Left Atrial Strain and Cryptogenic Stroke

Official title

Left Atrial Strain: A Biomarker for Cryptogenic Stroke Prevention

Overview

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.

Detailed description

Cryptogenic stroke accounts for nearly one-third of ischemic strokes, yet its underlying mechanism often remains unidentified, leaving patients without targeted therapy. Atrial fibrillation (AF) is detected up to one third of cryptogenic strokes, but its detection frequently requires prolonged monitoring due to subclinical paroxysmal episodes. Increasing evidence suggests that structural and functional abnormalities of the left atrium (LA) precede AF and contribute to thromboembolic risk independently of rhythm disturbances.

This multicenter retrospective study aims to determine whether impaired LA strain, a sensitive echocardiographic measure of atrial function, is associated with cryptogenic stroke and can predict recurrent events. Echocardiographic images of the patients who were referred to the echocardiography laboratory as part of stroke work up will be analyzed offline, using standardized speckle-tracking software. De-identified clinical and imaging data will be collected in the central core laboratory at the University of Pittsburgh for uniform analysis and validation.

By establishing LA strain as a biomarker of atrial cardiopathy and cryptogenic stroke risk, this study seeks to bridge the current gap between stroke classification and management. Demonstrating the independent association between LA dysfunction and cryptogenic stroke and the recurrence of cryptogenic stroke independently of AF could support the use of LA strain as a risk marker to for monitoring patient and developing preventive strategies such as anticoagulation without documented AF. Hence, our findings may improve preventive care and reduce the burden of disabilities due to cryptogenic stroke.

Primary outcome measures

• Correlation between left atrial strain (percent deformation) and the rate of cryptogenic stroke [Time frame: Baseline]

Secondary outcome measures (3)

• Prediction of recurrent cryptogenic stroke by left atrial strain (percent deformation) [Time frame: Up to 1 year from date of index transthoracic echocardiography.]
• Incidence of cardiovascular and cerebrovascular mortality among patients with impaired LA strain (percent deformation) [Time frame: Up to 1 year from date of index transthoracic echocardiography.]
• Incidence of newly detected atrial fibrillation among patients with impaired LA strain [Time frame: Up to 1 year from date of index transthoracic echocardiography.]

Eligibility criteria

Inclusion criteria

• 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.

2- Patients with an established diagnosis of stroke by stroke neurologists.

3- Patients in sinus rhythm documented at the time of referral.

4- Availability of adequate echocardiographic images for strain quantification.

5- Clinical follow-up data available for evaluation of study endpoints, including stroke recurrence, atrial fibrillation development, and mortality.

6- Patients from collaborating centers will be included with de-identified echocardiographic images and clinical data meeting the above criteria.

Exclusion criteria

Incomplete or technically difficult transthoracic echocardiography (TTE) studies and studies from subjects younger than 18 years of age will be excluded. Additional exclusion criteria include:

1- 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.

2 -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.

3- Coagulopathy: Patient having disease leading to hypercoagulable (thrombus formation) state will be excluded (presence of cancer, antiphospholipid antibodies, hematological diseases).

4- 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.

5- Poor image quality for strain analysis: Patients having echo exams with inadequate image quality that prevent reliable strain quantification will be excluded.

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Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• UPMC Presbyterian — Pittsburgh

Publications

• 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
• 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
• 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
• 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 PMID 39812172
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT07224178 · STUDY25010088

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗