Growing a healthier heart

The heart responds to chronic or repetitive external stressors with a change in shape, function and/or structure, collectively termed myocardial remodelling. Myocardial hypertrophy is commonly part of this process (Bisping et al. 2014). While hypertrophy was long regarded as a necessary and universal compensatory response to increased haemodynamic needs, over the last two decades a dualistic view of good and bad myocardial hypertrophy has been adopted. Hypertrophy is regarded as either from early on maladaptive and ultimately associated with increased morbidity and mortality due to contractile dysfunction and arrhythmias, or physiological (adaptive), as it occurs with endurance training or during pregnancy, with enhanced or normal cardiac function and prognosis (Bisping et al. 2014). In a study published in this journal, Roof et al. (2015) demonstrate that simultaneous external stimulation of physiological hypertrophy (with insulin-like growth factor-1, IGF-1) can shift the process of maladaptive myocardial remodelling towards a more adaptive cardiac phenotype. In the light of the contrasting fates of physiological vs. maladaptive myocardial hypertrophy and remodelling, extensive efforts have been made to dissect underlying signalling pathways. One important distinction is the nature of the hypertrophic trigger. Neurohormones, such as catecholamines, angiotensin II and endothelin-1, are elevated upon myocardial injury or chronic mechanical load. These mediators lead to downstream activation of G-protein-coupled kinases (GRK), protein kinase C (PKC) and D (PKD), as well as Ca2+-sensors Ca2+-/calmodulin-dependent kinase II (CaMKII), which have been linked to loss of adrenergic responsiveness, contractile dysfunction, as well as de-inhibition of maladaptive hypertrophic gene expression in the nucleus (Bisping et al. 2014). Much less is known about mediators of physiological hypertrophy. IGF-1, neuregulin-1 and also potentially other growth factors have been identified. During physiological exercise, catecholamines and IGF-1, but not the other above mentioned neurohormones, are increased in the blood serum. However, exercise-induced cardiac catecholamine elevations do not correlate with the degree of (physiological) hypertrophy, but rather with improved contractility. The mechanisms underlying the differential effects of catecholamines on cardiac remodelling depending on either a physiological (exercise) or a maladaptive trigger have not yet been elucidated (Fig. 1). In a model of isoproterenol-induced cardiomyopathy in rats, Roof et al. (2015) demonstrate that in the presence of elevated catecholamines a concomitant increase in IGF-1 (as it would be expected with exercise) may shift maladaptive programming towards a more physiological phenotype. A large body of evidence has identified IGF-1 as an essential mediator for cell proliferation, growth and metabolism in ontogenesis and homoeostasis. Synthesis of IGF-1 occurs primarily in the liver and is controlled by growth hormone (GH). IGF-1 activity in the blood is modulated by IGF-binding proteins (IGFBP), which regulate the concentration of free IGF-1. IGF-1 effects are mediated by the IGF-1 receptor (IGF1R) complex-activating tyrosine kinase. Downstream regulation of gene expression, metabolism and contractility has been attributed to RAS/RAF/MAPK- but also to PI3-K/Akt-mTor-dependent signalling, resulting in anabolism, proliferation and ultimately improved cell survival. However, PI3-K and mTor activation also mediate carcinoma cell growth, which remains a concern with regard to long-term systemic IGF-1 therapy. Adding to the complexity, two isoforms of PI3-K with opposing downstream effects exist, promoting either physiological (PI3-K p110α) or maladaptive (PI3-K p110γ) remodelling (Bisping et al. 2014). In their recent study, Roof et al. (2015) demonstrate that IGF-1-mediated expression of p110α correlates with improved left ventricular (LV) diastolic function and less fibrosis even in the presence of catecholamines which elevate PI3-K p110γ, suggesting PI3-K p110α as a potent game-changer in hypertrophic remodelling. Due to the inherently observational nature of these expression studies, however, it remains to be determined whether p110α-related activation of downstream Akt alone is sufficient to overcome the well-documented detrimental effects of chronic sympathetic activation, as concomitant IGF-1 treatment may affect cardiac remodelling beneficially along other signalling pathways. As another caveat IGF-1 treatment also prevented the isoproterenol-induced increase in blood pressure in this model, which by itself attenuates maladaptive remodelling. While somewhat complicating the mechanistic interpretation in the isoproterenol model, in the clinical setting these ‘pleiotropic effects of IGF-1’ (Roof et al. 2015) may also positively impact on arterial hypertension as a common comorbidity in left ventricular remodelling. An interesting point of this study is also that treatment with IGF-1 in the presence of catecholamines improved cardiac function without additive effect on the degree of LV hypertrophy. This relates well to the only weak correlation between LV hypertrophy and diastolic function in patients (Heinzel et al. 2015), which may accordingly be partially explained by a varying contribution of physiological and maladaptive hypertrophy that shape the individual cardiac phenotype. Limited information is available on effectors of contractile function acting downstream of the IGF-1 - PI3-K p110α – AKT pathway. von Lewinski et al. (2003) found that IGF-1 acutely enhanced Na/H-exchanger activity in human myocardium, thus increasing intracellular Ca2+ and inotropy. In contrast, in a recent study on rat cardiomyocytes IGF-1 decreased Na/H activity triggered by acidosis and also decreased the acute contractile response (Yeves et al. 2014). Reasons for these differential effects have not been addressed. Roof et al. (2015) now provide evidence suggesting that chronic IGF-1 treatment leads to increased nitric oxide (NO) bioavailability in cardiomyocytes. NO-cGMP-dependent signalling has been linked to improved myocardial passive stiffness in multiple experimental studies, even though clinical translation has yet remained elusive. In the animal model of Roof et al. (2015), IGF-1 treatment preserves adrenergic inotropic responsiveness during isoproterenol-induced myocardial remodelling. This is an interesting finding, not only because chronic catecholamine treatment is a strong stimulus for adrenergic desensitization but also? preserved adrenergic responsiveness is a hallmark of physiological hypertrophy. Intriguingly and in contrast, in a heterologous expression system, IGF-1 was found to internalize beta-1 adrenoceptors and thus to reduce cAMP levels in response to isoproterenol as well (Gavi et al. 2007). This indicates that the interplay between G-protein-coupled (adrenergic) receptor signalling and tyrosine kinase-dependent (IGF-1) receptor signalling in cardiomyocytes is complex and yet unsatisfactorily understood. In a variety of models of acquired heart disease, activation of IGF1R-dependent signalling in the heart was unanimously associated with the attenuation of maladaptive remodelling, supporting translation into the clinic. Yet, as usual in studies on hypertrophy, experiments were mainly performed in young animals. However, LV hypertrophy and diastolic dysfunction are diseases of the aged. Recent experimental data suggests that IGF-1 signalling, while locally beneficial, systemically may promote senescence, and its inhibition may attenuate age-dependent maladaptive myocardial remodelling. Chronically high systemic levels of growth hormone and IGF-1 as in patients with acromegaly lead to maladaptive remodelling with biventricular hypertrophy, arrhythmias and (in late stages) heart failure. Still, cumulative evidence suggests that low levels of IGF-1 may be mechanistically relevant in chronic heart failure. Randomized clinical trials on IGF-1 treatment in chronic heart failure are lacking. Acute infusion of IGF-1 may be complicated by hypotension, tachycardia and hypoglycaemia – with gender differences regarding response (Flanagan et al. 2006). IGF-1 stimulation by growth hormone has been evaluated in chronic heart failure with mixed results, which may be related to individual responsiveness to the hormone but also to varying IGF-1 levels at baseline. A recent study taking both into account was stopped prematurely due to insufficient enrolment (clinicaltrials.gov NCT01235273). In summary, solid evidence from experimental models indicates beneficial effect of IGF-1-/AKT-mediated signalling on cardiac remodelling and dysfunction under controlled conditions of cardiac stress. The study of Roof et al. identified IGF-1 as a game-changer in catecholamine-related hypertrophic remodelling (Fig. 1). At the same time, the findings highlight the complexity of downstream intracellular signalling. Mixed results for growth hormone therapy in chronic heart failure in the clinic may reflect heterogeneity in the activation of maladaptive and adaptive pathways based on patient's age, aetiology or stage of the disease. Translation into clinical application will profit from extensive clinical phenotyping to identify better candidates and experimental evidence for additional modulators of the response. Until then, as supported by the current study of Roof et al., exercise remains a valid approach for all to improve and prevent contractile dysfunction and remodelling. No conflict of interest related to this editorial.