Abstract / Summary
Background Traditional paradigms frame atrial fibrillation and nonischemic reentrant ventricular tachycardia as isolated electrical or structural issues of the myocardium. Yet, clinical data demonstrates a high bidirectional correlation in their prevalence and remodeling characteristics. We propose that their induction and maintenance may be driven by a self-amplifying gut-liver-heart axis, wherein environmental xenobiotics and an unhealthy lifestyle destabilize cardiac tissue to create arrhythmogenic substrate. Method Anthropocene xenobiotics, visceral adiposity, and physical inactivity generate localized oxidative stress, causing duodenal mucosal micro-leaks and tight-junction degradation. This enables an unfiltered influx of macromolecular fragments and Gram-negative bacterial lipopolysaccharide into the portal circulation. Upon sensing portal endotoxemia and systemic T-cell-derived Interleukin-2 (IL-2), the liver undergoes a profound transcriptomic overhaul via the Hepatic Acute-Phase Response (APR). The hyper-reactive hepatic parenchyma transitions into an emergency immune organ, broadcasting an inflammatory load into the systemic vasculature that is delivered directly to the coronary circulation. Results This vascularly delivered cardiotoxic cargo drives four distinct patterns of myocardial substrate remodeling: 1. Interstitial and Endomysial Fibrosis: Cytokine-activated cardiac fibroblasts induce lateral uncoupling and zig-zag conduction, causing incoming electrical waves to split and stall, generating refractory gradients. 2. Architectural Impedance Mismatch: Inflammatory wall stress induces myocyte hypertrophy, altering cell-to-cell coupling currents at fiber bundle mergers. The resulting downregulation of specific potassium currents (Ito, IKr) and disruption of intracellular calcium handling (RyR2) accelerate spatial dispersion of refractoriness. 3. Autonomic Ganglionated Plexi Hyperreactivity: Neuro-inflammatory cascades hypersensitize clustered intrinsic cardiac nerves near pulmonary vein ostia. Erratic localized acetylcholine release activates potassium channels (IK,ACh), driving abrupt, focal patches of shortened action potential duration. 4. Focal Ectopic Triggers: Localized myocardial oxidative stress causes intracellular calcium leaks, prompting delayed afterdepolarizations (DADs) and early afterdepolarizations (EADs) that initiate fast-firing point sources. The premature impulses exploit existing refractory discontinuities, forming lines of functional unidirectional conduction block. Conclusions The gut-liver-heart axis framework redefines atrial fibrillation and nonischemic ventricular tachycardia as interrelated manifestations of systemic kinetic failure. In thin-walled atria, high-frequency foci and autonomic-driven refractory gradients near the pulmonary veins perpetuate rotational activity. In the ventricles, patchy endomysial fibrotic channels provide the anatomical substrate required to anchor and sustain macroreentrant circuits.