For decades, B-type natriuretic peptide has served as our primary molecular window into heart failure severity. BNP and its N-terminal fragment have guided countless clinical decisions, from emergency department triage to outpatient medication titration. Yet this single biomarker approach increasingly reveals its limitations as we recognize heart failure not as one disease, but as a heterogeneous syndrome with fundamentally distinct molecular architectures.

High-throughput proteomic platforms now enable simultaneous measurement of thousands of circulating proteins, revealing molecular signatures that stratify patients into phenotypically distinct subtypes. These aren't merely academic classifications—they represent fundamentally different pathophysiological processes requiring different therapeutic strategies. A patient whose proteomic profile signals inflammation-predominant disease may derive minimal benefit from intensifying neurohormonal blockade while potentially responding dramatically to targeted anti-inflammatory intervention.

The clinical translation of proteomics represents precision medicine's next frontier in cardiovascular care. Emerging platforms like SomaScan and Olink Explore can quantify 5,000+ proteins from a single blood sample, generating molecular portraits of unprecedented resolution. The challenge now shifts from technical capability to clinical implementation: identifying which proteomic signatures predict therapeutic response, validating these panels across diverse populations, and integrating them into treatment algorithms that genuinely personalize care rather than merely adding laboratory complexity.

Unsupervised clustering analyses of proteomic data consistently identify at least three major heart failure molecular subtypes, each characterized by distinctive protein expression patterns reflecting different predominant pathophysiology. Inflammation-predominant phenotypes show elevated C-reactive protein, tumor necrosis factor receptors, interleukins, and complement pathway components. Fibrosis-predominant subtypes demonstrate increased collagen processing markers, matrix metalloproteinases, and profibrotic growth factors. Metabolic dysfunction phenotypes feature altered adipokines, insulin signaling proteins, and mitochondrial enzyme profiles.

These molecular classifications transcend traditional clinical phenotyping based on ejection fraction, symptom severity, or comorbidity burden. Patients with identical New York Heart Association class and similar BNP levels may harbor fundamentally different proteomic signatures. The HFpEF population demonstrates particular heterogeneity, with proteomics revealing subgroups that clinical assessment alone cannot distinguish. This explains decades of neutral therapeutic trials—we've been treating molecularly distinct diseases as if they were one.

The PHFS-BIO study demonstrated that proteomic subtyping predicts clinical trajectory independent of established risk scores. Patients classified as inflammation-predominant experienced higher rates of hospitalization and mortality even after adjustment for clinical variables. More critically, response to therapeutic interventions varied dramatically by molecular subtype. Spironolactone benefit concentrated in the metabolic dysfunction subtype, while inflammation-predominant patients showed minimal response.

Fibrosis-predominant heart failure presents unique challenges and opportunities. These patients typically demonstrate progressive structural remodeling with elevated soluble ST2, galectin-3, and carboxy-terminal propeptide of procollagen type I. Traditional neurohormonal antagonism may slow but not reverse established fibrosis. Emerging antifibrotic strategies—including pirfenidone and selective tyrosine kinase inhibitors—show promise specifically in this molecular subtype, though prospective trials stratified by proteomic phenotype remain ongoing.

The practical implication is profound: molecular subtyping should precede therapeutic intensification. A patient failing standard therapy may not need more aggressive neurohormonal blockade—they may need phenotype-directed treatment addressing their specific underlying pathophysiology. This represents a fundamental paradigm shift from treating heart failure as a syndrome to treating the individual patient's molecular disease.

Takeaway

Heart failure comprises at least three molecularly distinct subtypes—inflammation-predominant, fibrosis-predominant, and metabolic dysfunction—each requiring different therapeutic strategies that proteomic profiling can identify before treatment selection.

While comprehensive proteomic platforms remain research tools, several specific biomarkers have accumulated sufficient validation evidence to inform clinical decision-making today. Galectin-3 reflects myocardial fibrosis and inflammatory activation, with levels above 17.8 ng/mL associated with substantially increased mortality risk. Unlike BNP, galectin-3 changes slowly, making it valuable for tracking disease trajectory over months rather than acute decompensation.

Soluble ST2 has emerged as perhaps the most promising single addition to standard biomarker assessment. This interleukin-1 receptor family member reflects myocardial stress and fibrosis independent of renal function—a critical advantage over natriuretic peptides. The PARADIGM-HF and ATMOSPHERE trials demonstrated that baseline and serial sST2 measurements provided incremental prognostic information beyond NT-proBNP, with sST2 reductions correlating with improved outcomes.

Growth differentiation factor-15 integrates signals from inflammation, oxidative stress, and metabolic dysfunction. GDF-15 levels predict mortality across heart failure phenotypes but particularly identify patients with metabolic dysfunction subtypes. Importantly, GDF-15 responds to metabolic interventions including SGLT2 inhibitors and weight reduction, potentially serving as a pharmacodynamic biomarker for metabolic therapies.

The clinical utility of multi-biomarker panels exceeds that of individual markers. The PARADIGM-HF biomarker substudy showed that combining NT-proBNP, high-sensitivity troponin T, and GDF-15 created a composite score that stratified patients into risk categories with dramatic outcome differences. Patients in the highest tertile for all three markers experienced 8.5-fold higher cardiovascular death rates than those in the lowest tertile for all markers.

Current guidelines from the American College of Cardiology acknowledge sST2 and galectin-3 as adjunctive prognostic markers, though specific therapeutic decision algorithms remain under development. The practical approach involves measuring these biomarkers at stable baseline, repeating them after therapeutic interventions, and using trajectories—not single values—to guide treatment intensity and patient counseling.

Takeaway

Galectin-3, soluble ST2, and GDF-15 provide validated prognostic information beyond BNP, with sST2 demonstrating particular value for its renal function independence and responsiveness to therapeutic intervention.

Proteomic phenotyping's ultimate value lies in guiding therapeutic selection rather than merely refining prognosis. Neurohormonal blockade—the foundation of heart failure pharmacotherapy—provides greatest benefit in patients without overwhelming inflammation or established fibrosis. Proteomic profiles showing primary neurohormonal activation without prominent inflammatory or fibrotic signatures predict robust response to ACE inhibitors, ARBs, beta-blockers, and mineralocorticoid receptor antagonists.

Anti-inflammatory approaches show particular promise in inflammation-predominant phenotypes. The CANTOS trial demonstrated that interleukin-1β inhibition reduced heart failure hospitalization in patients with elevated high-sensitivity CRP. Proteomics can identify which patients have inflammation as primary driver versus epiphenomenon, potentially selecting responders to colchicine, IL-1 antagonists, or other anti-inflammatory strategies while sparing non-inflammatory phenotypes from ineffective treatment.

Metabolic modulators including SGLT2 inhibitors have demonstrated remarkable benefits across heart failure populations, but proteomic evidence suggests particularly dramatic responses in metabolic dysfunction subtypes. Patients with elevated GDF-15, disturbed adipokine profiles, and insulin resistance signatures may represent an especially responsive population. The ongoing DELIVER and EMPEROR-Preserved trials' proteomic substudies will illuminate whether molecular phenotyping enhances treatment effect prediction.

For fibrosis-predominant phenotypes, emerging antifibrotic agents offer hope beyond current options. Pirfenidone, approved for pulmonary fibrosis, demonstrates cardiac antifibrotic effects in preclinical models and early-phase trials. Selective application to patients whose proteomic profiles confirm active fibrogenesis could maximize benefit-risk ratios. Similarly, galectin-3 inhibitors enter clinical development with proteomics-guided patient selection strategies.

Implementation requires integrating proteomic results into therapeutic algorithms. A practical framework: patients with inflammation-predominant profiles warrant aggressive anti-inflammatory consideration before or alongside neurohormonal optimization. Fibrosis-predominant patients should be monitored for emerging antifibrotic trial eligibility while maximizing conventional therapy. Metabolic dysfunction phenotypes may particularly benefit from early SGLT2 inhibitor initiation and comprehensive metabolic optimization including weight management and glucose control.

Takeaway

Proteomic phenotyping enables prospective treatment matching—selecting neurohormonal blockade for neurohormonal phenotypes, anti-inflammatory strategies for inflammation-predominant disease, and metabolic modulators for metabolic dysfunction subtypes.

The transition from BNP-centric assessment to comprehensive proteomic phenotyping represents heart failure medicine's evolution from syndrome management to precision therapeutics. We now possess the technical capability to classify patients by molecular architecture, identifying inflammation, fibrosis, and metabolic dysfunction as distinct therapeutic targets rather than indistinguishable contributors to a single syndrome.

Clinical implementation proceeds along parallel tracks: validated single biomarkers like sST2, galectin-3, and GDF-15 offer immediately actionable prognostic refinement, while comprehensive proteomic platforms advance through validation studies toward eventual clinical deployment. The key insight is that these approaches complement rather than replace clinical judgment—they reveal the molecular reality underlying patients' presentations.

For practitioners managing complex heart failure cases, the actionable message is clear: consider multi-biomarker assessment beyond natriuretic peptides, recognize that treatment non-response may reflect phenotype mismatch rather than disease severity, and anticipate a future where proteomic profiling guides first-line therapy selection. The era of phenotype-directed heart failure care has begun.