Immune-Driven Clinical Phenotypes and Outcomes in Heart Failure: A Structured Evidence Synthesis

Abstract

Background: Heart failure (HF) is increasingly recognized as an immune-mediated syndrome, where systemic inflammation, endothelial activation, and fibrotic remodeling influence prognosis. However, evidence linking specific immune biomarkers to clinical outcomes remains fragmented. Emerging multi-omic studies suggest that inflammatory and fibrotic signaling coexist in varying proportions across patients, indicating distinct immune–pathophysiologic phenotypes. Our work synthesized clinical evidence on immune biomarkers associated with mortality, hospitalization, and adverse remodeling in HF to define immune-driven phenotypes with prognostic relevance.

Methods: A structured literature synthesis was conducted across major databases for human HF studies published between 2015–2025 evaluating associations between immune-related biomarkers and clinical outcomes. Data were extracted from high-quality observational and clinical trial studies. Biomarkers were grouped by dominant immune pathway, and outcome patterns were summarized through descriptive qualitative analysis to identify reproducible phenotype–outcome relationships.

Results: We identified three reproducible immune-linked phenotypes in heart failure. The inflammation-dominant phenotype, characterized by elevated interleukin-6 (IL-6) and neutrophil-to-lymphocyte ratio (NLR), was consistently associated with higher all-cause mortality and recurrent hospitalization, reflecting systemic immune activation. The fibrosis-dominant phenotype, marked by increased galectin-3, correlated with progressive myocardial fibrosis, reduced reverse remodeling, and elevated risk of both mortality and subsequent HF hospitalizations, suggesting a maladaptive structural remodeling pathway. Finally, the endothelial-dysfunction phenotype, defined by raised VCAM-1 and ICAM-1 levels, indicated microvascular inflammation and impaired endothelial signaling, and was linked to reduced functional capacity and greater rehospitalization risk.Together, these phenotypes represent overlapping yet distinct immune axes driving HF progression and may explain heterogeneity in clinical trajectories. Across studies, these biomarkers added prognostic value beyond natriuretic peptides, particularly in HFpEF.

Conclusion: Distinct immune-driven phenotypes, characterized by inflammation, fibrosis, or endothelial dysfunction, are linked to specific HF outcomes. Recognizing these patterns leads to more tailored risk stratification, monitoring, and therapeutic decision-making in heart failure management.