Cation dyshomeostasis and cardiomyocyte necrosis

The Fleckenstein hypothesis revisited

Brian J. Borkowski, Yaser Cheema, Atta U. Shahbaz, Syamal Bhattacharya, Karl Weber

Research output: Contribution to journalReview article

32 Citations (Scopus)

Abstract

An ongoing loss of cardiomyocytes to apoptotic and necrotic cell death pathways contributes to the progressive nature of heart failure. The pathophysiological origins of necrotic cell loss relate to the neurohormonal activation that accompanies acute and chronic stressor states and which includes effector hormones of the adrenergic nervous system. Fifty years ago, Albrecht Fleckenstein and coworkers hypothesized the hyperadrenergic state, which accompanies such stressors, causes cardiomyocyte necrosis based on catecholamine-initiated excessive intracellular Ca2 accumulation (EICA), and mitochondrial Ca2 overloading in particular, in which the ensuing dysfunction and structural degeneration of these organelles leads to necrosis. In recent years, two downstream factors have been identified which, together with EICA, constitute a signaltransducereffector pathway: (i) mitochondria-based induction of oxidative stress, in which the rate of reactive oxygen metabolite generation exceeds their rate of detoxification by endogenous antioxidant defences; and (ii) the opening of the mitochondrial inner membrane permeability transition pore (mPTP) followed by organellar swelling and degeneration. The pathogenesis of stress-related cardiomyopathy syndromes is likely related to this pathway. Other factors which can account for cytotoxicity in stressor states include: hypokalaemia; ionized hypocalcaemia and hypomagnesaemia with resultant elevations in parathyroid hormone serving as a potent mediator of EICA; and hypozincaemia with hyposelenaemia, which compromise antioxidant defences. Herein, we revisit the Fleckenstein hypothesis of EICA in leading to cardiomyocyte necrosis and the central role played by mitochondria.

Original languageEnglish (US)
Pages (from-to)1846-1853
Number of pages8
JournalEuropean Heart Journal
Volume32
Issue number15
DOIs
StatePublished - Aug 1 2011

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Cardiac Myocytes
Cations
Necrosis
Mitochondria
Antioxidants
Takotsubo Cardiomyopathy
Hypokalemia
Hypocalcemia
Mitochondrial Membranes
Parathyroid Hormone
Organelles
Adrenergic Agents
Nervous System
Catecholamines
Permeability
Oxidative Stress
Cell Death
Heart Failure
Hormones
Oxygen

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Cation dyshomeostasis and cardiomyocyte necrosis : The Fleckenstein hypothesis revisited. / Borkowski, Brian J.; Cheema, Yaser; Shahbaz, Atta U.; Bhattacharya, Syamal; Weber, Karl.

In: European Heart Journal, Vol. 32, No. 15, 01.08.2011, p. 1846-1853.

Research output: Contribution to journalReview article

Borkowski, Brian J. ; Cheema, Yaser ; Shahbaz, Atta U. ; Bhattacharya, Syamal ; Weber, Karl. / Cation dyshomeostasis and cardiomyocyte necrosis : The Fleckenstein hypothesis revisited. In: European Heart Journal. 2011 ; Vol. 32, No. 15. pp. 1846-1853.
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