Functional autoantibodies and coronary microvascular obstruction in STEMI: a translational link between immune mechanisms and prognostic outcomes

TL;DR

This study shows that certain autoantibodies can damage heart microvessels in STEMI patients, leading to poor outcomes and suggesting new treatment strategies.

Contribution

The study demonstrates a direct causal link between agonistic autoantibodies and coronary microvascular injury in STEMI patients.

Findings

Higher autoantibody titers correlate with increased CMVO and worse clinical outcomes in STEMI patients.

Patient-derived immunoglobulins induce endothelial dysfunction and oxidative stress in vitro.

Pharmacological blockade of AT1R and ETAR reduces endothelial injury and oxidative stress.

Abstract

Despite timely primary percutaneous coronary intervention, coronary microvascular obstruction (CMVO) continues to limit myocardial reperfusion and worsen prognosis in patients with ST-elevation myocardial infarction (STEMI). Agonistic autoantibodies targeting the angiotensin II type 1 (AT1R) and endothelin-1 type A (ETAR) receptors have been associated with CMVO, but whether they directly contribute to microvascular injury remains unclear.

We prospectively enrolled 287 STEMI patients and evaluated CMVO, left ventricular remodeling, and major adverse cardiovascular events during a median follow-up of 460 days. Immunoglobulins were isolated from a subset of patients with the highest AT1R-AA and ETAR-AA titers and from seronegative controls. Human cardiac microvascular endothelial cells were exposed to patient-derived or control immunoglobulins, with or without pharmacological receptor blockade.

Patients with higher autoantibody titers showed a greater prevalence of CMVO and worse clinical outcomes. In vitro, immunoglobulins from seropositive patients rapidly induced endothelial dysfunction, characterized by cytoskeletal disorganization, junctional disruption, endothelial activation, and increased mitochondrial oxidative stress. These alterations were most pronounced at 24 hours and progressed to reduced cell viability and increased cytotoxicity at 48 hours. Immunoglobulins from seronegative controls had no relevant effects. Blockade of AT1R and ETAR significantly mitigated endothelial injury and oxidative stress.

Agonistic autoantibodies against AT1R and ETAR directly damage coronary microvascular endothelium and reproduce key features of CMVO observed in STEMI patients. These findings support a clinically relevant, immune-mediated mechanism of microvascular injury and suggest that receptor antagonism represents a biologically plausible, receptor-dependent mechanism warranting further investigation as a potential microvascular protective strategy in high-risk STEMI patients.

Figures