had a diagnosis of ischemic embolic stroke in whom no clear embolic source was identified after standard diagnostic evaluation (TOAST classification: Embolic Stroke of Undetermined Source) and who had transthoracic echocardiography (TTE) as part of the stroke work up will constitute the first group.

Non-Cryptogenic Stroke Cohort (Comparator Group)

Subjects in sinus rhythm who had a non-cryptogenic stroke (e.g., large artery atherosclerosis, small vessel disease, hemorrhagic) and who underwent transthoracic echocardiography as part of the clinical stroke workup. This group will serve as a comparator for the primary analysis to determine whether LA strain determines cryptogenic stroke among other stroke subtypes.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Participants will be selected from adult patients evaluated for stroke at the University of Pittsburgh Medical Center (UPMC) and collaborating university hospitals that serve as tertiary care centers with established cardiovascular imaging programs. Only subjects who have already undergone transthoracic echocardiography as part of their stroke workup, and who have clinical and imaging data available for retrospective analysis will be included. The UPMC will provide both the data collection platform -REDCap- and Echocardiography Core Laboratory for centralized image analysis.

You may qualify if:

• Adult patients (age \> 18 years and \< 80 years) who had a complete transthoracic echocardiography (TTE) exam at the University of Pittsburgh Medical Center (UPMC) Presbyterian Echocardiography Lab with a referral diagnosis of suspected stroke.
• Patients with an established diagnosis of stroke by stroke neurologists.
• Patients in sinus rhythm documented at the time of referral.
• Availability of adequate echocardiographic images for strain quantification.
• Clinical follow-up data available for evaluation of study endpoints, including stroke recurrence, atrial fibrillation development, and mortality.
• Patients from collaborating centers will be included with de-identified echocardiographic images and clinical data meeting the above criteria.

You may not qualify if:

• Pre-existing atrial fibrillation (AF): Patients with a documented history AF prior to the index echocardiography study will be excluded because it is well established that AF justifies cryptogenic stroke requiring anticoagulation.
• Structural heart disease: Patients with significant structural abnormalities, such as moderate or severe mitral stenosis, moderate or severe mitral regurgitation, prosthetic heart valves, devices in the left atrium, atrial septal defect or patent foramen ovale will be excluded as these conditions are known causes of stroke and abnormal left atrial function.
• Coagulopathy: Patient having disease leading to hypercoagulable (thrombus formation) state will be excluded (presence of cancer, antiphospholipid antibodies, hematological diseases).
• Inadequate clinical follow-up: Patients with insufficient follow-up data or missing medical records that preclude evaluation of study endpoints (e.g., stroke recurrence, AF development) will be excluded unless death is documented.
• Poor image quality for strain analysis: Patients having echo exams with inadequate image quality that prevent reliable strain quantification will be excluded.

Sponsors & Collaborators

• University of Pittsburgh: lead

Study Sites (1)

UPMC Presbyterian

Pittsburgh, Pennsylvania, 15213, United States

RECRUITING

Related Publications (10)

• Maheshwari A, Norby FL, Inciardi RM, Wang W, Zhang MJ, Soliman EZ, Alonso A, Johansen MC, Gottesman RF, Solomon SD, Shah AM, Chen LY. Left Atrial Mechanical Dysfunction and the Risk for Ischemic Stroke in People Without Prevalent Atrial Fibrillation or Stroke : A Prospective Cohort Study. Ann Intern Med. 2023 Jan;176(1):39-48. doi: 10.7326/M22-1638. Epub 2022 Dec 20.

  PMID: 36534978 BACKGROUND

• Masini G, Wang W, Ji Y, Eaton A, Inciardi RM, Soliman EZ, Passman RS, Solomon SD, Shah AM, De Caterina R, Chen LY. Markers of Left Atrial Myopathy: Prognostic Usefulness for Ischemic Stroke and Dementia in People in Sinus Rhythm. Stroke. 2025 Apr;56(4):858-867. doi: 10.1161/STROKEAHA.124.047747. Epub 2025 Mar 7.

  PMID: 40052267 BACKGROUND

• Sade LE, Keskin S, Can U, Colak A, Yuce D, Ciftci O, Ozin B, Muderrisoglu H. Left atrial mechanics for secondary prevention from embolic stroke of undetermined source. Eur Heart J Cardiovasc Imaging. 2022 Feb 22;23(3):381-391. doi: 10.1093/ehjci/jeaa311.

  PMID: 33206942 BACKGROUND

• Sade LE, Faletra FF, Pontone G, Gerber BLM, Muraru D, Edvardsen T, Cosyns B, Popescu BA, Klein A, Marwick TH, Cameli M, Saric M, Thomas L, Ajmone Marsan N, Fontes-Carvalho R, Podlesnikar T, Fontana M, La Gerche A, Petersen SE, Moharem-Elgamal S, Bittencourt MS, Vannan MA, Glikson M, Peichl P, Cochet H, Stankovic I, Donal E, Thomas D, Marta RS. The role of multi-modality imaging for the assessment of left atrium and left atrial appendage: a clinical consensus statement of the European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC). Eur Heart J Cardiovasc Imaging. 2025 Mar 3;26(3):385-413. doi: 10.1093/ehjci/jeaf014.

  PMID: 39812172 BACKGROUND

• Clark A, Ferkh A, Vandenberg J, Elhindi J, Thomas L. Altered left atrial metrics in patients with cryptogenic stroke: A systematic review and meta-analysis. Eur J Clin Invest. 2024 Jun;54(6):e14175. doi: 10.1111/eci.14175. Epub 2024 Feb 2.

  PMID: 38308431 BACKGROUND

• Ozbay B, Rearick C, Satyavolu BS, Soman P, Wong TC, Starr M, Pillai B, Zhu J, Azhar AZ, Katz WE, Sade LE. Primary Left Atrial Cardiopathy in Transthyretin Amyloidosis Cardiomyopathy by Multimodality Imaging: Implications for Thrombotic Events. JACC Cardiovasc Imaging. 2025 Aug;18(8):867-881. doi: 10.1016/j.jcmg.2025.04.007. Epub 2025 Jul 3.

  PMID: 40608042 BACKGROUND

• Habibi M, Lima JA, Khurram IM, Zimmerman SL, Zipunnikov V, Fukumoto K, Spragg D, Ashikaga H, Rickard J, Marine JE, Calkins H, Nazarian S. Association of left atrial function and left atrial enhancement in patients with atrial fibrillation: cardiac magnetic resonance study. Circ Cardiovasc Imaging. 2015 Feb;8(2):e002769. doi: 10.1161/CIRCIMAGING.114.002769.

  PMID: 25652181 BACKGROUND

• Goldberger JJ, Arora R, Green D, Greenland P, Lee DC, Lloyd-Jones DM, Markl M, Ng J, Shah SJ. Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate. Circulation. 2015 Jul 28;132(4):278-91. doi: 10.1161/CIRCULATIONAHA.115.016795.

  PMID: 26216085 BACKGROUND

• Kamel H, Longstreth WT Jr, Tirschwell DL, Kronmal RA, Marshall RS, Broderick JP, Aragon Garcia R, Plummer P, Sabagha N, Pauls Q, Cassarly C, Dillon CR, Di Tullio MR, Hod EA, Soliman EZ, Gladstone DJ, Healey JS, Sharma M, Chaturvedi S, Janis LS, Krishnaiah B, Nahab F, Kasner SE, Stanton RJ, Kleindorfer DO, Starr M, Winder TR, Clark WM, Miller BR, Elkind MSV; ARCADIA Investigators. Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial. JAMA. 2024 Feb 20;331(7):573-581. doi: 10.1001/jama.2023.27188.

  PMID: 38324415 BACKGROUND

• Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, Kamel H, Kernan WN, Kittner SJ, Leira EC, Lennon O, Meschia JF, Nguyen TN, Pollak PM, Santangeli P, Sharrief AZ, Smith SC Jr, Turan TN, Williams LS. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021 Jul;52(7):e364-e467. doi: 10.1161/STR.0000000000000375. Epub 2021 May 24. No abstract available.

  PMID: 34024117 BACKGROUND

MeSH Terms

Conditions

Ischemic Stroke; Hemorrhagic Stroke; Stroke

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Leyla E Sade, MD

  University of Pittsburgh Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Leyla E Sade, MD

CONTACT

412-215-3464; sadele2@upmc.edu

Benay Ozbay, MD

CONTACT

412-450-2774; ozbayb@upmc.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: October 28, 2025
• First Posted: November 4, 2025
• Study Start: December 17, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: January 7, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: IPD and supporting documents will be available starting 6 months after publication of the primary results and will remain accessible for 5 years thereafter.
• Access Criteria: Access to the dataset will be granted to researchers upon submission of a formal request, outlining the study objectives and analysis plan. Approval will be contingent upon compliance with ethical guidelines, data privacy regulations, and institutional review board (IRB) requirements. Researchers will be required to sign a data-sharing agreement (DSA) before receiving access with the University of Pittsburgh..

Locations

US (1)