Chemically induced cardiotoxicity: Role of voltage dependent ion channels

Chemicals pervade human environments, with> 350,000 synthetic compounds driving unintentional exposures and pollution-linked deaths exceeding those from infectious diseases or violence. This review discusses the mechanisms of chemically induced cardiotoxicity (including pesticides, pollutants, heavy metals, and chemotherapeutics), emphasizing modulation of voltage-gated ion channels in cardiomyocytes, which disrupts action potential (AP) dynamics, excitation-contraction coupling (ECC), and predisposes to arrhythmogenesis. Key currents, sodium (I_Na), calcium (I_CaL, I_CaT), and potassium (I_to, I_Kr, I_K1), are differentially altered. Pyrethroid pesticides (e.g., deltamethrin) amplify late I_Na, prolong AP, and trigger afterdepolarizations. Organochlorines (e.g., aldrin) suppress peak I_Na; organophosphates, carbamates, and fungicides (e.g., tebuconazole) inhibit I_CaL, I_Na, and K+ currents, often via oxidative stress. Glyphosate-based herbicides impair I_CaL; rodenticides (e.g., phosphides) block K+ hERG channel, mimicking Brugada syndrome. Environmental pollutants lack direct ion-channel block properties evidence but provoke arrhythmias via inflammation/fibrosis (diesel exhaust), NO/redox inhibition (CO: I_Na, hERG, K_ir), current enhancement (SO₂: I_Na, I_to, I_CaL), or ROS-CaMKII activation (particulate matter). Heavy metals attenuates channels class-specifically: Pb²⁺ (I_CaL), Ni²⁺ (I_CaT), Cd²⁺ (I_Na, I_CaL), Hg²⁺ (I_to, I_CaL); Se/Zn modulate K⁺/Ca₂₊ currents in deficiency/excess. Chemotherapeutics exacerbate cardiovascular risk: anthracyclines (e.g., doxorubicin) boost I_CaL and RyR2 leak; platinums delay I_Na decay; TKIs (e.g., ibrutinib) broadly suppress currents kinase-dependently. Integrating in vitro/experimental molecular data, this review maps class-specific electrophysiological impacts in the heart, highlighting safety pharmacology's role in risk mitigation and informing therapeutic, regulatory, and public health strategies to safeguard cardiovascular resilience against pervasive chemical threats.