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Review
. 2020 Jan 30;21(3):918.
doi: 10.3390/ijms21030918.

Electrophysiologic Effects of Growth Hormone Post-Myocardial Infarction

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Free PMC article
Review

Electrophysiologic Effects of Growth Hormone Post-Myocardial Infarction

Konstantinos V Stamatis et al. Int J Mol Sci. .
Free PMC article

Abstract

Myocardial infarction remains a major health-related problem with significant acute and long-term consequences. Acute coronary occlusion results in marked electrophysiologic alterations that can induce ventricular tachyarrhythmias such as ventricular tachycardia or ventricular fibrillation, often heralding sudden cardiac death. During the infarct-healing stage, hemodynamic and structural changes can lead to left ventricular dilatation and dysfunction, whereas the accompanying fibrosis forms the substrate for re-entrant circuits that can sustain ventricular tachyarrhythmias. A substantial proportion of such patients present clinically with overt heart failure, a common disease-entity associated with high morbidity and mortality. Several lines of evidence point toward a key role of the growth hormone/insulin-like growth factor-1 axis in the pathophysiology of post-infarction structural and electrophysiologic remodeling. Based on this rationale, experimental studies in animal models have demonstrated attenuated dilatation and improved systolic function after growth hormone administration. In addition to ameliorating wall-stress and preserving the peri-infarct myocardium, antiarrhythmic actions were also evident after such treatment, but the precise underlying mechanisms remain poorly understood. The present article summarizes the acute and chronic actions of systemic and local growth hormone administration in the post-infarction setting, placing emphasis on the electrophysiologic effects. Experimental and clinical data are reviewed, and hypotheses on potential mechanisms of action are discussed. Such information may prove useful in formulating new research questions and designing new studies that are expected to increase the translational value of growth hormone therapy after acute myocardial infarction.

Keywords: electrophysiologic remodeling; growth hormone; myocardial infarction; structural remodeling; ventricular tachyarrhythmias.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Growth hormone (GH) in myocardial infarction. The actions of GH differ along the course of myocardial infarction. It appears that the potential benefit of GH-treatment diminishes over time, pointing toward treatment strategies that aim to prevent adverse remodeling.
Figure 2
Figure 2
Ventricular tachyarrhythmias during acute infarction. (A) The total duration of tachyarrhythmias was shorter in the GH-treated group, mainly during phase II. Representative examples are shown in panel (B) From Elaiopoulos et al. Clin. Sci. (Lond), 112 (2007) 385–391 [12], with permission.
Figure 3
Figure 3
Proposed mechanisms of antiarrhythmic effects of GH. Two mechanisms may explain the antiarrhythmic effects of growth hormone, namely cytoprotection and reduced norepinephrine (NE) interstitial content.
Figure 4
Figure 4
Structural remodeling. (A) Infarct thickness (Heidenhain’s AZAN-trichrome staining, scale: 500 mm) was preserved after treatment with growth hormone (GH), administered via an alginate scaffold. (B) Myofibroblast density in the peri-infarct-area (α-smooth-muscle-actin staining, arrows, scale: 50 mm) was higher after treatment. Adapted from Daskalopoulos et al., Growth Factors 33 (2015) 250–258 [37], with permission.
Figure 5
Figure 5
Angiogenesis. Angiogenesis in the peri-infarct area was enhanced after intra-coronary growth hormone (GH) (B), compared to controls (A). From Mitsi et al., Growth Horm IGF Res. 16 (2006) 93–100 [40], with permission.
Figure 6
Figure 6
Electrophysiologic remodeling. Two proposed mechanisms of ameliorated electrophysiologic remodeling after treatment with growth hormone (GH), administered via an alginate (alg.) scaffold: prevention of fibrosis in the non-infarcted myocardium (left panel), and preservation of the peri-infarct area (right panel), resulting in improved conduction and repolarization indices. Containing data from Kontonika et al., Growth Factors 35 (2017) 1–11 [43], with permission.
Figure 7
Figure 7
Cardiomyocyte hypertrophy. A possible mechanism of hypertrophy induced by growth hormone may be mediated by Fas, which inhibits glycogen synthase kinase 3β (GSK3β) and activates Akt/protein kinase B. This process is dependent on the activation of the phosphoinositide 3-kinase (PIP3). Containing data from Hatzistergos et al., Growth Horm IGF Res 18 (2008) 157–165 [19], with permission.
Figure 8
Figure 8
Growth hormone (GH) prevents fibrosis in the non-infarcted myocardium. GH inhibits transforming growth factor-β (TGF-β) signaling via TGF-β-activated kinase 1 (TAK1), leading to de-phosphorylation of p38 MAPK. As a result, the extracellular matrix is preserved, as shown by the absence of metalloproteinase activity (in situ zymography, (A). Furthermore, the expression of proteins related to TGF-β, such as plasminogen activator inhibitor-1 (PAI-1), fibronectin, collagen-I and collagen-III is reduced (B), and fibrosis is prevented in the remote myocardium (C). These effects contrast the fibrogenic effects of angiotensin-II (angio), pointed by arrows in (A) and by asterisks in (B). From Imanishi et al., Mol Cell Endocrinol (2004), 218, 137–146 [58], with permission.
Figure 9
Figure 9
Routes for Growth hormone (GH) administration. GH could be administered via the intracoronary route in patients undergoing primary percutaneous interventions (PCI) for acute myocardial infarction. Direct intra-myocardial injections present an alternative route in patients undergoing coronary artery bypass grafting (CABG); it has the advantage of sustained action of GH via scaffolds enabling controlled release. Systemic administration is a valid option in the remaining patients.

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