Peptides 57 (2014) 20–30

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How does stress possibly affect cardiac remodeling? Dejana Popovic a,∗ , Bosiljka Plecas-Solarovic b , Vesna Pesic b , Milan Petrovic a , Bosiljka Vujisic-Tesic a , Bojana Popovic c , Svetlana Ignjatovic a , Arsen Ristic a , Svetozar S. Damjanovic c a b c

Division of Cardiology, Faculty of Medicine, University of Belgrade, Visegradska 26, 11000 Belgrade, Serbia Department of Physiology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia Division of Endocrinology, Faculty of Medicine, University of Belgrade, Dr Subotica 13, 11000 Belgrade, Serbia

a r t i c l e

i n f o

Article history: Received 19 February 2014 Received in revised form 5 April 2014 Accepted 7 April 2014 Available online 18 April 2014 Keywords: Stress Adrenocorticotropic hormone Cortisol Adrenocorticotropic hormone receptor polymorphism Left ventricular remodeling

a b s t r a c t The aim of this study was to evaluate the predictive value of adrenocorticotropic hormone (ACTH), cortisol and ACTH receptor polymorphism (ACTHRP) for left ventricular (LV) remodeling. Thirty-six elite male athletes, as chronic stress adaptation models, and twenty sedentary age and sex-mached subjects emabarked on standard and tissue Doppler echocardiography to assess cardiac parameters at rest. They performed maximal cardiopulmonary test, which was used as an acute stress model. ACTH and cortisol were measured at rest (10 min before test), at beginning, at maximal effort, at 3rd min of recovery, using radioimmunometric and radioimmunoassey techniques, respectively. Promoter region of ACTHR gene (18p11.2) was analysed from blood samples using reverse polymerization reaction with the analysis of restriction fragment length polimorphisam by SacI restriction enzyme. Normal genotype was CTC/CTC, heterozygot for ACTHRP CTC/CCC and homozygot CCC/CCC. In all participants, ACTH and cortisol increased during acute stress, whereas in recovery ACTH increased and cortisol remained unchanged. 49/56 examiners manifested CTC/CTC, 7/56 CTC/CCC and 0/56 CCC/CCC. There was no difference in ACTHRP frequency between groups (2(1) = 0.178, p = 0.67). LV mass (LVM) and LV end-diastolic volume (LVVd) were higher in athletes than in controls (p < 0.01) and lower in CTC/CTC than in CTC/CCC genotype (219.43 ± 46.59(SD)g vs. 276.34 ± 48.86(SD)g, p = 0.004; 141.24 ± 24.46(SD)ml vs. 175.29 ± 37.07(SD)ml, p = 0.002; respectively). In all participants, predictors of LVM and LVVd were ACTH at rest (B = −1.00,−0.44; ˇ = −0.30,−0.31; p = 0.026,0.012, respectively) and ACTHRP (B = 56.63,34; ˇ = 0.37,0.40; p = 0.003,0.001, respectively). These results demonstrate that ACTH and ACTHRP strongly predict cardiac morphology suggesting possible regulatory role of stress system activity and sensitivity in cardiac remodeling. © 2014 Elsevier Inc. All rights reserved.

Abbreviations: A, left ventricular late diastolic filling velocity; ACTH, adrenocorticotropic hormone; ACTHR, adrenocorticotropic hormone receptor; ACTHRP, adrenocorticotropic hormone receptor polymorphism; A duration, late diastolic filling duration; BMI, body mass index; BSA, body surface area; BW, body weight; CPET, cardiopulmonary exercise test; CCC/CCC, homozygot for adrenocorticotropic hormone receptor polymorphism; CTC/CCC, heterozygot for adrenocorticotropic hormone receptor polymorphism; CTC/CTC, normal genotype (absence of adrenocorticotropic hormone receptor polymorphism); DBP, diastolic arterial blood pressure; E, left ventricular early diastolic filling velocity; e , average annular left ventricular early diastolic filling velocity; FFM, fat free mass; FM, fat mass; LV, left ventricle; LVVd, left ventricular end-diastolic volume; RV, right ventricle; RV A, right ventricular late diastolic filling velocity; RV E, right ventricular early diastolic filling velocity; RVe , right ventricular lateral annular early diastolic filling velocity; RVs , right ventricular lateral annular systolic velocity; s , average annular left ventricular systolic velocity; SV, stroke volume; SBP, systolic arterial blood pressure; TDI, tissue Doppler imaging; VO2 , oxygen uptake; VO2 /kg, relative oxygen uptake. ∗ Corresponding author at: Division of Cardiology, Faculty of Medicine, University of Belgrade, Veljka Dugosevica 27g, 11000 Belgrade, Serbia. Tel.: +381 64 3709684; fax: +381 11 3615630. E-mail address: [email protected] (D. Popovic). http://dx.doi.org/10.1016/j.peptides.2014.04.006 0196-9781/© 2014 Elsevier Inc. All rights reserved.

D. Popovic et al. / Peptides 57 (2014) 20–30

Introduction Stress condition increases metabolic demands [43,49,76] and consequently exposure to stress influences cardiac performance [14,15,61]. Hormones have been documented to have a crucial role in adaptation to stress [43] and they also act in accomodation of cardiac function to stress conditions [14,15,61]. The adaptive changes in athletes, as chronic stress adaptation models, go in the direction of the cardiac enlargement and the whole body’s improvement ability [15,61]. On the other hand, there is so called “broken heart syndrome”, or stress – induced cardiomyopathy, characterized by temporary enlargement of some parts of the heart which lose their ability to contract and which is brought on by the heart’s reaction to a serge of stress hormones [57]. In that case, stress adaptive changes exhibit marked variability [62], depending on type of stress, but also on age [32], gender, race, [9], nutrition [4], psychological factors [46,71], physical activity and genetic factors [2,16]. Stress system activation implies secretion of hypothalamic corticotropin releasing hormone, which stimulates pituitary proopiomelanocortin (POMC) secretion [82]. POMC is the precursor peptide of adrenocorticotropic hormone (ACTH), which partially regulates cortisol secretion from adrenal glands [23,48]. ACTH and cortisol, besides epinephrine and norepinephrine, are the most important stress hormones [1]. There is a correlation of circulating ACTH with lactate plasma level, and increased lactate level is considered as marker of peracute stress [78]. Thereby, a certain level of ACTH is a reliable measure of acute stress, unlike the cortisol, which is more a measure of chronic stress and has protective role [52,78]. It is known that ACTH and cortisol have complex role in the regulation of carbohydrate, lipid and protein metabolism as well as energy homeostasis [13], and also in the regulation of body fluids and body composition, which are directly related to cardiac function [67,68,76]. Furthermore, there are some reports showing that ACTH and cortisol are also involved in the regulation of blood pressure and heart rate [67,68,76]. However, cardiac effects of stress hormones and the mechanisms of their action are still not completely elucidated [76]. In the past decade it has been demonstrated that genetic factors might play an important role in the morpho-functional cardiac changes due to chronic stress. Thereby, they determine to some extent the increase in the left ventricular (LV) mass and diameter, as well as fractional shortening. For example, there is a correlation of DD genotype of anigiotensin – converting enzyme (I/D polymorhism) and LV hypertrophy in endurance athletes [54]. Furthermore, the relation of T allele homozygot of angiotensin gene M235T polymorphism and left ventricular mass (LVM) was shown [40]. Additionally, the synergism of anigiotensin – converting enzyme polymorhism and angiotensin gene M235T polymorphism in the determination of the LVM was predicted [24]. However, there are no data on the association of the ACTH receptor polymorhism (ACTHRP) and the morpho-functional cardiac adaptive changes. Considering the fact that the endocrine system plays a key role in stress situation, including physical activity, which is frequently used as a stress model [18,64], the aim of this study was to evaluate the predictive value of stress hormones, ACTH and cortisol, and ACTHRP for the cardiac remodeling in athletes. Materials and methods Participants Participants in this study were 36 elite male athletes and 20 sedentary age and sex-mached subjects. Athletes have been successfully competitive in water polo and wrestling at the international level for the past five years and have trained intensively for more than 10 years. They performed combined strength and

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endurance training protocols and were in a period of preparations for the international competition at the time they were examined. Wrestlers had 9 h of wrestling a week, 4 h of power training in the gym so as to improve the explosive strength and 4 h of high intensity running a week. Water polo athletes trained 12 h a week in the pool, with at least 2 km of swimming per each training, and three additional hours a week in the gym where they performed both power and endurance exercises. Control subjects were not engaged in sporting activities other than at recreational level (lesser then 2 h a week for the last 10 years). Participants underwent the study after they have been given an informed consent. They declared any diseases, chast pain, loss of conciousness and risk factors (hypertrophic cardiomyopathy, hypertension, arrhythmias, diabetes, renal diseases, cardiac and other infections, smoking, anabolic steroids usage etc.), which were the exclusion criteria because of the influence on myocardial function and total functional capacity of the body. There was no family history of hypertrophic cardiomyopathy and sudden cardiac death. Physical examination and blood tests showed that all of them were healthy and normotensive. ECG was physiological. The study was approved by the Local Ethical Committee. Anthropometry Tanita weight (phase sensitive multi-frequency analyzer Data Input GmbH 2000, using software Nutri 3) was used to obtain body weight, fat mass (FM) and fat free mass (FFM) by bioelectrical impedance analysis. Body surface area (BSA) was calculated according to the Du Bois and Du Bois formula [25]. Ergospirometry Participants embarked on progressive continuous cardiopulmonary exercise test on treadmill based on breath-by-breath method to obtain peak oxygen consumption (peakVO2 ), as the measure of the functional capacity. The testing of all subjects was performed at the same time of the day. The protocol was made by pretesting nine randomly chosen subjects, to optimize the duration of the test (8–12 min) as recommended. It involved 3 min rest, 2 min at speed 6 km/h and 2% inclination, 2 min at speed 9 km/h and 2% inclination, with an increase of inclination for 2% every 2 min after, until the criteria for maximal test were reached, and 3 min recovery [34,83]. Echocardiography Two-dimensional, M-mode, pulsed Doppler and Tissue Doppler echocardiography were performed on a Sequoia 512 ultrasound device with a 2.5 MHz transducer. Echocardiograms were obtained by two experienced readers according to criteria of the American Society of Echocardiography [31,44,55,70] and met standard criteria of the technical quality. Echosonographer had no knowledge of the study participants background. Three to five consecutive beats during quiet respiration were used for calculation of the Doppler variables in apical four-chamber views with standard transducer positions. Using this method early (E), late (A) diastolic filling velocities and A duration of both ventricles were obtained. M-mode echocardiography was performed to assess wall thickness and cavity dimension. Left ventricular end-diastolic volume (LVVd) was derived from LV internal dimensions by Teicholz’s formula. Left ventricular mass was calculated from Penn-cube formula: LVM (g) = 1.04 [(LVDd + IVSd + PWTd)3 − LVDd] − 13.6, where LVDd is left ventricular end-diastolic diameter, IVSd interventricular septum thickness in diastole and PWTd posterior wall thickness in diastole [20]. Circumferentional end-systolic wall stress was calculated as: WS (g/m2 ) = [SBP × 0.5 LVDs2

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D. Popovic et al. / Peptides 57 (2014) 20–30

{1 + [(0.5 LVDs + PWTs)2 /(0.5 LVDs + 0.5 PWTs)2 ]}]/[(0.5 LVDs + PWTs)2 − 0.5 LVDs2 ], where SBP is systolic blood pressure, LVDs left ventricular end-systolic diameter, PWTs systolic posterior wall thickness diastole [30]. Tissue Doppler imaging (TDI) was recorded in apical four chamber view during end – expiration at sweep speed of 50 mm/s. Doppler signal angle was less than 25%. Sample volume was positioned at 1 cm within the septal and lateral insertion sites of the mitral leaflets and lateral insertion of the tricuspid leaflets. Digitally stored loops of tissue Doppler imaging were used for off line calculations of myocardial velocities. Average values of left ventricular lateral and septal annular early diastolic filling velocities (e ) and systolic velocities (s ) were assessed to evaluate left ventricular diastolic and systolic function. Lateral right ventricular annular early diastolic filling velocity (RVe ) and lateral annular right ventricular systolic velocity (RVs ) were assessed to evaluate right ventricular filling and systolic function [55,56]. In addition, novel global diastolic index (E/e )/RVe was determined, as a good correlate of total functional capacity of the body [63]. Reproducibility of measuring annular velocities was determined in 10 randomly chosen subjects. Intraobserver variability was examined using Bland–Altman analysis. The 95% confidence limits of a single estimate of the measurements were √ calculated as 2 × SD/ 2 and reported as percent of the mean value [6]. All obtained echocardiographic variables were adjusted for heart rate [55,56]. Blood analysis Blood was taken in four phases of the test as follows: 20 ml at rest, 10 min before CPET (phase 1); 20 ml at the beginning of CPET (phase 2); 20 ml at the maximal effort (phase 3) and 20 ml at the 3rd min of recovery (phase 4). Participants were free of food and drink (except water) at least three hours before collecting blood samples. All blood samples were taken from braunii which was placed into the patient’s brachial vein before the test in order to avoid hormonal stimulation by needle punctuation. Samples were centrifuged on 4000 rpm and kept at −80 ◦ C. ACTH was measured using immunoradiometric method (ELSA-ACTH, CIS BioInternational, Gif-Sur-Yvette Cedex, France with lower sensitivity limit 2 ng/l). Cortisol was measured by radioimmunoassay (CORT-CT2, CIS BioInternational, Gif-Sur-Yvette Cedex, France, with lower sensitivity limit 4.6 nmol/l). The intra- and interassay coefficient of variation was lesser then 10% for all assays.

were tested by analysis of variance (ANOVA): post hoc multiple group comparisons were assessed with Bonferroni’s method and LSD method. Kruskal Wallis nonparametric ANOVA followed by the Man Whitney test was used for the variables that deviated from normal distribution. Pearson’s correlation test and Spearman’s rank correlation test were performed to test the correlations between variables. Multiple regression analysis was used to adjust for body surface area and heart rate when examining the differences between the groups for Doppler measurements and cavity dimensions. The difference was considered significant when a p value was lesser than 0.05, and is highly significant when a p value was lesser than 0.01. Results Clinical, echocardiographic and hormonal analysis of athletes and controls Clinical characteristics of the study groups are presented in Table 1. The participants were similar in age. BW, BSA, BMI and FFM were significantly higher in athletes, whereas FM was similar in both groups. HR and SBP were higher in control population, and peakVO2 lower. LVDd, LVVd, LVM and LV SV were higher in athletes than in control population as seen in Table 2. Standard echocardiographic diastolic filling properties of the left and right ventricle were similar in both groups, except LV A duration, which was longer in athletes. TDI revealed lower e and higher global diastolic index (E/e )/RVe in athletes, whereas there were no differences in systolic properties of both ventricles (Table 2). In both controls and athletes plasma ACTH significantly increased between phases of the test (phase 1 vs. phase 2 p = 0.01; phase 2 vs. phase 3 p < 0.001; phase 3 vs. phase 4 p < 0.001) as seen in Fig. 1. Circulating ACTH was higher in athletes than in controls in first three phases of the test (p = 0.027; 0.044; 0.026, respectively), whereas in phase 4 it tended to be higher in athletes but it did not reach statistical significance (p = 0.072). Besides, the magnitude of changes in ACTH plasma level between phases of experiment in athletes and controls were not different (p > 0.05), which indicates similar response.

Genetic analysis

p=0.072, ns

Promoter region of ACTH receptor (ACTHR) gene (18p11.2) was analysed from blood samples at rest using reverse polymerization reaction (PCR) with the analysis of restriction fragment length polimorphism (RFLP) by SacI restriction enzyme. Purified PCR products were afterwords sequenced by ALFExpress II device using Thermo Sequenase Cy5 Terminator Cycle Sequencing Kit (GE Healthcare). Normal genotype (wild type), which considers absence of ACTHR polymorphisam (ACTHRP), was presented as CTC/CTC. Heterozygot for ACTHRP was presented as CTC/CCC and homozygot as CCC/CCC.

p=0.026

p=0.044 p=0.027

Statistics SPSS software (SPSS version 10.0, SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Classic descriptive parameters like median for not normally distributed variables, and mean and standard deviation for parametric variables were used to express the results. The analysis of distribution of the observed variables was performed by Kolmogorov–Smirnov test in order to apply parametric analytical methods. The differences between the groups

Fig. 1. Circulating levels of ACTH in athletes and controls in four phases of CPET (10 min before the test – phase 1, at beginning of the test – phase 2, at maximal effort – phase 3, at 3rd min of recovery – phase 4). p values delineate statistical differences among groups at corresponding phase.

D. Popovic et al. / Peptides 57 (2014) 20–30

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Table 1 Baseline characteristics of the study groups. Parameter

Controls (n = 20 males)

Age (years) BW (kg) BSA (m2 ) BMI (kg/m2 ) FFM (kg) FM (kg) HR rest (bpm) SBP (mm Hg) DBP (mm Hg) peakVO2 (ml/min) peakVO2 /kg (ml/min/kg)

21.35 78.07 1.97 24.14 67.92 10.14 77 121.00 79.25 3918.70 49.52

± ± ± ± ± ± ± ± ± ± ±

2.08 7.25 0.10 2.02 4.31 4.31 11 17.67 12.17 415.08 5.10

Athletes (n = 36 males) 22.21 87.76 2.13 26.03 75.58 12.01 65 115.80 83.24 4961.1 57.85

± ± ± ± ± ± ± ± ± ± ±

Controls vs athletes (p)

3.56 10.49 0.19 2.77 7.12 6.08 12 10.76 6.89 578.46 4.93

ns 0.001 0.001 0.009 0.05), also in athletes (2(1) = 0.2,

Fig. 2. Circulating levels of cortisol in athletes and controls in four phases of CPET (10 min before the test – phase 1, at beginning of the test – phase 2, at maximal effort – phase 3, at 3rd min of recovery – phase 4). p values delineate statistical differences among groups at corresponding phase.

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D. Popovic et al. / Peptides 57 (2014) 20–30 ACTHRP presence in all participants

p=0.004

No, n=49 Heterozygot, n=7

p>0.05

p0.05

p 0.05) and controls (2(1) = 0.06, p > 0.05) separately, as seen in Table 3. Considering the fact that there were no homozygots for ACTHRP, in further analysis all participants were divided in two groups based on the presence of ACTHRP (group with normal genotype presented as CTC/CTC and group with ACTHRP heterozygot manifestation presented as CTC/CCC). Clinical, echocardiographic and hormonal analysis of ACTHRP carriers and noncarriers There were no differences in BW, BSA, BMI, FFM, FM, SBP, DBP, peakVO2 and peakVO2 /kg between ACTHRP carriers and non carriers (p > 0.05), whereas HR at rest was significantly higher in CTC/CTC than in CTC/CCC (70 ± 13 bpm vs. 60 ± 9 bpm, p = 0.023). When athletes were analysed separately, HR tended to be higher in CTC/CTC, but it did not reach statistical significance (66 ± 12 bpm vs. 57 ± 8 bpm, p > 0.05). LVDd, LVVd, LVM, LV SV and WS were higher in ACTHRP carriers than in non carriers as seen in Table 4. Standard echocardiographic diastolic filling properties of the left and right ventricle were similar in both groups, except LV E was lower and LV A duration shorter in CTC/CCC. TDI revealed lower global diastolic index (E/e )/RVe in CTC/CCC, whereas there were no differences in e , RVe , s and RVs (Table 4). The differences remained significant for LVDd, LVVd, LVM, WS, A duration and (E/e )/RVe when athletes were analysed separately (Table 5). Additionally, the differences between athletes non carriers and controls non carriers were significant for LVDd,

p>0.05

Fig. 4. Circulating levels of ACTH depending on ACTHRP presence in all participants in four phases of CPET (10 min before the test – phase 1, at beginning of the test – phase 2, at maximal effort – phase 3, at 3rd min of recovery – phase 4). p values delineate statistical differences among groups at corresponding phase.

LVVd, LVM, e , A duration, and (E/e )/RVe . When athletes carriers and controls noncarriers were analysed separately, the differences between groups were significant for LV SV, LVDd, LVVd, LVM, WS and MV E (Table 5). In both CTC/CTC and CTC/CCC plasma ACTH remained unchanged between phases 1 and 2, and significantly increased between 2 and 4 (phase 1 vs. phase 2 p = 0.09; phase 2 vs. phase 3 p < 0.001; phase 3 vs. phase 4 p < 0.001), as seen in Fig. 4. In all participants together circulating ACTH was similar in CTC/CTC and CTC/CCC in all phases of the test (p > 0.05). Besides, the changes in ACTH plasma level between phases of experiment in CTC/CTC and CTC/CCC were not different (p > 0.05), which indicates similar response (Fig. 4). However, when data obtained in athletes were analyzed separately, plasma levels of ACTH at rest were significantly lower in noncarriers than in carriers (14.53 ± 9.35 ng/l vs. 26.32 ± 18.53 ng/l, p = 0.031). Circulating ACTH at the beginning of the test, at maximal effort and in recovery phase was not different between carriers and non-carriers in the group of athletes, as well as the changes of circulating ACTH between the phases of the test (p > 0.05). We observed significant changes of circulating cortisol during the test in both CTC/CTC and CTC/CCC (p < 0.001) as seen in Fig. 5. Circulating cortisol increased from phase 1 to phase 3 (phase 1 vs. phase 2 p = 0.005; phase 2 vs. phase 3 p < 0.001). There was no significant change in circulating cortisol from phase 3 to phase 4 (phase 3 vs. phase 4 p > 0.05). Circulating cortisol, analysed in all participants together and athletes separately, did not differ significantly between CTC/CTC and CTC/CCC in any phase of the test (p > 0.05) The changes in cortisol plasma levels between the phases of experiment in CTC/CTC and CTC/CCC were also similar (p > 0.05), which indicates similar response (Fig. 5). Besides, by analyzing all participants together and athletes separately, significant changes between ACTHRP carriers and noncarriers in ACTH/cortsol ratio were found only in the group of athletes. ACTH/cortisol ratio was lower in CTC/CTC than in CTC/CCC athletes in the first three phases of the test (at phase 1: 0.06 ± 0.04 vs. 0.1 ± 0.07, p = 0.03; at phase 2: 0.05 ± 0.03 vs. 0.1 ± 0.06, p = 0.009; at phase 3: 0.16 ± 0.14 vs. 0.33 ± 0.25, p = 0.047), whereas there were no differences in phase 4. In all participants together, and athletes separately, the response of ACTH/cortisol ratio during

D. Popovic et al. / Peptides 57 (2014) 20–30

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Table 4 Analysis of echocardiographic variables in ACTHRP carriers and non carriers. Parameter

CTC/CTC genotype (n = 49)

LV SV (ml) LVDd (cm) LVVd (ml) LVM (g) E (cm/s) A (cm/s) A duration (ms) RV E (cm/s) RV A (cm/s) RV A duration (ms) e (cm/s) s (cm/s) RVe (cm/s) RVs (cm/s) (E/e )/RVe WS (g/cm2 )

95.32 5.38 141.24 219.43 0.81 0.47 143.49 0.58 0.36 151.15 19.88 13.42 18.71 17.01 0.32 108.46

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

pa

CTC/CCC genotype (n = 7)

16.95 0.40 24.46 46.59 0.13 0.12 37.18 0.10 0.09 32.53 6.79 3.58 6.67 4.39 0.25 21.19

109.77 5.90 175.29 276.34 0.66 0.46 119.14 0.57 0.44 161.29 20.61 11.46 18.27 15.21 0.19 126.61

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

23.84 0.55 37.07 48.86 0.11 0.13 23.20 0.19 0.22 35.58 3.25 2.44 5.42 2.50 0.07 23.82

0.049 0.003 0.002 0.004 0.003 ns 0.037 ns ns ns ns 0.092 ns ns 0.009 0.041

Results are presented as mean ± SD. CTC/CTC – normal genotype, CTC/CCC – heterozygot for ACTH receptor polymorphism, LV SV – left ventricular stroke volume, LVDd – left ventricular end-diastolic diameter, LVVd – left ventricular end-diastolic volume, LVM – left ventricular mass, E – left ventricular early diastolic filling velocity, A – left ventricular late diastolic filling velocity, RV E – right ventricular early diastolic filling velocity, RV A – right ventricular late diastolic filling velocity, e – average left ventricular annular early diastolic filling velocity, s – average left ventricular annular systolic velocity, RVe – lateral right ventricular annular early diastolic filling velocity, RV s – lateral right ventricular annular systolic velocity, WS – end-systolic wall stress. a Adjusted for HR and BSA. Table 5 Analysis of echocardiographic variables in athletes ACTHRP carriers and non carriers and controls non carriers. Parameter

Controls CTC/CTC (n = 18)

LV SV (ml) LVDd (cm) LVVd (ml) LVM (g) E (cm/s) A (cm/s) A duration (ms) RV E (cm/s) RV A (cm/s) RV A duration (ms) e (cm/s) s (cm/s) RVe (cm/s) RVs (cm/s) (E/e )/RVe WS (g/cm2 )

85.59 5.15 127.37 180.75 0.85 0.45 122.44 0.60 0.40 141.50 20.64 13.21 21.13 16.29 0.25 105.41

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

15.57 0.30 16.70 30.37 0.14 0.08 21.59 0.11 0.08 25.25 6.47 3.76 5.75 3.77 0.15 21.47

Athletes CTC/CTC (n = 31) 100.97 5.51 149.29 241.90 0.80 0.48 154.72 0.57 0.37 157.14 15.83 13.38 17.09 17.21 0.43 110.23

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

15.25 0.40 24.83 31.13 0.12 0.14 40.01 0.09 0.09 35.42 5.27 3.55 6.89 4.79 0.34 21.17

Athletes CTC/CCC (n = 5) 113.26 6.08 187.32 297.66 0.68 0.39 114.8 0.64 0.33 157.2 17.54 11.3 18.48 15.70 0.22 136.73

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

26.17 0.52 35.72 30.23 0.12 0.07 16.59 0.17 0.10 0.10 2.40 1.87 4.37 1.71 0.06 18.13

Controls CTC/CTC vs athletes CTC/CTC (pa )

Controls CTC/CTC vs athletes CTC/CCC (pa )

Athletes CTC/CTC vs Athletes CTC/CCC (pa )

0.001 0.001 0.001 p < 0.001 ns ns 0.002 ns ns ns 0.024 ns 0.052 ns 0.015 ns

0.006 0.05 p>0.05

p>0.05

p>0.05

correlated with BMI (r = 0.29, p = 0.029), FM (r = 0.34, p = 0.009) and FFM (r = −0.37, p = 0.005). We also observed in all participants together that ACTH at 1 and 2 correlated with FFM (r = −0.39, −0.38; p = 0.003, 0.004, respectively). Additionally, ACTH at 2 correlated with BMI (r = −0.28, p = 0.037) and BSA (r = −0.32, p = 0.017). There were no correlations of anthropometric variables with cortisol plasma levels and ACTHRP (p > 0.05). ACTH/cortisol ratio at phase 1 correlated with FFM (r = −0.29, p = 0.038), at phase 2 correlated with BMI, BSA, FFM (r = −0.29, p = 0.038, r = −0.28, p = 0.039, r = −0.36, p = 0.006; respectively), at phase 3 correlated with FFM (r = −0.30, p = 0.026). Predictors of echocardiographic variables

Fig. 5. Circulating levels of cortisol depending on ACTHRP presence in all participants in four phases of CPET (10 min before the test – phase 1, at beginning of the test – phase 2, at maximal effort – phase 3, at 3rd min of recovery – phase 4). p values delineate statistical differences between groups at corresponding phase.

1,25

Observed Inverse

All participants together n=56 for 1/ACTH at 3 β= 0.50, p

How does stress possibly affect cardiac remodeling?

The aim of this study was to evaluate the predictive value of adrenocorticotropic hormone (ACTH), cortisol and ACTH receptor polymorphism (ACTHRP) for...
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