untitled


‘Paracelcus’ rediscovered: searching
for the right dose of physical training

Christian Schmied

To cite: Schmied C.
‘Paracelcus’ rediscovered:
searching for the right dose
of physical training. Open
Heart 2014;1:e000027.
doi:10.1136/openhrt-2013-
000027

Accepted 5 February 2014

▸ http://dx.doi.org/10.1136/
openhrt-2013-000005

Clinic of Cardiology,
University Heart Center,
Zurich, Switzerland

Correspondence to
Dr Christian Schmied;
christian.schmied@usz.ch

‘All things are poison and nothing is without
poison, only the dose makes a thing not a
poison’.
When Phillipus Aureolus Theofrastus

Bombastus von Hohenheim—better known
as ‘Paracelsus’—a Swiss German Renaissance
physician, botanist, astrologer and philoso-
pher coined this well-known quote about
500 years ago, he might not have thought
about dose-dependent ‘toxic’ effects of
regular sport. Nevertheless, these words per-
fectly fit a highly debated hot topic in sports
cardiology: where is the upper limit of
‘healthy’ physical exercise and up from
which ‘dose’ it might be even harmful?
Although quite much is known about the

minimal efforts of physical exercise that have
to be provided to gain health benefits, so far
no ‘upper limit’ has been defined.1 However,
adverse longtime effects of regular strenuous
endurance training (eg, in cross-country
skiers and bicycle racers) could be defined:
as such, a multitude of studies proved an
increased rate of atrial fibrillation in endur-
ance athletes at an older age compared with
age-matched controls.2 3 The underlying
morphological substrates are miscellaneous,
consisting of inflammation, fibrosis and
cavity dilation (figure 1).3

Another important ‘weak spot’, particularly
in ambitious endurance athletes’ hearts, is
the right ventricle. As such, postrace dilation
and decreased function of the right ventricle
have been demonstrated impressively in
cyclists, recently.4 Moreover, these changes
are regressive but it might take a few weeks
or months for the right ventricle to regain its
primary function.
Thus, the border between acute and

chronic adaptations caused by regular
(endurance) training have become indistinct
and should be interpreted as a ‘grey zone’.

ACUTE ADAPTATIONS ON PHYSICAL EFFORTS
—DOES THE DOSE REALLY MATTER?
Marathon races, nowadays, have become
mass events, where many of the competitors

face a physical burden they are by far not suf-
ficiently prepared for. The fact that the
average finishing times of nearly all of the
large city marathons increased continuously
in the past years reflects this behaviour;
recently, marathon running has become a
‘grassroots sport’ (figure 2).
This situation reflects an extreme discrep-

ancy between the sedentarity of a better part
of the population on one side and extreme
physical efforts of a growing subgroup on the
other side. As a relevant part of the popula-
tion competes at marathon events, these ath-
letes have been in the focus of various
surveys conducted recently; although mara-
thon runners show a relevant postrace
increase of cardiac biomarkers (eg, troponin
I, troponin T, B-type natriuretic peptide),
sometimes associated with transient dilation
of the right atrium and particularly of the
right ventricle and reduction of right ven-
tricular ejection fraction, cardiovascular MRI
suggests that this is not a result of serious
ischaemic or inflammatory injury to any
cardiac chamber.5 6

Not only after the ‘RACER’ study, a large
survey in North-American marathon runners,
that demonstrated a decreased risk for
sudden cardiac arrest within the first half of
a marathon run compared to the second
half, the debate is going on whether half-
marathon harbours a justifiable risk for
sportive individuals.7 In this issue of the
journal, Dalla Vecchia and colleagues high-
light the effects of half-marathon running on
amateur athletes to add data to that particu-
lar subgroup performing at a relatively mod-
erate level. Therefore, they enrolled a
relatively small number of amateur athletes
(at the age of 42±7 years). Their findings
could mostly be anticipated, however, the
authors could demonstrate related (transi-
ent) changes that have been observed in
marathon runners.5 6 8

Yet another unsolved issue is the question
which individuals are particularly prone to
acute structural, functional or biochemical
response to high physical efforts: in a current

Schmied C. Open Heart 2014;1:e000027. doi:10.1136/openhrt-2013-000027 1

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http://dx.doi.org/10.1136/openhrt-2013-000005
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http://openheart.bmj.com/


meta-analysis including 16 studies of 939 marathon
runners with elevated postrace troponin-T (cTn) levels,
the pooled OR for converting from a normal prerace to
an elevated postrace cTn was 51.84 (95% CI 16 to 168,
I2=66%, p<0.001).8

CHRONIC ADAPTATIONS ON PHYSICAL EFFORTS—
CLASSICAL ‘CARDIAC FATIGUE’ VERSUS ‘ADVERSE
REMODELLING’
Multiple studies have pointed out increases in cardiac
troponin and natriuretic peptides, as well as left and
right ventricular dysfunctionality following an intense
prolonged exercise. The term ‘cardiac ‘fatigue’ has
often been used to express relatively prompt and,

particularly, complete cardiac recovery. However, as
aforementioned, the cut-off between acute and chronic
cardiac adaptations lies within a grey-zone, particularly if
focusing on right ventricular function that is more fre-
quently and more profoundly affected. Moderate right
ventricular dysfunction has been demonstrated using
various imaging techniques.4 6 However, the reason for
this preponderance of right ventricular impairment is
still unclear and it raises the hypothesis that repeated
insults could explain a chronic right ventricular injury
triggering potentially fatal arrhythmias.
Benito et al 9 demonstrated another aspect of sustained

intensive exercise in an animal model: ‘Ultra marathon
rats’ were conditioned to run vigorously for 4, 8 and
16 weeks. Compared with their matched sedentary
antipodes, the ‘marathon rats’ developed eccentric
hypertrophy and diastolic dysfunction, together with
atrial dilation. Furthermore, they demonstrated collagen
deposition in the right ventricle. Messenger RNA and
protein expression of fibrosis markers in the atria and
right ventricle were significantly greater than in seden-
tary rats at 16 weeks. In 42% of the ‘marathon rats,’ ven-
tricular tachycardia could be induced (significantly
more than in sedentary rats). Moreover, the fibrotic
changes provoked by 16 weeks of intensive exercise
appeared reverse after an 8-week exercise cessation.
Although these mechanisms need to be confirmed in
humans—this study supports the hypothesis that long-
term (repetitive) vigorous endurance training may lead
to ‘adverse cardiac remodelling’ which leads to impair-
ment and increased arrhythmic inducibility.

ARE GENETICS THE KEY?
Not only the results of the study with ‘marathon rats’
implicate that there is still an individual risk for acute
and chronic adaptations to physical training that is most

Figure 1 The ‘Triangle of
Coumel’ illustrating the interplay

between different factors that

promote and preserve atrial

fibrillation, particularly in an

athlete (adapted from Mont

et al3).

Figure 2 Number of finishers and average finishing times at
the Chicago marathon from the year 2000 to 2012 (source:

‘Marathon Guide: Chicago Marathon’. MarathonGuide. 2012.

Retrieved 9 October 2012).

2 Schmied C. Open Heart 2014;1:e000027. doi:10.1136/openhrt-2013-000027

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likely independent from the physical burden (within a
certain range).9 In this context, it will be crucial to gain
further data in the field of genetic susceptibility of an
individual. A recent small study highlighted a possible
role of microRNAs.10 Mooren et al could demonstrate
that these crucial intracellular mediators, that also affect
the cardiovascular system, significantly increase after a
marathon race. Moreover, none of the microRNAs corre-
lated with cardiac injury markers such as troponin T,
troponin I and pro-BNP. Probably, these muscle and
heart-specific microRNAs not only have a potential role
as biomarkers of aerobic capacity but also as markers for
cardiac adaptations and even for the individual cardiac
risk in athletes.10

Thus, at the bottom line, what would be of real impact
is the question whether regular training (and competi-
tion) of an individual who performs on a relatively mod-
erate level (eg, as half-marathon racers) provokes less
longtime adverse effects on the athlete’s heart.
However, to answer this question, randomised studies

in larger cohorts are needed that observe not only
acute, but long-time, effects of regular physical training
at different levels.
Finally, the crucial question that asks for the perfect

dose of physical activity still remains unanswered, but it
will be—with the help of an individually tailored and
adapted recommendation based on well-established and
further developed tools as cardiopulmonary exercise
tests and imaging techniques combined with genetic
analysis. However, as this aim is still far from clinical
practice, it completes the circuit—bringing me back to
another famous ‘Paracelsus’ quote:
‘Dreams must be heeded and accepted. For a great

many of them come true. ’

Competing interests None.

Provenance and peer review Commissioned; internally peer reviewed.

Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
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2. Elosua R, Arquer A, Mont L, et al. Sport practice and the risk of lone
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9. Benito B, Gay-Jordi G, Serrano-Mollar A, et al. Cardiac
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