Neural Mechanisms of Heart-Lung Crosstalk in Chronic Heart Failure

The cardiac sympathetic afferent reflex and pulmonary spinal afferent reflex amplify sympathetic activity and may contribute to chronic heart failure. We hypothesized that cardiac injury triggers a cardiac nerve-mediated cytokine uptake cascade that propagates neural inflammation in thoracic dorsal root ganglia (DRGs) and drives reciprocal cardiopulmonary afferent sensitization through suppression of voltage-gated potassium channels after myocardial infarction (MI).

MI was induced in rats by coronary ligation. Molecular profiling, immunofluorescence, tissue clearing, and functional assays were used to assess neuroinflammation and reflex responses.

Post-MI, thoracic DRGs showed macrophage infiltration, glial activation, cytokine upregulation, and reduced voltage-gated potassium channel expression. Bulk RNA-sequencing identified enrichment of macrophage activation-related genes, and in vitro studies confirmed that proinflammatory cytokines and activated macrophages suppressed voltage-gated potassium channels and increased DRG neuron excitability. Epicardial injection of biotinylated TNF-α (tumor necrosis factor-α) demonstrated cardiac afferent-mediated cytokine transport to DRGs, inducing macrophage infiltration via a cytokine receptor-dependent mechanism. Anti-inflammatory interventions, including oral minocycline, systemic macrophage depletion, and local epidural delivery of thermo-responsive hydrogel-forming dexamethasone prodrug (ProGel-Dex), significantly reduced DRG neuroinflammation, restored voltage-gated potassium channel levels, and attenuated exaggerated cardiac sympathetic afferent reflex and pulmonary spinal afferent reflex responses. Minocycline and ProGel-Dex also improved cardiac chamber dilation in the post-MI rats.

These findings identify a neural inflammatory cascade involving cytokine uptake, glial activation, and macrophage activation as a contributor to cardiopulmonary afferent sensitization after MI. Targeting DRG inflammation, particularly with sustained dexamethasone delivery using ProGel-Dex, offers a prospect of precision medicine to dampen pathological sympathetic activation and improve cardiac outcomes in chronic heart failure.