Normal abundance of immune cells in left ventricular myocardium from patients with heart failure and preserved ejection fraction

AIMS: Myocardial inflammation has been proposed as a central mechanism in heart failure with preserved ejection fraction (HFpEF), supported by experimental work suggesting immune cell-mediated activation of pro-fibrotic signalling. However, bulk transcriptomic analyses of human HFpEF myocardium did not demonstrate an activation of pro-inflammatory mediators or pathways. Here we investigated whether immune cell enrichment is present in human HFpEF myocardium. METHODS: We analysed left ventricular (LV) epicardial biopsies from 28 adults undergoing elective coronary artery bypass grafting with preserved LV ejection fraction (≥50%). Participants were classified as referent controls (n = 10), preclinical HFpEF Stage B (n = 10), or overt HFpEF Stage C (n = 8). High-resolution spatial transcriptomics and quantitative immunofluorescence for CD45, CD68, and CD3G were used to determine the abundance and phenotypic composition of immune lineage cells. RESULTS: Heart failure with preserved ejection fraction patients were older and more obese when compared to control subjects. Spatial transcriptomic profiling revealed normal immune cell abundances across all groups (mean 0.68 ± 0.52% in controls, 0.90 ± 0.49% in HFpEF Stage B, and 0.78 ± 0.29% in HFpEF Stage C; P = NS), without differences in immune cell subsets or adaptive immune cell signatures. Immunofluorescence confirmed the absence of differences. CONCLUSIONS: Spatially resolved human myocardial profiling did not demonstrate an increase in immune lineage cells in preclinical or overt HFpEF, challenging the concept that myocardial immune cell infiltration is a major driver of HFpEF. These findings support a model in which haemodynamic load and systemic factors, rather than local immune cell expansion, drive myocardial hypertrophy and fibrosis in HFpEF.