Abstract
Runners with exercise‐induced high blood pressure have recently been reported to exhibit higher levels of cardiac markers, vasoconstrictors, and inflammation. The authors attempted to identify correlations between exercise‐related personal characteristics and the levels of biochemical/cardiac markers in marathon runners in this study. Forty healthy runners were enrolled. Blood samples were taken both before and after finishing a full marathon. The change in each cardiac/biochemical marker over the course of the marathon was determined. All markers were significantly (P<.001) increased immediately after the marathon (creatine kinase‐MB [CK‐MB]: 7.9±2.7 ng/mL, cardiac troponin I (cTnI): 0.06±0.10ng/mL, N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP): 95.7±76.4, endothelin‐1: 2.7±1.16, high‐sensitivity C‐reactive protein [hs‐CRP]: 0.1±0.09, creatine kinase [CK]: 315.7±94.0, lactate dehydrogenase [LDH]: 552.8±130.3) compared with their premarathon values (CK‐MB: 4.3±1.3, cTnI: 0.01±0.003, NT‐proBNP: 27.6±31.1, endothelin‐1: 1.11±0.5, hs‐CRP: 0.06±0.07, CK: 149.2±66.0, LDH: 399±75.1). In middle‐aged marathon runners, factors related to increased blood pressure were correlated with marathon‐induced increases in cTnI, NT‐proBNP, endothelin‐1, and hs‐CRP. These correlations were observed independent of running history, records of finishing, and peak oxygen uptake.
Appropriate aerobic exercise may decrease cardiovascular disease and events,1, 2 improve diabetes3 and high blood pressure (BP),4 and enhance quality of life.5 Endurance events such as marathon running may also have health benefits6; however, the incidence of sudden cardiac deaths7, 8 that have occurred during marathons imply an element of risk as well. Cardiac markers are induced by myocardial infarction9 or cardiac insufficiency10 and are often increased above their upper reference limits after endurance exercises such as extreme marathons and ultramarathons.11 A number of studies have investigated that intense exercise increases cardiac markers12, 13; however, it has not yet been proven whether exercise truly induces this elevation. The induction of cardiac troponin after excessive exercise has been reported to be primarily affected by exercise intensity, whereas the induction of N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP) is related to exercise duration.14, 15 According to recent reports, cardiac troponin I (cTnI), NT‐proBNP, and endothelin‐1 (ET‐1) are induced to higher levels in marathon runners with exercise‐induced high BP,16 whereas NT‐proBNP, creatine kinase (CK), and high‐sensitivity C‐reactive protein (hs‐CRP) are induced to higher levels in 100‐km ultramarathon runners with exercise‐induced high BP.17 Previous studies were conducted with only a small number of cases and lack of variability of exercise‐induced hypertension. In addition, correlations of various BP‐related factors (resting BP [RBP], maximum systolic BP [MSBP], maximum pulse pressure [MPP]) with cardiac markers have not been analyzed in previous studies. Exercise‐induced high BP is defined as a systolic BP (SBP) ≥230 mm Hg18 and is a risk factor for future high BP19 and cardiovascular disease.20 The aim of this study was to look for the correlations between various personal characteristics of runners and their hemodynamic responses and induction of cardiac markers after finishing a marathon. The markers that we identified, including ET‐1, CK, lactate dehydrogenase (LDH), and hs‐CRP, merit future study. These biomarkers may be involved in the mechanisms underlying exercise‐induced sudden death and the elevation of cardiac markers in marathon runners.
Materials and Methods
Participants and Exercise Protocol
Normotensive male volunteers aged between 40 and 60 years who had finished at least three marathons were enrolled in this study. Exclusion criteria included high BP (≥140/90 mm Hg), diabetes, cardiovascular disease, renal disease, liver disorder, and runners who failed to finish or took more than 5 hours to complete the marathon. The experimental protocol was approved by the University of Inje University Research Committee and all participants provided written informed consent. A total of 55 volunteers underwent a 2‐week exercise tolerance test that concluded the week before the marathon. Among these volunteers, 15 were excluded for the following reasons: four had an RBP ≥140/90 mm Hg as measured twice over a 5‐minute interval, six failed to finish the marathon, four took longer than 5 hours to complete the marathon, and one had diabetes. The remaining 40 were included in the final study. For the reasonable sample size of this study, a priori power analyses was computed as a function of 0.80 of the power level, 0.18 of effect size, 0.05 of α error probability, and six predictors for the linear multiple regression with t test of test family. As a result, the total sample size for this study was 37 with an actual power of 0.81. None of the final volunteers had high BP, diabetes, cardiovascular disease, renal disease, or a liver disorder. However, 13 (32.5%) were runners with exercise‐induced hypertension whose RBP was <140/90 mm Hg and whose MSBP in the test was ≥230 mm Hg. Blood samples were collected from the participants 2 hours before the race and immediately after the race. The start time was 9 am and the weather conditions were 15°C with 35% humidity. Personal data and medical histories of the volunteers were collected via questionnaires.
Graded Exercise Testing
The exercise tolerance test was performed according to the Bruce protocol. The test used a 12‐channel real‐time electrocardiograph (Quinton Q‐4500; Quinton Instrument Co, Boston, MA), a respiratory gas analyzer (QMC; Quinton Metabolic Cart, Quinton Instrument Co), an automated BP and pulse oximeter (Model 412; Quinton Instrument Co), and a treadmill (Medtrack ST 55; Quinton Instrument Co). The integrated headset was used to ensure the correct identification of Korotkoff sounds by the automated monitor. The test was stopped if any subjective symptoms were present, such as chest pain or dizziness, or if any dangerous cardiac events or abnormal BP responses were observed based on the guidelines of the American College of Cardiology/American Heart Association.21 Resting heart rate (RHR) and BP were measured before the test. Heart rate, BP, rate of perceived exertion, respiratory exchange ratio, and oxygen consumption were then recorded 1 minute before each step. The various hemodynamic responses measured are listed below:
MSBP (mm Hg)
RSBP (mm Hg)
MSBP–RSBP (mm Hg)
ΜPP (mm Hg)
Μaximum heart rate (MHR; beats per minute [bpm])
RHR (bpm)
MHR–RHR (bpm)
Blood Sampling
To identify changes in blood composition induced by the marathon, blood samples were collected from each participant before and after the marathon. Samples were collected according to Clinical and Laboratory Standards Institute (CLSI) guidelines, and the serum levels of CK, LDH, creatine kinase‐MB (CK‐MB), cTnI, NT‐proBNP, ET‐1, and hs‐CRP were analyzed. Samples were collected using a vacuum SST blood collecting tube (BD Vacutainer Serum Separator Tube, Franklin Lakes, NJ), which included a gel and a blood‐clotting accelerant. Samples were spun by centrifugation for 10 minutes at 3400 rpm to separate the serum, which was stored at −70°C until analysis.
Blood Analysis
The levels of CK and LDH were measured with Denka‐Seiken test kits (Denka Seiken Co, Ltd, Tokyo, Japan) according to the method outlined by the Japan Society of Clinical Chemistry. The levels of hs‐CRP were measured by an immunoturbidimetric assay with the HBI reagent (HBI Co, Ltd, Gyeonggi‐do, Korea) and a TBA‐200FR NEO automated chemistry analyzer (Toshiba, Tokyo, Japan). The levels of cTnI were measured by a chemiluminescence immunoassay using the ADVIA Centaur instrument (Siemens, Munich, Bavaria, Germany).
The levels of CK‐MB and NT‐proBNP were measured using an electrochemiluminescence immunoassay with the Modular Analytics E170 immunology analyzer (Roche Diagnostics, Mannheim, Germany). The levels of ET‐1 were measured by an enzyme immune assay using the Human Endothelin‐1 QuantiGlo ELISA kit (R&D System, Minneapolis, MN). The normal reference ranges in this study were: CK, 58 to 348 IU/L; CK‐MB, ≤4.94 ng/mL; cTnI, ≤0.78 ng/mL; NT‐proBNP, ≤125 pg/mL; hs‐CRP, 0.3 mg/dL; LDH, ≤260 IU/L; and ET‐1, 0.401 pg/mL to 2.83 pg/mL. The coefficients of variation, which indicate the variability of the measurements with respect to the mean, for each parameter were: CK, 1.2%; CK‐MB, 3.8%; cTnI, 11.8%; NT‐proBNP, 2%; hs‐CRP, 10.32%; LDH, 4%; and ET‐1, 6.7%.
Statistical Analysis
For each measurement, the average and standard deviation were calculated for each marathon runner. The paired t test was performed to identify significant differences between premarathon and postmarathon values. Pearson's correlation coefficients were calculated for the difference between the postmarathon and premarathon values for each parameter and exercise characteristics, in addition to the hemodynamic responses. Multiple linear regression analysis was also performed for identifying the independent determinants of candidate cardiac biomarkers for hemodynamic responses to the marathon exercise after finding the correlation coefficients. The significance level of hypothesis verification was set to P<.05. SPSS version 18.0 (SPSS, IBM, Armonk, NY) was used for statistical analysis.
Results
The 40 volunteers in this study were all healthy marathon runners with the absence of high BP, diabetes, cardiovascular diseases, and liver disorders; however, 13 (32.5%) had exercise‐induced high BP (Table 1). All measured markers were significantly (P<.001) increased immediately after the marathon (CK‐MB: 7.9±2.7 ng/mL, cTnI: 0.06±0.10 ng/mL, NT‐proBNP: 95.7±76.4, ET‐1: 2.7±1.16, hs‐CRP: 0.1±0.09, CK: 315.7±94.0, LDH: 552.8±130.3) compared with their premarathon values (CK‐MB: 4.3±1.3 ng/mL, cTnI: 0.01±0.003 ng/mL, NT‐proBNP: 27.6±31.1, ET‐1: 1.11±0.5, hs‐CRP: 0.06±0.07, CK: 149.2±66.0, LDH: 399±75.1) (Table 2).
Table 1.
Characteristics of the Volunteers (N=40)
| Variable | Mean±Standard Deviation |
|---|---|
| Age, y | 50.8 (8.2) |
| Height, cm | 168.6 (5.8) |
| Weight, kg | 63.0 (5.2) |
| Body mass index, kg/m2 | 22.0 (1.4) |
| Resting heart rate, beats per min | 62.7 (9.1) |
| Maximal heart rate, beats per min | 171.0 (10.1) |
| Resting systolic blood pressure, mm Hg | 122.1 (10.9) |
| Resting diastolic blood pressure, mm Hg | 79.4 (7.6) |
| Maximum systolic blood pressure, mm Hg | 213.6 (26.4) |
| Maximum diastolic blood pressure, mm Hg | 70.7 (11.9) |
| Peak oxygen uptake, mL/kg/min | 50.3 (6.3) |
| Race time, min | 222.1 (30.6) |
| Running history, y | 6.6 (3.6) |
| Resting hypertension, % | 0 |
| Exercise‐induced hypertension, No. (%) | 13 (32.5) |
| Diabetes, % | 0 |
| Cardiovascular disease, % | 0 |
| Renal disease, % | 0% |
| Hepatic disease, % | 0 |
Table 2.
Changes in Cardiac Markers, Endothelin‐1, and hs‐CRP Over the Course of a Marathon
| Pre‐Race | Post‐Race | df | P Value | |
|---|---|---|---|---|
| CK‐MB, ng/mL | 4.5 (1.3) | 7.9 (2.7) | 3.3 (2.0) | Increase (<.001) |
| cTnI, ng/mL | 0.01 (0.003) | 0.06 (0.10) | 0.05 (0.1) | Increase (<.001) |
| NT‐proBNP, pg/mL | 27.6 (31.1) | 95.7 (76.4) | 68.8 (56) | Increase (<.001) |
| Endothelin‐1, pg/mL | 1.11 (0.5) | 2.7 (1.16) | 1.6 (0.83) | Increase (<.001) |
| hs‐CRP, mg/dL | 0.06 (0.07) | 0.1 (0.09) | 0.03 (0.03) | Increase (<.001) |
| CK, IU/L | 149.2 (66.0) | 315.7 (94.0) | 166.5 (67.9) | Increase (<.001) |
| LDH, IU/L | 399.8 (75.1) | 552.8 (130.3) | 153.0 (136.0) | Increase (<.001) |
Abbreviations: CK, creatine kinase; CK‐MB, creatine kinase MB; cTnI, cardiac troponin I; df, degrees of freedom; hs‐CRP, high‐sensitivity C‐reactive protein; LDH, lactate dehydrogenase; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide. Values are presented as means (standard deviations).
To determine the change in each marker over the duration of the marathon, the premarathon value was subtracted from the postmarathon value. None of these differences exhibited a significant Pearson's correlation coefficient with the running history of the individual or with peak oxygen uptake. However, race time was significantly correlated with CK‐MB (r=−0.37, P<.05) and CK (r=−0.31, P<.05) premarathon to postmarathon differences but was not significantly correlated with any other parameter (Table 3).
Table 3.
Pearson's Correlation Coefficients Between Exercise Characteristics and Changes in the Levels of Cardiac Markers, Endothelin‐1, hs‐CRP, and LDH
| Running History, y | Race Time, min | VO2max, mL/kg/min | ||||
|---|---|---|---|---|---|---|
| R 2 | P Value | R 2 | P Value | R 2 | P Value | |
| CK‐MB, ng/mL | 0.08 | NS | −0.37 | <.05 | 0.27 | NS |
| cTnI, ng/mL | −0.11 | NS | −0.24 | NS | 0.03 | NS |
| NT‐proBNP | −0.23 | NS | −0.06 | NS | −0.16 | NS |
| Endothelin‐1, pg/mL | −0.51 | NS | −0.04 | NS | −0.06 | NS |
| hs‐CRP, mg/dL | −0.22 | NS | −0.14 | NS | −0.03 | NS |
| CK, IU/L | 0.02 | NS | −0.31 | <.05 | 0.04 | NS |
| LDH, IU/L | −0.81 | NS | −0.02 | NS | 0.09 | NS |
Abbreviations: CK, creatine kinase; CK‐MB, creatine kinase MB isoenzyme; cTnI, cardiac troponin I; hs‐CRP, high‐sensitivity C‐reactive protein; NS, not significant; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; VO2max, peak oxygen uptake. Values are presented as means (standard deviations).
Pearson's correlation coefficients of the premarathon to postmarathon differences with various hemodynamic parameters (MSBP, MSBP‐RSBP, MPP, MHR, and MHR‐RHR) are shown in Table 4. Correlation coefficients of premarathon to postmarathon differences with CK, CK‐MB, cTnI, NT‐proBNP, ET‐1, hs‐CRP, and LDH are also shown in Table 4.
Table 4.
Pearson's Correlation Coefficients Between Blood Pressure Factors and Changes in the Levels of Cardiac Markers, Endothelin‐1, hs‐CRP, and LDH
| Post‐Pre Difference | MSBP | MSBP‐RSBP | MPP | |||
|---|---|---|---|---|---|---|
| R | β | R | β | R | β | |
| CK‐MB, ng/mL | −0.08 | – | −0.20 | – | 0.06 | – |
| cTnI, ng/mL | 0.40a | 0.449b | 0.33a | 0.346a | 0.41b | 0.426b |
| NT‐proBNP, pg/mL | 0.43b | 0.419b | 0.32a | 0.334a | 0.41b | 0.428b |
| Endothelin‐1 | 0.40a | – | 0.37a | – | 0.48b | – |
| hs‐CRP, mg/dL | 0.51b | – | 0.47b | – | 0.48b | – |
| CK, IU/L | −0.10 | – | −0.16 | – | −0.07 | – |
| LDH, IU/L | 0.01 | – | 0.04 | – | 0.03 | – |
Abbreviations: CK, creatine kinase; CK‐MB, creatine kinase MB; cTnI, cardiac troponin I; hs‐CRP, high‐sensitivity C‐reactive protein; LDH, lactate dehydrogenase; MPP, maximum pulse pressure; MSBP, maximum systolic blood pressure; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; RSBP, resting systolic blood pressure. Values are presented as means (standard deviations) and coefficients (R). a P<.05, b P<.01, β is the standardized coefficient for the multiple‐linear regression analysis (dependent variable=MSBP, or MSBP‐RSBP, or MPP, independent variable=cTnI and NT‐proBNP as cardiac biomarker).
MSBP was significantly correlated with cTnI (R: 0.40, P<.05), NT‐proBNP (R: 0.43, P<.01), ET‐1 (R: 0.40, P<.05), and hs‐CRP (R: 0.51, P<.01); however, no significant correlations were observed with CK‐MB, CK, or LDH. The predictive formula based on results of regression analysis on MSBP‐related cardiac biomarkers is as follows: MSBP=0.213ΔNT‐proBNP+108ΔcTnI+193 (P<.05, variance inflation factor [VIF]=1.002) (Table 4).
MSBP‐RSBP was significantly correlated with cTnI (R: 0.33, P<.05), NT‐proBNP (R: 0.32, P<.05), ET‐1 (R: 0.37, P<.05), and hs‐CRP (R: 0.47, P<.01), whereas no significant correlations were observed with CK‐MB, CK, or LDH. The predictive formula based on results of regression analysis on MSBP‐related cardiac biomarker is: MSBP‐RSBP=0.152ΔNT‐proBNP+85.4ΔcTnI+76.9 (P<.05, VIF=1.002) (Table 4).
MPP was significantly correlated with cTnI (R: 0.41, P<.01), NT‐proBNP (R: 0.41, P<.01), ET‐1 (R: 0.38, P<.05), and hs‐CRP (R: 0.48, P<.01), but not with CK‐MB, CK, or LDH. The predictive formula based on results of regression analysis on MSBP‐related cardiac biomarker is as follows: MPP=0.217ΔNT‐proBNP+117ΔcTnI+122 (P<.05, VIF=1.002) (Table 4.
Discussion
This study was conducted to identify the personal exercise characteristics and hemodynamic parameters that correlate with changes in cardiac and biochemical markers (ET‐1, hs‐CRP, CK, and LDH) in marathon runners over the course of a race. For each runner who finished the marathon, all cardiac markers and other factors investigated were significantly increased after the race compared with their pre‐race values (Table 2).
Neither the exercise history nor the peak oxygen uptake was significantly correlated with any marker examined. However, the finishing time was significantly correlated with premarathon to postmarathon CK‐MB and CK values. These findings indicate that finishing the race in a faster time was associated with a greater increase in CK, implying that muscular injury is particularly affected by exercise intensity.22 Since the CK‐MB increase was not correlated with cTnI, an indicator of myocardial injury, the increased CK might indicate muscular injury. Among all the hemodynamic responses included in the exercise tolerance test, SBP was significantly correlated with the premarathon to postmarathon differences in cardiac markers, ET‐1, and hs‐CRP.
Both cTnI and cTnT are clinical indicators for diagnosing myocardial infarction.9 Markers of myocardial injury are known to be induced in extreme sports such as marathons; however, no clear evidence has been obtained to show that these increased markers are actually accompanied by myocardial injury.12, 13 This extreme exercise‐induced increase in cTnI has been hypothesized to be an effect of intercellular calcium overload that is accompanied by calpain activation, actions of free radicals, increased catecholamine, rapid synthesis, and mechanically induced injury to the myocardial cell membrane.23, 24, 25 Meanwhile, although NT‐proBNP is not a marker of myocardial injury, it has been shown to increase in response to cardiac insufficiency brought about by stress, increased volume pressure of cardiac muscles,10 or extreme exercise.11, 24 Extreme exercise may cause stress in the myocardial wall that induces the production of NT‐proBNP, a hormone that causes natriuesis, sympathetic nerve blockade, and vasodilation. NT‐proBNP has been shown to reduce preload, afterload, and stress in the myocardial wall.11 These responses are hypothesized to be cytoprotective and to exert growth‐regulating effects.11, 24, 26 In our study, both cTnI and NT‐proBNP exhibited significantly positive correlations with MSBP, MSBP‐RSBP, and MPP on exercise tolerance test. Even though it is not mentioned in the results (Table 4), we have found no significant correlations between RSBP and MSBP or between RBP and post‐pre differences of cardiac markers. In addition, since none of the markers were correlated with the finishing time of the marathon (Table 3), SBP may serve as an independent factor that influences cTnI and NT‐proBNP. Runners who exhibit excessive increases in BP during marathons have also been shown to have an increased afterload via increased peripheral vessel resistance caused by vasodilatation disability, which then results in increased volume pressure and RPP in the left ventricle.18 Hypertrophic cardiomyopathy is the most common cause of sudden death during marathons in runners 35 years and younger, whereas myocardial ischemia is the most common in runners 35 years and older.27 Being of middle age is a known cardiovascular risk factor. Middle‐aged runners with excessive increases in BP may experience higher loads to their cardiac muscles when they participate in marathons or conduct higher‐intensity exercise than usual. As of yet, no comprehensive study has examined the incidence of sudden death in runners with exercise‐induced hypertension. However, cTnI and NT‐proBNP were recently reported to be increased in runners with exercise‐induced hypertension in marathons and ultramarathons.16, 17 These data, in combination with the results shown in the present study, support the following hypothesis: middle‐aged marathon runners with potential ischemic cardiovascular disease and excessive increases in BP may undergo increased myocardial ischemia caused by increased oxygen demand of the myocardia, which, in turn, induces cardiac events such as arrhythmia. In this study, 13 (32.5%) of 40 runners exhibited exercise‐induced hypertension. Future longitudinal, large‐scale studies are needed to examine the arterial stiffness, changes in BP, and most appropriate treatment for such runners.
ET‐1 is a strong vasoconstrictor,28 and the hs‐CRP–mediated inflammatory response is known to be a clinical factor for predicting arteriosclerosis progress and cardiocerebrovascular disease.29 In particular, hs‐CRP has been shown to increase after vigorous or extreme exercise, such as ultramarathons.12, 30 In this study, both ET‐1 and hs‐CRP exhibited significant positive correlations with MBP, MBP‐RBP, and MPP. The association between ET‐1 and BP implies that runners with high BP during exercise also exhibit increased load to the cardiac muscles, presumably as a result of the higher contraction of vessels during the marathon. In addition, the BP‐related increase in hs‐CRP may be caused by increased inflammation in the active muscles as a result of vasodilatation disability in the peripheral vessels. As described above, the increases in cTnI, NT‐proBNP, ET‐1, and hs‐CRP in middle‐aged marathon runners whose BP increased excessively during exercise were related to increased cardiac muscle load, presumably via peripheral vessel resistance.
Limitations
There were several limitations to this study. First, we did not perform a long‐term clinical follow‐up of this study. Consequently, the various cardiovascular markers that were elevated were not necessarily associated with undesirable clinical outcomes. Future studies will focus on the relationship between elevated cardiovascular markers during exercise and clinical outcomes. Second, actual RPP measurements were not conducted since real‐time pulse rate and BP measurements were not possible during the marathons. Third, consistent regulation of water consumption by the runners was not possible. Fourth, the blood sample collected immediately after the race may not have completely reflected the physiological state of the runner. Fifth, cTnI measurements along with echocardiography were not conducted to examine myocardial dysfunction during the recovery phase. Finally, cause and effect associations could not be drawn in this analysis because of the cross‐sectional design of the study. Further studies should be conducted that take into account these limitations.
Conclusions
This study found that when middle‐aged marathon runners exhibited exercise‐induced hypertension, their increases in cTnI, NT‐proBNP, ET‐1, and hs‐CRP were significantly correlated with contraction in the peripheral vessels, high cardiac muscle load, and inflammation in the active muscles.
Disclosures
None.
Acknowledgments
None.
J Clin Hypertens (Greenwich). 2015;17:868–873. DOI 10.1111/jch.12591. © 2015 Wiley Periodicals, Inc.
The first two authors contributed equally to this work.
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