Left ventricular systolic dysfunction results from complex structural, cellular, and molecular disorders affecting the contractile apparatus of the myocardium and its energy homeostasis. This review discusses the key mechanisms of this process, with emphasis on myocardial contraction and its regulation by calcium dynamics and integrity of the sarcomeres. The main factors leading to the development of systolic dysfunction are presented: volume and tension overload, ischemia, infl ammation, amyloid and other deposits, neurohormonal activation and endocrine disorders, oxidative stress. In addition, cellular and molecular mechanisms are presented, such as defects in SERCA2a, and Na+/Ca 2+ exchanger, pathological Ca 2+ effl ux through RyR2, alterations in titin phosphorylation, myofi lament damage, proteasome dysfunction, impaired autophagy, epigenetic regulation, endoplasmic reticulum stress, and abnormalities in intercellular connectivity. The complex interaction between these processes leads to progressive myocardial remodeling, fi brosis, energ
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