Ischemic stroke and the emerging role of left atrial function

Figures & data

Figure 1. Proposed relationship between reduced left atrial function, atrial fibrillation (AF), and ischemic stroke.AF is a well-established causal factor for ischemic stroke, with anti-coagulant treatment reducing stroke risk. Reduced left atrial function, both a product and risk marker for AF, is associated with increased stroke risk, although the underlying mechanism remains unclear. It is uncertain whether treating reduced left atrial function, in the absence of AF, reduces ischemic stroke risk.

Figure 2. Volumetric and functional phases of the LA. (a) Volume curve, (b) Strain curve. LA, left atrial; LA_max, left atrial maximal volume; LA_preA, left atrial volume before atrial contraction; LA_min, left atrial minimal volume; LA TEF, left atrial total emptying fraction; LA PEF, left atrial passive emptying fraction; L A AEF, left atrial active emptying fraction.

Table 1. Comparison of imaging modalities and strength and weakness of specific echocardiographic LA measures.

Imaging modality comparison	Strengths	Limitations
Transthoracic echocardiography	Widely available Bedside Low cost No radiation or safety issues Timely Adequate temporal resolution	Low level of detailed anatomy Angle-dependency Feasibility, image quality, and reproducibility influenced by patient-specific factors (body stature, rib space, lung disease, positioning).
Cardiac magnetic resonance imaging	High level of anatomical details LGE quantification High reproducibility Angle-independency	Costly Limited availability Several contraindications Lower temporal resolution
Specific echocardiographic left atrial measures
2-dimensional echocardiography	Strengths	Potential pitfalls and considerations
Left atrial dimensions	Established normative values High feasibility Specific for LA enlargement Widely established association to clinical outcomes	Heavy geometric assumptions, low sensitivity for LA enlargement Sex-specific differences Indexation to body surface area invalid with abnormal body stature and weight changes No dynamic insight into LA function
Left atrial volumes	Established normative values Specific for LA enlargement and more sensitive than LA dimension Established correlation to filling pressures Widely established association to clinical outcomes	Geometric assumptions Potential foreshortening of LA Confounded by external factors: anemia, physical activity level, etc. No dynamic insight into LA function Sex-specific differences Race- and ethnic-specific differences Age-dependent changes Indexation to body surface area invalid with abnormal body stature and weight changes Low feasibility and reproducibility with varying image quality and artifact dropouts (i.e. valvular calcification)
Left atrial emptying fractions	Relative changes in atrial volumes, thereby unaffected by body size Provides insights into all aspects of atrial function Studies have linked measures to filling pressures, although not as widely documented as LA volume	Time consuming with multiple biplane volume-measurements Reliability depends on adequate image quality for volume measurements Indirect assessment of atrial function Normative values not available for all measurements Ambiguous findings concerning age-related changes
Left atrial strain measures	Quick, automatic, and reproducible Provides insights into all aspects of atrial function Direct tissue measurement Unaffected by body stature Proposed normative values available (although not guideline-established) Dedicated algorithms now available Angle-independency Linked to filling pressure and fibrosis	Lower feasibility Most studies are based on non-dedicated software measurements Non-dedicated software with suboptimal tissue definition and potential issues with surrounding structures (pulmonary veins, prominent coronary sinus, prominent LA appendage, thin interatrial septum). Vendor-dependency in algorithms Sex-specific differences Confounding factors still not well-delineated
3-dimensional echocardiography	Strengths	Potential pitfalls and considerations
	No geometric assumptions Less issue with foreshortening Dedicated software now available Time-efficient, automatic, and reproducible Provides details on all measurements (volumes, emptying fractions, strain) at once Proposed normative values available (although not guideline-established) Linked to filling pressures and fibrosis	Lower feasibility Requires high image quality Requires patient cooperation for breath-hold Requires stable heart rhythm Lower temporal resolution Not as widely studied as 2D Sex-specific differences

LA: left atrium; LGE: late gadolinium enhancement.

Table 2. Measures of left atrial function and subsequent risk of atrial fibrillation or ischemic stroke.

First author, year	Population & Study design	Sample size, mean age	Left atrial functional measure	Modality	Findings
Atrial fibrillation
Habibi et al. 2016 [80]	General population, case/cohort	519, 65 years	Total, passive and active LAEF, and LA reservoir strain	CMR	Total and passive LAEF, and LA reservoir strain was associated with incident AF
Olsen et al. 2019 [78]	General population, prospective	1,951, 59 years	Total LAEF	TTE	LAEF was associated with incident AF
Patel et al. 2020 [83]	General population, prospective	4,341, 73 years	LA reservoir strain	TTE	LA reservoir strain was associated with incident AF
Bertelsen et al. 2020 [81]	General population 70–90 years of age and CHA2DS2-VASc-score ≥2	203, 76 years	Total, passive and active LAEF, and LA strain	CMR	Total and passive LAEF, reservoir and booster LA strain were associated with subclinical AF as detected by implanted loop recorder.
Huber et al. 2022 [84]	General population, prospective	1,441,73 years	LA Strain (Reservoir, conduit, and booster)	TTE	Reservoir and booster LA strain was associated with subclinical AF
Hauser et al. 2022 [82]	General population, prospective	3,590, 55 years	LA Strain (Reservoir, conduit, and booster)	TTE	Reservoir and booster LA strain was associated with incident AF
Mannina et al. 2023 [85]	General population, prospective	824, 71 years	LA reservoir strain	TTE	LA reservoir strain was associated with incident AF
Olsen et al. 2024 [86]	General population 70–90 years of age and CHA2DS2-VASc-score ≥2	956, 74 years	LA Strain (Reservoir, conduit, and booster)	TTE	Reservoir and booster LA strain was associated with subclinical AF as detected by implanted loop recorder
Ischemic stroke
Habibi et al. 2019 [17]	General population, prospective	4,261, 61 years	Total, passive and active LAEF, and LA reservoir strain	CMR	Reduced total LAEF, but not LA volumes, was associated with a combined endpoint of stroke and TIA beyond incident AF.
Kamel et al. 2021 [29]	General population, prospective	4,000, 73 years	LA reservoir strain	TTE	LA reservoir strain was associated with both incident ischemic stroke and cardioembolic stroke including cardioembolic stroke related to incident AF
Maheshwari et al. 2022 [22]	General population, prospective	4,917, 75 years	LA Strain (Reservoir, active and passive)	TTE	LA reservoir strain, but not conduit and active strain, was associated with ischemic stroke.
Larsen et al. 2023 [21]	General population, prospective	1,866, 58 years	Total LAEF	TTE	Reduced total LAEF, but not LA volumes, was associated with ischemic stroke beyond incident AF
Mannina et al.2023 [20]	Community-based, prospective	806, 71 years	LA Strain (Reservoir) and strain rate	TTE	Lowest quintile longitudinal strain and lowest quintile negative longitudinal SR were associated with ischemic stroke (only in patients with LA volume < median value 23.7 mL/m^2)

CHA2DS2-VASc, congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female; CMR, Cardiac magnetic resonance imaging; LA, left atrial; LAEF, left atrial emptying fraction; SR, Strain rate; TTE, transthoracic echocardiography.

Table 3. Studies examining atrial cardiomyopathy, subclinical atrial fibrillation, and anticoagulation for stroke prevention.

First author, year published, study acronym	Population	Study design	Sample size, mean age, sex	Randomization groups	Primary outcome measure	Findings
Secondary prevention of ischemic stroke in patients with ESUS
Healey et al. [23] 2019 NAVIGATE ESUS trial substudy	ESUS + LA diameter > 4,6 cm	Multicenter, double-blind RCT	361, 67 years, 38% female	Rivaroxaban 15 mg q.d. vs. aspirin 100 mg q.d.	Recurrent ischemic stroke	Risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year)
Geisler et al. [33] 2023 ATTICUS trial	ESUS + biomarkers of atrial cardiomyopathy	Multicenter, open label, blinded outcome RCT	352, 68 years, 48% female	Apixaban 5 mg b.i.d. vs. aspirin 100 mg q.d.	Any new ischemic lesion on brain MRI at 12-month follow up	Apixaban treatment was not superior in preventing new ischemic lesion on brain MRI. Stopped for futility after interim analysis
Kamel et al. [34] 2024 ARCARDIA trial	ESUS + biomarkers of atrial cardiomyopathy	Multicenter, double-blind RCT	1015, 68 years, 54% female	Apixaban 5 mg b.i.d. vs. aspirin 81 mg q.d.	Recurrent stroke of any type	Apixaban treatment did not significantly reduce recurrent stroke. Stopped for futility after interim analysis
Primary & secondary prevention of ischemic stroke in device detected AF
Svendsen et al. [94] 2021 LOOP Study	General population 70–90 years of age and CHA2DS2-VASc-score ≥2	Multicenter, blinded outcome RCT	6004, 75 years, 47% female	ILR with anticoagulation if SCAF ≥6 min. vs. standard care	Time to first stroke or systemic arterial embolism	ILR screening tripled atrial fibrillation detection and anticoagulation initiation but did not significantly reduce stroke or systemic arterial embolism risk
Kirchhof et al. [95] 2023 NOAH-AFNET 6 trial	Implanted cardiac device, ≥65 years, CHA2DS2-VASc-score ≥2, and SCAF ≥6 min.,	Multicenter double-blind, double-dummy RCT	2536, 78 years, 37% female	Edoxaban 60 mg q.d. vs. placebo (or aspirin 100 mg q.d. if indicated)	Composite of cardiovascular death, stroke, or systemic embolism	Edoxban treatment did not reduce the primary outcome compared to placebo, but increased a composite of death and major bleeding incidence
Healey et al. [96] 2023 ARTESIA trial	Implanted cardiac device, ≥55 years, CHA2DS2-VASc-score ≥2, SCAF ≥6 min. <24 hours	Multicenter double-blind, double-dummy RCT	4012, 77 years, 36% female	Apixaban 5 mg b.i.d. vs. aspirin 81 mg q.d.	Composite of stroke or systemic embolism	Apixaban treatment lowered the risk of the composite endpoint compared to aspirin but increased major bleeding risk

ESUS: embolic stroke of undetermined source; ILR: implantable loop recorder; RCT: randomized clinical trial; SCAF: subclinical atrial fibrillation.

Habibi M, Samiei S, Venkatesh BA, et al. Cardiac magnetic resonance–measured left atrial volume and function and incident atrial fibrillation. Circ Cardiovasc Imaging. 2016;9(8):1–8. doi: 10.1161/CIRCIMAGING.115.004299

 Web of Science ®Google Scholar

Olsen FJ, Møgelvang R, Jensen GB, et al. Relationship between left atrial functional measures and incident atrial fibrillation in the general population: the Copenhagen city heart study. JACC Cardiovasc Imaging. 2019;12(6):981–989. doi: 10.1016/j.jcmg.2017.12.016

 PubMed Web of Science ®Google Scholar

Patel RB, Delaney JA, Hu M, et al. Characterization of cardiac mechanics and incident atrial fibrillation in participants of the cardiovascular health study. JCI Insight. 2020;5(19). doi: 10.1172/jci.insight.141656

 Web of Science ®Google Scholar

Bertelsen L, Diederichsen SZ, Haugan KJ, et al. Left atrial volume and function assessed by cardiac magnetic resonance imaging are markers of subclinical atrial fibrillation as detected by continuous monitoring. EP Europace. 2020;22(5):724–731. doi: 10.1093/europace/euaa035

 PubMed Web of Science ®Google Scholar

Huber MP, Pandit JA, Jensen PN, et al. Left atrial strain and the risk of atrial arrhythmias from extended ambulatory cardiac monitoring: MESA. J Am Heart Assoc. 2022;11(21):11. doi: 10.1161/JAHA.122.026875

 Web of Science ®Google Scholar

Hauser R, Nielsen AB, Skaarup KG, et al. Left atrial strain predicts incident atrial fibrillation in the general population: the Copenhagen city heart study. Eur Heart J Cardiovasc Imaging. 2022;23(1):52–60. doi: 10.1093/ehjci/jeab202

 Web of Science ®Google Scholar

Mannina C, Ito K, Jin Z, et al. Left atrial strain and incident atrial fibrillation in older adults. Am J Cardiol. 2023;206:161–167. doi: 10.1016/j.amjcard.2023.08.060

 PubMed Web of Science ®Google Scholar

Olsen FJ, Diederichsen SZ, Jørgensen PG, et al. Response by Olsen et al to letter regarding article, “left atrial strain predicts subclinical atrial fibrillation detected by long-term continuous monitoring in elderly high-risk individuals”. Circ Cardiovasc Imaging. 2024;17(6):E016197. doi: 10.1161/CIRCIMAGING.124.016897

 PubMed Web of Science ®Google Scholar

Habibi M, Zareian M, Ambale Venkatesh B, et al. Left atrial mechanical function and incident ischemic cerebrovascular events Independent of AF. JACC Cardiovasc Imaging. 2019;12(12):2417–2427. doi: 10.1016/j.jcmg.2019.02.021

 PubMed Web of Science ®Google Scholar

Kamel H, Bartz TM, Longstreth WT, et al. Cardiac mechanics and incident ischemic stroke: the cardiovascular health study. Sci Rep. 2021;11(1):1–9. doi: 10.1038/s41598-021-96702-z

 PubMed Web of Science ®Google Scholar

Maheshwari A, Norby FL, Inciardi RM, et al. 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;176(1):39–48. doi: 10.7326/M22-1638

 PubMed Web of Science ®Google Scholar

Larsen BS, Olsen FJ, Andersen DM, et al. Left atrial volumes and function, and long‐term incidence of ischemic stroke in the general population. J Am Heart Assoc. 2022;11(18):27031. doi: 10.1161/JAHA.122.027031

 Web of Science ®Google Scholar

Mannina C, Ito K, Jin Z, et al. Association of left atrial strain with ischemic stroke risk in older adults. JAMA Cardiol. 2023;8(4):317–325. doi: 10.1001/jamacardio.2022.5449

 PubMed Web of Science ®Google Scholar

Healey JS, Gladstone DJ, Swaminathan B, et al. Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial. JAMA Neurol. 2019;76(7):764–773. doi: 10.1001/jamaneurol.2019.0617

 PubMed Web of Science ®Google Scholar

Geisler T, Keller T, Martus P, et al. Apixaban versus aspirin for embolic stroke of undetermined source. NEJM Evid. 2023;3(1):1–12. doi: 10.1056/EVIDoa2300235

 Google Scholar

Kamel H, Longstreth WT, Tirschwell DL, et al. Apixaban to prevent recurrence after cryptogenic stroke in patients with atrial cardiopathy: the ARCADIA randomized clinical trial. JAMA. 2024;331(7):573–581. doi: 10.1001/jama.2023.27188

 PubMed Web of Science ®Google Scholar

Svendsen JH, Diederichsen SZ, Højberg S, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (the LOOP study): a randomised controlled trial. Lancet. 2021;398(10310):1507–1516. doi: 10.1016/S0140-6736(21)01698-6

 PubMed Web of Science ®Google Scholar

Kirchhof P, Toennis T, Goette A, et al. Anticoagulation with edoxaban in patients with atrial high-rate episodes. N Engl J Med. 2023;2023(13):1167–1179. doi: 10.1056/NEJMoa2303062

 Google Scholar

Healey JS, Lopes RD, Granger CB, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. N Engl J Med. 2023:107–117.

 PubMed Web of Science ®Google Scholar