title: Disturbances in calcium metabolism and cardiomyocyte necrosis: the role of calcitropic hormones.
abstract: A synchronized dyshomeostasis of extra- and intracellular Ca(2+), expressed as plasma ionized hypocalcemia and excessive intracellular Ca(2+) accumulation, respectively, represents a common pathophysiologic scenario that accompanies several diverse disorders. These include low-renin and salt-sensitive hypertension, primary aldosteronism and hyperparathyroidism, congestive heart failure, acute and chronic hyperadrenergic stressor states, high dietary Na(+), and low dietary Ca(2+) with hypovitaminosis D. Homeostatic responses are invoked to restore normal extracellular [Ca(2+)](o), including increased plasma levels of parathyroid hormone and 1,25(OH)(2)D(3). However, in cardiomyocytes these calcitropic hormones concurrently promote cytosolic free [Ca(2+)](i) and mitochondrial [Ca(2+)](m) overloading. The latter sets into motion organellar-based oxidative stress, in which the rate of reactive oxygen species generation overwhelms their detoxification by endogenous antioxidant defenses, including those related to intrinsically coupled increments in intracellular Zn(2+). In turn, the opening potential of the mitochondrial permeability transition pore increases, allowing for osmotic swelling and ensuing organellar degeneration. Collectively, these pathophysiologic events represent the major components to a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis. From necrotic cells, there follows a spillage of intracellular contents, including troponins, and a subsequent wound healing response with reparative fibrosis or scarring. Taken together, the loss of terminally differentiated cardiomyocytes from this postmitotic organ and the ensuing replacement fibrosis each contribute to the adverse structural remodeling of myocardium and progressive nature of heart failure. In conclusion, hormone-induced ionized hypocalcemia and intracellular Ca(2+) overloading comprise a pathophysiologic cascade common to diverse disorders and that initiates a mitochondriocentric pathway to nonischemic cardiomyocyte necrosis.
authors: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Jawwad
authors: J
authors: Yusuf
authors: M Usman
authors: MU
authors: Khan
authors: Yaser
authors: Y
authors: Cheema
authors: Syamal K
authors: SK
authors: Bhattacharya
authors: Karl T
authors: KT
authors: Weber
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002128:Calcium Metabolism Disorders / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020013:Calcium Signaling; D005355:Fibrosis; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D006996:Hypocalcemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008929:Mitochondria, Heart / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress
chemical_list: D006728:Hormones; D002118:Calcium