Nature <i>versus</i> exposure: matched exposure to circulatory stressors of different natures elicits adaptive remodelling

The systemic circulation consists of a pulsatile pump that delivers blood into a proximal vascular capacitor, subsequently distributing blood to the periphery with minimal variation in flow and pressure. In the face of chronic workload elevations, hypertrophic growth pathways activated in the left ventricle (LV) are thought to be an adaptive response to normalize wall stress and augment or maintain cardiac output via a proportionate increase in wall thickness and/or chamber size. Although initially compensatory, the long-term pattern of cardiac hypertrophy is thought to be dependent on the nature of the overload stimulus, with chronic workload elevations elicited by exercise training or systemic hypertension having been linked to divergent adaptive and maladaptive patterns of cardiac hypertrophic growth, respectively. While these findings suggest the nature of the overload stimuli drive the pattern of cardiac remodelling, recently, long-term, high-intensity, high-volume exercise has been associated with adverse structural and electrical cardiac remodelling (La Gerche et al. 2012). These observations suggest that excessive stimulation of physiological systems may result in adverse responses, and that the mode of cardiac stress may not be as important as the balance of frequency, duration and intensity of the cardiac overload in dictating whether an adaptive or maladaptive pattern of remodelling is observed. Recently, Moreira-Gonçalves et al. (2015) examined whether the LV hypertrophic response to chronic overload is dependent on the features of the overload (magnitude and duration) rather than the inducing nature. Male Wistar rats were subjected to controlled chronic intermittent exercise training or pharmacological β-adrenergic stimulation (dobutamine). Both groups were trained/treated for 8 weeks, 5 days per week. The dobutamine dose that could elicit a haemodynamic demand similar to the exercise training intervention was determined a priori, with both producing an approximate 40% increase in heart rate and 15% increase in peak systolic pressure. Following treatment, LV hypertrophy was evident in both treated groups, at both the chamber and myocyte levels. Mitochondrial complexes and SERCA2a were upregulated similarly following both treatments, along with activation of physiological hypertrophic pathways, without evidence of myocardial fibrosis. LV chamber performance was evaluated in vivo during resting baseline measurements, during a 120 min pressure overload challenge, and during non-ejecting beats, with evidence of improved diastolic function in both treated groups. The authors concluded that intermittent cardiac stress brought about by either exercise or dobutamine stimulates an adaptive hypertrophic response that improves tolerance to future stress, and that the specific attributes (rather than the nature) of cardiac overload are determinants of remodelling. There has been considerable debate in the literature regarding the relationship between the nature of the cardiac overload stimulus and the pattern of remodelling induced. The authors used an elegant study design to match duration and magnitude of two different cardiovascular stresses. Although intriguing and important evidence was reported, the study does not conclusively demonstrate that these structural and functional remodelling patterns are entirely independent of the nature of the stimulus. As a pharmacological analogue of exercise, dobutamine stimulation affects similar haemodynamic parameters to exercise, namely contractility and, to some extent, peripheral resistance and heart rate. By design, systolic blood pressure and heart rate, as well as treatment duration and frequency, were matched within a ‘tolerable’ range; further, both exercise and dobutamine activate β-adrenergic signalling. As such, despite their different natures, both physiological stresses would be expected to elicit convergent changes in haemodynamic and sympathetic states, especially in the short term. As these are factors that will be sensed and transduced into an adaptive or maladaptive remodelling process, the question of whether a circulatory stress that is less well matched for these integrated cardiovascular parameters, such as intermittent pacing and/or thoracic aortic banding, would induce a differential response would be an interesting future direction of enquiry. This is relevant in light of findings by Perrino et al. (2006) in which 4 weeks of intermittent pressure overload triggers cardiac dysfunction independently of stress duration or hypertrophic growth, as well as animal model studies showing that sympathomimetic agents induce cardiac hypertrophy independently of the mechanical stimuli (Zierhut & Zimmer, 1989). The molecular pathways involved in physiological and pathological hypertrophy are well established. As both exercise and dobutamine elicited a similar hypertrophic phenotype in the current study, the authors assessed Akt/mTOR and calcineurin protein expression to evaluate whether hypertrophy was adaptive or maladaptive. The Akt/mTOR pathway was upregulated in both treatment groups while the calcineurin pathway was not, suggesting that matched stimulus intensity and volume induced adaptive hypertrophy through a common pathway regardless of the different stimulation modes. Despite these findings, it is unclear whether the currently observed pattern of ‘physiological’ remodelling represents an intermittent phenotype or whether a different pattern of activation may be expected if the overload stress was significantly exacerbated. Prolonged β-adrenergic receptor stimulation has been shown to result in a time- and frequency-dependent shift from a positive to negative inotropic effect (Bovo et al. 2012), the latter being associated with increased cytoplasmic calcium overload, calcineurin upregulation, diastolic dysfunction, and increased arrhythmogenesis. It is possible that these factors contribute to a threshold above which divergent pathways are activated, influencing a shift in the pattern of remodelling from adaptive to maladaptive. This might explain evidence of cardiac hypertrophy associated with increased interstitial fibrosis, cell death and cardiac dysfunction linked to chronic, long-term catecholamine treatment (Briest et al. 2001). While it is still unclear how biomechanical stress is perceived by the heart and how this stress is transduced into a pro-hypertrophic response, the contention that there is a threshold beyond which a cardiac overload stimulus may switch from ‘physiological’ to ‘pathological’ remodelling and the factors that contribute to this dose–response relationship are intriguing. In the present study by Moreira-Gonçalves et al. (2015), LV chamber performance following treatment was evaluated at baseline, in response to sustained acute afterload increase, and in terms of isovolumetric LV performance. All groups appeared able to sustain the 35% increase in systolic pressure for 120 min. Rats in both treatment groups had preserved LV end-diastolic pressure and isovolumic relaxation time constant (Tau), in contrast to control rats, suggesting that diastolic performance may be augmented, as would be expected from chronic training. During non-ejecting beats, isovolumetric LV maximal pressure was stable across groups, while again, Tau was lower in treated rats. Thus, all groups appeared to tolerate 120 min of pressure overload, but exercise-trained or dobutamine-treated rats demonstrated enhanced diastolic function typical of physiological adaptation, and the LV appears well suited to increased pressure load. An interesting future direction would be to evaluate right ventricular (RV) performance, which delivers the same cardiac output as the LV, at much lower pressures. The haemodynamic alterations brought about by exercise, including increased ventricular volume during diastole and isovolumetric contraction, coupled with increased systolic pressures, may exact a disproportionately greater stress on the thin-walled RV, which is significantly more afterload sensitive than the LV. Indeed, both acute prolonged exercise and chronic strenuous training appear to disproportionately impact the atria and RV, with evidence of transient dysfunction, myocardial fibrosis, and arrhythmogenesis in high-level endurance athletes (La Gerche et al. 2012). As such, an expanded understanding of the RV response to different properties of cardiac loading is warranted, as the threshold for deleterious RV remodelling may lie below that of the LV. Exercise training elicits well-recognized morphological and functional cardiac remodelling, including resting bradycardia, and increases in LV myocardial mass, end-diastolic volume and stroke volume. These modifications serve to dramatically increase cardiac reserve that can be recruited under stress, and are generally considered ‘adaptive’. Moreira-Gonçalves et al. (2015) highlight a currently evolving literature considering the concept of ‘excessive’ exercise training as support for the concept that stimulus quantity (volume) is an important determinant of remodelling pattern (Benito et al. 2011), potentially more so than quality (type). It is increasingly recognized that long-term, vigorous training is linked to elevated risk of atrial fibrillation, and such athletes may reflect coupled electro-mechanical derangement related to hypertrophic remodelling. The current study supports the position that the external quality of the stimulus may not be a primary determinant of the resultant pattern of functional and particularly morphological remodelling; a logical and interesting next step would be to test the effect of manipulating the components of the stimulus (i.e. intensity, duration, frequency) and the resultant circulatory properties (i.e. blood pressure, heart rate, time under stress, recovery period) on patterns of remodelling. Such a characterization would further clarify the relative importance of these properties, advance our understanding of the dose–response relationship between exercise and circulatory remodelling, and improve our understanding of mechanisms of maladaptive cardiac remodelling that may be activated when training volume crosses the threshold from physiological to ‘excessive’ and pathological. Moreira-Gonçalves et al. (2015) demonstrate that matched haemodynamic loads activate similar pathways, and produce similar patterns of remodelling, regardless of the modality. Although this supports the hypothesis that supposedly beneficial stress such as exercise can be ‘too much of a good thing’, further work involving more strenuous interventions is required to understand the exercise dose–response relationship and the mechanisms by which ‘excessive’ stimulation is sensed and transduced to promote maladaptive remodelling. Future work should also consider the relative stress imposed on the right heart, which may be proportionately greater than that experienced by the left heart. None declared. We would like to thank Dr Susanna Mak for her helpful insights and review of this manuscript.

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