Cardiac sarcoidosis (CS) is one of the most challenging inflammatory heart diseases to diagnose and understand. Its true prevalence is difficult to determine, in large part because the disease is frequently missed or recognised late. CS often develops without pain or obvious early symptoms, yet over time it can lead to irreversible heart failure, dangerous arrhythmias, and sudden cardiac death. Despite these serious consequences, progress has long been limited by the lack of sensitive diagnostic tools and faithful models for studying the disease in human tissue.
A new study led by researchers at Wesley Research Institute, published in the European Heart Journal—one of the world’s most widely read cardiology journals—marks a significant advance. Titled “Cardiac sarcoidosis: new insights beyond the granuloma using spatial proteomics,” the study provides the first spatially resolved map of immune activity in cardiac sarcoidosis, revealing disease processes that extend well beyond the traditional diagnostic focus on granulomas.
A Disease That Often Goes Undetected
Diagnosing cardiac sarcoidosis remains notoriously difficult. Clinicians typically rely on heart biopsies to detect granulomas, which are small clusters of inflammatory cells that define sarcoidosis. However, granulomas are patchy and unpredictably distributed throughout the heart, meaning they are frequently missed during routine biopsy.
As a result, only around 20% of clinical heart biopsies successfully capture a granuloma. Many patients experience prolonged diagnostic delays and are only diagnosed after severe complications develop, including advanced heart failure, life-threatening arrhythmias, heart transplantation, or even sudden death.
These delays have serious consequences: untreated inflammation can lead to irreversible cardiac damage and missed opportunities for early intervention.
A New Approach: High-Plex Spatial Protein Analysis
Because no reliable animal models exist for sarcoidosis, researchers must study the disease directly in human tissue, often relying on archived clinical biopsy samples stored in pathology departments. Until recently, these preserved tissues were largely inaccessible for deep molecular and mechanistic analysis.
In this study, researchers applied high-plex digital spatial proteomics, an advanced technology that enables simultaneous measurement of dozens of proteins within intact tissue while preserving spatial context and cellular relationships. This allowed the team to examine immune activation, tissue injury, and repair processes across different regions of the heart at an unprecedented level of detail.
Key Findings
The study revealed three major insights that fundamentally reshapes current understanding of cardiac sarcoidosis:
1. Disease activity extends far beyond visible granulomas
Even in regions of heart tissue that appeared normal under conventional microscopy, the researchers identified strong immune, fibrotic, and metabolic signatures unique to cardiac sarcoidosis. These areas, which under traditional sarcoidosis diagnostic thinking would have been considered ‘disease-free’, were in fact biologically active and engaged in ongoing immune and injury-response processes. These results reframe how we think about sarcoidosis, demonstrating that the disease effects are far more widespread than previously recognised.
2. Granuloma-independent diagnostic signals can identify disease
The distinct disease signatures detected with the advanced ‘spatial biology’ methods used in this research were able to reliably distinguish cardiac sarcoidosis tissue from non-sarcoidosis heart failure tissue – even in samples where granulomas were completely absent. This finding challenges long-standing granuloma-centric diagnostic paradigms and opens the door for developing a new generation of diagnostic tools for sarcoidosis patients.
3. Dramatically improved diagnostic performance
Drawing on the previous finding, the researchers developed a simplified model based on the spatial protein signatures which best predicted sarcoidosis involvement. Compared with the approximately 20% sensitivity of traditional biopsy, the spatial proteomics approach demonstrated near-perfect diagnostic accuracy in this large and well-characterised cohort. This represents one of the strongest demonstrations to date that spatial biology profiling of human tissues can lead to clinically important breakthroughs for cardiovascular disease patients.
Research Impact: Beyond the Findings
This research fundamentally reshapes how clinicians and scientists understand cardiac sarcoidosis. By revealing that disease activity extends far beyond granulomas, the study provides a new scientific foundation for improving diagnostic sensitivity, reducing delays to treatment, and identifying patients at risk of progressive cardiac injury.
These findings represent a transformative step forward in how we diagnose and understand cardiac sarcoidosis.
Dr Eliot Peyster, Director of Cardiovascular Translational Medicine at Wesley Research Institute
“By revealing disease activity beyond granulomas, we can begin to develop more sensitive diagnostic tools and improve outcomes for patients who currently face prolonged uncertainty and risk.”
The authors acknowledge the collaborative contributions of researchers from Wesley Research Institute, the University of Pennsylvania, the Children’s Hospital of Philadelphia, and QIMR Berghofer.
Publication
Eliot G Peyster, David Smith, Therese Bittermann, Paco E Bravo, Kenneth B Margulies, Cardiac sarcoidosis: new insights beyond the granuloma using spatial proteomics, European Heart Journal, 2025;, ehaf990, https://doi.org/10.1093/eurheartj/ehaf990