The presenter of today’s ESC William Harvey Lecture in Basic Science is Professor Matthias Nahrendorf (Massachusetts General Brigham, Harvard Medical School - Boston, USA), whose work has accelerated our understanding of the role of immunity in CVD. He describes an emerging view in which cardiac immune cells are not simply bystanders but actively create the structural and electrical conditions that maintain, but also disturb, the heart’s rhythm.
“In one of our first studies in this area, we showed that macrophages are involved in normal and aberrant cardiac conduction. This was noted following ECG observations consistent with an AV block in a murine model of macrophage depletion [1]. We next focused on atrial fibrillation (AF) – which often occurs during inflammatory crises – and deciphered the contribution of immune and stromal cells. Single-cell analysis of atrial tissue from patients with persistent AF revealed a prominent macrophage population expressing SPP1, which encodes osteopontin, a signalling protein linked to inflammation and fibrosis. In a murine model of human atrial disease, incorporating hypertension, obesity and mitral valve regurgitation, we demonstrated that recruited macrophages and macrophage-derived osteopontin promote fibroblast activation, atrial scarring and susceptibility to AF [2].
The next step was to develop an antibody–siRNA conjugate (ARC) drug candidate to silence SPP1 [3]. The ARC relies on an anti-TREM2 antibody for delivering SPP1-targeted siRNA to the pathogenic macrophage subset. The ARC specifically targeted atrial TREM2+ macrophages, reducing osteopontin production, fibroblast activation, atrial fibrosis and AF in mice [3]. It also achieved target silencing in human myocardial tissue in vitro.
The treatment of post-MI ventricular tachycardia (VT) represents another area of clinical unmet need. In our studies using murine models, neutrophils were found to release a non-specific antibacterial protein, resistin-like molecule γ (RELMγ), that becomes misdirected towards stressed cardiomyocytes, causing membrane leakage, abnormal electrical activity, cell death and VT [4]. The corresponding human protein, resistin, shows similar membrane-damaging activity. Notably, we were able to show that preventing RELMγ production within acute infarcts in mice reduced VT occurrence.
Agents targeting immune components already provide important treatment approaches in disease areas, such as oncology. Our studies indicate that there is no reason to believe that we cannot achieve something similar for arrhythmias.”
