Archive for May, 2014

Minimising the risks: chronic inflammation

May 24, 2014

In my recent post I summarised the evidence indicating that running, at least in amounts up to 50 minutes of vigorous activity per day, is likely to increase your life expectancy, but nonetheless some endurance runners suffer serious ill-health attributable at least in part to their running. There is unequivocal evidence indicating transient heart muscle damage after endurance event such as a marathon; and unequivocal evidence that endurance athletes are at increased long-term risk of heart rhythm disturbance, such as atrial fibrillation. There is quite strong evidence that many years of marathon training increases the risk of fibrosis of the heart muscle and calcification of the coronary arteries. While the beneficial effects appears to outweigh the adverse effects for the majority, at least some endurance athletes suffer serious adverse effects. On the other hand, the evidence that the benefits appear to outweigh the adverse effects in the majority suggests that is sensible to try to identify what causes the serious adverse effects and take steps to minimise them, thereby increasing the likelihood of being among those who derive more benefit than harm.

Although the mechanisms of cardiac damage are not well established, there is a great deal of evidence regarding plausible mechanisms. We are not detached observers who can afford the luxury of waiting until the mechanisms are established beyond doubt, like climate change deniers who prefer to wait until the outcome is certain before acting. Rather, we are each an experiment of one, and we must make our decision for action or inaction based on the current evidence.

Inflammation and myocardial fibrosis

Perhaps the most plausible mechanism for adverse cardiac effects is a mechanism based on inflammation. Prolonged mechanical stress on heart muscle produces damage, which in turn elicits an increase in cytokines, the chemical messengers that circulate in the blood and trigger the events of inflammation which lead to laying down of fibrous tissue. This is the body’s mechanism for repairing damage and increasing the strength of tissues. But the initial deposition of fibrous tissue is slap-dash and unless redundant fibres are removed, the future function of the relevant body tissue is likely to be impaired. In the long term calcium is deposited at the site of damage, making the tissues stiff and inflexible.

In the case of tissues such as the plantar fascia, the misaligned fibres cause the pain of plantar fasciitis and the deposited calcium gives rise to the heel spurs visible on x-ray. In the case of the heart muscle, misplaced fibrous tissue has the potential to interfere with the electrical conduction pathways producing disturbance of rhythm. In the case of the lining of blood vessels such as the coronary arteries, the process is a bit more complex. The accumulation of cholesterol at the sites of damage to the lining of the artery plays a key role in triggering the inflammatory response. The Wellcome Trust have produced an excellent video depicting the sequence of events.

Minimising the risks

From what we understand of the mechanism, there are three key things we can do to minimise the risk of damage:

1)      Allow adequate recovery after heavy training and racing. Studies in animals and humans demonstrate that much of the fibrosis, though perhaps not all, resolves during an adequate recovery period.


3)      Consume a diet that minimises chronic inflammation. Current evidence indicates that a Mediterranean diet, in which the pro-inflammatory omega 6 fats prevalent in the Western diet are balanced by omega 3 fats from fish and/or nuts and green leafy vegetables, is a heart-healthy diet.


It is noteworthy that these three strategies not only have the potential to reduce the risk of serious long term adverse effects on the heart, but are also likely to maximises the long term improvement in running performance.

In future posts I will discuss the more complex issue of cortisol and also the exacerbation of rhythm disturbances by excess potassium that is released from damaged muscle cells


The big debates of the past decade: 5) Is running good for your health?

May 19, 2014

Is running good for your health? Once the answer seemed simple.  However, the sadly premature deaths of several charismatic advocates of endurance running, Jim Fixx, John (Hadd) Walsh and Caballero Blanco, have provided grounds for questioning the claim that a large volume of running is healthy.

The past decade has seen a vigorous debate driven by enthusiasts who claim that the evidence indicates that any more than about 2.5 hours of moderate intensity exercise per week is harmful.   The high priest preaching warnings about the risks is James O’Keefe, a cardiologist from Kansas City, who summarised his views in a review in the respected Mayo Clinic Proceedings and also popularised them in an evangelistic TED talk.   I have discussed O’Keefe’s views previously in a post in Jan 2013. Though I consider that he himself comes across as something of an evangelist, the evidence that he assembles does indeed confirm beyond reasonable doubt that endurance athletes are not immune from either coronary heart disease or from potentially fatal disturbances of cardiac rhythm.

My own belief is that the overall balance between health benefit and harm of running is inclined towards greater benefit than harm, at least up to upper limit of running done by the majority of recreational runners. I reviewed the evidence in my post in Jan 2013, and will not present the details again here. Instead, I will provide an update on the evidence that has been assembled since Jan 2013.

However, my main interest is not on the statistical evidence for or against harm, but rather on what research of the past decade has revealed about likely mechanisms by which running might be expected to cause harm, with the ultimate goal of developing strategies for minimising the risk of harm. Even if the balance of evidence suggests that running is of greater benefit than harm to health, the undeniable evidence that at least some runners do suffer harm suggests to me that the sensible approach is to take what steps we can to minimise the risk of unnecessary harm.

Life expectancy

The picture is moderately clear: life expectancy increases with increasing amount of exercise, but the rate of increase levels off at higher levels. For example, in the study by Wen and colleagues, the reduction in mortality rate (that is the number of deaths that occurred compared with the number expected during the follow-up period) was observed to increase with increasing amount of exercise, but levelled off at a mortality reduction of around 45%  for 50 minutes or more of vigorous exercise per day.   Although there was little evidence of an actual decrease in life expectancy with very large amounts of exercise, the number of individuals exercising at extreme levels is small, so it is difficult to draw statically robust conclusions.

Perhaps the most thought provoking evidence comes from the Copenhagen Heart Risk study, a longitudinal study of nearly 18000 people followed over a period of up to 35 years. As in other relevant studies, the main conclusion regarding the effects of exercise is that jogging reduces mortality. The age-adjusted increase in survival with jogging was 6.2 years in men and 5.6 years in women. However the investigators reported a U-shaped relationship, with best outcome in those who jogged less than 2.5 hours a week at a slow pace. But the numbers in the relevant groups were very small. In those reporting that they jogged slowly, there were 3 deaths in 178 people, whereas among the fast group there were 5 deaths among 201.   These numbers are too small to justify robust conclusions.

In contrast , a study of mortality in a cohort of 49 219 men and 24 403 women who participated in any of the Vasaloppet long-distance ski races in Sweden (90Km for men; 90 and 30Km for women) during 1989–1998,revealed substantially reduced standardised mortality rate (SMR) from all major causes of death including heart disease and cancer. Overall, 410 deaths occurred up to Dec 1999, compared with 851 expected, yielding an SMR of 0.48.   It is reasonable to assume that the majority of competitors in these races had undertaken extensive training.

More recently, a study by Dr Jodi Zilinki and colleagues at Massachusetts General Hospital, reported at this year’s American College of Cardiology meeting in Washington, found evidence of decreased cardiac risk factors following marathon training in 45 recreational runners aged 35-65 who had not achieved Boston Qualifying time for the 2013 event but had nonetheless obtained places to raise money for charity. Half had run at least three marathons in their lifetime. Prior to an 18 week training program, over half had at least one risk factor for heart disease, such as high cholesterol, high blood pressure or a family history of heart disease. During training, potentially harmful low density lipoprotein (LDL) cholesterol decreased by 5% while triglycerides decreased by 15%. Thus for the majority of recreational runners, it appears that marathon training is likely to be good for their health

Specific cardiovascular risks


With regard to cardiovascular risks, the most compelling evidence indicates increased risk of disturbance of heart rhythm, such as atrial fibrillation, in middle-aged male endurance athletes. This is revealed by many studies (which I reviewed in a post in Jan 2012), though the question of whether or not this results in greater mortality is not clearly established. It is possible that other health benefits of running might outweigh the risks associated with arrhythmia. For example, the reduced blood pressure, lower levels of harmful low density lipoprotein cholesterol associated with endurance training would be expected to confer protection.

Coronary artery disease

Perhaps the most worrying issue is the possibility of increased coronary artery disease.   There have been a many of reports of clogged coronary arteries revealed by coronary angiography in endurance athletes. The most substantial of these was a study of 50 men who had competed in the Twin Cities (Minneapolis-St Paul) Marathon for twenty five consecutive years. The proportion of individuals with atheroma was similar in the two groups (atheroma in 60% on marathon runners, and 52% percent of controls), while the extent of the atheroma was significantly greater in the runners. This finding was initially reported at the American College of Cardiology meeting in Atlanta, Georgia in 2010. However, only an abstract was published at that time.

The definitive publication by Robert Schwartz and colleagues appeared in 2014 in a relatively obscure journal, Missouri Medicine. The list of co-authors includes James O’Keefe, who is an Editorial Board Member of Missouri Medicine Preventive Medicine.  I mention the details about publication because when a paper as potentially important as this appears belatedly in a relatively low profile journal, the first question that occurs to me is: why was this not published in a more authoritative journal.   Was it was rejected by other journals?

I am not a cardiologist, though I do frequently provide peer review of scientific and medical manuscripts submitted to high-profile journals. If I had been asked to review this manuscript, my greatest concern would have been for the procedure used to match runners and controls. In any study in which participants of interest are compared with a control group it is important that the two groups are matched on factors that might have an independent effect on outcome. For example, it is usually necessary to match for age, sex and social class. It is often desirable to match for other factors relevant to the condition of interest, such as family history of heart disease. However it is usually undesirable to match for factors that reflect the mechanism by which the ‘treatment’ (in this case, running multiple marathons) might achieve its benefit or harm. For example, because exercise tends to decrease the levels of harmful lipids in the blood, it might be misleading to match the groups on these variables. Such matching would be expected to produce a control group who happen to exhibit below-average risk of cardiovascular disease for incidental reasons related to their genes or environment.   But this is precisely what Schwartz and colleagues did. In effect, they determined the effect of marathon running after allowing for some of the anticipated benefits of marathon running.  Thus the statistical comparison of the two groups is biased and must be interpreted with extreme caution.

Nonetheless, whatever one makes of the statistical comparison, the number of marathon runners with atheroma in their coronary arteries and the extent of their atheroma was alarmingly high.  If I had been the referee reviewing this manuscript, I would have recommended publication subject to a critical discussion of the possible bias introduced by the matching procedure. I think it would be unwise to brush aside these findings simply because of some flaws in the science – there are very few medical studies that are totally free of all possible bias.  In evaluating medical evidence it is necessary to weigh up the whole picture, including the plausibility of the findings on the basis of what we know of human physiology.

Plausible mechanism for cardiovascular damage

I consider that there are at least three plausible mechanisms by which prolonged or intense endurance exercise might lead to cardiovascular damage. These are elevation of cortisol, chronic inflammation and acute release of potassium due to breakdown of muscle cell membranes.

Cortisol is a key hormone that mediates the body’s acute response to stress, but if elevation of cortisol is sustained, it damages most tissues of the body.   Skoluda and colleagues have presented evidence that endurance athletes tend to have sustained elevation of cortisol.

Inflammation is the process by which the body repairs itself following acute damage. It is probable that acute inflammation plays a central role in the repair and strengthening of the body after vigorous training. Thus, it is a key mediator of training effects. However inflammation that becomes chronic is harmful and probably plays a large part in the over-training syndrome. Furthermore, chronic inflammation promotes the formation of coronary atheroma.

The imbalance of concentration of potassium ions across cell membranes plays a central role in nerve conduction and muscle contraction, in both skeletal muscle and in the heart. Potassium concentration within cells is normally high while levels in extra-cellular tissues including blood are low. Damage to muscle cell membranes during vigorous exercise releases potassium into the extracellular tissues. The mechanism for pumping potassium back into muscle cells and also the action of the kidneys can normally cope with this tendency towards excess extra-cellular potassium. But under some rare circumstances, potassium can rise to high levels causing fatal cardiac arrest.

The important thing about all three of these mechanisms is that there are things we can adjust about our training and our lifestyle, including diet, that have the potential to ameliorate all of these risks. Thus, even though for most of us, the health risks of endurance training and racing are small and likely to be outweighed by the benefits, we can shift the balance even further in the direction of benefit by adjusting our training and lifestyle. In future posts I will present my conclusions regarding the best strategies for achieving this.