Heart failure has always been classified by its causes: a blocked artery here, a stiffened or enlarged heart muscle there, a viral infection or an inherited cardiomyopathy somewhere else. But a sweeping new analysis of the proteins inside failing human hearts suggests that this clinical taxonomy may conceal a far more meaningful biological divide. In a study published in Nature Cardiovascular Research, researchers led by Omar Hamed, Cristine Reitz and Anthony Gramolini at the University of Toronto and the Ted Rogers Centre for Heart Research profiled the proteomes and phosphoproteomes of 149 patients with advanced heart failure spanning nine distinct clinical etiologies, and found that the disease collapses into two molecularly defined patient groups with markedly different biology and clinical trajectories.
The team began with a strikingly simple question: if you look at the complete inventory of proteins in a failing left ventricle, do hearts that failed for different reasons actually look different from one another? To answer it, they used high-resolution mass spectrometry to quantify 3,788 proteins in cardiac tissue samples collected from patients undergoing advanced care, alongside non-failing control hearts. The patients spanned ischemic cardiomyopathy, dilated and hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, myocarditis, adult congenital heart disease and non-ischemic dilated cardiomyopathy, among other diagnoses. Statistical models adjusted for age, sex and batch effects compared protein abundance in each etiology group against controls.
The first major finding was one of convergence. When patients were grouped by clinical diagnosis, the vast majority of significantly altered proteins were shared across etiologies rather than unique to any single one. Upset plots and enrichment analyses showed that common changes dwarfed diagnosis-specific ones, and functional enrichment mapped all the heart failure groups onto a shared landscape: metabolic reprogramming, altered contractile machinery, extracellular matrix remodeling and inflammatory signaling appeared everywhere. In other words, by the time the heart reaches end-stage failure, the terminal proteomic state looks remarkably similar regardless of what started the decline. This convergence echoes earlier single-nucleus RNA sequencing work, which likewise found common transcriptional signatures across cardiomyopathies, and it helps explain why a one-size-fits-all therapeutic approach has historically achieved only incremental gains.
But convergence at the disease endpoint was only half the story. When the researchers abandoned clinical labels altogether and let an unbiased computational method, non-negative matrix factorization, sort patients purely by proteomic similarity, the cohort split cleanly into two groups. Group 1 and Group 2, comprising 59 and 63 patients with reduced ejection fraction respectively, cut across every clinical etiology: a patient with ischemic disease and a patient with myocarditis could sit in the same molecular camp, while two patients with the same diagnosis could fall into opposing ones. The clustering was robust, reproducible in principal component analyses, and independent of demographic confounders.
What distinguished the two groups was not the cause of disease but the character of the heart’s remodeling response. Group 2 hearts were enriched for proteins derived from activated fibroblasts, smooth muscle cells and pro-inflammatory myeloid cells, signatures consistent with aggressive scar formation and immune infiltration. Overlaying the protein signatures onto a published atlas of 15 cardiac cell types from single-cell transcriptomics revealed that Group 2 mirrored the cellular states observed in dilated cardiomyopathy, including expansions of disease-associated cardiomyocyte populations, activated fibroblast states FB5 through FB9, and pro-inflammatory macrophages, monocytes and dendritic cells. Group 1, by contrast, retained a profile closer to non-failing tissue, relatively enriched for cardiomyocyte contractile and metabolic proteins. The subgrouping was independently validated in bulk RNA sequencing data from 198 heart failure samples in a public cohort, where the same protein signature reproduced the same molecular split at the transcript level.
The researchers then descended one level deeper into biology by profiling the phosphoproteome, the layer of phosphate tags that flip proteins on and off and transmit signals through kinases. From the same tissues they quantified 3,014 phosphosites, and the phosphorylation patterns reproduced the proteomic stratification, confirming that the two subgroups differ not only in which proteins they contain but in which signaling circuits are actually running. Critically, phosphoproteomics is where drug discovery lives: kinases, phosphatases and their downstream effectors are among the most pharmacologically tractable targets in medicine.
By integrating protein abundance, phosphosite regulation and prior knowledge networks of kinases, transcription factors and upstream regulators, the team identified selectively activated, druggable signaling networks confined to one molecular subgroup. Among the circuits implicated were RhoA and ROCK2 signaling, components of the actin cytoskeleton such as the Arp2/3 complex, and mitogen-activated protein kinase pathways including ERK1/2 and p38, alongside regulatory nodes such as glycogen synthase kinase 3 and RAF1. The researchers cross-referenced these targets against the Drug Repurposing Hub, ChEMBL, Open Targets and Mendelian randomization evidence for causal heart failure associations, filtering for known cardiac toxicity, and assembled a shortlist of candidate therapeutic entry points that would apply only to the molecularly defined patients whose networks show that activation. This is precision cardiology at the level of the cell’s control systems rather than its genome.
Perhaps the most clinically consequential result came from the UK Biobank. The remodeling-associated protein signature, originally discovered in end-stage explanted hearts, was tested against plasma proteomic data from an entirely independent cohort of heart failure patients who are, on average, at much earlier stages of disease and treated in the community rather than the transplant center. The signature stratified these patients into subgroups and predicted survival trajectories, with accelerated failure time modeling showing that the molecular group assignments carried prognostic information. This extends the relevance of the tissue-based findings far beyond the operating theater: a blood test grounded in the same biology may eventually help identify which ambulatory patients carry a fibrotic, inflammatory molecular phenotype and which do not.
The implications for drug development are considerable. Heart failure trials have long been plagued by modest average effect sizes, and a plausible explanation is that molecularly heterogeneous populations dilute real benefits among patients whose disease is not driven by the targeted pathway. If a candidate anti-fibrotic or kinase inhibitor benefits only Group 2 biology, enrolling an unstratified population would bury the signal. Stratifying trials by these protein-defined subgroups could sharpen effect estimates, reduce required sample sizes and rescue otherwise promising mechanisms. The prognostic signal in plasma also raises the prospect of patient stratification with routine blood draws rather than myocardial biopsy, something no clinician would contemplate for diagnosis in most heart failure settings.
The study also leaves open questions that will shape the next phase of work. The cohorts are dominated by end-stage disease and reduced ejection fraction, so the behavior of the subgrouping in heart failure with preserved ejection fraction remains untested. The two groups describe biology at a moment in time, and longitudinal studies will need to establish whether patients transition between molecular states as disease evolves, or whether subgroup membership is fixed from the outset. And while the plasma findings demonstrate prognostic value, translating them into a clinically deployable test will require targeted assays and prospective validation. Still, the message of the work is unambiguous: the failing heart’s molecular interior tells a story that diagnosis codes cannot, and listening to that story, in both tissue and blood, may finally make it possible to match heart failure therapies to the biology of the individual patient rather than the label on the chart.
Subject of Research: Molecular subgrouping of human heart failure by proteomic and phosphoproteomic profiling of cardiac tissue
Article Title: Cardiac proteomic and phosphoproteomic profiling defines clinically relevant molecular subgroups in human heart failure
Article References: Hamed, O., Reitz, C. J., Kuzmanov, U., Gramolini, S., Hu, M., Halpern, J., Billia, F., & Gramolini, A. O. (2026). Cardiac proteomic and phosphoproteomic profiling defines clinically relevant molecular subgroups in human heart failure. Nature Cardiovascular Research. https://doi.org/10.1038/s44161-026-00880-w
Image Credits: AI Generated
DOI: 10.1038/s44161-026-00880-w
Keywords: heart failure, proteomics, phosphoproteomics, cardiac remodeling, precision medicine, biomarkers, UK Biobank, fibrosis, kinase signaling, cardiomyopathy, left ventricle, mass spectrometry
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Ophelia Keating. (September 25, 2026). Two Molecular Heart Failure Types Revealed by Deep Protein Maps of the Failing Heart. Scienmag. https://scienmag.com/two-molecular-heart-failure-types-revealed-by-deep-protein-maps-of-the-failing-heart/
Ophelia Keating. “Two Molecular Heart Failure Types Revealed by Deep Protein Maps of the Failing Heart.” Scienmag, 25 September 2026, https://scienmag.com/two-molecular-heart-failure-types-revealed-by-deep-protein-maps-of-the-failing-heart/. Accessed 25 September 2026.
Ophelia Keating. “Two Molecular Heart Failure Types Revealed by Deep Protein Maps of the Failing Heart.” Scienmag. September 25, 2026. https://scienmag.com/two-molecular-heart-failure-types-revealed-by-deep-protein-maps-of-the-failing-heart/
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Tags: advanced heart failure patient stratificationbiological subtypes of heart failureBiomarkerscardiac remodelingcardiomyopathyclinical trajectories of molecular heart failure typesdeep protein mapping in heart diseasedistinct molecular signatures in cardiomyopathiesfibrosisheart failureheart failure proteomicshigh-resolution mass spectrometry in cardiologykinase signalingleft ventriclemass spectrometrymolecular classification of heart failuremolecular pathways in heart failurephosphoproteomicsphosphoproteomics of failing heartsPrecision medicineproteome profiling in cardiomyopathyproteomic biomarkers for heart failureProteomicsUK Biobank
