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Acute stressor states are linked to neurohormonal activation that includes the adrenergic nervous system. Elevations in circulating epinephrine and norepinephrine unmask an interdependency that exists between K+ and Mg2+ based on their regulation of a large number of Mg2+-dependent Na+-K+-ATPase pumps present in skeletal muscle. The hyperadrenergic state accounts for a sudden translocation of cations into muscle with the rapid appearance of hypokalemia and hypomagnesemia. The resultant hypokalemia and hypomagnesemia will cause a delay in myocardial repolarization and electrocardiographic QTc prolongation raising the propensity for supraventricular and ventricular arrhythmias. In this review, we focus on the interdependency between K+ and Mg2+, which is clinically relevant to acute hyperadrenergic stressor states found in patients admitted to intensive care units.

Heightened cardiac adrenergic nervous system (ANS) activity and progression of left ventricular (LV) remodeling are temporally related in patients with systolic heart failure. Whether cardiac ANS activation directly contributes to or merely accompanies LV remodeling remains an unresolved issue. Human and experimental data that directly link cardiac ANS activation to LV remodeling and worsening heart failure are first reviewed, including cardiac norepinephrine spillover. Alterations of beta adrenergic receptor signaling pathways are then addressed with emphasis on the mechanisms that may mediate the beneficial effect of beta adrenergic receptor blockade on LV remodeling. Lastly, alternative approaches to beta adrenergic receptor blockade for lessening cardiac ANS activation and reversing cardiac ANS-induced LV remodeling are discussed. A large body of work now links LV remodeling to cardiac ANS activation. However, the precise mechanisms that link cardiac ANS activation to LV remodeling are still to be fully understood. Fully understanding of these mechanisms may uncover new therapeutic approaches.

Acute stressor states are inextricably linked to neurohormonal activation which includes the adrenergic nervous system. Consequent elevations in circulating epinephrine and norepinephrine unmask an interdependency that exists between K+, Mg2+ and Ca2+. Catecholamines, for example, regulate the large number of Mg2+-dependent Na/K ATPase pumps present in skeletal muscle. A hyperadrenergic state accounts for a sudden translocation of K+ into muscle and rapid appearance of hypokalemia. In the myocardium, catecholamines promote Mg2+ efflux from cardiomyocytes, whereas intracellular Ca2+ influx and overloading account for the induction of oxidative stress and necrosis of these cells with leakage of their contents, including troponins. Accordingly, acute stressor states can be accompanied by nonischemic elevations in serum troponins, together with the concordant appearance of hypokalemia, hypomagnesemia and ionized hypocalcemia, causing a delay in myocardial repolarization and electrocardiographic QTc prolongation raising the propensity for arrhythmias, including atrial fibrillation and polymorphic ventricular tachycardia. In this review, we focus on the interdependency between K+, Mg2+ and Ca2+ which are clinically relevant to acute stressor states.

The progressive nature of heart failure is linked to multiple factors, including an ongoing loss of cardiomyocytes and necrosis. Necrotic cardiomyocytes leave behind several footprints: the spillage of their contents leading to elevations in serum troponins; and morphologic evidence of tissue repair with scarring. The pathophysiologic origins of cardiomyocyte necrosis relates to neurohormonal activation, including the adrenergic nervous system. Catecholamine-initiated excessive intracellular Ca accumulation and mitochondria Ca overloading in particular initiate a mitochondriocentric signal-transducer-effector pathway to necrosis and which includes the induction of oxidative stress and opening of their inner membrane permeability transition pore. Hypokalemia, ionized hypocalcemia and hypomagnesemia, where consequent elevations in parathyroid hormone further account for excessive intracellular Ca accumulation, hypozincemia and hyposelenemia each compromise metalloenzyme-based antioxidant defenses. The necrotic loss of cardiomyocytes and adverse structural remodeling of myocardium is related to the central role played by a mitochondriocentric pathway initiated by neurohormonal activation.