Uncovering Distinct Phenotypes of Early Onset Heart Failure in Women
- 1Johns Hopkins University School of Medicine
Abstract
Background: Heart failure in younger women is understudied and may reflect heterogeneous pathways and risk not adequately captured by conventional classifications. We aimed to identify clinically distinct phenotypes of early-onset heart failure in women, assess their prognostic significance, and evaluate their transportability in an independent national cohort. Methods: We identified women aged 18-55 years with heart failure using electronic health record data from a large multi-hospital system. A variational deep embedding model incorporating 283 clinical features was used for unsupervised phenotyping. Associations with subsequent inpatient hospitalization, emergency department utilization, and mortality were evaluated using age-stratified Cox models. Phenotype transportability was assessed by both applying the institutionally trained model and by independent de novo clustering as a replication analysis in the All of Us cohort. Results: Among 1,407 young women with heart failure (median age, 45 years), four phenotypes were identified: hypertensive pregnancy (n=494), cardiorenal (n=276), autoimmune (n=394), and cardiometabolic-ischemic (n=243), with a bootstrap adjusted Rand index of 0.65 and silhouette score of 0.45. Compared with the hypertensive pregnancy phenotype, risks of inpatient hospitalization were highest for the cardiorenal (HR 2.86 [95% CI, 2.35?3.49]) and autoimmune (HR 2.25 [95% CI, 1.87?2.70]) phenotypes; mortality risks were similarly elevated (HR 4.65 [95% CI, 3.17?6.82] and HR 4.38 [95% CI, 3.03?6.31], respectively) in these two groups. In All of Us participants (n=682), transferred phenotypes retained their principal clinical characteristics and continued to stratify hospitalization risk. Independent clustering most strongly reproduced the cardiorenal phenotype (Jaccard index, 0.744). Conclusions: Early-onset heart failure in women comprises distinct cardio-obstetric, cardiorenal, autoimmune, and cardiometabolic-ischemic phenotypes with divergent clinical outcomes. These findings support a life-course approach to heart failure classification in women that complements conventional frameworks and incorporates pregnancy history and female-predominant systemic conditions.
Related
- Adolescent and Early-Onset Adenomyosis: Phenotypes, Diagnostic Challenges, and Fertility-Conscious Care.
- Distinct risk profiles of heart failure and non-heart failure major adverse cardiovascular events among patients with early breast cancer: a competing-risk analysis
- Distinct NGS mutational landscape and prognostic implications in early-onset colorectal cancer: A dual-cohort analysis of TCGA PanCancer Atlas and MSK-IMPACT 50K
- AN INTEGRATED HEART-ON-A-CHIP NAM RESOLVES DISTINCT CLINICAL PHENOTYPES OF MYOCARDIAL ISCHEMIA-REPERFUSION INJURY
- Blood Cytokine Profiling Reveals Distinct Inflammatory Signatures in Phenotypes A and B of Polyendocrine Metabolic Ovarian Syndrome (PMOS; formerly PCOS).
BibTeX
@misc{khorsandi2026uncovering,
title = {{Uncovering Distinct Phenotypes of Early Onset Heart Failure in Women}},
author = {J. Khorsandi and Y. Yu and D. Tinnium and S. Ganesh and R. Alahapphan and P. Oyinloye and K. Mueller and S. Ardekani and C. O. Taylor and J. L. Greenstein and C. E. Ndumele and E. D. Michos and C. N. Bairey Merz and R. B. Barrett and A. S. Minhas},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.26367323},
url = {https://www.medrxiv.org/content/10.64898/2026.11.04.26367323v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Uncovering Distinct Phenotypes of Early Onset Heart Failure in Women
AU - J. Khorsandi
AU - Y. Yu
AU - D. Tinnium
AU - S. Ganesh
AU - R. Alahapphan
AU - P. Oyinloye
AU - K. Mueller
AU - S. Ardekani
AU - C. O. Taylor
AU - J. L. Greenstein
AU - C. E. Ndumele
AU - E. D. Michos
AU - C. N. Bairey Merz
AU - R. B. Barrett
AU - A. S. Minhas
PY - 2026
DA - 2026/11/04
PB - medRxiv
DO - 10.64898/2026.11.04.26367323
UR - https://www.medrxiv.org/content/10.64898/2026.11.04.26367323v1
AB - Background: Heart failure in younger women is understudied and may reflect heterogeneous pathways and risk not adequately captured by conventional classifications. We aimed to identify clinically distinct phenotypes of early-onset heart failure in women, assess their prognostic significance, and evaluate their transportability in an independent national cohort. Methods: We identified women aged 18-55 years with heart failure using electronic health record data from a large multi-hospital system. A variational deep embedding model incorporating 283 clinical features was used for unsupervised phenotyping. Associations with subsequent inpatient hospitalization, emergency department utilization, and mortality were evaluated using age-stratified Cox models. Phenotype transportability was assessed by both applying the institutionally trained model and by independent de novo clustering as a replication analysis in the All of Us cohort. Results: Among 1,407 young women with heart failure (median age, 45 years), four phenotypes were identified: hypertensive pregnancy (n=494), cardiorenal (n=276), autoimmune (n=394), and cardiometabolic-ischemic (n=243), with a bootstrap adjusted Rand index of 0.65 and silhouette score of 0.45. Compared with the hypertensive pregnancy phenotype, risks of inpatient hospitalization were highest for the cardiorenal (HR 2.86 [95% CI, 2.35?3.49]) and autoimmune (HR 2.25 [95% CI, 1.87?2.70]) phenotypes; mortality risks were similarly elevated (HR 4.65 [95% CI, 3.17?6.82] and HR 4.38 [95% CI, 3.03?6.31], respectively) in these two groups. In All of Us participants (n=682), transferred phenotypes retained their principal clinical characteristics and continued to stratify hospitalization risk. Independent clustering most strongly reproduced the cardiorenal phenotype (Jaccard index, 0.744). Conclusions: Early-onset heart failure in women comprises distinct cardio-obstetric, cardiorenal, autoimmune, and cardiometabolic-ischemic phenotypes with divergent clinical outcomes. These findings support a life-course approach to heart failure classification in women that complements conventional frameworks and incorporates pregnancy history and female-predominant systemic conditions.
ER -