Adrenaline and stress-induced cardiomyopathies: Three competing hypotheses for mechanism(s) of action

Stress-induced cardiomyopathies such as Tako-Tsubo Syndrome (also known as "Broken-Heart Syndrome") primarily affect post-menopausal women who have experienced a sudden emotional shock. Clinical presentation includes symptoms mimicking a myocardial infarction (severe chest pain and S-T elevation on EKG), but do not show significant occlusion of the coronary arteries. Instead, patients display left ventricular (LV) dysfunction characterized by hypo- or a-kinetic regions that appear to "balloon-out", particularly in the region near the apex, and thus is sometimes referred to as "Apical-Ballooning Syndrome" . Some patients have been reported with high circulating levels of adrenaline, and symptoms have been effectively managed in many cases by treatment with beta-adrenergic receptor blockers. It is not entirely clear, however, why only specific regions of the LV were affected in these patients, nor is it understood why postmenopausal women are so susceptible relative to the rest of the population. With respect to the first question, we will review three competing, though not necessarily mutually exclusive, hypotheses to explain how adrenaline plays a key role in precipitating stress-induced cardiomyopathies. The first of these is a vascular microspasm hypothesis which focuses on stress-induced changes in the coronary microvasculature feeding the LV, leading to microspasms, interrupted regional blood-flow, and corresponding myocardial dysfunction in affected areas of the LV (Sato et al., 1990 and Dote et al., J Cardiol 1991;21:203) [6, 7]. The second hypothesis will be referred to as the differential β-receptor expression hypothesis, which postulates there is a higher density of β-adrenergic, (especially β₂-adrenergic) receptors in the apical region of the LV compared to other regions, thereby making it more sensitive to adrenergic overload and myocardial stunning due to agonist-mediated switch from Gs to Gi coupling of the β₂-adrenergic receptors in this region relative to other regions of the heart (Lyon et al., Nature Clin Pract Cardiovasc Med 2008;5:22) [10]. A third hypothesis focuses on differential local production of adrenergic hormones within the left myocardium itself (Kume et al., Circ J 2008; 72:106 and Osuala et al., PLoS One 2011;8:e22811) [1, 3]. From this third hypothesis, selective myocardial stunning in the LV results from local overload of adrenergic stimulation due to autocrine/paracrine actions of adrenaline (epinephrine) and noradrenaline (norepinephrine) in addition to sympathetic stimulation and circulating catecholamines in periods of stress. The evidence for each hypothesis is critically evaluated, with discussion of potential future directions for work in this field in relation to the role of gender (sex), age, and menopausal status.