Downloaded from http://heart.bmj.com/ on June 12, 2015 - Published by group.bmj.com
Editorial
Let’s keep running… exercise, basic science and the knowledge gaps André La Gerche,1,2 Julie R McMullen1,3 The health benefits of exercise are greater than the sum of the parts. The overall mortality benefit from physical activity is even greater than would be expected from its efficacy in improving all cardiac risk factors, preventing cancer, chronic disease and disability.1 It is valuable to dissect the mechanisms by which exercise promotes better health outcomes, and in this edition of Heart, Wilson et al2 elegantly detail the ways in which basic science investigations have advanced our understanding of exercise-dependent cardiovascular modifications. Study of the molecular pathways offers promise of new targets for therapies that may elicit exercise-like benefits for cardiovascular health. Furthermore, in the growing epidemic of chronic disease related to a sedentary lifestyle, it is hoped that increasing the evidence base linking exercise to health may motivate societal change. As enthusiastic pro-exercise scientific clinicians/researchers, we share the optimism of our colleagues and seek to extol the virtues of exercise but we also take the opportunity here to critically appraise some of the limitations in the exercise science translational model. 1. Where are the outcomes? This is perhaps our greatest failing. While our rodents are getting fitter, our community is getting fatter and there is a clear need to improve the translation of our scientific discoveries into more effective public health interventions. Perhaps there is a need to extend our focus to study the psychosocial impediments to exercise or the individual variation explaining why exercise is a joy for some and a chore for others. 2. Exercise is not a binary intervention: The public may be confused by the mixed messages coming from our laboratories. On the one hand, exercise is reported to promote healthy physiological heart growth in adult rodents2 while other investigators have used a slightly more 1
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; 2KU Leuven, Leuven, Belgium; 3 Monash University, Melbourne, Australia Correspondence to Dr André La Gerche, Head, Sports Cardiology, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia; [email protected] 742
intensive exercise regime to promote ventricular arrhythmias through extracellular matrix expansion.3 These vastly different clinical conclusions are perplexing and possibly reflect differing cellular responses to exercise of differing intensity, frequency and duration. The dose–response curve of exercise has only partially been delineated in humans (see figure 1). There is a wealth of observational data to imply clear benefit from exercise up until moderate exercise conditioning, but additional health gains beyond the ‘asymptote of benefit’ described by Blair in 19894 remain uncertain. 3. The cellular response to exercise may not be binary: An often used construct is to divide cardiac remodelling into ‘physiological’ and ‘pathological’ subtypes. Physiological remodelling describes the myocardial response to the intermittent volume load of exercise or the more constant volume load of pregnancy and is typically associated with good health outcomes. This is contrasted with the adverse outcomes from remodelling due to hypertension or valvular heart disease. Areas of physiological overlap were noted by Morganroth in his seminal hypothesis that likened the haemodynamic stressors
of endurance exercise to that of regurgitant valvular heart disease.5 Mitral regurgitation, for example, initially causes eccentric LV hypertrophy and an increase in contractile function, a response very similar to that of athletic training. In some patients, this transforms into decompensated heart disease, but the factors responsible for this transition have not been fully elucidated. Does the analogy with athlete’s heart extend this far? Can athletes also enter a decompensated phase? This may be an important topic for basic science studies but would require the development of new animal models as it is unlikely to be adequately addressed with the common approach of contrasting exercise with aortic constriction. 4. Signalling pathways activated in settings of physiological and pathological cardiac remodelling are complex and not entirely distinct: As highlighted by Wilson et al, it is generally accepted that different signalling pathways play key roles in mediating physiological heart growth (eg, IGF1-PI3K( p110α)-Akt) and pathological heart growth (eg, GPCR-Gαq). However, rather than distinct activation of any one pathway in an adaptive or maladaptive setting, it is probably more accurate to consider the resulting morphological and functional cardiac outcome a consequence of a balance between the activation of numerous signalling cascades (ie, IGF1PI3K( p110α)-Akt signalling dominating in a physiological setting and GPCR-Gαq dominating in a pathological setting; see figure 2). Furthermore, with the
Figure 1 The benefits of moderate exercise and the issue of extrapolation. Epidemiological data modified from Blair et al4 demonstrate reductions in mortality associated with increasing fitness. The benefit appears to plateau around 10 metabolic equivalents (METS), which is approximately 50% of the fitness of an elite cyclist. Illustrated in the figure is a 23-year-old non-athlete (left) as compared with a 23-year-old elite cyclist with a VO2max of 78 mL/min/kg (approximately 22 METS). Note that the echocardiographic images of the heart are presented to scale (15 cm marker in yellow circle). Thus, the increase in cardiac size in the cyclist is considerable and the clinical consequences of such profound remodelling remain uncertain (as signified by the dotted extrapolation of the efficacy curve). La Gerche A, et al. Heart May 2015 Vol 101 No 10
Downloaded from http://heart.bmj.com/ on June 12, 2015 - Published by group.bmj.com
Editorial
Figure 2 Signalling pathways and mediators that contribute to physiological and pathological cardiac remodelling. IGF1-PI3K( p110α)-Akt signalling predominates in a setting of physiological/ adaptive heart growth, whereas GPCR-Gαq signalling predominates in a setting of pathological/ maladpative heart growth. CaMK, calcium-/calmodulin-dependent protein kinase; ERK, extracellular signal-regulated kinase; gp130, glycoprotein 130; GPCR, G protein-coupled receptor; HSF1, heat shock transcription factor 1; IGF1, insulin-like growth factor 1; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C. development of more sophisticated genetic mouse models and tools, it is apparent that some signalling cascades (eg, MAPKs, calcineurin, Gp130) can contribute to both adaptive and maladaptive processes.6 Accurately assessing the activation and contribution of dynamic signalling pathways (ranging in time course from minutes to hours) in response to an intermittent stimulus such as exercise is challenging, but will be required to target these mechanisms as new therapeutic strategies. 5. While great for novel discoveries, animal models are an imperfect surrogate of human physiology: Small animals represent powerful tools for understanding mechanisms because they can be used to delineate the role of specific genes (using knock-out and transgenic constructs), can be studied with targeted therapies and used for histological evaluation. However, it is important not to forget the considerable hormonal, metabolic and genetic differences between the species. This is likely to explain, at least in part, why only a portion of murine discoveries are translated into efficacious human therapies. As a simple example, female mice and rats develop more La Gerche A, et al. Heart May 2015 Vol 101 No 10
profound myocardial hypertrophy with equivalent exercise stress,7 whereas human females have a similar, if not lesser, hypertrophic response compared with males.8 The pathway from promising discoveries in rodents to validation in larger animal models is a proven, cost-effective and efficient means of identifying clinically useful therapies.6 Although some findings prove to be species specific, it would be near impossible to test and refine basic molecular hypotheses in humans. Thus, a balance needs to be sought between the practicalities of animal models and the realisation that some findings may not directly translate. 6. All animals are not equal: In the dawning era of precision medicine, it is important to consider the differences between risks in a population and risks in an individual. While there is growing consensus that the risk of some arrhythmias, such as atrial fibrillation, may be more prevalent among endurance athletes, there is very little understanding of the factors that predict why 1 athlete is affected and the other 99 are not. This is the most important question for our patients: “Yes, but will I be affected?” but receives limited
attention in the scientific literature. The intriguing work of Claude Bouchard and others has demonstrated considerable individual variability in the response to exercise training with important minority groups of ‘non-responders’ and ‘super-responders’.9 This raises very important questions at both ends of the exercise continuum: what factors determine sedentary behaviour? Why do some athletes develop more profound remodelling and more frequent arrhythmias? There is some evidence suggesting that exercise-induced atrial enlargement may be a risk factor for atrial fibrillation in athletes,10 but we do not understand the inter-individual variability in atrial remodelling. Identifying these factors, genetic or otherwise, will be of considerable clinical relevance. Wilson et al provide a comprehensive description of the molecular pathways that may be responsible for the cardiovascular benefits derived from regular exercise training. We share their optimism that these investigations may identify key factors that may be targeted to achieve better health outcomes. However, like the champion athlete who trains like he/she is number 2 to stay number 1, exercise scientists need to recognise the obstacles that remain to be hurdled. Let’s keep running! Contributors Both authors contributed to manuscript preparation. Funding ALG is supported by a Career Development Scholarship from the National Health and Medical Research Council (NHMRC 1089039) and a Future Leaders Fellowship from the National Heart Foundation of Australia (100409). JRM is supported by an NHMRC Senior Research Fellowship (1078985). Competing interests None declared. Provenance and peer review Commissioned; externally peer reviewed.
To cite La Gerche A, McMullen JR. Heart 2015;101:742–744.
▸ http://dx.doi.org/10.1136/heartjnl-2014-306596 Heart 2015;101:742–744. doi:10.1136/heartjnl-2015-307557
REFERENCES 1
Myers J, McAuley P, Lavie CJ, et al. Physical activity and cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status. Prog Cardiovasc Dis 2015;57:306–14.
743
Downloaded from http://heart.bmj.com/ on June 12, 2015 - Published by group.bmj.com
Editorial 2
3
4
744
Wilson MG, Ellison GM, Cable NT. Basic science behind the cardiovascular benefits of exercise. Heart 2015;101:758–65. Bernardo BC, Weeks KL, Pretorius L, et al. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 2010;128:191–227. Benito B, Gay-Jordi G, Serrano-Mollar A, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011;123:13–22.
5
6
7
Blair SN, Kohl HW III, Paffenbarger RS Jr, et al. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989;262:2395–401. Morganroth J, Maron BJ, Henry WL, et al. Comparative left ventricular dimensions in trained athletes. Ann Intern Med 1975;82:521–4. Tham YK, Bernardo BC, Ooi JY, et al. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol 2015 PMID:25708889.
8
9 10
11
Wang Y, Wisloff U, Kemi OJ. Animal models in the study of exercise-induced cardiac hypertrophy. Physiol Res 2010;59:633–44. Prior DL, La Gerche A. The athlete’s heart. Heart 2012;98:947–55. Bouchard C, Rankinen T, Timmons JA. Genomics and genetics in the biology of adaptation to exercise. Compr Physiol 2011;1:1603–48. Wilhelm M, Roten L, Tanner H, et al. Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes. Am J Cardiol 2011;108:580–5.
La Gerche A, et al. Heart May 2015 Vol 101 No 10
Downloaded from http://heart.bmj.com/ on June 12, 2015 - Published by group.bmj.com
Let's keep running… exercise, basic science and the knowledge gaps André La Gerche and Julie R McMullen Heart 2015 101: 742-744
doi: 10.1136/heartjnl-2015-307557 Updated information and services can be found at: http://heart.bmj.com/content/101/10/742
These include:
References Email alerting service
Topic Collections
This article cites 10 articles, 3 of which you can access for free at: http://heart.bmj.com/content/101/10/742#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Sport and exercise medicine (6) Drugs: cardiovascular system (8370) Epidemiology (3482) Hypertension (2839) Clinical diagnostic tests (4594) Echocardiography (2017)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Editorial
Let’s keep running… exercise, basic science and the knowledge gaps André La Gerche,1,2 Julie R McMullen1,3 The health benefits of exercise are greater than the sum of the parts. The overall mortality benefit from physical activity is even greater than would be expected from its efficacy in improving all cardiac risk factors, preventing cancer, chronic disease and disability.1 It is valuable to dissect the mechanisms by which exercise promotes better health outcomes, and in this edition of Heart, Wilson et al2 elegantly detail the ways in which basic science investigations have advanced our understanding of exercise-dependent cardiovascular modifications. Study of the molecular pathways offers promise of new targets for therapies that may elicit exercise-like benefits for cardiovascular health. Furthermore, in the growing epidemic of chronic disease related to a sedentary lifestyle, it is hoped that increasing the evidence base linking exercise to health may motivate societal change. As enthusiastic pro-exercise scientific clinicians/researchers, we share the optimism of our colleagues and seek to extol the virtues of exercise but we also take the opportunity here to critically appraise some of the limitations in the exercise science translational model. 1. Where are the outcomes? This is perhaps our greatest failing. While our rodents are getting fitter, our community is getting fatter and there is a clear need to improve the translation of our scientific discoveries into more effective public health interventions. Perhaps there is a need to extend our focus to study the psychosocial impediments to exercise or the individual variation explaining why exercise is a joy for some and a chore for others. 2. Exercise is not a binary intervention: The public may be confused by the mixed messages coming from our laboratories. On the one hand, exercise is reported to promote healthy physiological heart growth in adult rodents2 while other investigators have used a slightly more 1
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; 2KU Leuven, Leuven, Belgium; 3 Monash University, Melbourne, Australia Correspondence to Dr André La Gerche, Head, Sports Cardiology, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia; [email protected] 742
intensive exercise regime to promote ventricular arrhythmias through extracellular matrix expansion.3 These vastly different clinical conclusions are perplexing and possibly reflect differing cellular responses to exercise of differing intensity, frequency and duration. The dose–response curve of exercise has only partially been delineated in humans (see figure 1). There is a wealth of observational data to imply clear benefit from exercise up until moderate exercise conditioning, but additional health gains beyond the ‘asymptote of benefit’ described by Blair in 19894 remain uncertain. 3. The cellular response to exercise may not be binary: An often used construct is to divide cardiac remodelling into ‘physiological’ and ‘pathological’ subtypes. Physiological remodelling describes the myocardial response to the intermittent volume load of exercise or the more constant volume load of pregnancy and is typically associated with good health outcomes. This is contrasted with the adverse outcomes from remodelling due to hypertension or valvular heart disease. Areas of physiological overlap were noted by Morganroth in his seminal hypothesis that likened the haemodynamic stressors
of endurance exercise to that of regurgitant valvular heart disease.5 Mitral regurgitation, for example, initially causes eccentric LV hypertrophy and an increase in contractile function, a response very similar to that of athletic training. In some patients, this transforms into decompensated heart disease, but the factors responsible for this transition have not been fully elucidated. Does the analogy with athlete’s heart extend this far? Can athletes also enter a decompensated phase? This may be an important topic for basic science studies but would require the development of new animal models as it is unlikely to be adequately addressed with the common approach of contrasting exercise with aortic constriction. 4. Signalling pathways activated in settings of physiological and pathological cardiac remodelling are complex and not entirely distinct: As highlighted by Wilson et al, it is generally accepted that different signalling pathways play key roles in mediating physiological heart growth (eg, IGF1-PI3K( p110α)-Akt) and pathological heart growth (eg, GPCR-Gαq). However, rather than distinct activation of any one pathway in an adaptive or maladaptive setting, it is probably more accurate to consider the resulting morphological and functional cardiac outcome a consequence of a balance between the activation of numerous signalling cascades (ie, IGF1PI3K( p110α)-Akt signalling dominating in a physiological setting and GPCR-Gαq dominating in a pathological setting; see figure 2). Furthermore, with the
Figure 1 The benefits of moderate exercise and the issue of extrapolation. Epidemiological data modified from Blair et al4 demonstrate reductions in mortality associated with increasing fitness. The benefit appears to plateau around 10 metabolic equivalents (METS), which is approximately 50% of the fitness of an elite cyclist. Illustrated in the figure is a 23-year-old non-athlete (left) as compared with a 23-year-old elite cyclist with a VO2max of 78 mL/min/kg (approximately 22 METS). Note that the echocardiographic images of the heart are presented to scale (15 cm marker in yellow circle). Thus, the increase in cardiac size in the cyclist is considerable and the clinical consequences of such profound remodelling remain uncertain (as signified by the dotted extrapolation of the efficacy curve). La Gerche A, et al. Heart May 2015 Vol 101 No 10
Downloaded from http://heart.bmj.com/ on June 12, 2015 - Published by group.bmj.com
Editorial
Figure 2 Signalling pathways and mediators that contribute to physiological and pathological cardiac remodelling. IGF1-PI3K( p110α)-Akt signalling predominates in a setting of physiological/ adaptive heart growth, whereas GPCR-Gαq signalling predominates in a setting of pathological/ maladpative heart growth. CaMK, calcium-/calmodulin-dependent protein kinase; ERK, extracellular signal-regulated kinase; gp130, glycoprotein 130; GPCR, G protein-coupled receptor; HSF1, heat shock transcription factor 1; IGF1, insulin-like growth factor 1; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C. development of more sophisticated genetic mouse models and tools, it is apparent that some signalling cascades (eg, MAPKs, calcineurin, Gp130) can contribute to both adaptive and maladaptive processes.6 Accurately assessing the activation and contribution of dynamic signalling pathways (ranging in time course from minutes to hours) in response to an intermittent stimulus such as exercise is challenging, but will be required to target these mechanisms as new therapeutic strategies. 5. While great for novel discoveries, animal models are an imperfect surrogate of human physiology: Small animals represent powerful tools for understanding mechanisms because they can be used to delineate the role of specific genes (using knock-out and transgenic constructs), can be studied with targeted therapies and used for histological evaluation. However, it is important not to forget the considerable hormonal, metabolic and genetic differences between the species. This is likely to explain, at least in part, why only a portion of murine discoveries are translated into efficacious human therapies. As a simple example, female mice and rats develop more La Gerche A, et al. Heart May 2015 Vol 101 No 10
profound myocardial hypertrophy with equivalent exercise stress,7 whereas human females have a similar, if not lesser, hypertrophic response compared with males.8 The pathway from promising discoveries in rodents to validation in larger animal models is a proven, cost-effective and efficient means of identifying clinically useful therapies.6 Although some findings prove to be species specific, it would be near impossible to test and refine basic molecular hypotheses in humans. Thus, a balance needs to be sought between the practicalities of animal models and the realisation that some findings may not directly translate. 6. All animals are not equal: In the dawning era of precision medicine, it is important to consider the differences between risks in a population and risks in an individual. While there is growing consensus that the risk of some arrhythmias, such as atrial fibrillation, may be more prevalent among endurance athletes, there is very little understanding of the factors that predict why 1 athlete is affected and the other 99 are not. This is the most important question for our patients: “Yes, but will I be affected?” but receives limited
attention in the scientific literature. The intriguing work of Claude Bouchard and others has demonstrated considerable individual variability in the response to exercise training with important minority groups of ‘non-responders’ and ‘super-responders’.9 This raises very important questions at both ends of the exercise continuum: what factors determine sedentary behaviour? Why do some athletes develop more profound remodelling and more frequent arrhythmias? There is some evidence suggesting that exercise-induced atrial enlargement may be a risk factor for atrial fibrillation in athletes,10 but we do not understand the inter-individual variability in atrial remodelling. Identifying these factors, genetic or otherwise, will be of considerable clinical relevance. Wilson et al provide a comprehensive description of the molecular pathways that may be responsible for the cardiovascular benefits derived from regular exercise training. We share their optimism that these investigations may identify key factors that may be targeted to achieve better health outcomes. However, like the champion athlete who trains like he/she is number 2 to stay number 1, exercise scientists need to recognise the obstacles that remain to be hurdled. Let’s keep running! Contributors Both authors contributed to manuscript preparation. Funding ALG is supported by a Career Development Scholarship from the National Health and Medical Research Council (NHMRC 1089039) and a Future Leaders Fellowship from the National Heart Foundation of Australia (100409). JRM is supported by an NHMRC Senior Research Fellowship (1078985). Competing interests None declared. Provenance and peer review Commissioned; externally peer reviewed.
To cite La Gerche A, McMullen JR. Heart 2015;101:742–744.
▸ http://dx.doi.org/10.1136/heartjnl-2014-306596 Heart 2015;101:742–744. doi:10.1136/heartjnl-2015-307557
REFERENCES 1
Myers J, McAuley P, Lavie CJ, et al. Physical activity and cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status. Prog Cardiovasc Dis 2015;57:306–14.
743
Downloaded from http://heart.bmj.com/ on June 12, 2015 - Published by group.bmj.com
Editorial 2
3
4
744
Wilson MG, Ellison GM, Cable NT. Basic science behind the cardiovascular benefits of exercise. Heart 2015;101:758–65. Bernardo BC, Weeks KL, Pretorius L, et al. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 2010;128:191–227. Benito B, Gay-Jordi G, Serrano-Mollar A, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011;123:13–22.
5
6
7
Blair SN, Kohl HW III, Paffenbarger RS Jr, et al. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989;262:2395–401. Morganroth J, Maron BJ, Henry WL, et al. Comparative left ventricular dimensions in trained athletes. Ann Intern Med 1975;82:521–4. Tham YK, Bernardo BC, Ooi JY, et al. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol 2015 PMID:25708889.
8
9 10
11
Wang Y, Wisloff U, Kemi OJ. Animal models in the study of exercise-induced cardiac hypertrophy. Physiol Res 2010;59:633–44. Prior DL, La Gerche A. The athlete’s heart. Heart 2012;98:947–55. Bouchard C, Rankinen T, Timmons JA. Genomics and genetics in the biology of adaptation to exercise. Compr Physiol 2011;1:1603–48. Wilhelm M, Roten L, Tanner H, et al. Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes. Am J Cardiol 2011;108:580–5.
La Gerche A, et al. Heart May 2015 Vol 101 No 10
Downloaded from http://heart.bmj.com/ on June 12, 2015 - Published by group.bmj.com
Let's keep running… exercise, basic science and the knowledge gaps André La Gerche and Julie R McMullen Heart 2015 101: 742-744
doi: 10.1136/heartjnl-2015-307557 Updated information and services can be found at: http://heart.bmj.com/content/101/10/742
These include:
References Email alerting service
Topic Collections
This article cites 10 articles, 3 of which you can access for free at: http://heart.bmj.com/content/101/10/742#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Sport and exercise medicine (6) Drugs: cardiovascular system (8370) Epidemiology (3482) Hypertension (2839) Clinical diagnostic tests (4594) Echocardiography (2017)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
