Number 32, 2006
Metabolic profile in heart disease

Altered AMP-activated protein kinase activity and pathologic cardiac disease

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Michael H. Gollob, Martin S. Green, John P. Veinot
Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Department of Pathology, Ottawa Civic Hospital, Ottawa, Ontario, Canada
Correspondence: Dr Michael Gollob, Arrhythmia Research Laboratory and Division of Cardiology, University of Ottawa Heart Institute, Room H350, 40 Ruskin St, Ottawa, Ontario, Canada K1Y 4W7.
Tel: +1 613 761 5016; fax: +1 613 761 5060; e-mail: mgollob@ottawaheart.ca

Case report
In 1985, a 23-year-old man experienced a sudden loss of consciousness, with a spontaneous recovery and without adverse clinical sequelae. Cardiovascular examinations identified ventricular pre-excitation (Wolff–Parkinson–White) on the 12-lead electrocardiogram (Figure 1). Two-dimensional echocardiography demonstrated significant left ventricular hypertrophy (septal thickness 20 mm) and a diagnosis of hypertrophic obstructive cardiomyopathy was made.

Discussion
The case presented exemplifies the characteristic features of the PRKAG2 cardiac syndrome, which we have described previously [2]. Typically, affected patients present in late adolescence with symptomatic palpitations and documented supraventricular tachycardias. Progressive disease is usual, with the paradoxical development of cardiac conduction system disease, including sinus node dysfunction and impaired atrioventricular node conduction, leading to the onset of bradycardic heart rhythms. Presumably, the impaired cellular metabolism caused by altered AMPK activity over decades is progressively toxic to cardiac myocytes and conductive tissue.
More than 70% of our patients harboring the Arg302Gln mutation have required a permanent pacemaker during or before their 4th decade of life. In excess of 80% of patients develop either paroxysmal or permanent atrial fibrillation, commonly during their 20s. Although our patient described developed severe cardiomyopathy, evidence of cardiac hypertrophy, dilatation, or dysfunction is observed in only 40% of patients harboring the Arg302Gln mutation. Clinical penetrance of this autosomal dominant genetic disease is 100%, as we have never observed carriers of a clinically silent mutation in adulthood.
The known role of AMPK in regulating key cellular metabolic pathways, particularly glucose metabolism, led to our original hypothesis that the cellular basis for the observed cardiac hypertrophy in many cases was secondary to abnormal glycogen storage in myocytes [2,3]. This hypothesis was supported after the development of transgenic mouse models expressing known disease-causing PRKAG2 mutations [4,5]. The histology presented in Figure 2 in this report confirms that the cellular enlargement and cardiac hypertrophy in affected humans are secondary to glycogen-filled vacuoles, and not a result of the presence of an increase in sarcomeric units, as occurs in the more common form of hypertrophic cardiomyopathy seen in adulthood. The mechanism by which altered AMPK activity results in accessory atrioventricular connections, the anatomic substrate for ventricular pre-excitation, remains unclear. Nevertheless, these accessory atrioventricular connections behave in a fashion similar to that observed in patients with Wolff–Parkinson–White syndrome but without this genetic disease. We have documented atrioventricular re-entrant tachycardia in patients with the Arg302Gln PRKAG2 mutation and confirmed the use of the accessory atrioventricular connection in the tachycardia circuit. In addition, we have performed successful radiofrequency ablation on accessory atrioventricular connections in such patients.
The propensity for frequent atrial arrhythmias in patients implies that AMPK may have a direct role in regulating cardiac ion channels, perhaps through phosphorylation. Evidence suggests that cardiac sodium channels may be a substrate of AMPK [6].
Although the genetic basis of this complex cardiac phenotype has been elucidated, the precise biochemical mechanism of the disease remains controversial. The biochemical effects on AMPK activity of known disease-causing mutations in PRKAG2 has been studied by various methodologies. Mutant AMPK activity has been measured by in-vitro assays, ex-vivo assays of transgenic mice heart extracts, and after expression in various mammalian cell types. Directly conflicting results have been reported, suggesting either a constitutive gain-of-function induced by PRKAG2 mutations, or a significant loss-of-function [4,5]. Recently, Burwinkel et al [7] obtained data suggesting that both a loss-of-function and a gain-of-function may be imposed by PRKAG2 mutations. The presence of the mutation abolished AMP-induced activation of AMPK, hence loss of function. However, the basal state of phosphorylation and activity of AMPK were increased in the presence of the mutation studied, resulting in a constitutive gain-of-function in the cell, independent of the need of AMP for activation [7]. These opposing data sets illustrate the challenges in understanding biochemical phenomena in experimental systems. It is hoped that future studies, perhaps through novel methodologies, will resolve the current controversy.

Conclusion
In view of the significant function of AMPK under conditions of myocardial ischemia and in regulating glucose metabolism, this enzyme has been considered as a potential target for drugs. However, the observation that genetically induced perturbations in AMPK activity may lead to a severe cardiac pathology must be considered in the context of the future development of drugs targeting this protein.

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