Marathon-Induced Cardiac Fatigue: A Review over the Last Decade for the Preservation of the Athletes’ Health

provide a state-of-the-art review of the last 10 years focusing on cardiac fatigue following a marathon. Methods: The PubMed, Bookshelf and Medline databases were queried during a time span of 10 years to identify studies that met the inclusion criteria. Twenty-four studies focusing only on the impact of marathons on the cardiac function and factors involved in cardiac fatigue were included in this review. Results: Sixteen studies focused on the impact of marathons on several biomarkers (e.g., C-reactive protein, cardiac troponin T). Seven studies focused on the left (LV) or right (RV) ventricular function following a marathon and employed cardiac magnetic resonance, echocardiography, myocardial speckle tracking and heart rate variability to analyze global and regional LV or RV mechanics and the impact of the autonomic nervous system on cardiac function. One study focused on serum pro ling and its association with cardiac changes after a marathon. Conclusions: This review reported a

(RV) ventricular function following a marathon and employed cardiac magnetic resonance, echocardiography, myocardial speckle tracking and heart rate variability to analyze global and regional LV or RV mechanics and the impact of the autonomic nervous system on cardiac function. One study focused on serum pro ling and its association with cardiac changes after a marathon. Conclusions: This review reported a negligible impact of marathons on LV and RV systolic and contractile function but a negative impact on LV diastolic function in recreational runners. These impairments are often associated with acute damage to the myocardium. Thus, the advice of the present review to athletes is to adapt their training and have a regular medical monitoring to continue to run marathons while preserving their cardiac health. Keywords:cardiac fatigue; cardiac stress; prevention; marathon; recreational athletes 1. Introduction The bene cial effect of regular physical exercise on heart function is now widely recog- nized by researchers in the eld of physical activity and sport around the world and more generally in society. Among the main bene cial effects are the improvement of the lipid pro le, carbohydrate homeostasis, decrease in resting blood pressure, blood coagulation, improvement of myocardial perfusion and an increase in cardiac output [1]. While the function of the heart pump is improved by regular exercise of moderate intensity [2], it was rst shown in 1964 that the function of the left ventricle (LV) was reduced after prolonged physical exercise (PPE) [3]. Almost twenty years later, work has shown impaired cardiac function in athletes who have achieved PPE and used the concept of Exercise-Induced Cardiac Fatigue for the rst time [4]. This phenomenon is de ned as a transient decrease in systolic and diastolic ventricular functions and is sometimes associated with an increase in markers of myocardial degradation (i.e., cardiac troponins I) [5]. Endurance activities have been very popular since the end of the 1990 0 s. The attraction to life in the great outdoors and the desire to know its limits lead more and more people to practice PPE each year [6]. Among these PPE, there are those of moderate duration

increase in markers of myocardial degradation (i.e., cardiac troponins I) [5]. Endurance activities have been very popular since the end of the 1990 0 s. The attraction to life in the great outdoors and the desire to know its limits lead more and more people to practice PPE each year [6]. Among these PPE, there are those of moderate duration such as the half-marathon (i.e., between 1–2 h of effort) and the marathon (i.e., 2–4 h), those with long duration such as the semi-triathlon distance “Ironman” (i.e., 5–8 h), and the “Ironman” distance triathlon with its 3.8 km of swimming, 180 km of cycling and 42.195 km of running (i.e., 9–16 h) and those with very long duration such as ultra-marathons or ultra-trails (some Int. J. Environ. Res. Public Health2021,18, 8676.

Int. J. Environ. Res. Public Health2021,18, 8676 2 of 11 events can exceed 24 h). The effect of these PPEs on the cardiac function of participants has been the subject of much scienti c research since the end of the 1990 0 s. The general methodology used in these various works includes the evaluation of echocardiographic parameters of the cardiac function before and after PPE under resting conditions. After a marathon running, the majority of studies have reported a decrease in LV and right ventricular (RV) diastolic function. Interestingly, the decrease in diastolic function was effective after 1 h of exercise [7]. More recently, it has been reported that cardiac fatigue is present but with left and right ventricular dysfunction, even more marked than at rest [8]. This study underlined the importance of the intensity of exertion during a marathon in the occurrence of cardiac fatigue. In summary, a moderate duration PPE results in a decrease in LV and RV diastolic function associated with a decrease in ventricular relaxation. The results concerning LV and RV systolic function are contradictory and seem to show that the myocardial alterations are rather dependent on the intensity with which the marathon is performed. It is important to note that the decreases in systolic function and diastolic function of LV and RV observed in the literature following various PPE have mainly been demonstrated by standard echocardiography and tissue Doppler variables. The development of speckle tracking has made it possible to go further in the evaluation of ventricular myocardial function. Thus, it was possible to assess regional myocardial deformities (e.g., apex, base), and the contractility and relaxation properties associated with these deformities and with the rates of myocardial deformation. The results concerning the studies carried out after a PPE of moderate duration are more contrasted [9–13]. Among these studies, only one was conducted after a marathon race. On the one hand, it is clearly established that this type of exercise leads to a decrease in LV and RV diastolic function associated with a decrease in myocardial relaxation. On the other hand, doubts remain concerning the systolic

after a PPE of moderate duration are more contrasted [9–13]. Among these studies, only one was conducted after a marathon race. On the one hand, it is clearly established that this type of exercise leads to a decrease in LV and RV diastolic function associated with a decrease in myocardial relaxation. On the other hand, doubts remain concerning the systolic function of the LV [7] and not that of the RV, which seems to be regularly affected by the different types of PPE [14]. In fact, the left ventricular deformities in systole are reduced after exercise while the associated systolic rates are not. These ndings may be due to tachycardia and higher circulating plasma catecholamine levels after EPP [15]. All these points show in particular the impact of the duration of the effort on the occurrence of cardiac fatigue in some athletes. In this context, the aim of the present review was to provide a state of the art of the last 10 years based on published studies focusing on cardiac fatigue following a marathon. The second objective was to give an advice to athletes to continue their passion by decreasing the impact of the most intense PPE on cardiac function and structure. 2. Materials and Methods This review analyzed the responses of the cardiovascular system after a marathon. The PubMed, Bookshelf and Medline databases were queried during a time span of 10 years (i.e., 1 January 2010 to 1 August 2021) using the following words: “cardiac fatigue AND marathon” and “cardiac stress AND marathon”. The PRISMA method has been used to perform this review. The inclusion criteria were: cardiovascular system structure and function evaluations (all experimental technics of analysis) performed before and immediately after a marathon (i.e., 42.2 km), and biomarkers and molecular responses to a marathon. The exclusion criteria were: all studies performed on half-marathon, on longer races (e.g., ultra-marathon), on exercises trying to mimic the duration and the intensity of a marathon (e.g., ergocycle, treadmill) and on marathons performed in extreme environments (e.g., mountain, desert). Exclusion criteria were also: (1) duplicates, (2) studies not assessing cardiac function

and biomarkers and molecular responses to a marathon. The exclusion criteria were: all studies performed on half-marathon, on longer races (e.g., ultra-marathon), on exercises trying to mimic the duration and the intensity of a marathon (e.g., ergocycle, treadmill) and on marathons performed in extreme environments (e.g., mountain, desert). Exclusion criteria were also: (1) duplicates, (2) studies not assessing cardiac function or biomarkers before and after a marathon. 3. Results 3.1. Search Results Figure and Medline databases were queried and the PRISMA method was used. A total of

Int. J. Environ. Res. Public Health2021,18, 8676 3 of 11 91 articles were identi ed. Following this search, duplicate references were removed. After this identi cation step, we proceeded to the screening step, which involved sifting through the titles and abstracts to check their relevance. Studies were selected if they were conducted only for marathons and if they studied the impact of this speci c running on cardiac fatigue or cardiac stress. Ninety-one papers were selected, and their full texts were reviewed by the authors for inclusion in the review. Following the expertise of the selected articles, 24 papers were considered in the writing of the review.Int. J. Environ. Res. Public Health 2021, 18, x FOR PEER REVIEW 3 of 12 3. Results 3.1. Search Results Figure 1 presents the selection process. To perform this review, the Pubmed, Book- shelf and Medline databases were queried and the PRISMA method was used. A total of 91 articles were identified. Following this search, duplicate references were removed. Af- ter this identification step, we proceeded to the screening step, which involved sifting through the titles and abstracts to check their relevance. Studies were selected if they were conducted only for marathons and if they studied the impact of this specific running on cardiac fatigue or cardiac stress. Ninety-one papers were selected, and their full texts were reviewed by the authors for inclusion in the review. Following the expertise of the selected articles, 24 papers were considered in the writing of the review. Figure 1. Flow chart of the published studies selection process of the review. 3.2. Biomarkers of Cardiac Fatigue and Cardiac Stress after a Marathon Sixteen papers were identified in this review and are presented in Table 1. All of them were experimental studies and investigated the change in specific biomarkers between pre- and post-marathon runs. At least 32 different biomarkers were identified in the dif- ferent studies. The majority of them were biomarker of skeletal muscle and myocardium damage [15–23]. In this family, the creatine kinase (CK), the highly sensitive cardiac tro- ponin I and T (hs cTnI; hs cTnT) were

experimental studies and investigated the change in specific biomarkers between pre- and post-marathon runs. At least 32 different biomarkers were identified in the dif- ferent studies. The majority of them were biomarker of skeletal muscle and myocardium damage [15–23]. In this family, the creatine kinase (CK), the highly sensitive cardiac tro- ponin I and T (hs cTnI; hs cTnT) were mainly measured in the plasma. It was demon- strated that CK and hs cTnT were significantly increased after a marathon run. A second family of biomarkers measured the cardiac injury after marathons [9,17–19,21,23–25]. The N-terminal pro brain natriuretic peptide (NT-proBNP) was mainly measured in the plasma and was significantly increased after a marathon. In addition, it was reported that the increment of this biomarker immediately after a marathon exhibited a positive curvi- linear relationship (r 2 = 0.359, p = 0.023) with the running time achieved by the runners [25]. A third family of biomarkers measured the systemic inflammation after marathons [23,26,27]. The interleukin-6 (IL-6) and the tumor necrosis factor-alpha (TNF-alpha) were mainly measured in the plasma. It was demonstrated that both biomarkers were signifi- cantly increased after a marathon run. Figure 1.Flow chart of the published studies selection process of the review. 3.2. Biomarkers of Cardiac Fatigue and Cardiac Stress after a Marathon Sixteen papers were identi ed in this review and are presented in Table. All of them were experimental studies and investigated the change in speci c biomarkers between pre- and post-marathon runs. At least 32 different biomarkers were identi ed in the different studies. The majority of them were biomarker of skeletal muscle and myocardium dam- age [15–23]. In this family, the creatine kinase (CK), the highly sensitive cardiac troponin I and T (hs cTnI; hs cTnT) were mainly measured in the plasma. It was demonstrated that CK and hs cTnT were signi cantly increased after a marathon run. A second fam- ily of biomarkers measured the cardiac injury after marathons [9,17–19,21,23–25]. The N-terminal pro brain natriuretic peptide (NT-proBNP) was mainly measured in the plasma and was signi cantly increased after a marathon. In addition, it

cTnT) were mainly measured in the plasma. It was demonstrated that CK and hs cTnT were signi cantly increased after a marathon run. A second fam- ily of biomarkers measured the cardiac injury after marathons [9,17–19,21,23–25]. The N-terminal pro brain natriuretic peptide (NT-proBNP) was mainly measured in the plasma and was signi cantly increased after a marathon. In addition, it was reported that the increment of this biomarker immediately after a marathon exhibited a positive curvilinear relationship (r 2 = 0.359,p= 0.023) with the running time achieved by the runners [25]. A third family of biomarkers measured the systemic in ammation after marathons [23,26,27]. The interleukin-6 (IL-6) and the tumor necrosis factor-alpha (TNF-alpha) were mainly measured in the plasma. It was demonstrated that both biomarkers were signi cantly increased after a marathon run. Three of the selected studies measured the heart-type fatty acid binding protein (H-FABP) (i.e., mainly found inside cardiomyocytes) after a marathon [15,18,23]. Despite an important variability between the studies, H-FABP was signi cantly increased after a marathon run in three studies. In addition, two studies measured the galactin-3 (gal-3) which is a protein involved in various biological activities in different organs, including apoptotic regulation, in amma-

Int. J. Environ. Res. Public Health2021,18, 8676 4 of 11 tion and brosis [15,18]. After a marathon, this protein was signi cantly increased in both studies. Another two studies measured the suppression of tumorigenicity 2 (ST2) [21,28] after a marathon. They both reported a signi cant increase of ST2 after running. Technical issues and determination of a diagnostic threshold have to be done to fully recognize the speci city of these biomarkers. Finally, only one study investigated the potential of circulating short nonprotein coding RNA (c-miRNA) to explore the impact of a marathon run [29]. In this study, which was conducted with 21 healthy male marathon runners, the authors demonstrated that all plasma levels of the selected c-miRNA (i.e., enriched in muscle: c-miR-1; c-miR-133a; c-miR- 499-5p; enriched in myocardium: c-miR-208a; enriched in vascular endothelium: c-miR-126; marker of in ammation: c-miR-146a) were signi cantly increased when compared to pre- marathon. The authors also stated that these c-miRNAs might represent real-time and tissue-speci c adaptation biomarkers of a marathon run. Table 1.Cardiac fatigue, cardiac stress and marathon. References Methods/Parameters Pre-Marathon Post-Marathon p-Value Biomarkers Analyses Traiperm [25] cTnT (ng/mL) NT-proBNP (pg/mL) Curvilinear relationship between NT-ProBNP increment and running time (r 2 = 0.359) <0.05 Kaleta-Duss [15] CK (U/l) 148 76.3 411 170 <0.001 hs-cTnI (ng/mL) 0.01 0.01 0.06 0.09 <0.001 H-FABP (ng/mL) 2.22 1.18 13.57 9.63 <0.001 BNP (pg/mL) 79.86 53.11 155.38 156.23 <0.001 NT-proANP (pg/mL) 469.25 155.44 753.3 176.60 <0.001 Gal-3 (ng/mL) 8.53 3.04 10.65 2.33 <0.001 GDF-15 (pg/mL) 50.97 27.61 137.34 85.19 <0.001 Martinez-Navarro [16] hs-cTnT (ng/L) 5.74 5.29 50.4 57.04 <0.001 Sierra [26] IL-6 (pg/mL) 581 1529 87 53 NS IL-8 (pg/mL) 3099 6511 1450 6233 NS IL-12p40 (pg/mL) 3775 12406 285 131 <0.05 IL-23 (pg/mL) 3722 12115 1004 254 <0.05 IL-33 (pg/mL) 412 1546 267 145 <0.05 TSLP (pg/mL) 387 1974 20 16 <0.05 eNO (ppb) 20 11 35 19 " Wegberger [17] Troponin I ( g/L) btw 0–0.01 0.03 (0.02–0.05) 0.016 CK (U/L) btw 0–250 425 (327–681) 0.001 Copeptin (pmol/L) btw 0–20 26.25 (16.29–39.02) 0.078 NT-proBNP (ng/L) btw 0–100 132 (64–198) 0.001 MR-proADM (nmol/L) btw 0.25–0.60 0.88 (0.55–0.99)

<0.05 IL-33 (pg/mL) 412 1546 267 145 <0.05 TSLP (pg/mL) 387 1974 20 16 <0.05 eNO (ppb) 20 11 35 19 " Wegberger [17] Troponin I ( g/L) btw 0–0.01 0.03 (0.02–0.05) 0.016 CK (U/L) btw 0–250 425 (327–681) 0.001 Copeptin (pmol/L) btw 0–20 26.25 (16.29–39.02) 0.078 NT-proBNP (ng/L) btw 0–100 132 (64–198) 0.001 MR-proADM (nmol/L) btw 0.25–0.60 0.88 (0.55–0.99) 0.023 de Gonzalo-Calvo [18] hs-cTnT (pg/mL) btw 0–5 btw 0–35 <0.01 NT-proBNP (pg/mL) btw 0–25 btw 0–110 <0.05 CK (U/L) btw 0–150 btw 0–300 <0.001 hFABP (ng/mL) btw 0–3 btw 0–24 <0.01 Gal-3 (ng/mL) btw 0–7 btw 0–22 <0.001 Kosowski [19] hs-cTnI (pg/mL) 3.67 (1.88–5.38) 22 (9.58–34.56) <0.001 NT-proBNP (pg/mL) 50 (33–73) 169 (112–365) <0.001 ET-1 (pg/mL) 3.03 (2.5–3.4) 5.22 (4.4–5.89) <0.001 Creatinine (mg/dL) 0.85 (0.79–0.98) 1.39 (1.22–1.56) <0.001

Int. J. Environ. Res. Public Health2021,18, 8676 5 of 11 Table 1.Cont. References Methods/Parameters Pre-Marathon Post-Marathon p-Value Richardson [20] cTnT (ng/L) 5.60 3.27 74.52 30.39 <0.001 Sengupta [9] NT-proBNP (pg/mL) 86.0 9.5 106.5 24.2 0.001 Clauss [24] Chromogranin A (pg/mL) btw 0–60 btw 0–90 <0.001 NT-proBNP (ng/mL) btw 0–30 btw 0–110 <0.001 Roca [21] NT-proBNP (ng/L) 70 (70–70) 92 (70–147) <0.001 ST2 (ng/mL) 34.2 (24.7–40.9) 54.2 (38.2–72.4) <0.001 hs-TnT (ng/L) 2.9 (1.7–7) 46.9 (24.1–91.1) <0.001 Bekos [28] sRAGE (pg/mL) btw 250–600 btw 400–750 <0.001 ST2 (pg/mL) btw 0–250 btw 125–400 <0.001 Niemelä [27] suPAR (ng/mL) btw 0.5–2 btw 1.2–3.5 <0.01 CD163 (ng/mL) btw 300–800 btw 500–1100 <0.05 CRP (mg/L) btw 0–12 btw 0–22 <0.05 IL-6 (pg/mL) btw 0–8 btw 17–25 <0.01 IL-8 (pg/mL) btw 5–12 btw 25–42 <0.05 IL-10 (pg/mL) btw 0–1 btw 1–3.5 <0.05 TNF- (pg/mL) btw 0–1 btw 1–2.5 NS TGF- (pg/mL) btw 500–1000 btw 0–1000 NS Martin [22] Creatinine (mg/dL) 0.94 0.12 1.42 0.24 <0.001 CK (U/L) 133 60 367 167 <0.001 White blood cells (thousand/ L) 5.75 1.19 15.77 3.29 <0.001 Neutrophils (cells/ L) 3420 1049 13580 3019 <0.001 Scherr [23] hs-cTnT (ng/L) 3 (3–5) 31 (19–47) <0.001 NT-proBNP (ng/L) 27 (14–40) 93 (57–150) <0.001 h-FABP (Kg/L) 7 (5–10) 45 (32–64) <0.001 hs-CRP (mg/L) 0.52 (0.30–0.93) 0.40 (0.24–0.85) <0.001 IL-6 (ng/L) 2.1 (1.9–2.2) 32 (21–41) <0.001 IL-10 (ng/L) 5.1 (4.9–5.4) 20 (11–50) <0.001 TNF- (ng/L) 9 (7–10) 10 (9–12) <0.001 Cystatin C (mg/L) 0.8 (0.7–0.9) 0.9 (0.9–1.0) <0.001 Baggish [29] c-miR-1 (fold change) 21.8 0.04 c-miR-126 (fold change) 1.9 <0.001 c-miR-133 (fold change) 18.5 0.02 c-miR-134 (fold change) 1.9 <0.001 c-miR-146a (fold change) 3.3 <0.001 hsCRP (fold change) 1.0 1.000 Echography, HRV & STE analyses Lewicka-Potocka [30] LV EF (%) 61.8 4.9 60.5 4.4 0.38 LV GLS (%) 19.9 2.3 19.4 2.1 0.41 RV 4CSL (%) 22.0 2.8 20.80 2.6 <0.05 TAPSE (mm) 25.0 3.6 24.0 3.7 0.56 RVd MID (cm) 3.4 0.6 3.7 0.5 <0.01 RVd BAS (cm) 3.8 0.4 3.8 0.5 0.44 LVd BAS (cm) 4.8 0.4 4.6 0.3 <0.001 RVd/LVd BAS 0.77 0.1 0.82 0.1 <0.05 Roeh [31] E/A 1.6 0.5 1.1 0.3

This review analyzes the impact of marathon running on cardiac function and health.