Basic Res Cardiol (2014) 109:391 DOI 10.1007/s00395-013-0391-8
ORIGINAL CONTRIBUTION
Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners Stefan Mo¨hlenkamp • Kirsten Leineweber • Nils Lehmann • Siegmund Braun • Ulla Roggenbuck Mareike Perrey • Martina Broecker-Preuss • Thomas Budde • Martin Halle • Klaus Mann • Karl-Heinz Jo¨ckel • Raimund Erbel • Gerd Heusch
•
Received: 20 August 2013 / Revised: 11 October 2013 / Accepted: 16 October 2013 / Published online: 19 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract We determined the prognostic value of transient increases in high-sensitive serum troponin I (hsTnI) during a marathon and its association with traditional cardiovascular risk factors and imaging-based risk markers for incident coronary events and all-cause mortality in recreational marathon runners. Baseline data of 108 marathon runners, 864 age-matched controls and 216 age- and risk factor-matched controls from the general population were recorded and their coronary event rates and all-cause mortality after 6 ± 1 years determined. hsTnI was measured in 74 marathon finishers before and after the race. Other potential predictors for coronary events, i.e., Framingham Risk Score (FRS), coronary artery calcium (CAC) and presence of myocardial fibrosis as measured by U. Laufs, Homburg/Saar, Germany, served as guest editor for the manuscript and was responsible for all editorial decisions, including the selection of reviewers. The policy applies to all manuscripts with authors from the editor’s institution. A comment to this article is available at doi:10.1007/s00395-0130395-4. S. Mo¨hlenkamp (&) Clinic of Cardiology and Intensive Care Medicine, Bethanien Hospital Moers, Bethanienstrasse 21, 47441 Moers, Germany e-mail: [email protected] K. Leineweber G. Heusch Institute for Pathophysiology, University Duisburg-Essen, Essen, Germany N. Lehmann U. Roggenbuck K.-H. Jo¨ckel Institute for Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany S. Braun Institute of Clinical Chemistry and Laboratory Medicine, German Heart Center, Munich, Germany
magnetic resonance imaging-based late gadolinium enhancement (LGE), were also assessed. An increase beyond the 99 % hsTnI-threshold, i.e., 0.04 lg/L, was observed in 36.5 % of runners. FRS, CAC, or prevalent LGE did not predict hsTnI values above or increases in hsTnI beyond the median after the race, nor did they predict future events. However, runners with versus without LGE had higher hsTnI values after the race (median (Q1/ Q3), 0.08 lg/L (0.04/0.09) versus 0.03 lg/L (0.02/0.06), p = 0.039), and higher increases in hsTnI values during the race (median (Q1/Q3), 0.05 lg/L (0.03/0.08) versus 0.02 lg/L (0.01/0.05), p = 0.0496). Runners had a similar cumulative event rate as age-matched or age- and risk factor-matched controls, i.e., 6.5 versus 5.0 % or 4.6 %, respectively. Event rates in runners with CAC scores\100, 100–399, and C400 were 1.5, 12.0, and 21.4 % (p = 0.002 for trend) and not different from either control group. Runners with coronary events had a higher prevalence of LGE than runners without events (57 versus 8 %, p = 0.003). All-cause mortality was similar in marathon runners (3/108, 2.8 %) and controls (26/864, 3.0 % or M. Perrey R. Erbel Clinic of Cardiology, West-German Heart Center Essen, University Duisburg-Essen, Essen, Germany M. Broecker-Preuss K. Mann Department of Endocrinology and Division of Laboratory Research, University Duisburg-Essen, Essen, Germany T. Budde Clinic of Internal Medicine and Cardiology, Alfried Krupp Krankenhaus, Essen, Germany M. Halle Department of Prevention and Sports Medicine, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Munich, Germany
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5/216, 2.4 %, respectively). Recreational marathon runners with prevalent myocardial fibrosis develop higher hsTnI values during the race than those without. Increasing coronary artery calcium scores and prevalent myocardial fibrosis, but not increases in hsTnI are associated with higher coronary event rates. All-cause mortality in marathon runners is similar to that in risk factor-matched controls. Keywords Cardiovascular events Coronary artery calcium Marathon Prognosis Troponin
Introduction The cardiovascular benefits of regular physical exercise are well established [15, 31]. On the other hand, vigorous exercise acutely increases the risk of coronary events [3, 34]. Coronary atherosclerosis is the main underlying cause of exercise-related coronary events, not only among elderly persons unaccustomed to exercise [14] but also in recreational athletes, including marathon runners [12, 21, 30]. Indeed, some marathon runners, especially those of older age, have subclinical coronary artery disease (CAD) [17]. Whether exhaustive exercise in these runners is truly ‘‘healthy in the long run’’ is not known. A transient increase in serum troponin in about 50 % of marathon runners [28] has raised concern about its diagnostic and prognostic relevance. In various clinical settings, increased serum troponin reflects myocardial necrosis [1, 4, 23, 33], and even minor elevations in serum troponin in acute coronary syndromes (ACS) translate into impaired prognosis [9]. In marathon runners, the observed serum troponin release is variable and possibly related to differences in fitness level, type and/or duration of exercise, timing of blood sampling, and troponin assay, notably its detection limit to define a ‘‘positive’’ troponin [28]. The observed serum troponin increase frequently just exceeds the upper limit of the norm [13, 28]. It is therefore unclear whether or not increased serum troponin during a marathon indeed reflects irreversible myocardial cell damage [27]. In this respect, of note, the majority of previous studies have been performed in marathon runners\50 years of age, who are less likely to have advanced CAD and suffer from ischemic events. In the present study, we used the Framingham Risk Score (FRS), the coronary artery calcium (CAC) score, and the presence of myocardial damage as measured by magnetic resonance imaging (MRI)-based late gadolinium enhancement (LGE) as potentially predictive baseline variables, and incident coronary events as the potential consequences of injury by exercise. For comparison, we used age-matched and age- and risk factor-matched controls from a large general population cohort.
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Methods Participants and study design The study was approved by the local ethics committee and the National Institute of Radiation Protection (Bundesamt fu¨r Strahlenschutz, Munich, Germany). All participants gave written informed consent prior to participation, including informed consent for clinical follow-up and evaluation of hospital records. The study design, recruitment, and baseline methods have been published [6, 17, 19]. In brief, participants were recruited in three ways: (1) through an advertisement in a German marathon journal (‘‘Runners World’’), (2) through a press conference at the inauguration of the study, and (3) through inclusion of colleagues and friends of participants, if inclusion criteria were met [17]. Males C50 years were eligible, if they had completed at least five full-distance marathons during the preceding 3 years. Exclusion criteria were history of established heart disease, diabetes mellitus, renal failure, and psychiatric disease. Baseline examinations were performed between April 2005 and January 2006. Matched controls were selected from the Heinz Nixdorf Recall (HNR) study [7, 18]. All 108 runners were invited to participate in the Du¨sseldorf Metro-Group Marathon in 2006 (7th May) and had blood samples taken before and immediately after the marathon. Of the 108 runners of the study cohort, 28 did not participate in the marathon due to skeletal muscle injury, insufficient training status, newly discovered cardiovascular disease (CVD), participation in other marathon running events in proximity to the Marathon race, or personal reasons. Of the 80 marathon runners, 74 completed the full marathon distance (Fig. 1). Cardiovascular risk factors and questionnaires Blood pressure was measured in a sitting position using an automated oscillometric blood pressure device (Omron, HEM-705CP), calculating the mean of the second and third value of three measurements [7, 18]. Body mass index [BMI (kg/m2)] was calculated from standardized measurements of height and weight. Current smoking was defined as a history of cigarette smoking during the past year. Participants were considered to have diabetes if they reported a physician diagnosis of diabetes or were taking anti-diabetic medication. From these risk factors, the Framingham Risk Score (i.e., predicted 10-year risk) was computed using previously reported methods [7, 18]. All participants were queried about known CVD and current regular cardiovascular medication using a physician-based questionnaire.
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Baseline:
n = 108 did not participate
n = 28
100 ms. The CAC Agatston score was computed by summing the CAC scores of all foci in the epicardial coronary system. The CAC score was not communicated to either the participants or their treating physician [7, 17, 18]. Cardiac magnetic resonance acquisition and analysis
Marathon:
n = 80 n = 6 non-finisher
hsTnI:
n = 74 n = 34
Follow-Up: Hard Events * Sign. CAD
*,#
n = 108 n=5 (5.4%)
n=2 (5.9%)
n=1
*: see Table 1 for details #: see Figure 4 for details
Fig. 1 Flowchart of runners, who (1) finished or (2) did not participate in or not finish the marathon, and their coronary event rates
Clinical chemistry Blood samples were taken from an antecubital vein using the MonovetteÒ vacuum system. For cytokine panel testing, 2.7 mL EDTA-blood (S-Monovette K3E, Sarstedt, Nu¨mbrecht) was immediately centrifuged for 10 min at 1,600–1,800g and 4 °C. The plasma was removed, and aliquots quickly snap-frozen in liquid nitrogen and stored at -80 °C until further use. Interleukin 6 (Il-6) was measured using a biochip array (Evidence InvestigatorTM; Randox, Crumlin, UK). N-terminal pro brain natriuretic peptide (NTproBNP) was measured from serum using the proBNP assay on an Elecsys analyzer (Roche, Mannheim, Germany). HsTnI was measured using a standard highsensitive assay (TnI-Ultra) on an ADVIA Centaur XP analyzer (Siemens Healthcare Diagnostics, Eschborn, Germany). Changes in plasma volume immediately after the marathon were estimated from serum osmolality and all parameters after the race were corrected accordingly. Coronary artery calcium (CAC) To quantify CAC, non-enhanced EBCT scans were performed with a C-150 scanner (GE Imatron, South San Francisco, US) in both studies using prospective ECG triggering at 80 % of the RR interval and contiguous 3 mm thick slices to the apex with an image acquisition time of
All examinations were performed on a 1.5 Tesla magnetic resonance imaging (MRI) scanner equipped with high-performance gradients (Magnetom Avanto, Siemens, Erlangen, Germany) as previously reported [6]. Sequences were acquired in short and long axis views 10–15 min after intravenous injection of 0.2 mmol/kg body weight gadoliniumDTPA (Schering AG, Berlin, Germany). Hyper-enhanced regions were defined to reflect myocardial damage [6]. Follow-up Controls from the general population were followed for a median of 6.5 years (mean 6.2 ± 1.0 years). Marathon runners were followed for a median of 6.5 years (mean 6.2 ± 1.2 years). All 108 marathon runners responded to a clinical questionnaire. In case of events, the runners and their physicians were queried about circumstances of events and physicians’ and hospital records. In matched controls from the Heinz Nixdorf Recall study, annual postal questionnaires assessed the morbidity status during follow-up, i.e., medication, hospital admissions, and outpatient diagnoses of cardiovascular disease. Self-reported incident coronary and fatal events were validated by review of hospital records and records of the attending physicians (see below). All death certificates of the three cities of recruitment, i.e., Essen, Mu¨lheim/Ruhr and Bochum, were regularly screened. In parallel, deceased participants were tracked back to obtain as much information as possible to verify the causes of death [7, 17, 18]. Study end points and verification of study end points Primary end points for this study included fatal and non-fatal coronary events and coronary revascularization, summarized as CVD events, based on unequivocally documented incident events that met predefined study criteria [7, 17–19]. We considered a myocardial infarction based on symptoms, electrocardiographic signs, and serum enzymes [levels of creatine kinase (CK-MB)] as well as troponin T or I, and necropsy as (1) non-fatal acute myocardial infarction and (2) coronary death, which occurred between the baseline examination and 6 years after study entry. Coronary revascularization was defined as PTCA usually with stent placement according to hospital or physicians’ records. For all study end points, hospital and nursing home records including electrocardiograms, laboratory values, and pathology reports were
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collected. For deceased subjects, death certificates were collected and interviews with general practitioners, relatives, and eyewitnesses were undertaken where possible. Medical records were obtained for all reported end points. An external end point committee blinded to conventional risk factor status and CAC scores reviewed all documents and classified the end points thereafter.
Table 1 HsTnI, NT-proBNP, and Il-6 before and after the marathon
Statistical analysis
Values given as median [Q1/Q3]
Data are given as mean ± standard deviation (SD) or median [interquartile range (Q1–Q3)] and count data as frequency and/or percentage. Differences in continuous data were statistically evaluated using ANOVA or Mann– Whitney U statistics; differences in proportions were evaluated with v2 statistics or Fisher’s exact test, as appropriate. Trends in proportions were evaluated using Cochran–Armitage trend statistics. After logarithmic transformation of the CAC score, log2(CAC ? 1), hazard ratios (HR) for events were calculated with their 95 % confidence intervals (CI) from Cox proportional hazard regression within the runners and the matched controls. Two-group comparisons of hsTnI after the race and the change in troponin during the race, respectively, were statistically evaluated using exact, two-sided Mann–Whitney statistics. Kaplan–Meier analysis followed by log-rank test or log-rank test of trend was applied to time-to-event data within the cohorts with respect to presence of LGE or the extent of CAC. Follow-up period in controls was defined as the median follow-up period in marathon runners. Furthermore, Cox regression embodying matching criteria by stratification was used to compare time to event between runners and the matched controls. For comparison with the general population, 1:8 age-matched controls and 1:2 age- and risk factor-matched controls for the marathon runners were drawn from the HNRS cohort, restricted to males without CAD, aged C50 (n = 1842) [17]. Matching criteria were: within ± 3 years of age, within ± 3 kg/m2 body mass index (BMI), within ±4 % Framingham risk per 10 years, and individually by smoking status (present/former/never smokers). Matching was performed using PROC SURVEYSELECT of SAS (SAS Institute Inc., Cary, NC, USA) as published [25]. A probability value of p \ 0.05 was considered as significant. Statistical analyses were performed using SAS (Cary, NC, version 9.2).
a
Normal range
Before
After
p value
HsTnI
\0.04 lg/L
0.01 (0/0.01)
0.03 (0.02/0.08) \0.0001
NTproBNP
\125 pg/mL
34 (22/59)
124 (73/188)
IL-6
\1.5 pg/mLa
0 (0/2.4)
46.3 (27.6/60.8) \0.0001
\0.0001
* p \ 0.05 versus before
Results Demographics Demographics and cardiovascular risk factors of marathon runners, the 864 age-matched controls and the 216 age- and
123
Age- and gender-matched reference values were obtained from the STANISLAS Cohort [5]
risk factor-matched controls from the general population have been published [17]. At baseline, runners had completed a median of 20 full-distance marathons (Q1– Q3 = 14–42). Seventy-four participants completed the marathon (average finishing times: 250 ± 33 min, range 186–352 min). Among the 74 finishers, FRS correlated with finishing times (r = 0.35, p = 0.002), which was in part related to systolic blood pressure (r = 0.25, p = 0.03), but not to age (r = 0.18, p = 0.12). Finishers had a similar FRS as those 34 runners, who did not participate or not finish the race (6.9 ± 3.2 versus 7.4 ± 4.5, p = 0.86). Serum troponin, NT-proBNP, and Il-6 The marathon-related changes in hsTnI, NT-proBNP, and Il-6 are shown in Table 1. HsTnI and NT-proBNP increased three- and fourfold, respectively, and interleukin 6 from non-detectable to detectable levels during the race. An increase in hsTnI was observed in 93.2 % of runners. An increase beyond 99 % hsTnI threshold, i.e., 0.04 lg/L, was observed in 36.5 % of runners. The thresholds of quartiles of increases in hsTnI were Q1 = 0.011, median (Q2) = 0.028, and Q3 = 0.055. Similar increases in hsTnI were observed in runners with finishing times below versus above the median of 247 min [DhsTnI = 0.02 (0.01–0.04) versus 0.03 (0.01–0.08), respectively, p = 0.26]. Serum troponin increase versus coronary risk characterization None of the variables of coronary risk at baseline, i.e., FRS, CAC, or the presence of LGE, predicted serum hsTnI values above the median immediately after the marathon or increases in hsTnI values beyond the median increase during the marathon (Fig. 2). However, runners with versus without LGE had higher hsTnI values after the race [median (Q1/Q3): 0.08 lg/L (0.04/0.09) versus 0.04 lg/L (0.03/0.06), p = 0.039] and higher increases in hsTnI
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Fig. 2 Four-by-four tables of hsTnI values above versus below the median after the marathon (upper row) or in differences in hsTnI values after versus before the marathon (bottom row)
FRS
CAC
0
total
< 10
≥ 10
total
neg
pos
≤ 0.0305 µg/L
22
15
37
13
24
37
15
22
37
30
> 0.0305 µg/L
17
20
37
14
23
37
19
18
37
35
total
39
35
74
27
47
74
34
40
74
65
median change in hsTnI after the race vs. before
p>0.99
FRS
total
no
yes
total
7
37
34
3
37
2
37
34
3
37
9
74
68
6
p=0.48
CAC
6-Year CAD-Events *
LGE
median hsTnI after the race
p=0.35
p=0.15
CAC
74
p>0.99
6-Year CAD-Events *
LGE
0
total
< 10
≥ 10
total
neg
pos
total
no
yes
total
≤ 0.0276 µg/L
19
18
37
15
22
37
17
20
37
31
6
37
34
3
37
> 0.0276 µg/L
20
17
37
12
25
37
17
20
37
34
3
37
34
3
37
total
39
35
74
27
47
74
34
40
74
65
9
74
68
6
p>0.99
*
CAC
p=0.63
p>0.99
p=0.48
74
p>0.99
Note that two runners with events did not participate in the race. One other runner without a coronary event but with ischemic coronary heart disease during follow-up (Figure 4) was included in the group of six runners with coronary events for the purpose of this analysis (see also Figure 1). p-values are given using Fisher’s exact test.
values during the race [median (Q1/Q3): 0.05 lg/L (0.03/ 0.08) versus 0.02 lg/L (0.01/0.05), p = 0.0496]. Changes in NT-pro-BNP and Il-6 were similar in runners with versus without prevalent LGE (data not shown). Runners without CAC were slightly younger (54.6 ± 4.7 versus 57.9 ± 5.7 years, p = 0.014), but had similar increases in hsTnI [DhsTnI = 0.03 (Q1–Q3 = 0.01–0.08) versus 0.02 (0.01–0.05), p = 0.74], in Il-6 [DIl-6 = 55.6 (24.0–86.5) versus 36.7 (27.0–56.8), p = 0.18], and in NT-proBNP [DNT-proBNP = 87 (43–147) versus 94 (65–138), p = 0.39], respectively. Runners with events had similar increases in hsTnI as those without events [DhsTnI = 0.04 (0.01–0.14) versus 0.03 (0.01–0.05), p = 0.35]. Coronary events and subclinical cardiac disease The characteristics of marathon runners with coronary events are shown in Table 2. Runners had a similar cumulative event rate as age-matched and age- and risk factor-matched controls (Table 3). The increase in events per doubling of the CAC score was similar when only those 74 runners who completed the marathon and experienced five coronary events during follow-up were included in the analysis [HR = 1.37 (1.00–1.89, p = 0.052]. Being a marathon runner (n = 7 events) was associated with a 6.2year coronary risk comparable to that in age- and risk factor-matched controls [n = 10 events, HR = 1.29 (0.57–2.91), p = 0.61]. When only the 74 finishers with five events during follow-up were included, the HR was 1.87 (0.66-5.32, p = 0.32). The cumulative coronary event rate increased with increasing CAC scores similarly in runners and controls (Table 3). An increase in the CAC score category, i.e., \100, 100–399, and C400, was associated with a shorter time to event in marathon runners and controls (Fig. 3).
Runners with coronary events had a higher prevalence of LGE than those without events (57 versus 8 %, p = 0.003), consistent with Kaplan–Meier analysis (logrank, p \ 0.0001), while their 10-year FRS was similar (7.9 ± 2.3 vs. 7.0 ± 3.7 %, p = 0.20). All-cause mortality Three runners (2.8 %) died during follow-up. One runner died from a coronary event (Table 2), one from a brain tumor at age 76 years, and one from non-Hodgkin lymphoma at age 59 years. All-cause mortality was similar as in age-matched controls and age- and risk factor-matched controls (2.8 % versus 26/864 (3.0 %) and 5/216 (2.4 %), respectively).
Discussion The present study shows that transient increases in serum hsTnI after a marathon do not confer an increased longterm coronary event risk. Yet, the observed greater increases in hsTnI during the race in runners with prevalent myocardial fibrosis suggest that these troponin elevations may not simply reflect ‘‘myocardial fatigue’’. Cardiomyocyte necrosis as the underlying mechanism of the observed serum troponin increase during exhaustive exercise has been questioned, because serum troponin kinetics following exhaustive exercise are different from those in patients with acute coronary syndromes (ACS) [13]. Yet, no longterm observational study to date has been performed in runners with evidence of coronary atherosclerosis or myocardial fibrosis and at an age when ACS typically occur. As runners with myocardial fibrosis had higher changes in hsTnI and higher coronary event rates, we
123
123
65
55
62
51
62
58
59
#2
#3
#4
#5
#6
#7
#8
24
25
55
8
140
65
22
14
Number of races*
12
7
9
6
9
4
9
11
FRS* (%/10 years)
213
3,060
369
13
128
171
472
874
CAC score*
?
?
–
–
?
?
–
?
LGE*
4:07:46
3:59:41
4:29:33
3:52:39
3:51:03
4:49:45
Did not participate
Did not participate
Run time (h:min:s)
0.01/0.20
0.01/0.03
0.00/0.01
0.00/0.14
0.01/0.02
0.02/0.09
n.a.
n.a.
hsTnI (lg/L)
35/120
20/93
70/282
32/101
19/57
42/176
n.a.
n.a.
NT-proBNP (pg/mL)
Before/after the race
0/20.1
67.0/48.3
0/33.5
3.4/54.4
0/28.1
0/28.6
n.a.
n.a.
Il-6 (pg/mL)
n.a.
2,162
1,471
1,459
561
260
72
4
Time to event** (days)
No event but severe obstructive CAD (2VD: left main, LCX and LAD with long myocardial bridge) diagnosed during follow-up, CABG recommended
CABG in 3 VD and ascending aortic replacement: the patient’s training pace declined, later on exertional angina, aortic root aneurysm
STEMI after 4 days of UAP starting the day after return from vacation, revascularization of LAD, 3 months later Dx. of renal cancer
Sudden death near the end of a sunday morning 20 k leisure training run with a friend
Resuscitated during low to moderate intensity resistance training, 2-VD, CABG surgery, ICD after surgery
ST-elevation on resting ECG after the race in septal leads, septal LGE, 1-VD (LAD) on invasive angiography proximal to a septal branch showing myocardial bridging, revascularization of LAD
LAD, LCX and left main disease, requiring CABG as published [16]
Resuscitated at 7 k during a 10 k race, 3-VD, revascularization of LAD, LCX and RCA
Event characteristics
* data at baseline, ** time from baseline, n.a. not applicable
k kilometers, VD vessel disease, CABG coronary artery bypass graft, ICD implantable cardioverter/defibrillator, STEMI ST-segment elevation myocardial infarction, UAP unstable angina pectoris, Dx. diagnosis, FRS Framingham Risk Score, CAC coronary artery calcium, LGE late gadolinium enhancement
67
#1
Age* (years)
Table 2 Characteristics of marathon runners with coronary events during follow-up
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Table 3 Number of events, cumulative risks, and crude and adjusted hazard ratios (HR) (95 % CI) of coronary events in the CAC categories in marathon runners and controls Marathon runners
Controls from the HNR study Age and RF matched
Age matched
Persons in group (n)
108
216
864
FRS (% in 10 years) [median (Q1–Q3)]
7 (4–9)
7 (6–9)
11 (9–18)
Follow-up (years ± SD)
6.2 ± 1.2
6.2 ± 1.0
6.2 ± 1.0
Coronary events [n (%)]
7 (6.5)
10 (4.6)
43 (5.0)
Coronary events by CAC score category
n (%)
Event rate
n (%)
Event rate
n (%)
Event rate
\100
69 (64)
1.5
169 (78)
2.4
550 (64)
2.0
100–399
25 (23)
12.0
29 (14)
10.3
197 (23)
6.6
C400
14 (13)
21.4
18 (8)
16.7
117 (13)
16.2
p value for trend Increase in events per doubling of CAC [log2(CAC ? 1)]
=0.002
\0.0001
1.49 (1.08–2.05)
1.35 (1.11–1.64)
1.38 (1.23–1.55)
p = 0.02
p = 0.003
p \ 0.0001
=0.002
HNR Heinz Nixdorf Recall study, RF risk factors, FRS Framingham Risk Score, CAC coronary artery calcium
cannot exclude a potential link between marathon running, myocardial cell damage, and future coronary events. In fact, in the same cohort we reported that the number of completed marathon races was associated with a higher risk of myocardial fibrosis [17], which has been confirmed by others [35]. Yet, we also found that the coronary atherosclerosis burden was associated with more prevalent LGE [17], and it is possible that prevalent subclinical CAD predisposes to myocardial fibrosis, and that both, LGE and CAC, contribute to cardiac events via different mechanisms. Interestingly, we found no association between hsTnI and the CAC burden. We previously demonstrated that recreational runners, who have already participated in and are still fit enough to sustain a marathon race, may nonetheless have an unexpectedly high burden of coronary atherosclerosis, which is in line with a preliminary report from the Twin-Cities Marathon and with a 30 k-race-study in senior runners [17, 24, 26]. The present study shows that not the transient increase in serum hsTnI during a marathon, but the coronary atherosclerosis burden helps to characterize the longterm coronary risk of recreational runners, with event rates comparable to our controls and findings from other population-based analyses [7, 8, 18]. In 60 non-elite participants of the Boston marathon, increases in troponin T-levels were inversely associated with training mileage [20]. We can only speculate that this association was most likely unrelated to the coronary atherosclerosis burden or myocardial ischemia, because these runners were young, 1/3 of them females, had low BMI and low systolic blood pressures, and hence a very low Framingham risk and presumably very low burden of obstructive CAD. However, long-term prognosis data have not been
reported. Recently, the Race Associated Cardiac Arrest Event Registry (RACER) study group reported very low incidence rates of cardiac arrest and sudden death during long-distance racing [11], in line with our current data, as no events in our study occurred during a marathon race. Longterm events unrelated to marathon races were not studied by the RACER study group. Both studies did not measure myocardial fibrosis or coronary atherosclerosis burden. The long-term coronary risk in our cohort of recreational runners appears unexpectedly high. Possibly, our study has attracted runners who were concerned about their cardiac disease risk and had converted to a healthier lifestyle. Apparently, such lifestyle conversion may reduce, but not eliminate the risk arising from prior long-term risk factor exposure such as smoking [10, 36]. Our data suggest that the actual state of vessel wall atherosclerosis and/or presence of myocardial fibrosis determines prognosis and not the history how this state has arisen. The coronary atherosclerosis burden can be measured using the CAC score. It integrates the pro-atherosclerotic effect of the changing risk factors during the preceding decades. A lifelong runner with a continuously low risk factor profile may never develop any atherosclerosis in his life. Yet, if he does for any reason, his risk of a coronary event seems as high as that in other persons with a comparable atherosclerosis burden. Hence, the observed coronary event rate is only ‘‘unexpectedly high’’ if one would expect most marathon runners to be at low risk. From our data, a low atherosclerosis burden reflecting low risk is present in about 2/3rd of runners aged [50 years, but this rate of low-risk runners may be higher in larger cohorts. The question remains if runners with a high coronary atherosclerosis burden or with myocardial injury on MRI should
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0 0 0 503 169 88 545 197 116 550 197 117 0 0 0
542 194 113
539 188 113
533 186 105
518 181 96
7 2 3 4 5 6 Follow-Up Time [Years] 1 0 7
160 24 15 164 26 15 166 26 15 167 26 16 167 26 16 167 29 16 4 0 0 64 22 11
Kaplan–Meier event-free survival curves in marathon runners, age-matched controls, and age- and risk factor-matched controls
be recommended to cease marathon running. In this respect, of note, none of the coronary events in this present study occurred during a competitive marathon, but were nevertheless precipitated by some degree of physical activity in four of the seven runners, in line with previous studies [34]. The only fatal event occurred in a runner without LGE and with the lowest CAC score among all runners with events. Two events were revascularizations unrelated to ACS in runners with few symptoms. These revascularizations occurred prior to the clinical introduction of fractional flow reserve (FFR) measurements, which today is recommended to guide coronary intervention. Because of the possibility of good intramyocardial microvascular function despite epicardial stenosis [16], it is possible that these two runners would not have been revascularized today because of a potentially normal FFR despite angiographically significant stenosis. In fact, later during follow-up, one runner was detected to have angiographically significant stenosis with little ischemia on SPECT imaging. This runner (#8 in Table 2; Fig. 4) denied revascularization, was treated medically, continued to exercise regularly, and remained event free to date. Whether this is truly safe remains to be seen. The PROSPECT trial showed that a residual luminal area\4 mm2, an area plaque burden[70 %, or thin-cap fibroatheroma (TCFA) was predictive of unanticipated events [29]. At least two of these criteria were present in all eight runners in Table 2. The generally low event rate during marathon races, the increased event rate in runners with CAC or LGE in this study, the lack of event prediction based on marathon racerelated increases in hsTnI, and the potential role of prothrombotic factors in ACS in marathon runners [2] show the complexity of mechanisms contributing to coronary events in marathon runners. The acute risk of recreational marathon running seems to be low and is probably not higher than that associated with any other physical activity [34], but a prospective trial on different counseling strategies in runners with coronary or myocardial disease is clearly needed [32].
69 24 12 69 25 14
Number at risk during follow-up by CAC score:
69 23 12
69 23 12
68 23 12
68 22 12
7 0
0.5
0.75
1.0
0
1
2 3 4 5 6 Follow-Up Time [Years]
0
0
169 29 18
1
log-rank p=0.0011 log-rank p=0.0018
Marathon Runners
Event-Free Survival Probability
123
CAC
ORIGINAL CONTRIBUTION
Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners Stefan Mo¨hlenkamp • Kirsten Leineweber • Nils Lehmann • Siegmund Braun • Ulla Roggenbuck Mareike Perrey • Martina Broecker-Preuss • Thomas Budde • Martin Halle • Klaus Mann • Karl-Heinz Jo¨ckel • Raimund Erbel • Gerd Heusch
•
Received: 20 August 2013 / Revised: 11 October 2013 / Accepted: 16 October 2013 / Published online: 19 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract We determined the prognostic value of transient increases in high-sensitive serum troponin I (hsTnI) during a marathon and its association with traditional cardiovascular risk factors and imaging-based risk markers for incident coronary events and all-cause mortality in recreational marathon runners. Baseline data of 108 marathon runners, 864 age-matched controls and 216 age- and risk factor-matched controls from the general population were recorded and their coronary event rates and all-cause mortality after 6 ± 1 years determined. hsTnI was measured in 74 marathon finishers before and after the race. Other potential predictors for coronary events, i.e., Framingham Risk Score (FRS), coronary artery calcium (CAC) and presence of myocardial fibrosis as measured by U. Laufs, Homburg/Saar, Germany, served as guest editor for the manuscript and was responsible for all editorial decisions, including the selection of reviewers. The policy applies to all manuscripts with authors from the editor’s institution. A comment to this article is available at doi:10.1007/s00395-0130395-4. S. Mo¨hlenkamp (&) Clinic of Cardiology and Intensive Care Medicine, Bethanien Hospital Moers, Bethanienstrasse 21, 47441 Moers, Germany e-mail: [email protected] K. Leineweber G. Heusch Institute for Pathophysiology, University Duisburg-Essen, Essen, Germany N. Lehmann U. Roggenbuck K.-H. Jo¨ckel Institute for Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany S. Braun Institute of Clinical Chemistry and Laboratory Medicine, German Heart Center, Munich, Germany
magnetic resonance imaging-based late gadolinium enhancement (LGE), were also assessed. An increase beyond the 99 % hsTnI-threshold, i.e., 0.04 lg/L, was observed in 36.5 % of runners. FRS, CAC, or prevalent LGE did not predict hsTnI values above or increases in hsTnI beyond the median after the race, nor did they predict future events. However, runners with versus without LGE had higher hsTnI values after the race (median (Q1/ Q3), 0.08 lg/L (0.04/0.09) versus 0.03 lg/L (0.02/0.06), p = 0.039), and higher increases in hsTnI values during the race (median (Q1/Q3), 0.05 lg/L (0.03/0.08) versus 0.02 lg/L (0.01/0.05), p = 0.0496). Runners had a similar cumulative event rate as age-matched or age- and risk factor-matched controls, i.e., 6.5 versus 5.0 % or 4.6 %, respectively. Event rates in runners with CAC scores\100, 100–399, and C400 were 1.5, 12.0, and 21.4 % (p = 0.002 for trend) and not different from either control group. Runners with coronary events had a higher prevalence of LGE than runners without events (57 versus 8 %, p = 0.003). All-cause mortality was similar in marathon runners (3/108, 2.8 %) and controls (26/864, 3.0 % or M. Perrey R. Erbel Clinic of Cardiology, West-German Heart Center Essen, University Duisburg-Essen, Essen, Germany M. Broecker-Preuss K. Mann Department of Endocrinology and Division of Laboratory Research, University Duisburg-Essen, Essen, Germany T. Budde Clinic of Internal Medicine and Cardiology, Alfried Krupp Krankenhaus, Essen, Germany M. Halle Department of Prevention and Sports Medicine, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Munich, Germany
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5/216, 2.4 %, respectively). Recreational marathon runners with prevalent myocardial fibrosis develop higher hsTnI values during the race than those without. Increasing coronary artery calcium scores and prevalent myocardial fibrosis, but not increases in hsTnI are associated with higher coronary event rates. All-cause mortality in marathon runners is similar to that in risk factor-matched controls. Keywords Cardiovascular events Coronary artery calcium Marathon Prognosis Troponin
Introduction The cardiovascular benefits of regular physical exercise are well established [15, 31]. On the other hand, vigorous exercise acutely increases the risk of coronary events [3, 34]. Coronary atherosclerosis is the main underlying cause of exercise-related coronary events, not only among elderly persons unaccustomed to exercise [14] but also in recreational athletes, including marathon runners [12, 21, 30]. Indeed, some marathon runners, especially those of older age, have subclinical coronary artery disease (CAD) [17]. Whether exhaustive exercise in these runners is truly ‘‘healthy in the long run’’ is not known. A transient increase in serum troponin in about 50 % of marathon runners [28] has raised concern about its diagnostic and prognostic relevance. In various clinical settings, increased serum troponin reflects myocardial necrosis [1, 4, 23, 33], and even minor elevations in serum troponin in acute coronary syndromes (ACS) translate into impaired prognosis [9]. In marathon runners, the observed serum troponin release is variable and possibly related to differences in fitness level, type and/or duration of exercise, timing of blood sampling, and troponin assay, notably its detection limit to define a ‘‘positive’’ troponin [28]. The observed serum troponin increase frequently just exceeds the upper limit of the norm [13, 28]. It is therefore unclear whether or not increased serum troponin during a marathon indeed reflects irreversible myocardial cell damage [27]. In this respect, of note, the majority of previous studies have been performed in marathon runners\50 years of age, who are less likely to have advanced CAD and suffer from ischemic events. In the present study, we used the Framingham Risk Score (FRS), the coronary artery calcium (CAC) score, and the presence of myocardial damage as measured by magnetic resonance imaging (MRI)-based late gadolinium enhancement (LGE) as potentially predictive baseline variables, and incident coronary events as the potential consequences of injury by exercise. For comparison, we used age-matched and age- and risk factor-matched controls from a large general population cohort.
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Methods Participants and study design The study was approved by the local ethics committee and the National Institute of Radiation Protection (Bundesamt fu¨r Strahlenschutz, Munich, Germany). All participants gave written informed consent prior to participation, including informed consent for clinical follow-up and evaluation of hospital records. The study design, recruitment, and baseline methods have been published [6, 17, 19]. In brief, participants were recruited in three ways: (1) through an advertisement in a German marathon journal (‘‘Runners World’’), (2) through a press conference at the inauguration of the study, and (3) through inclusion of colleagues and friends of participants, if inclusion criteria were met [17]. Males C50 years were eligible, if they had completed at least five full-distance marathons during the preceding 3 years. Exclusion criteria were history of established heart disease, diabetes mellitus, renal failure, and psychiatric disease. Baseline examinations were performed between April 2005 and January 2006. Matched controls were selected from the Heinz Nixdorf Recall (HNR) study [7, 18]. All 108 runners were invited to participate in the Du¨sseldorf Metro-Group Marathon in 2006 (7th May) and had blood samples taken before and immediately after the marathon. Of the 108 runners of the study cohort, 28 did not participate in the marathon due to skeletal muscle injury, insufficient training status, newly discovered cardiovascular disease (CVD), participation in other marathon running events in proximity to the Marathon race, or personal reasons. Of the 80 marathon runners, 74 completed the full marathon distance (Fig. 1). Cardiovascular risk factors and questionnaires Blood pressure was measured in a sitting position using an automated oscillometric blood pressure device (Omron, HEM-705CP), calculating the mean of the second and third value of three measurements [7, 18]. Body mass index [BMI (kg/m2)] was calculated from standardized measurements of height and weight. Current smoking was defined as a history of cigarette smoking during the past year. Participants were considered to have diabetes if they reported a physician diagnosis of diabetes or were taking anti-diabetic medication. From these risk factors, the Framingham Risk Score (i.e., predicted 10-year risk) was computed using previously reported methods [7, 18]. All participants were queried about known CVD and current regular cardiovascular medication using a physician-based questionnaire.
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Baseline:
n = 108 did not participate
n = 28
100 ms. The CAC Agatston score was computed by summing the CAC scores of all foci in the epicardial coronary system. The CAC score was not communicated to either the participants or their treating physician [7, 17, 18]. Cardiac magnetic resonance acquisition and analysis
Marathon:
n = 80 n = 6 non-finisher
hsTnI:
n = 74 n = 34
Follow-Up: Hard Events * Sign. CAD
*,#
n = 108 n=5 (5.4%)
n=2 (5.9%)
n=1
*: see Table 1 for details #: see Figure 4 for details
Fig. 1 Flowchart of runners, who (1) finished or (2) did not participate in or not finish the marathon, and their coronary event rates
Clinical chemistry Blood samples were taken from an antecubital vein using the MonovetteÒ vacuum system. For cytokine panel testing, 2.7 mL EDTA-blood (S-Monovette K3E, Sarstedt, Nu¨mbrecht) was immediately centrifuged for 10 min at 1,600–1,800g and 4 °C. The plasma was removed, and aliquots quickly snap-frozen in liquid nitrogen and stored at -80 °C until further use. Interleukin 6 (Il-6) was measured using a biochip array (Evidence InvestigatorTM; Randox, Crumlin, UK). N-terminal pro brain natriuretic peptide (NTproBNP) was measured from serum using the proBNP assay on an Elecsys analyzer (Roche, Mannheim, Germany). HsTnI was measured using a standard highsensitive assay (TnI-Ultra) on an ADVIA Centaur XP analyzer (Siemens Healthcare Diagnostics, Eschborn, Germany). Changes in plasma volume immediately after the marathon were estimated from serum osmolality and all parameters after the race were corrected accordingly. Coronary artery calcium (CAC) To quantify CAC, non-enhanced EBCT scans were performed with a C-150 scanner (GE Imatron, South San Francisco, US) in both studies using prospective ECG triggering at 80 % of the RR interval and contiguous 3 mm thick slices to the apex with an image acquisition time of
All examinations were performed on a 1.5 Tesla magnetic resonance imaging (MRI) scanner equipped with high-performance gradients (Magnetom Avanto, Siemens, Erlangen, Germany) as previously reported [6]. Sequences were acquired in short and long axis views 10–15 min after intravenous injection of 0.2 mmol/kg body weight gadoliniumDTPA (Schering AG, Berlin, Germany). Hyper-enhanced regions were defined to reflect myocardial damage [6]. Follow-up Controls from the general population were followed for a median of 6.5 years (mean 6.2 ± 1.0 years). Marathon runners were followed for a median of 6.5 years (mean 6.2 ± 1.2 years). All 108 marathon runners responded to a clinical questionnaire. In case of events, the runners and their physicians were queried about circumstances of events and physicians’ and hospital records. In matched controls from the Heinz Nixdorf Recall study, annual postal questionnaires assessed the morbidity status during follow-up, i.e., medication, hospital admissions, and outpatient diagnoses of cardiovascular disease. Self-reported incident coronary and fatal events were validated by review of hospital records and records of the attending physicians (see below). All death certificates of the three cities of recruitment, i.e., Essen, Mu¨lheim/Ruhr and Bochum, were regularly screened. In parallel, deceased participants were tracked back to obtain as much information as possible to verify the causes of death [7, 17, 18]. Study end points and verification of study end points Primary end points for this study included fatal and non-fatal coronary events and coronary revascularization, summarized as CVD events, based on unequivocally documented incident events that met predefined study criteria [7, 17–19]. We considered a myocardial infarction based on symptoms, electrocardiographic signs, and serum enzymes [levels of creatine kinase (CK-MB)] as well as troponin T or I, and necropsy as (1) non-fatal acute myocardial infarction and (2) coronary death, which occurred between the baseline examination and 6 years after study entry. Coronary revascularization was defined as PTCA usually with stent placement according to hospital or physicians’ records. For all study end points, hospital and nursing home records including electrocardiograms, laboratory values, and pathology reports were
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collected. For deceased subjects, death certificates were collected and interviews with general practitioners, relatives, and eyewitnesses were undertaken where possible. Medical records were obtained for all reported end points. An external end point committee blinded to conventional risk factor status and CAC scores reviewed all documents and classified the end points thereafter.
Table 1 HsTnI, NT-proBNP, and Il-6 before and after the marathon
Statistical analysis
Values given as median [Q1/Q3]
Data are given as mean ± standard deviation (SD) or median [interquartile range (Q1–Q3)] and count data as frequency and/or percentage. Differences in continuous data were statistically evaluated using ANOVA or Mann– Whitney U statistics; differences in proportions were evaluated with v2 statistics or Fisher’s exact test, as appropriate. Trends in proportions were evaluated using Cochran–Armitage trend statistics. After logarithmic transformation of the CAC score, log2(CAC ? 1), hazard ratios (HR) for events were calculated with their 95 % confidence intervals (CI) from Cox proportional hazard regression within the runners and the matched controls. Two-group comparisons of hsTnI after the race and the change in troponin during the race, respectively, were statistically evaluated using exact, two-sided Mann–Whitney statistics. Kaplan–Meier analysis followed by log-rank test or log-rank test of trend was applied to time-to-event data within the cohorts with respect to presence of LGE or the extent of CAC. Follow-up period in controls was defined as the median follow-up period in marathon runners. Furthermore, Cox regression embodying matching criteria by stratification was used to compare time to event between runners and the matched controls. For comparison with the general population, 1:8 age-matched controls and 1:2 age- and risk factor-matched controls for the marathon runners were drawn from the HNRS cohort, restricted to males without CAD, aged C50 (n = 1842) [17]. Matching criteria were: within ± 3 years of age, within ± 3 kg/m2 body mass index (BMI), within ±4 % Framingham risk per 10 years, and individually by smoking status (present/former/never smokers). Matching was performed using PROC SURVEYSELECT of SAS (SAS Institute Inc., Cary, NC, USA) as published [25]. A probability value of p \ 0.05 was considered as significant. Statistical analyses were performed using SAS (Cary, NC, version 9.2).
a
Normal range
Before
After
p value
HsTnI
\0.04 lg/L
0.01 (0/0.01)
0.03 (0.02/0.08) \0.0001
NTproBNP
\125 pg/mL
34 (22/59)
124 (73/188)
IL-6
\1.5 pg/mLa
0 (0/2.4)
46.3 (27.6/60.8) \0.0001
\0.0001
* p \ 0.05 versus before
Results Demographics Demographics and cardiovascular risk factors of marathon runners, the 864 age-matched controls and the 216 age- and
123
Age- and gender-matched reference values were obtained from the STANISLAS Cohort [5]
risk factor-matched controls from the general population have been published [17]. At baseline, runners had completed a median of 20 full-distance marathons (Q1– Q3 = 14–42). Seventy-four participants completed the marathon (average finishing times: 250 ± 33 min, range 186–352 min). Among the 74 finishers, FRS correlated with finishing times (r = 0.35, p = 0.002), which was in part related to systolic blood pressure (r = 0.25, p = 0.03), but not to age (r = 0.18, p = 0.12). Finishers had a similar FRS as those 34 runners, who did not participate or not finish the race (6.9 ± 3.2 versus 7.4 ± 4.5, p = 0.86). Serum troponin, NT-proBNP, and Il-6 The marathon-related changes in hsTnI, NT-proBNP, and Il-6 are shown in Table 1. HsTnI and NT-proBNP increased three- and fourfold, respectively, and interleukin 6 from non-detectable to detectable levels during the race. An increase in hsTnI was observed in 93.2 % of runners. An increase beyond 99 % hsTnI threshold, i.e., 0.04 lg/L, was observed in 36.5 % of runners. The thresholds of quartiles of increases in hsTnI were Q1 = 0.011, median (Q2) = 0.028, and Q3 = 0.055. Similar increases in hsTnI were observed in runners with finishing times below versus above the median of 247 min [DhsTnI = 0.02 (0.01–0.04) versus 0.03 (0.01–0.08), respectively, p = 0.26]. Serum troponin increase versus coronary risk characterization None of the variables of coronary risk at baseline, i.e., FRS, CAC, or the presence of LGE, predicted serum hsTnI values above the median immediately after the marathon or increases in hsTnI values beyond the median increase during the marathon (Fig. 2). However, runners with versus without LGE had higher hsTnI values after the race [median (Q1/Q3): 0.08 lg/L (0.04/0.09) versus 0.04 lg/L (0.03/0.06), p = 0.039] and higher increases in hsTnI
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Fig. 2 Four-by-four tables of hsTnI values above versus below the median after the marathon (upper row) or in differences in hsTnI values after versus before the marathon (bottom row)
FRS
CAC
0
total
< 10
≥ 10
total
neg
pos
≤ 0.0305 µg/L
22
15
37
13
24
37
15
22
37
30
> 0.0305 µg/L
17
20
37
14
23
37
19
18
37
35
total
39
35
74
27
47
74
34
40
74
65
median change in hsTnI after the race vs. before
p>0.99
FRS
total
no
yes
total
7
37
34
3
37
2
37
34
3
37
9
74
68
6
p=0.48
CAC
6-Year CAD-Events *
LGE
median hsTnI after the race
p=0.35
p=0.15
CAC
74
p>0.99
6-Year CAD-Events *
LGE
0
total
< 10
≥ 10
total
neg
pos
total
no
yes
total
≤ 0.0276 µg/L
19
18
37
15
22
37
17
20
37
31
6
37
34
3
37
> 0.0276 µg/L
20
17
37
12
25
37
17
20
37
34
3
37
34
3
37
total
39
35
74
27
47
74
34
40
74
65
9
74
68
6
p>0.99
*
CAC
p=0.63
p>0.99
p=0.48
74
p>0.99
Note that two runners with events did not participate in the race. One other runner without a coronary event but with ischemic coronary heart disease during follow-up (Figure 4) was included in the group of six runners with coronary events for the purpose of this analysis (see also Figure 1). p-values are given using Fisher’s exact test.
values during the race [median (Q1/Q3): 0.05 lg/L (0.03/ 0.08) versus 0.02 lg/L (0.01/0.05), p = 0.0496]. Changes in NT-pro-BNP and Il-6 were similar in runners with versus without prevalent LGE (data not shown). Runners without CAC were slightly younger (54.6 ± 4.7 versus 57.9 ± 5.7 years, p = 0.014), but had similar increases in hsTnI [DhsTnI = 0.03 (Q1–Q3 = 0.01–0.08) versus 0.02 (0.01–0.05), p = 0.74], in Il-6 [DIl-6 = 55.6 (24.0–86.5) versus 36.7 (27.0–56.8), p = 0.18], and in NT-proBNP [DNT-proBNP = 87 (43–147) versus 94 (65–138), p = 0.39], respectively. Runners with events had similar increases in hsTnI as those without events [DhsTnI = 0.04 (0.01–0.14) versus 0.03 (0.01–0.05), p = 0.35]. Coronary events and subclinical cardiac disease The characteristics of marathon runners with coronary events are shown in Table 2. Runners had a similar cumulative event rate as age-matched and age- and risk factor-matched controls (Table 3). The increase in events per doubling of the CAC score was similar when only those 74 runners who completed the marathon and experienced five coronary events during follow-up were included in the analysis [HR = 1.37 (1.00–1.89, p = 0.052]. Being a marathon runner (n = 7 events) was associated with a 6.2year coronary risk comparable to that in age- and risk factor-matched controls [n = 10 events, HR = 1.29 (0.57–2.91), p = 0.61]. When only the 74 finishers with five events during follow-up were included, the HR was 1.87 (0.66-5.32, p = 0.32). The cumulative coronary event rate increased with increasing CAC scores similarly in runners and controls (Table 3). An increase in the CAC score category, i.e., \100, 100–399, and C400, was associated with a shorter time to event in marathon runners and controls (Fig. 3).
Runners with coronary events had a higher prevalence of LGE than those without events (57 versus 8 %, p = 0.003), consistent with Kaplan–Meier analysis (logrank, p \ 0.0001), while their 10-year FRS was similar (7.9 ± 2.3 vs. 7.0 ± 3.7 %, p = 0.20). All-cause mortality Three runners (2.8 %) died during follow-up. One runner died from a coronary event (Table 2), one from a brain tumor at age 76 years, and one from non-Hodgkin lymphoma at age 59 years. All-cause mortality was similar as in age-matched controls and age- and risk factor-matched controls (2.8 % versus 26/864 (3.0 %) and 5/216 (2.4 %), respectively).
Discussion The present study shows that transient increases in serum hsTnI after a marathon do not confer an increased longterm coronary event risk. Yet, the observed greater increases in hsTnI during the race in runners with prevalent myocardial fibrosis suggest that these troponin elevations may not simply reflect ‘‘myocardial fatigue’’. Cardiomyocyte necrosis as the underlying mechanism of the observed serum troponin increase during exhaustive exercise has been questioned, because serum troponin kinetics following exhaustive exercise are different from those in patients with acute coronary syndromes (ACS) [13]. Yet, no longterm observational study to date has been performed in runners with evidence of coronary atherosclerosis or myocardial fibrosis and at an age when ACS typically occur. As runners with myocardial fibrosis had higher changes in hsTnI and higher coronary event rates, we
123
123
65
55
62
51
62
58
59
#2
#3
#4
#5
#6
#7
#8
24
25
55
8
140
65
22
14
Number of races*
12
7
9
6
9
4
9
11
FRS* (%/10 years)
213
3,060
369
13
128
171
472
874
CAC score*
?
?
–
–
?
?
–
?
LGE*
4:07:46
3:59:41
4:29:33
3:52:39
3:51:03
4:49:45
Did not participate
Did not participate
Run time (h:min:s)
0.01/0.20
0.01/0.03
0.00/0.01
0.00/0.14
0.01/0.02
0.02/0.09
n.a.
n.a.
hsTnI (lg/L)
35/120
20/93
70/282
32/101
19/57
42/176
n.a.
n.a.
NT-proBNP (pg/mL)
Before/after the race
0/20.1
67.0/48.3
0/33.5
3.4/54.4
0/28.1
0/28.6
n.a.
n.a.
Il-6 (pg/mL)
n.a.
2,162
1,471
1,459
561
260
72
4
Time to event** (days)
No event but severe obstructive CAD (2VD: left main, LCX and LAD with long myocardial bridge) diagnosed during follow-up, CABG recommended
CABG in 3 VD and ascending aortic replacement: the patient’s training pace declined, later on exertional angina, aortic root aneurysm
STEMI after 4 days of UAP starting the day after return from vacation, revascularization of LAD, 3 months later Dx. of renal cancer
Sudden death near the end of a sunday morning 20 k leisure training run with a friend
Resuscitated during low to moderate intensity resistance training, 2-VD, CABG surgery, ICD after surgery
ST-elevation on resting ECG after the race in septal leads, septal LGE, 1-VD (LAD) on invasive angiography proximal to a septal branch showing myocardial bridging, revascularization of LAD
LAD, LCX and left main disease, requiring CABG as published [16]
Resuscitated at 7 k during a 10 k race, 3-VD, revascularization of LAD, LCX and RCA
Event characteristics
* data at baseline, ** time from baseline, n.a. not applicable
k kilometers, VD vessel disease, CABG coronary artery bypass graft, ICD implantable cardioverter/defibrillator, STEMI ST-segment elevation myocardial infarction, UAP unstable angina pectoris, Dx. diagnosis, FRS Framingham Risk Score, CAC coronary artery calcium, LGE late gadolinium enhancement
67
#1
Age* (years)
Table 2 Characteristics of marathon runners with coronary events during follow-up
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Table 3 Number of events, cumulative risks, and crude and adjusted hazard ratios (HR) (95 % CI) of coronary events in the CAC categories in marathon runners and controls Marathon runners
Controls from the HNR study Age and RF matched
Age matched
Persons in group (n)
108
216
864
FRS (% in 10 years) [median (Q1–Q3)]
7 (4–9)
7 (6–9)
11 (9–18)
Follow-up (years ± SD)
6.2 ± 1.2
6.2 ± 1.0
6.2 ± 1.0
Coronary events [n (%)]
7 (6.5)
10 (4.6)
43 (5.0)
Coronary events by CAC score category
n (%)
Event rate
n (%)
Event rate
n (%)
Event rate
\100
69 (64)
1.5
169 (78)
2.4
550 (64)
2.0
100–399
25 (23)
12.0
29 (14)
10.3
197 (23)
6.6
C400
14 (13)
21.4
18 (8)
16.7
117 (13)
16.2
p value for trend Increase in events per doubling of CAC [log2(CAC ? 1)]
=0.002
\0.0001
1.49 (1.08–2.05)
1.35 (1.11–1.64)
1.38 (1.23–1.55)
p = 0.02
p = 0.003
p \ 0.0001
=0.002
HNR Heinz Nixdorf Recall study, RF risk factors, FRS Framingham Risk Score, CAC coronary artery calcium
cannot exclude a potential link between marathon running, myocardial cell damage, and future coronary events. In fact, in the same cohort we reported that the number of completed marathon races was associated with a higher risk of myocardial fibrosis [17], which has been confirmed by others [35]. Yet, we also found that the coronary atherosclerosis burden was associated with more prevalent LGE [17], and it is possible that prevalent subclinical CAD predisposes to myocardial fibrosis, and that both, LGE and CAC, contribute to cardiac events via different mechanisms. Interestingly, we found no association between hsTnI and the CAC burden. We previously demonstrated that recreational runners, who have already participated in and are still fit enough to sustain a marathon race, may nonetheless have an unexpectedly high burden of coronary atherosclerosis, which is in line with a preliminary report from the Twin-Cities Marathon and with a 30 k-race-study in senior runners [17, 24, 26]. The present study shows that not the transient increase in serum hsTnI during a marathon, but the coronary atherosclerosis burden helps to characterize the longterm coronary risk of recreational runners, with event rates comparable to our controls and findings from other population-based analyses [7, 8, 18]. In 60 non-elite participants of the Boston marathon, increases in troponin T-levels were inversely associated with training mileage [20]. We can only speculate that this association was most likely unrelated to the coronary atherosclerosis burden or myocardial ischemia, because these runners were young, 1/3 of them females, had low BMI and low systolic blood pressures, and hence a very low Framingham risk and presumably very low burden of obstructive CAD. However, long-term prognosis data have not been
reported. Recently, the Race Associated Cardiac Arrest Event Registry (RACER) study group reported very low incidence rates of cardiac arrest and sudden death during long-distance racing [11], in line with our current data, as no events in our study occurred during a marathon race. Longterm events unrelated to marathon races were not studied by the RACER study group. Both studies did not measure myocardial fibrosis or coronary atherosclerosis burden. The long-term coronary risk in our cohort of recreational runners appears unexpectedly high. Possibly, our study has attracted runners who were concerned about their cardiac disease risk and had converted to a healthier lifestyle. Apparently, such lifestyle conversion may reduce, but not eliminate the risk arising from prior long-term risk factor exposure such as smoking [10, 36]. Our data suggest that the actual state of vessel wall atherosclerosis and/or presence of myocardial fibrosis determines prognosis and not the history how this state has arisen. The coronary atherosclerosis burden can be measured using the CAC score. It integrates the pro-atherosclerotic effect of the changing risk factors during the preceding decades. A lifelong runner with a continuously low risk factor profile may never develop any atherosclerosis in his life. Yet, if he does for any reason, his risk of a coronary event seems as high as that in other persons with a comparable atherosclerosis burden. Hence, the observed coronary event rate is only ‘‘unexpectedly high’’ if one would expect most marathon runners to be at low risk. From our data, a low atherosclerosis burden reflecting low risk is present in about 2/3rd of runners aged [50 years, but this rate of low-risk runners may be higher in larger cohorts. The question remains if runners with a high coronary atherosclerosis burden or with myocardial injury on MRI should
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Basic Res Cardiol (2014) 109:391
0 0 0 503 169 88 545 197 116 550 197 117 0 0 0
542 194 113
539 188 113
533 186 105
518 181 96
7 2 3 4 5 6 Follow-Up Time [Years] 1 0 7
160 24 15 164 26 15 166 26 15 167 26 16 167 26 16 167 29 16 4 0 0 64 22 11
Kaplan–Meier event-free survival curves in marathon runners, age-matched controls, and age- and risk factor-matched controls
be recommended to cease marathon running. In this respect, of note, none of the coronary events in this present study occurred during a competitive marathon, but were nevertheless precipitated by some degree of physical activity in four of the seven runners, in line with previous studies [34]. The only fatal event occurred in a runner without LGE and with the lowest CAC score among all runners with events. Two events were revascularizations unrelated to ACS in runners with few symptoms. These revascularizations occurred prior to the clinical introduction of fractional flow reserve (FFR) measurements, which today is recommended to guide coronary intervention. Because of the possibility of good intramyocardial microvascular function despite epicardial stenosis [16], it is possible that these two runners would not have been revascularized today because of a potentially normal FFR despite angiographically significant stenosis. In fact, later during follow-up, one runner was detected to have angiographically significant stenosis with little ischemia on SPECT imaging. This runner (#8 in Table 2; Fig. 4) denied revascularization, was treated medically, continued to exercise regularly, and remained event free to date. Whether this is truly safe remains to be seen. The PROSPECT trial showed that a residual luminal area\4 mm2, an area plaque burden[70 %, or thin-cap fibroatheroma (TCFA) was predictive of unanticipated events [29]. At least two of these criteria were present in all eight runners in Table 2. The generally low event rate during marathon races, the increased event rate in runners with CAC or LGE in this study, the lack of event prediction based on marathon racerelated increases in hsTnI, and the potential role of prothrombotic factors in ACS in marathon runners [2] show the complexity of mechanisms contributing to coronary events in marathon runners. The acute risk of recreational marathon running seems to be low and is probably not higher than that associated with any other physical activity [34], but a prospective trial on different counseling strategies in runners with coronary or myocardial disease is clearly needed [32].
69 24 12 69 25 14
Number at risk during follow-up by CAC score:
69 23 12
69 23 12
68 23 12
68 22 12
7 0
0.5
0.75
1.0
0
1
2 3 4 5 6 Follow-Up Time [Years]
0
0
169 29 18
1
log-rank p=0.0011 log-rank p=0.0018
Marathon Runners
Event-Free Survival Probability
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CAC
