Atrial Cardiomyopathy in Patients With Stroke of Undetected Mechanism

Study Overview
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Brief Summary
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The goal of this study is to evaluate left atrial structural and functional abnormalities in stroke of undetected mechanism and atherosclerotic stroke with cardiac MRI.

Detailed Description
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Aims and objectives: The goal of this study is to evaluate left atrial structural and functional abnormalities in patients with stroke of likely cardio-embolic origin compared with healthy age and sex matches controls and patients with atherosclerotic stroke using cardiac MRI. Background: Despite standard work up for the etiology of ischemic stroke, about 30% of the cases remain unexplained. It is increasingly accepted that these unexplained cases arise from disease outside of the brain. Paroxysmal AF (Atrial fibrillation) may often be suspected as the source but fewer than one third of patients with stroke of undetermined source manifest AF in any form even after 3 years of continuous heart rhythm monitoring. Emerging evidence suggest that atrial functional and structural abnormalities may convey a comparable risk of stroke in which AF is only one of several features. These abnormalities have been termed atrial cardiomyopathy and may be an efficient and practical approach to identify patients at high risk of AF and ischemic stroke. Methods and materials: Cross sectional and prospective cohort study with 3 different groups: 50 patients with stroke of undetected mechanism, 50 patients with atherosclerotic stroke (large or small vessel disease) admitted to the University Hospital of Bispebjerg and Frederiksberg and 50 sex and age matched controls with no history of stroke or AF from the Copenhagen City Heart Study (ØBUS) will be included during a 2 year-period. The study will measure atrial structural abnormalities using cardiac magnetic resonance imaging (MRI) and atrial functional abnormalities by cardiac MRI and echocardiography. A 1 year follow up will examine the incidence of silent brain infarction with MRI and incidence of stroke, atrial fibrillation, acute myocardial infarction and cardiovascular death. Secondary endpoints are to examine the association of functional and structural changes found by MRI with echocardiography, rhythm abnormalities and biomarkers with the purpose of finding clinical easily applicable methods to diagnose atrial cardiomyopathy. Expected outcome and perspectives: The investigators hypothesize that patients with stroke of likely cardio-embolic origin have significantly more atrial fibrotic degeneration and reduced atrial emptying function than patients with atherosclerotic stroke and the control subjects. The investigators expect a higher incidence of silent brain infarction in the group with stroke of likely cardio-embolic origin. With atrial cardiomyopathy investigated thoroughly in patients with stroke of likely cardio-embolic origin the future work-up and treatment strategies could be more efficient and may thus improve the prognosis in terms of mortality and disability for a considerable number of patients.

Official Title
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Atrial Cardiomyopathy in Patients With Stroke of Undetected Mechanism

Conditions
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Stroke

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Patients): Stroke of likely cardioembolic cause or of undetected mechanism: Lesions in at least one territory on MRI & absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% in arteries supplying the ischemic area(s) & absence of severe small vessel disease including micro-bleeds on MRI. Patients with central retinal artery occlusion documented by perimeter and absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% & absence of severe small vessel disease including micro-bleeds on MRI are included independent of acute MRI findings. Large or small vessel stroke (atherosclerotic stroke): Large vessel stroke: Acute lesions in one vascular territory on MRI, significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% leading to the infarcted territory & absence of severe small vessel disease including micro-bleeds on MRI Small Vessel stroke: MRI documenting lacunar infarction, absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% and presence of severe small vessel disease possibly including micro bleeds. Ischemic stroke within 30 days prior to inclusion Age > 18 years Life expectancy of at least one year Informed consent Stenosis: % defined by Ultrasound Small vessel disease: defined according to STRIVE criteria Inclusion Criteria (Controls) 1. Age and sex matched healthy controls. Matched with the group with stroke of likely cardioembolic stroke. Exclusion Criteria (Patients): Prior AF or AF >30 sec on at least 6 hours of monitoring during hospitalization. Other major cardio-embolic risk sources assumed as cause of stroke (e.g. endocarditis, myocardial infarction within last 4 weeks, prosthetic cardiac valve) Contraindications to MRI (Including eGFR<30 or other contraindications for the contrast agent used during Cardiac MRI) Assumed unable to participate in the study by investigator (including but not restricted to psychiatric condition, dementia) Exclusion Criteria (Controls): History of stroke or AF Contraindications to MRI (Including eGFR<30 mL/min/1.73 m2 or other contraindications for the contrast agent used during Cardiac MRI) Assumed unable to participate in the study by the investigator (For the same reasons listed above)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Stroke of likely cardioembolic cause or undetected mechanism<br>Lesions in at least one territory on MRI & absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% in arteries supplying the ischemic area(s) & absence of severe small vessel disease including micro-bleeds on Patients with central retinal artery occlusion documented by perimeter and absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% & absence of severe small vessel disease including micro-bleeds on MRI are included independent of acute MRI findings. | |
| Atherosclerotic stroke<br>Large vessel stroke: Acute lesions in one vascular territory on MRI, significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% leading to the infarcted territory & absence of severe small vessel disease including micro-bleeds on MRI Small Vessel stroke: MRI documenting lacunar infarction, absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% and presence of severe small vessel disease possibly including micro bleeds. | |
| Controls<br>Age and sex matched healthy controls with no history of stroke or AF. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extent of the fibrosis in the Left Atrium (LA) | Measured with gadolinium enhanced cardiac MRI | Within 12 weeks from index event | 
| Left Atrial Emptying Function (LAEF) | Measured with gadolinium enhanced cardiac MRI | Within 12 weeks from index event | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observational study: Incidence of silent brain infarctions | Incidence of silent brain infarctions assessed by follow-up MR-cerebrum (Only in patients) | Between 1-2 years from index event | 
| Left atrial volume | Assessed by cardiac MRI | Within 12 weeks from index event | 
| Left atrial appendage morphology | Assessed by cardiac MRI | Within 8 weeks from index event | 
| Left atrium volume | 2D and 3D left atrial volume assessed by transthoracic echocardiography | Within 12 weeks from index event | 
| Left atrium ejection fraction (LAEF) | Assessed by transthoracic echocardiography | Within 12 weeks from index event | 
| Speckle tracking of LA | Assessed by transthoracic echocardiography | Within 12 weeks from index event | 
| Atrial rhythm abnormalities: Number of premature atrial contractions (PAC) per hour. Number and length of runs of PAC | Assessed by 48-hours Holter monitoring | Within 4 weeks from index event | 
| Heart rate variability (HRV) | Time domain variables (meanNN, SDNN, SDANN, SDNNidx, RMSSD, pNN50) | Within 4 weeks from index event | 
| Thrombophilia biomarkers | Assessment of hypercoagulability | Within 12 weeks from index event | 
| Cardiac specific biomarkers | Atrial Natriuretic Peptide, pro NT-Brain Natriuretic Peptide, High Sensitive Troponins. | Within 12 weeks from index event | 
| Inflammatory biomarkers | High Sensitive CRP, Interleukins: IL1, IL1b, IL6, IL18 | Within 12 weeks from index event | 
| Fibrosis related markers | Collagen type I and III | Within 12 weeks from index event | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardioembolic stroke, Cardiac MRI, Heart disease, Vascular disease