ABSTRACT

Background Risk stratification strategies for cancer therapeutics-related cardiac dysfunction (CTRCD) rely on serial monitoring by specialized imaging, limiting their scalability and affordability.

Objectives To examine an artificial intelligence (AI)-enhanced electrocardiographic (AI-ECG) surrogate for imaging-based risk biomarkers, and its association with CTRCD.

Methods Across five hospitals of a U.S.-based health system (2013-2023), we identified patients with breast cancer or non-Hodgkin lymphoma (NHL) who received anthracyclines (AC) and/or trastuzumab (TZM), as well as a (negative) control cohort of patients receiving immune checkpoint inhibitors (ICI). We deployed a validated AI model of left ventricular systolic dysfunction (LVSD) to ECG images (≥0.1, positive screen) and explored the association between the model’s predictions and: i) global longitudinal strain (GLS) measurements within 15 days; ii) future CTRCD (new cardiomyopathy, heart failure, or left ventricular ejection fraction (LVEF) decrease to <50%), and LVEF decrease <40%. In a negative control analysis of patients receiving ICI, we correlated baseline AI-ECG LVSD predictions with downstream myocarditis.

Results Higher AI-ECG LVSD predictions were associated with progressively worse GLS (−18% [IQR: −20 to −17%] for AI-ECG predictions <0.1, to −12% [-15 to −9%] for ≥0.5 (p<0.001), n=7,271). In 1,308 patients receiving AC/TZM (age 59 [IQR 49-67] years, 999 [76.4%] women, 80 [IQR 42-115] follow-up months) a positive baseline AI-ECG LVSD screen was associated with ∼2-fold and ∼4.8-fold increase in the incidence of CTRCD (HRadjusted 2.22 [95%CI: 1.63-3.02]), and LVEF <40% (HRadjusted 4.76 [95%CI: 2.62-8.66], p<0.001), respectively. Among 2,056 patients receiving ICI (age 65 [IQR 57-73] years, 913 (44.4%) women, follow-up 63 [IQR 28-99] months) AI-ECG predictions were not associated with ICI myocarditis risk (HRadjusted 1.36 [0.47-3.93]).

Conclusion AI applied to baseline ECG images can stratify the risk of CTRCD associated with anthracycline or trastuzumab exposure.

CONDENSED ABSTRACT There is an unmet need for scalable and affordable biomarkers to stratify the risk of cancer therapeutics-related cardiac dysfunction (CTRCD). In this hospital system-based, decade-long cohort of patients without cardiomyopathy receiving anthracyclines or trastuzumab, a validated artificial intelligence algorithm applied to baseline electrocardiographic (AI-ECG) images identified individuals with a 2-fold and 4.8-fold risk of developing any cardiomyopathy or left ventricular ejection fraction <40%, respectively. This supports a role for AI-ECG interpretation of images as a scalable approach for the baseline risk stratification of patients initiating cardiotoxic chemotherapy.

Competing Interest Statement

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 U.S. Provisional Patent Applications 63/177,117, 63/428,569, 63/346,610, 63/484,426, and 63/508,315, and a co-founder of Ensight-AI, Inc. R.K. and E.K.O. are co-founders of Evidence2Health, a health analytics company. E.K.O. is a co-inventor in patent applications (US17/720,068, 63/619,241, 63/177,117, 63/580,137, 63/606,203, 63/619,241, WO2018078395A1, WO2020058713A1), has been an ad hoc consultant for Caristo Diagnostics, Ltd, and has received royalty fees from technology licensed through the University of Oxford. H.M.K. works under contract with the Centers for Medicare & Medicaid Services to support quality measurement programs, was a recipient of a research grant from Johnson & Johnson, through Yale University, to support clinical trial data sharing; was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; receives payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation, from the Martin Baughman Law Firm for work related to the Cook Celect IVC filter litigation, and from the Siegfried and Jensen Law Firm for work related to Vioxx litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; was a member of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science, the Advisory Board for Facebook, and the Physician Advisory Board for Aetna; and is the co-founder of Hugo Health, a personal health information platform, and co-founder of Refactor Health, a healthcare AI-augmented data management company, and Ensight-AI, Inc. All other authors declare no competing interests.

Funding Statement

This study did not receive any funding.

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 study has been approved by the Yale School of Medicine Institutional Review Board.

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

Footnotes

Disclosures: 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 U.S. Provisional Patent Applications 63/177,117, 63/428,569, 63/346,610, 63/484,426, and 63/508,315, and a co-founder of Ensight-AI, Inc. R.K. and E.K.O. are co-founders of Evidence2Health, a health analytics company. E.K.O. is a co-inventor in patent applications (US17/720,068, 63/619,241, 63/177,117, 63/580,137, 63/606,203, 63/619,241, WO2018078395A1, WO2020058713A1), has been an ad hoc consultant for Caristo Diagnostics, Ltd, and has received royalty fees from technology licensed through the University of Oxford. H.M.K. works under contract with the Centers for Medicare & Medicaid Services to support quality measurement programs, was a recipient of a research grant from Johnson & Johnson, through Yale University, to support clinical trial data sharing; was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; receives payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation, from the Martin Baughman Law Firm for work related to the Cook Celect IVC filter litigation, and from the Siegfried and Jensen Law Firm for work related to Vioxx litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; was a member of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science, the Advisory Board for Facebook, and the Physician Advisory Board for Aetna; and is the co-founder of Hugo Health, a personal health information platform, and co-founder of Refactor Health, a healthcare AI-augmented data management company, and Ensight-AI, Inc. All other authors declare no competing interests.

Data Availability

All data produced in the present study are available upon reasonable request to the authors

ABBREVIATIONS LISTACanthracyclinesAIartificial intelligenceCCS(R)Clinical Classification Software (Refined)CIconfidence intervalCTRCDcancer therapeutics-related cardiac dysfunctionECGelectrocardiographyEHRelectronic health recordGLSglobal longitudinal strainHER2human epidermal growth factor receptor-2 (HER2) receptor inhibitorsHRhazard ratioICDInternational Classification of DiseasesICIimmune checkpoint inhibitorsIQRinterquartile rangeLVSDleft ventricular systolic dysfunction.