Abstract <p>The impact of micro- and hypergravity on the cardiovascularsystem represents a multi-level pathological process that beginswith organ-level disorders and has a profound cellular and molecularbasis. Despite more than sixty years of human spaceflight and increasinggravitational loads in modern aviation, a key link—the role of mechano-electrical feedback(MEF) and mechanosensitive channels in cardiomyocytes—remains insufficientlystudied, which defines the scientific and practical significanceof this review. We aimed to analyze and summarize current data onthe effects of simulated micro- and hypergravity on the molecularand physiological mechanisms of cardiomyocyte function, focusingon MEF disruption in the heart as a central pathogenetic link. Theobjectives of this review are: (1) to compare the systemic hemodynamiceffects of hypergravity (compensatory tachycardia, elevated bloodpressure, myocardial hypertrophy, increased risk of arrhythmias)and microgravity (cephalad fluid shift, hypovolemia, myocardialatrophy, orthostatic intolerance upon return to Earth); (2) to characterizeat the molecular and cellular level the opposing regulation of cardiomyocytemechanosensitivity: hypergravity induces a hypersensitivity phenotypeby upregulating the expression of mechanosensitive channels (e.g.,TRPM7) and enhancing mechano-induced ionic currents, whereas microgravitydownregulates the expression of the same channels, leading to cellularhyposensitivity and atrophy; (3) to demonstrate that cardiac pathologyin micro- and hypergravity arises from the synergy of systemic hemodynamicshifts and profound reprogramming of cardiomyocyte mechanosensitivity.The understanding of this hierarchical relationship, from clinicalmanifestations to molecular mechanisms, is a prerequisite for developingtargeted strategies to protect the cardiovascular system duringspaceflight and under gravitational overloads experienced by pilots, especiallycombat pilots.</p>