Improved outcome up to ten years after intravenous immunoglobulin therapy in patients with dilated cardiomyopathy

BACKGROUND AND AIMS: A previous trial of intravenous immunoglobulin therapy (IVIg) added to guideline-directed medical therapy (GDMT) in patients with dilated cardiomyopathy (DCM) and cardiac parvovirus-B19 (B19V) persistence showed no improvement of cardiac function at six months follow-up. We investigated whether IVIg confers long-term clinical benefits and analyzed its molecular and cellular effects in cardiac tissue to elucidate the immunomodulatory mechanisms underlying the observed long-term clinical improvement. METHODS: Fifty patients with DCM and cardiac B19V were blindly randomized to receive either IVIg (n=26; 2g/kg/day over 4 days) or placebo (n=24). The composite clinical endpoint–cardiac death, heart failure hospitalization, and life-threatening arrhythmia–was assessed after a median follow-up of 6.8 [5.6-10.3] years. To investigate IVIg-associated molecular changes in the heart, single-nuclear RNA sequencing (snRNA-seq) sequencing on endomyocardial biopsies (EMB) obtained at baseline (prior to treatment) and at six months after randomization was performed. RESULTS: The IVIg group experienced fewer composite endpoint events (n=1/26) than the placebo group (8/24; p=0.0075). Comparison of baseline and six-month EMBs by snRNA-seq showed that IVIg treatment reduced cardiac monocyte infiltration and, unlike placebo, prevented the expansion of injured cardiomyocytes. IVIg induced transcriptomic reprogramming across immune cells, fibroblasts, and cardiomyocytes, including diminished myeloid-to-fibroblast signaling with reduced TGFβ activity, decreased pro-fibrotic and pro-inflammatory pathways and metabolic shifts in cardiomyocytes characterized by enhanced oxidative phosphorylation. CONCLUSION: In patients with DCM and cardiac B19V persistence, IVIg added to GDMT correlated with improved long-term clinical outcome. IVIg may attenuate myeloid-driven fibrosis formation and mitigate cardiomyocyte deterioration.