Cation dyshomeostasis and cardiomyocyte necrosis: the Fleckenstein hypothesis revisited

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 Ca(2+) accumulation (EICA), and mitochondrial Ca(2+) 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 signal-transducer-effector 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.

Figure 1

Heart failure involves an ongoing loss of cardiomyocytes to apoptosis and necrosis. See text.

Figure 2

Catecholamine-mediated cellular and subcellular Ca²⁺ overloading with induction of oxidative stress and reactive oxygen species generation and opening of the mitochondrial inner membrane permeability transition pore that leads to solute entry, osmotic swelling and structural degeneration of these organelles. Cell death follows with a leak of intracellular troponins, which raise serum troponin levels, and ultimate appearance of replacement fibrosis, or scarring.

Figure 3

An acute stressor state, such as bodily injury, activates the hypothalamic–pituitary–adrenal axis with resultant release of adrenocorticotropin hormone, which promotes the adrenals’ release of cortisol and aldosterone, and catecholamines from the adrenal medulla. The acute phase reactant, angiotensinogen, is released by the liver during stressor states and is accompanied by activation of the renin–angiotensin–aldosterone system . In turn, elevated plasma catecholamines, norepinephrine, and epinephrine, promote a coordinated cation translocation from the vascular space to tissue compartment accounting for a concordant fall in their serum concentrations and presenting as hypokalaemia, ionized hypocalcaemia and hypomagnesaemia, hypozincaemia and hyposelenaemia.

Figure 4

An acute stressor state with elevated circulating catecholamines is responsible for intracellular Ca²⁺ overloading with a subsequent fall in plasma ionized [Ca²⁺]_o, which in turn provokes the parathyroid glands to release parathyroid hormone, a calcitropic hormone, also contributing to intracellular Ca²⁺ overloading. In cardiomyocytes this is accompanied by the induction of oxidative stress, which leads to the opening of the mitochondrial permeability transition pore and osmotic injury of these organelles. The necrosis of cardiomyocytes follows accompanied by the leak of intracellular troponins into the interstitial space accounting for the ultimate rise in plasma troponins. Cardiac myocytes lost to necrosis are replaced by fibrous tissue, or scarring, which preserves the structural integrity of the myocardium. Adapted from Whitted AD et al. Am J Med Sci. 2010;340:48–53.

Figure 5

The sodium pump of the cardiomyocyte is an energy consuming, Mg²⁺-dependent Na⁺/K⁺ ATPase which is responsible for the extrusion of three Na⁺ ions and entry of two K⁺ ions. Pump activity falters with Mg²⁺ deficiency accompanied by reduced intracellular K⁺ and prolongation of the QTc interval of the electrocardiogram. In the presence of hypokalaemia and hypomagnesaemia, digoxin, a Na⁺/K⁺ ATPase inhibitor, would further reduce intracellular K⁺ to raise the potential for arrhythmias.