The interesting comments by Thomas, Rick, Paul and others during the past week on my post discussing atrial fibrillation, confirm that disturbances of heart rhythm are common in athletes. These disturbances range from benign forms of supra-ventricular tachycardia (SVT) to the much more dangerous ventricular tachycardia (VT) that originates in a rogue site in the walls of the ventricle. SVT, which arises from an aberrant source above the ventricles (i.e in the atrium or in the walls of the pulmonary veins) is less dangerous than VT on account of the modifying influence of the atrio-ventricular (AV) node. The AV node is the gateway through which the electrical impulses that drive contraction pass from atria to ventricles. There is an upper limit to the rate at which the AV node can transmit impulses, so in cases of SVT the ventricles are protected from extreme rates. On the other hand, VT can cause the ventricles to contract at rates so high that efficient filling is impossible and the ventricle rapidly becomes exhausted and fails.
The AV node also prevents the chaotic contractions of atrial fibrillation (AF) being transmitted to the ventricles. However, AF creates a different risk. The chaotic atrial rhythm can lead to pooling, and subsequent clotting, of blood in a recess of the atrium known as the atrial appendage. If the clot breaks free and subsequently lodges in the brain, it can cause a stroke. The dangers of an abnormal rhythm in an individual case depend on various associated risk factors, but as a rough guide, SVT, AF and VT present an increasing hierarchy of risk of serious consequences.
Paul drew attention in his comment, to two of Australia’s greatest triathletes, Greg Welch and Emma Carney; both winners of multiple world championship events; both of legendary toughness, whose careers were abruptly terminated by VT. Perhaps this was coincidence, but in light of the evidence I discussed last week indicating the risk of AF is increased by endurance training, it is natural to speculate that endurance training might play a role in all three of the classes of rhythm disturbances: SVT, AF and VT.
It is crucial to open any speculation on this issue with a caveat that in general, keeping fit increases life expectancy. Today I will examinee the evidence that the mechanism by which physical exercise strengthens the heart is intimately related to the mechanism by which it might produce long term damage. If this is the case, it is crucial to understand the nature of the relationship between these intimately related processes in the hope that we can maximize the benefits while minimizing the risks.
I believe the key to understanding the paradox is inflammation. This is a hypothesis; it is not a proven fact, but I believe the evidence is sufficiently strong that it I am using this hypothesis to guide my own judgment as I seek the optimum balance between benefits and risks of endurance training.
Inflammation is the response to tissue damage that initiates repair. It is essentially a protective process that entails a complex cascade of biochemical and cellular events triggered by tissue damage, that mobilize a set of processes that limit the damage, clean up debris and promote healing. Cells in the vicinity of damage release various substances, including immune system mediators and messengers known as cytokines, that coordinate a complex set of reactions, including increased flow of blood to the regions of damage, and an increase in the permeability of the walls of small blood vessels allowing white blood cells to leak into the surrounding tissue. These white cells include neutrophils and lymphocytes responsible for the immune reactions that limit cellular damage, and macrophages that mop up cellular debris. Various biochemical mediators mobilize cells that promote healing and hypertrophy. For example in skeletal muscle, it appears that a class of cells called satellite cells (primitive muscle cells) are mobilized and fuse with existing muscle cells resulting in hypertrophy. However the repair processes do not always result in a strengthening of functionally useful tissue. It can also result in the development of a fibrous scaffold that confers mixed blessings. In the short term, fibrous tissue might play a useful role, but in the longer term, replacement of previously functioning cells by fibrous scar tissue is likely to result in a loss of function.
Acute and chronic inflammation
The immediate response to acute tissue trauma is a transient inflammatory response that is manifest as redness and local heating due to increased local blood flow, swelling due to leakage from blood vessels, and pain if the tissue concerned has a rich supply of sensory nerve terminals. Although temporarily inconvenient and sometimes even disabling, these processes are essentially beneficial as they reflect the mobilization of the healing process. However, inflammation can become chronic, either due to repeated trauma without adequate time for the healing process, and/or due to derangement of the immune system that results in auto-immunity – an attack by the immune system on one’s own body.
Chronic inflammation can affect many different types of tissue. One form of chronic inflammation that appears increasingly common in athletes is asthma – an over-reaction of the defense mechanism in the small airways of the bronchial tree, resulting in shortness of breath and wheezing. In rheumatoid arthritis, chronic inflammation affects joints and can also affect the heart. There are also other causes chronic inflammation of the heart muscle ( chronic myocarditis) such as the aftermath of bacterial infection. Chronic inflammation is generally more harmful than beneficial, and the possibility of converting acute inflammation to chronic inflammation provides a very strong reason why one should not exercise when exhbiting systemic (ie generalized) signs of infection, such as fever.
In light of the evidence for increased risk of occurrence of heart rhythm disturbances in athletes, it is perhaps important to ask whether or not endurance training might produce sub-clinical inflammation of the heart that has significant effects on function, either for better or for worse. But first of all, it is informative to consider what we know about inflammation, healing, and hypertrophy of skeletal muscle following vigorous exercise.
The consequences of tissue trauma can be visualized by using an electron microscope to examine skeletal muscle tissue acquired via muscle biopsy. In my post on April 12th 2009, I discussed the evidence that running, especially down-hill running, can produce visible disruption of the points where the actin and myosin chains are attached to the framework of the myofibril. This overt evidence of structural damage is known as Z-line streaming. (For photographs, see for example, Gibala and colleagues, Journal of Applied Physiology, Vol 78, 702-708, 1995). It is possible that it is due to shorter myofibrils being torn asunder by the powerful contraction of adjacent longer fibrils in the same bundle. Such damage would be expected to release chemical messengers that initiate inflammation.
It is plausible that less severe tissue trauma will result in the activation of chemical messengers even without such dramatic disruption of the myofibrils. In particular, reactive molecules known as free radicals can be produced as a consequence of the degradation of the high energy molecule ATP, that is the immediate fuel for muscle contraction. Free radicals can produce damaging oxidation of tissues.
The short term effect the various processes that can damage muscle during exercise is a loss of muscle power, but provided damage is not too severe and there is adequate time for repair, the eventual consequence is mobilization of satellite cells that fuse with myofibrils and strengthen the muscle. This is the training effect that we seek. If there is inadequate opportunity for recovery, the balance is unlikely to swing in favor of repair, and we will suffer a sustained loss of performance: the over-training syndrome from which recovery can takes months or years. The theory that chronic inflammation is the key process in over-training was put forward several years ago by Lucille Lakier Smith in a paper entitled ‘Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress?’ (Med Sci Sports Exerc. 2000 Feb;32(2):317-31.)
The factors that determine the balance between potentially harmful processes such as mechanical disruption or damage by free radicals, and constructive strengthening, are not clearly established. The observation that athletes have a limited period at the very top of the rankings suggests that extreme training might produce a gradual accumulation of free radical damage or fibrosis. But perhaps this is not inevitable. Perhaps the long term deterioration is only the consequence of occasional episodes when athletes push themselves too far – it might be possible to remain consistently very near the top of the rankings by judicious adjustment of training that recognizes when it is necessary to ease off and allow the body to recover. The relative longevity at the top level of female marathon runners, illustrated by individuals such as Catherine Ndereba, who apparently trains conservatively and has remained consistently near the top of the marathon rankings for almost a decade, suggests that a conservative approach minimizes the risk of long term damage.
Heart muscle is less easy to biopsy than skeletal muscle, but it is possible to measure proteins that are released when heart muscle is damaged – one of the most sensitive is cardiac troponin. A level of cardiac troponin greater than 0.05 micrograms per litre detected in the blood is regarded a marker for an acute heart attack. However, endurance events also produce an increase in troponin in the blood. This was dramatically illustrated is a study of blood levels of troponin in 29 cyclists completing the Otztal Radmarathon in 2004. This challenging 238 km marathon involves 5,500 meters of climbing over 4 alpine passes (Kuhtai, Brenner, Jaufenpass and Timmelsjoch). Cardiac troponin was not detectable in the blood of any competitors before the race, but afterwards 45% of the cyclists exhibited detectable levels, with 8 (28%) individuals having values in the range 0.043 to 0.224 micrograms /litre (Neumayr G et al. Effect of competitive marathon cycling on plasma N-terminal pro-brain natriuretic peptide and cardiac troponin T in healthy recreational cyclists. Am J Cardiol. 2005 ;96(5):732-5.). However the levels had returned to normal within one day, leading the authors to conclude that the effects were due to cardiac muscle fatigue rather than overt damage.
Perhaps more relevant to athletes who engage in less extreme events, a study of 72 non-elite competitors in the London marathon in 2002 and 2003 demonstrated that 56 (78%) had a detectable rise in troponin levels after the event (Shave et al, Heart, 2005; 91:1219–1220.). Of the 76 runners, 26 (36%) had a level above 0.05, the level regarded as indicative of an acute heart attack Thus the proportion of non-elite athletes exhibiting post-marathon troponin levels in the range conventionally regarded as indicative of a heart attack was actually slightly higher than the proportion in cyclists completing the Otztal Radmarathon.
Although levels of troponin were not measured on the day following the London marathon, the evidence from the study of the Otztal Radmarathon suggests that it is likely the elevation of troponin was only transient. It is unlikely that the increased levels reflected overt damage to cardiac muscle. Most heart attacks involve local damage to a relatively small volume of heart muscle that has been acutely deprived of blood following blockage of a coronary artery: a myocardial infarction. Heart muscle cells in the region of infarction are visible disrupted. It is plausible that in the competitors in the London marathon, a minor degree of leakage from widespread regions of the heart had produced a transient rise in troponin. Furthermore, in both the Otztal Radmarathon and the London Marathon, the rise was seen after relatively sustained exercise – rather than acute burst of high intensity exercise, consistent with the proposal that it is slow leakage rather than dramatic disruption.
Prolonged endurance exercise also results in a loss of cardiac function. In the study of London Marathon competitors, echo cardiography was employed to assess the rate of flow of blood into the chambers of the heart in a non-invasive manner. The ratio of early to late filling of the ventricles was found to have decreased after the marathon, indicating slower, less efficient, filling. However there was no correlation between the amount of troponin released and the slowing of ventricular filling so it is unclear whether or not these phenomena are related. Nonetheless, it is clear that endurance events result in release of proteins of the type seen following overt damage of heart muscle and also in transient decrease in the efficiency of heart muscle function
Overall, the evidence suggests that similar events occur in both cardiac muscle and skeletal muscle in response to endurance exercise. It is therefore possible that the increase in troponin and the transient decrease in speed of ventricular filling reflect a transient impairment that initiates a beneficial training effect, provided there is adequate opportunity for recovery
Inflammation and Atrial Fibrillation
In my post last week I mentioned that C-reactive protein, which is a marker for inflammation, is quite strongly associated with the development of atrial fibrillation in clinical cases. Similar evidence led Don Swanson of the University of Chicago to propose that chronic inflammation associated with over-training might contribute to the increased risk of AF in endurance athletes. (Swanson, Atrial fibrillation in athletes: Implicit literature-based connections suggest that overtraining and subsequent inflammation may be a contributory mechanism. Medical Hypotheses (2006) 66, 1085–1092)
Summary and Conclusions
The crucial question raised by a comparison of the events in heart and skeletal muscle following demanding endurance exercise, is whether or not the transient increase in troponin is actually a marker for a protective process that promotes healing and strengthening; while in contrast, extreme exercise and/or inadequate periods of recovery might result in long term damage.
My provisional conclusions are:
1) moderate exercise, even perhaps of the degree involved in running a marathon, might actually strengthen the heart provided the runner has prepared adequately, and allows sufficient time for subsequent recovery;
2) extreme exercise (ie exercise beyond that which the heart is fit enough to cope with) raises the possibility of sustained damage to heart muscle;
3) chronic inflammation might underlie the over-training syndrome. Failure to allow adequate periods of recovery from training might result in damage from which recovery is likely to take months or years, and perhaps in some cases might be permanent.
This conclusion fits with the accepted wisdom that consecutive days of hard training should be avoided, as should heavy training when there is evidence, such as fever, indicating systemic inflammation. But is there any method other than ‘listening to the body’ to judge when we are in danger of over-training? This is a topic I have addressed in the past. I do not think there is a simple answer to this question, but nonetheless, I will once again turn my attention to the question of systematic procedures for assessing over-training, in the near future.