Exercise, load and remodelling: do we know what we think we know?
Email: email@example.com (Dr Michael Ibrahim)
The mammalian heart is exquisitely stretch sensitive and is ordinarily capable of profound changes from the subcellular to systems levels in order to handle changes in cardiac workload encountered during pregnancy, exercise training and initially also when challenged by disease processes such as aortic stenosis and hypertension (Ellison et al. 2012). Classically, increases in cardiac load may be physiological (e.g. exercise) or pathological (e.g. hypertension), the former resulting in reversible physiological hypertrophy without diminished cardiac function, and the latter in maladaptive, irreversible changes. The last two to three decades have seen multiple studies which challenge this dogma.
In a recent issue of The Journal of Physiology da Costa Rebelo et al. describe their study of the biochemical and physiological consequences of high-intensity but voluntary exercise in spontaneously hypertensive rats (SHRs) (da Costa Rebelo et al. 2012). They find that exercise in SHRs induces no change in systolic blood pressure, increases fibrosis and impairs cardiac function (e.g. left ventricular (LV) developed pressure). Exercise is widely thought to be beneficial in the setting of heart disease in general and hypertension in particular (Wexler et al. 2012). On the hypothesis that the exercise-induced maladaptive changes are angiotensin II dependent, the authors tested whether captopril was able to ameliorate these effects. The addition of captopril partially prevented the increased fibrosis and the impaired LV function; moreover, the combined use of captopril and exercise training resulted in reverse remodelling at the cellular level (sarcoendoplamic reticulum Ca2+ ATPase/Na+ Ca2+ exchanger (SERCA/NCX) ratio). Sedentary SHRs developed further hypertension. Captopril alone was the only intervention to significantly reduce the final systolic blood pressure and reduce LV hypertrophy (indeed training induces LV hypertrophy, unless captopril is used). These results raise a number of interesting issues.
Physiological hypertrophy: friend or foe?
These results challenge the widely held view that exercise is safe and effective in the setting of cardiovascular disease (Wexler et al. 2012). Exercise reduces all cause cardiovascular death (Rosengren & Wilhelmsen, 1997). Apart from the beneficial role of exercise in normalising the metabolic state, its other physiological and psychological benefits, it is thought to promote physiological hypertrophy which might enable the heart to better handle the demands of a hypertensive vascular tree (Ellison et al. 2012). That is, physiological hypertrophy might enhance the adaptive reserve.
da Costa et al. show that exercise induces maladaptive change (despite a very modest reduction from their starting blood pressure (BP)) in the context of hypertension. The profound reduction in BP (though they remain hypertensive) achieved by isolated use of captopril was not seen in the context of training. Unfortunately we are not told whether this is accompanied by a change in LV function (although captopril alone did not change fibrosis levels). These new data add a new level of detail to our understanding of the interaction between cardiac disease and exercise. The hypertensive animals presumably have diminished adaptive reserve which is exhausted following training, and subsequently causes them to develop heart failure (severely impaired cardiac function and increased mortality). Whether this would be different were exercise started at a less severe or shorter duration of hypertension is an essential question for further studies. Multiple studies show that significant cardiac improvement is possible when duration of overload is short (e.g. Derumeaux et al. 2002).
Although patients are often encouraged to undertake exercise, this would be of a low intensity form, and they would mostly already be on optimal medical therapy, which would include blocking angiotensin II with angiotensin-converting-enzyme (ACE) inhibitors or receptor antagonists. Although voluntary, the nature of the high intensity exercise protocol in this study may have produced quite different results to a more moderate exercise training programme. The protocol used resulted in the death of 50% of the SHR animals and significant hypertrophy. On the other hand, the voluntary nature of the exercise may indicate exercise capacity. Presumably the animals ran until they were tired. This is rather like a clinical exercise test. If so, it may indicate that those with the highest exercise capacity who then ‘abuse it’ deplete their adaptive reserve. This is difficult to interpret but could support the authors’ concept that exercise should be used with caution. An important question for the future is whether the onset of training in the setting of hypertension but before cardiac dysfunction ensues would be protective. Also to what extent would the findings be different if hypertension of a different aetiology were used?
This study is important in that it raises questions about how exercise ought to be used in heart disease. The animals in this study were clearly unable to adapt to increased workload and exercise, therefore maladaptive changes resulted. This could be true for the end-stage heart failure patient. However, the interacting processes (disease, adaptation, physiological hypertrophy) are almost certainly more complex than that and depend on the size of the ‘adaptive reserve’ in the individual patient. The clinical protocols in current use adopt lifestyle modification (diet and exercise) as first line therapy and drug therapy is commenced for more severe forms of hypertension. This implies that exercise is most rigorously advocated in the least impaired patients. Those undergoing more rigorous physical rehabilitation, would most likely be on a regimen of anti-failure medications.
One of the major contributions of the present article is that it shows that the modulation of the biochemical pathways activated during these various conditions can have a powerful effect on the outcome. By captopril enabling ACE inhibition, the beneficial reverse remodelling effects of exercise were unlocked, resulting in a training-dependent improvement in the SERCA/NCX ratio. This may explain the improved cardiac function in those animals. Clearly, further dissection of the molecular pathways involved could help to design an optimal medical strategy during which exercise is not only safe but beneficial. The elucidation of these details may help to better define exercise candidates as well as expand our understanding of the reasons for these conflicting findings.