ABSTRACT

Background Accurate aortic stenosis (AS) phenotyping requires access to multimodality imaging which has limited availability. The Digital Aortic Stenosis Severity Index (DASSi), an AI biomarker of AS-related remodeling on 2D echocardiography, predicts AS progression independent of Doppler measurements. Whether DASSi-enhanced echocardiography provides a scalable alternative to multimodality AS imaging remains unknown. We sought to evaluate the ability of DASSi to define personalized AS progression profiles and validate its performance against multimodality imaging features of functional, structural, and biological disease severity.

Methods In the SALTIRE-2 trial of participants with mild-or-moderate AS, we performed blinded DASSi measurements (probability of severe AS, 0-to-1) on baseline transthoracic echocardiograms. We evaluated the association between baseline DASSi and (i) disease severity by hemodynamic (peak aortic valve velocity [AV-Vmax]), structural (CT-derived aortic valve calcium score [AVCS]) and biological features ([18F]sodium fluoride [NaF] uptake on Positron Emission Tomography-CT), (ii) disease progression (change in AV-Vmax and AVCS), and (iii) incident aortic valve replacement (AVR). We used generalized linear mixed, or Cox models adjusted for risk factors and aortic valve area, as appropriate.

Results We analyzed 134 participants (72 [IQR: 69-78] years, 27 [20.1%] women) with a mean baseline DASSi of 0.51 (standard deviation [SD]: 0.19). DASSi was independently associated with disease severity: each SD increase was associated with higher AV-Vmax (+0.21 [95%CI: 0.12-0.30] m/sec), AVCS (+284 [95%CI: 101-467] AU) and [18F]NaF TBRmax (+0.17 [95%CI: 0.04-0.31]). Higher DASSi was also associated with disease progression by Doppler (AV-Vmax) and CT (AVCS) at 24 months (pinteraction for DASSi (x) time<0.001), and future AVR (75 events over 5.5 [IQR: 2.4-7.2] years, adj.HR 1.47 [95%CI: 1.12-1.94] per SD).

Conclusions DASSi is associated with functional, structural and biological features of AS severity as well as disease progression and outcomes. DASSi-enhanced echocardiography provides a readily accessible alternative to multimodality imaging of AS which has potential value both in clinical practice and as a clinical trial biomarker.

Competing Interest Statement

The authors report the following disclosures: E.K.O. is a co-founder of Evidence2Health LLC, has been an ad hoc consultant for Ensight-AI Inc, and Caristo Diagnostics Ltd, a co-inventor in patent applications (18/813,882, 17/720,068, 63/508,315, 63/580,137, 63/619,241, 63/562,335 through Yale University) and patents (US12067714B2, US11948230B2 through the University of Oxford), and has received royalty fees from technology licensed through the University of Oxford outside this work. R.K. is an Associate Editor of JAMA and receives research support, through Yale, from the Blavatnik Foundation, Bristol-Myers Squibb, Novo Nordisk, and BridgeBio. He is a coinventor of Pending Patent Applications WO2023230345A1, US20220336048A1, 63/346,610, 63/484,426, 63/508,315, 63/580,137, 63/606,203, 63/619,241, and 63/562,335, and a co-founder of Ensight-AI, Inc and Evidence2Health, LLC. All other authors declare no competing interests.

Funding Statement

The authors acknowledge support from the National Heart, Lung, And Blood Institute of the National Institutes of Health (under award numbers R01HL167858 and K23HL153775 to R.K., and F32HL170592 to E.K.O.), the National Institute on Aging of the National Institutes of Health (under award number R01AG089981 to R.K.), and the Doris Duke Charitable Foundation (under award number 2022060 to R.K.). The SALTIRE II trial was funded by the British Heart Foundation (FS/14/78/31020). N.C. is supported by the Medical Research Council (MR/Y009932/1). M.R.D. (FS/SCRF/21/32010) and D.E.N. (CH/09/002/26360) are supported by the British Heart Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding bodies.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This is a post-hoc analysis of the SALTIRE-2 trial (NCT02132026) which was previously approved by the Scotland A Research Ethics Committee (14/SS/0064).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

DATA AVAILABILITY

An executable or containerized version of the DASSi algorithm is available and can be made accessible for research use by contacting the corresponding author. The SALTIRE-2 trial data were made available by the study’s principal investigator, Dr. Marc Dweck (University of Edinburgh). No transfer of images or videos occurred across sites.

ABBREVIATIONSASaortic stenosisAV-Vmaxpeak aortic valve velocityAVCSaortic valve calcium scoreAVRaortic valve replacementCMRcardiac magnetic resonance imagingCTcomputed tomographyDASSiDigital Aortic Stenosis Severity IndexPET-CTpositron emission tomography - computed tomographyPLAXparasternal long axisRCTrandomized clinical trialsTBRtarget-to-background ratio