Lungs: The Unsung Heroes in Heart Failure?
"New research reveals the surprising role of lungs in producing a key heart failure marker, opening doors to novel treatment strategies."
Heart failure, a condition where the heart struggles to pump enough blood to meet the body's needs, is a leading cause of disability and death worldwide. Scientists are constantly seeking new ways to understand and combat this complex disease. One area of intense research focuses on a molecule called ST2 (interleukin-1 receptor-like 1), a known prognostic marker in heart conditions.
While traditionally linked to the heart, recent evidence suggests that ST2 production might extend beyond the heart itself. This raises an important question: Could other organs be contributing to the levels of ST2 in the body, and if so, what impact might that have on heart failure?
New research has pinpointed the lungs as a significant, previously underestimated source of ST2 in heart failure. This discovery challenges existing views of the disease and opens exciting new avenues for developing targeted therapies to improve outcomes for patients.
U.S. Heart Failure Statistics
The Heart Failure Society of America’s HF Stats report is an annually updated reference on U.S. heart-failure epidemiology and outcomes. Its 2026 update covers risk, incidence, prevalence, mortality, hospitalizations, current treatment, and cost. The 2024 report highlighted worsening burden, particularly among younger people, racial and ethnic minority groups, and people with multiple health conditions.
ST2 as an Adjunct Biomarker
Soluble ST2 (sST2) reflects processes including myocardial stretch and inflammation, and ST2/IL-33 signaling can modulate cardiac hypertrophy and fibrosis. It is recognized as an adjunct for prognosis and monitoring, and was included in the 2017 American College of Cardiology/American Heart Association heart-failure guideline update. Sources describe sST2 as useful for assessing acute heart failure and predicting chronic heart-failure outcomes, but the supplied material does not specify limitations of established methods.
From Dropsy to Hemodynamics
A 2025 century-view account traces heart failure’s history from 17th-century dropsy, treated with bloodletting, leeching, and lancing, to foundational advances in cardiovascular understanding. It describes William Harvey’s early accounts of circulation and Frank-Starling’s laws of hemodynamics. Starling’s observations connected end-diastolic volume with cardiac performance, helping establish a physiological framework for understanding heart function.
How Lungs Contribute to Heart Failure: The ST2 Connection
The study, published in Circulation: Heart Failure, used an experimental model of ischemic heart failure to investigate ST2 production in various organs. Researchers measured ST2, its membrane-bound form (ST2L), and a related molecule called IL-33 in the lungs, heart, kidneys, and liver at different stages of heart failure. They also examined lung tissue and cells from patients with and without heart failure.
- Lungs step up: In the experimental model, ST2 levels increased significantly in the lungs early in heart failure.
- Heart's response: While ST2 also increased in the heart, the related molecules ST2L and IL-33 responded differently in the lungs and heart, suggesting distinct regulatory mechanisms.
- Lung cells pitch in: ST2 was found to be produced by type II pneumocytes, specialized cells in the lungs responsible for gas exchange. When these cells were subjected to mechanical strain (simulating the stress of fluid buildup in the lungs during heart failure), they released even more ST2.
- Human connection: Analyzing lung fluid from patients with cardiogenic pulmonary edema (fluid buildup in the lungs due to heart failure), researchers found significantly higher ST2 levels compared to patients with lung problems from other causes.
Emerging Research on sST2
A review on biomarkers and AI describes heart failure as a leading cause of death and disability globally, estimating more than 56 million patients annually and projecting that occurrence will increase. Research on sST2 has also examined bronchial aspirates: one prospective study reported correlations between aspirate sST2, serum sST2, NT-proBNP, and cardiac troponin. A review of lung congestion and injury reports that type II alveolar cells have been identified as a major source of sST2 expression and synthesis in heart failure, and notes that PRIDE found sST2 strongly predicted one-year mortality in dyspnoeic patients with or without acute heart failure. A separate study reports predictive performance for mortality and heart-failure-related readmission or hospitalization, while calling for further validation in clinical practice.
Comparing Heart-Failure Biomarkers
A 2014 head-to-head analysis set out to compare soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), and highly sensitive troponin T (hsTnT), including the prognostic role of serial measurements in chronic heart failure. Natriuretic peptides have been widely recommended as the ideal biomarker in heart failure, while sST2 may be used alone or alongside them for prognosis. In a 2003 report cited in a later JACC article, short-term sST2 changes predicted mortality or transplantation in severe heart failure independently of natriuretic peptide levels.
What This Means for Heart Failure Treatment
This research suggests that the lungs are not merely passive bystanders in heart failure but active participants in the disease process. By identifying the lungs as a significant source of ST2, scientists gain a deeper understanding of the complex interplay between the heart and other organs in heart failure.
sST2’s Prognostic Promise
Reviews describe sST2 as associated with inflammatory and immune processes and examine its prognostic value in both acute and chronic heart failure. However, findings on its diagnostic performance have been inconsistent across studies, prompting a meta-analysis of its diagnostic value in heart failure. Taken together, the supplied sources support continued evaluation of sST2 as a prognostic biomarker while indicating that its diagnostic role remains unsettled.
This knowledge could lead to the development of new therapies specifically targeting ST2 production in the lungs. By reducing ST2 levels in the lungs, it might be possible to interrupt the harmful signaling pathways that contribute to heart failure progression and improve patient outcomes.
Future research will need to explore the precise mechanisms by which the lungs produce ST2 in heart failure and how this production contributes to overall disease severity. However, this study provides a compelling case for considering the lungs as a key player in heart failure and a potential target for future therapies.