Physiological Left Ventricular Hypertrophy Research Articles

Diagnosing Hypertrophic Cardiomyopathy in Athletes

Sudden cardiac death (SCD) in a young asymptomatic individual is a devastating, unpredictable event, with a widespread impact on the public health system. Hypertrophic cardiomyopathy (HCM) is the most common form of genetic heart disease, and considered one of the leading causes of SCD affecting young and frequently asymptomatic patients. A diagnosis of HCM is challenging particularly in young athletes due to overlapping clinical phenotypesbetween pathological left ventricular hypertrophy (LVH) and exercise-induced physiological LVH. Severalinvestigational tools have been used to differentiate these two distinct entities. This review article focuses upon the diagnosis of HCM in young athletes, SCD risk assessment, and current recommendations for exercise in athletic individuals with HCM.

Case Report on Hypertrophic Cardiomyopathy – How to Detect it in Middle-Aged Amateur Athletes

The safety of exercise in athletes with hypertrophic cardiomyopathy (HCM) and the emphasis on shared decision-making has led to the updating of the most recent recommendations, which have reduced restrictions on exercise and competitive sports activity in this population. This case report confirms that obstructive HCM reduces fitness in the amateur athlete, even if paucisymptomatic or asymptomatic, leading to a physical limitation to practicing high-intensity sports. It also points out how it is possible to differentiate physiological left ventricular (LV) hypertrophy from morphologically mild but pathological one, outlining the clinical aspects from a morphological and functional point of view.

Proteomic analysis of exercise-induced hypertrophy reveals sex-related mitochondrial differences mediated by AMPK

Abstract Background Regular physical activity results in characteristic structural and functional changes in the heart, which are collectively referred to as the athlete's heart. However, the extent of exercise-induced left ventricular (LV) hypertrophy and functional changes show significant differences between men and women, the molecular background of which is not fully elucidated. Objective The aim of this study was to provide a proteomic characterization of long-term, intense exercise-induced LV myocardial hypertrophy in a rat model, with a focus on sex-related differences. Methods Our rats were divided into trained (FEx) and control female (FCo) as well as trained (MEx) and control male (MCo) groups. In the trained groups, athlete's heart was induced by a 12-week swimming protocol. Myocardial hypertrophy was confirmed by echocardiography and functional adaptation by pressure-volume analysis. Proteomic measurements based on liquid chromatograph-coupled mass spectrometry were performed on proteins isolated from our LV myocardial samples. Results Echocardiography and post-mortem myocardial mass showed significant LV hypertrophy in both sexes, which was more pronounced in female animals (tibial length normalized LV muscle mass: + 17.4% MEx vs. MCo, + 31.0% FEx vs. FCo). LV contractility increased to the same extent in both sexes. Relative expression of 3074 proteins were determined by proteomics. There was a significant change in expression of 229 proteins in males and 599 in females compared to the level of same-sex controls. Based on our gene ontological analysis, physiological LV remodeling in females is characterized by increased expression of proteins in mitochondrial function (cellular respiration and fatty acid oxidation) and biogenesis, whereas in males, proteins that bind to the actin cytoskeleton is primarily increased. Further investigation revealed that the quantity of AMP-activated protein kinase (AMPK) and sirtuin 3 (SIRT3) was increased only in female animals. Conclusions Our data suggests that physiological LV hypertrophy resulting from regular, balanced exercise is associated with sex-specific changes in the myocardial proteome. The main differences might be associated with different regulation of mitochondrial function and biogenesis, related to AMPK pathway. Our results contribute to the understanding of the development of physiological myocardial hypertrophy. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Bolyai János Research Scholarship (BO/00837/21) to OANational Research, Development and Innovation Office (NKFIH) K135076 to B.M.

Left Ventricular Hypertrophy: Etiology-Based Therapeutic Options.

Determining the etiologies of left ventricular hypertrophy (LVH) can be challenging due to the similarities of the different manifestations in clinical presentation and morphological features. Depending on the underlying cause, not only left ventricular mass but also left ventricular cavity size, or both, may increase. Patients with LVH remain asymptomatic for a few years, but disease progression will lead to the development of systolic or diastolic dysfunction and end-stage heart failure. As hypertrophied cardiac muscle disrupts normal conduction, LVH predisposes to arrhythmias. Distinguishing individuals with treatable causes of LVH is important for prevention of cardiovascular events and mortality. Athletic’s heart with physiological LVH does not require treatment. Frequent causes of hypertrophy include etiologies due to pressure/volume overload, such as systemic hypertension, hypertrophic cardiomyopathy, or infiltrative cardiac processes such as amyloidosis, Fabry disease, and sarcoidosis. Hypertension and aortic valve stenosis are the most common causes of LVH. Management of LVH involves lifestyle changes, medications, surgery, and implantable devices. In this review we systematically summarize treatments for the different patterns of cardiac hypertrophy and their impacts on outcomes while informing clinicians on advances in the treatment of LVH due to Fabry disease, cardiac amyloidosis, and hypertrophic cardiomyopathy.

Myocardial work efficiency in physiologic left ventricular hypertrophy of power athletes

The athlete's heart in power training is characterized by physiologic concentric remodeling. Our aim was to analyze left ventricular (LV) myocardial deformation and contractile reserve (CR) in top-level power athletes (PA) at rest and during exercise and their possible correlations with functional capacity. Standard echo, lung ultrasound, and LV 2D speckle-tracking strain were performed at rest and during exercise in PA and in age- and sex-comparable healthy controls. 250 PA (male: 62%; 33.6 ± 4.8 years) and 180 age- and sex-comparable healthy controls were enrolled. LV ejection fraction (EF) at baseline was comparable between the two groups, while LV global longitudinal strain (GLS) was reduced in PA (GLS: -17.8 ± 2.4 in PA vs. -21.9 ± 3.8 in controls; P < 0.01). Conversely, myocardial work efficiency (MWE) did not show significant difference between the two groups (94.4 ± 3.2 in PA vs. 95.9 ± 4.6% in controls; P NS). At peak exertion during exercise stress echocardiography (ESE), PA showed better exercise capacity and peak VO2 consumption (51.6 ± 10.2 in EA vs. 39.8 ± 8.2 mL/Kg/min in controls, P < 0.0001), associated with augmented pulmonary artery systolic pressure (PASP). By multivariable analysis, MWE at rest was the most predictive factor of maximal watts (P < 0.0001), peak VO2, (P < 0.0001), PASP (P < 0.001), and number of B-lines (P < 0.001), all measured at peak effort. In power athletes, MWE showed less load dependency than GLS. Normal resting values of MWE in PA suggest a physiological LV remodeling, associated with a better exercise capacity and preserved CR during physical stress.

MTOR signaling-related microRNAs as cardiac hypertrophy modulators in high-volume endurance training.

Aerobic exercise training (ET) promotes cardiovascular adaptations, including physiological left ventricular hypertrophy (LVH). However, the molecular mechanisms underlying these changes are unclear. The study aimed to elucidate specific microRNAs (miRNAs) and target genes involved with the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in high-volume ET-induced LVH. Eight-week-old female Wistar rats were assigned to three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5 times/wk, for 10 wk. P2 consisted of the same protocol as P1 until the 8th week; in the 9th week rats trained 2 times/day, and in the 10th week they trained 3 times/day. Subsequently, structure and molecular parameters were evaluated in the heart. Trained groups demonstrate higher values of peak oxygen uptake ([Formula: see text]), exercise tolerance, and LVH in a volume-dependent manner. The miRNA-26a-5p levels were higher in P1 and P2 compared with the SC group (150 ± 15%, d = 1.8; 148 ± 16%, d = 1.7; and 100 ± 7%, respectively; P < 0.05). In contrast, miRNA-16-5p levels were lower in P1 and P2 compared with the SC group (69 ± 5%, d = 2.3, P < 0.01; 37 ± 4%, d = 5.6, P < 0.001; and 100 ± 6%, respectively). Additionally, miRNA-16-5p knockdown and miRNA-26a-5p overexpression significantly promoted cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. Both miRNAs were selected, with the DIANA Tools bioinformatics website, for acting in the mTOR signaling pathway. The protein expression of AKT, MTOR, ribosomal protein S6 kinase beta-1 (P70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) were greater in P1 and even more pronounced in P2. Nonetheless, glycogen synthase kinase 3 beta (GSK3β) protein expression was lower in trained groups. Together, these molecular changes may contribute to a pronounced physiological LVH observed in high-volume aerobic training.NEW & NOTEWORTHY Physiological hypertrophic growth of the heart as a compensatory response to exercise training (ET) is coupled with recent progress in dissecting the microRNA (miRNA)-mediated molecular basis of hypertrophy. Aerobic ET seems to reduce miRNA-16-5p and increase miRNA-26a-5p expression in a volume-dependent mode, activating protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathways, and likely produces an enhanced left ventricular hypertrophy (LVH) in high-volume endurance training. New insight into these mechanisms can be useful in understanding physiological LVH and how it might be harnessed as a therapeutic application.

MTOR Signaling-Related MicroRNAs As Cardiac Hypertrophy Modulators In High- Volume Endurance Training

Aerobic exercise training (ET) promotes cardiovascular adaptations, including physiological left ventricular hypertrophy (LVH), but not all mechanisms that underlie these changes are clear. PURPOSE: To elucidate the molecular mechanisms involved in high-volume ET-induced physiological LVH. METHODS: Eight-week old female Wistar rats were assigned to three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 minutes/day of swimming, 5x/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week; in the 9th week, rats trained 2x/day, and in the 10th week, rats trained 3x/day. Structural and molecular parameters were evaluated in the heart. RESULTS: Trained groups demonstrated an enhanced VO2 Peak (P1: 29% and P2: 34%; p < 0.001), exercise tolerance (P1: 28%, p < 0.05; P2: 50%, p < 0.01), and LVH (P1: 14% and P2: 28%; p < 0.001) when compared to SC group. Exercise tolerance and LVH increase in a volume-dependent manner (p < 0.05). Furthermore, an increase of 50% (P1) and 48% (P2) in the miRNA-26a-5p levels was observed in the heart compared to SC (p < 0.05). In contrast, miRNA-16-5p was reduced by 31% (P1) and 63% (P2) compared to SC (p < 0.01). Additionally, the miRNA-16-5p knockdown increase 86% (p < 0.001) of the cardiomyocyte size in neonatal rat cardiomyocytes. Also, the miRNA-26a-5p overexpression increase 60% (p < 0.001) of the cardiomyocyte size in neonatal rat. These miRNAs were selected because of their relation to the mTOR signaling pathway using Diana Tolls bioinformatics website. The protein expression were increased more pronounced in P2, AKT increased 77% (P1) and 130% (P2), mTOR 65% (P1) and 75% (P2), p70S6k 30% (P2), and 4E-BP1 30% (P2). Nonetheless, GSK3β protein expression was reduced 22% (P1) and 20% (P2). All protein expression was compared to control (p < 0.05). CONCLUSION: In this study, ET reduced the miRNA-16-5p levels, consequently increasing the expression of the target genes Akt, mTOR, and p70S6k. ET also increased the miRNA-26a-5p levels, which then reduced the expression of the target gene GSK3β. Together, these changes contributed to the physiological LVH observed in high-volume training. Supported by FAPESP Grant: #2015/22814-5 and #2015/17275-8; CNPq Grant: #313479/2017-8; CAPES-PROEX Grant: #88887.484856/2020-00.

Molecular mechanisms underlying fructose-induced cardiovascular disease: exercise, metabolic pathways and microRNAs.

What is the central question of this study? What are the mechanisms underlying the cardiac protective effect of aerobic training in the progression of a high fructose-induced cardiometabolic disease in Wistar rats? What is the main finding and its importance? At the onset of cardiovascular disease, aerobic training activates the p-p70S6K, ERK and IRβ-PI3K-AKT pathways, without changing the miR-126 and miR-195 levels, thereby providing evidence that aerobic training modulates the insulin signalling pathway. These data contribute to the understanding of the molecular cardiac changes that are associated with physiological left ventricular hypertrophy during the development of a cardiovascular disease. During the onset of cardiovascular disease (CVD), disturbances in myocardial vascularization, cell proliferation and protein expression are observed. Aerobic training prevents CVD, but the underlying mechanisms behind left ventricle (LV) hypertrophy are not fully elucidated. The aim of this study was to investigate the mechanisms by which aerobic training protects the heart from LV hypertrophy during the onset of fructose-induced cardiometabolic disease. Male Wistar rats were allocated to four groups (n=8/group): control sedentary (C), control training (CT), fructose sedentary (F) and fructose training (FT). The C and CT groups received drinking water, and the F and FT groups received d-fructose (10% in water). After 2weeks, the CT and FT rats were assigned to a treadmill training protocol at moderate intensity for 8weeks (60min/day, 4days/week). After 10weeks, LV morphological remodelling, cardiomyocyte apoptosis, microRNAs and the insulin signalling pathway were investigated. The F group had systemic cardiometabolic alterations, which were normalised by aerobic training. The LV weight increased in the FT group, myocardium vascularisation decreased in the F group, and the cardiomyocyte area increased in the CT, F and FT groups. Regarding protein expression, total insulin receptor β-subunit (IRβ) decreased in the F group; phospho (p)-IRβ and phosphoinositide 3-kinase (PI3K) increased in the FT group; total-AKT and p-AKT increased in all of the groups; p-p70S6 kinase (p70S6K) protein was higher in the CT group; and p-extracellular signal-regulated kinase (ERK) increased in the CT and FT groups. MiR-126, miR-195 and cardiomyocyte apoptosis did not differ among the groups. Aerobic training activates p-p70S6K and p-ERK, and during the onset of a CVD, it can activate the IRβ-PI3K-AKT pathway.

Differentiation between physiological sport adaptation and hypertrophic cardiomyopathy in highly trained athletes using cardiac magnetic resonance

Abstract Differentiation between hypertrophic cardiomyopathy (HCM) patients and healthy athletes (HA) is a common clinical conundrum. We aimed to analyze cardiac magnetic resonance (CMR) characteristics of HA, sedentary HCM and athletic HCM patients and to determine CMR parameters which can help to diagnose HCM in athletes. Male sedentary HCM patients with slightly elevated maximal end-diastolic wall thickness (EDWT 13–18 mm, n=40, 47.6±14.7y) and HA (n=30, 27.5±5.6y) were consecutively enrolled. Additionally, athletes with HCM were enrolled (n=16, 29.6±13.4 y), where a comprehensive investigation confirmed the diagnosis of HCM. We determined conventional CMR parameters (left ventricular (LV) ejection fraction (EF), end-diastolic (EDVi) and end-systolic volume index, mass index (Mi)), derived parameters such as EDWT/LVEDVi, LVM/LVEDV ratio and strain parameters such as global longitudinal (GLS), radial (GRS) and circumferential strain (GCS), SD of peak LS and CS using feature tracking. Presence of late gadolinium enhancement (LGE) was also determined. CMR parameters representing LV hypertrophy pattern or LV function were analyzed using a logistic regression to detect the best CMR parameters to predict HCM in athletes. To differentiate between HA and athletes with HCM optimal cut-off values for CMR parameters were calculated using receiver operating curve analysis. Comparing the three groups significant differences were found regarding conventional and derived CMR parameters and strain values. None of the HA showed LGE, 75% of athletic HCM and 82% of sedentary HCM patients showed LGE. The univariate regression model showed that LVEF, EDWT, EDWT/LVMi, LVM/LVEDV, GCS, GRS, SD of peak LS and CS are determinants of the diagnosis of HCM among athletes. Multivariate regression revealed that EDWT/LVMi and GCS are independent disease predictors in athletes (p&amp;lt;0.05). Cut-off value for GCS ≤−32.5 and for EDWT/LVEDVi &amp;gt;0.126 discriminate athletic HCM from HA with a sensitivity of 81.3 and 87.5% (AUC 0.93), and a specificity of 96.7 and 83.3% (AUC 0.95), respectively (Figure 1). CMR characteristics of sedentary and athletic HCM may differ, therefore establishing diagnostic parameters based on comparison between athletic HCM and HA is essential. CMR based strain and derived parameters may help to differentiate between physiological and pathological left ventricular hypertrophy in athletes. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA) and National Research, Development and Innovation Office (NFKIH) of Hungary.

Chronic swimming training resulted in more relaxed coronary arterioles in male and enhanced vasoconstrictor ability in female rats.

Exercise training is associated with hypertrophy of left ventricle (LV). The aim of the present study is to evaluate sex differences in the adaptation of the coronary contractile function in physiological left ventricular hypertrophy induced by long-term swim training. Thirty-two Wistar rats were randomly divided into 4 groups: exercised male (ExM), exercised female (ExF), untrained control male (CoM), and untrained control female (CoF). The trained animals underwent a 12-week-long swim training program. After finishing the training program, LV morphology and function were checked by echocardiography. The spontaneous tone, thromboxane (TxA<inf>2</inf>) agonist-induced vascular contractility and non-endothelial dilatation of the isolated intramural coronary resistance artery were examined by pressure microangiometry. The thromboxane receptor (TxA<inf>2</inf>R) protein expression in the wall of coronary arteries was examined using immunohistochemistry. The LV mass index was significantly higher in the ExM and ExF groups, furthermore the LV mass index was significantly higher in female than in male animals. ExM animals had lower spontaneous tone than ExF. TxA<inf>2</inf> agonist-induced tone was raised only in ExF animals. The resistance coronary artery of exercised male animals had a significantly lower level of TxA<inf>2</inf>R positivity compared to exercised females. Both sexes broaden their range of contractility following chronic swimming, but the vessel tone shifted toward contraction in exercised female rats, while these values shifted toward relaxation in males. These observations underline the significance of identifying potential gender differences in the chronic exercise-induced coronary vascular remodeling in human athletes.

Downregulation of miR-26b-5p, miR-204-5p, and miR-497-3p Expression Facilitates Exercise-Induced Physiological Cardiac Hypertrophy by Augmenting Autophagy in Rats.

Exercise-induced autophagy is associated with physiological left ventricular hypertrophy (LVH), and a growing body of evidence suggests that microRNAs (miRNAs) can regulate autophagy-related genes. However, the precise role of miRNAs in exercise induced autophagy in physiological LVH has not been fully defined. In this study, we investigated the microRNA–autophagy axis in physiological LVH and deciphered the underlying mechanism using a rat swimming exercise model. Rats were assigned to sedentary control (CON) and swimming exercise (EX) groups; those in the latter group completed a 10-week swimming exercise without any load. For in vitro studies, H9C2 cardiomyocyte cell line was stimulated with IGF-1 for hypertrophy. We found a significant increase in autophagy activity in the hearts of rats with exercise-induced physiological hypertrophy, and miRNAs showed a high score in the pathway enriched in autophagy. Moreover, the expression levels of miR-26b-5p, miR-204-5p, and miR-497-3p showed an obvious increase in rat hearts. Adenovirus-mediated overexpression of miR-26b-5p, miR-204-5p, and miR-497-3p markedly attenuated IGF-1-induced hypertrophy in H9C2 cells by suppressing autophagy. Furthermore, miR-26b-5p, miR-204-5p, and miR-497-3p attenuated autophagy in H9C2 cells through targeting ULK1, LC3B, and Beclin 1, respectively. Taken together, our results demonstrate that swimming exercise induced physiological LVH, at least in part, by modulating the microRNA–autophagy axis, and that miR-26b-5p, miR-204-5p, and miR-497-3p may help distinguish physiological and pathological LVH.

Long-term exercise results in morphological and biomechanical changes in coronary resistance arterioles in male and female rats

BackgroundBiomechanical remodeling of coronary resistance arteries in physiological left ventricular hypertrophy has not yet been analyzed, and the possible sex differences are unknown.MethodsWistar rats were divided into four groups: male and female sedentary controls (MSe and FSe) and male and female animals undergoing a 12-week intensive swim training program (MEx and FEx). On the last day, the in vitro contractility, endothelium-dependent dilatation, and biomechanical properties of the intramural coronary resistance arteries were investigated by pressure microarteriography. Elastica and collagen remodeling were studied in histological sections.ResultsA similar outer radius and reduced inner radius resulted in an elevated wall to lumen ratio in the MEx and FEx animals compared to that in the sedentary controls. The wall elastic moduli increased in the MEx and FEx rats. Spontaneous and TxA2 agonist-induced tone was increased in the FEx animals, whereas endothelium-dependent relaxation became more effective in MEx rats. Arteries of FEx rats had stronger contraction, while arteries of MEx animals had improved dilation.ConclusionsAccording to our results, the coronary arterioles adapted to an elevated load during long-term exercise, and this adaptation depended on sex. It is important to emphasize that in addition to differences, we also found many similarities between the sexes in the adaptive response to exercise. The observed sport adaptation in the coronary resistance arteries of rats may contribute to a better understanding of the physiological and pathological function of these arteries in active and retired athletes of different sexes.

An Electrocardiographic System With Anthropometrics via Machine Learning to Screen Left Ventricular Hypertrophy among Young Adults.

The prevalence of physiological and pathological left ventricular hypertrophy (LVH) among young adults is about 5%. A use of electrocardiographic (ECG) voltage criteria and machine learning for the ECG parameters to identify the presence of LVH is estimated only 20-30% in the general population. The aim of this study is to develop an ECG system with anthropometric data using machine learning to increase the accuracy and sensitivity for a screen of LVH. In a large sample of 2,196 males, aged 17–45 years, the support vector machine (SVM) classifier is used as the machine learning method for 31 characteristics including age, body height and body weight in addition to 28 ECG parameters such as axes, intervals and voltages to link the output of LVH. The diagnosis of LVH is based on the echocardiographic criteria for young males to be 116 gram/meter2 (left ventricular mass (LVM)/body surface area) or 49 gram/meter2.7 (LVM/body height2.7). On the purpose of increasing sensitivity, the specificity is adjusted around 70-75% and all data tested in proposed model reveal high sensitivity to 86.7%. The area under curve (AUC) of the Precision-Recall (PR) curve is 0.308 in the proposed model which is better than 0.109 and 0.077 using Cornell and Sokolow-Lyon voltage criteria for LVH, respectively. Our system provides a novel screening tool using age, body height, body weight and ECG data to identify most of the LVH among young adults. It provides a fast, accurate and practical diagnosis tool to identify LVH.

Intact DNA Repair in Differentiated Cardiomyocytes is Essential for Maintaining Cardiac Function in Response to Physiological Stimulus

IntroductionDNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage‐induced aging‐related diseases. Evidence indicates that DNA damage is associated with heart failure. We have shown that unrepaired endogenously generated DNA damage drives the early onset of progressive heart failure (de Boer et al. Cardiovasc Res, 2018;114:S105). Here we studied the effects of a physiological stimulus on cardiac function in a mouse model with deficient DNA repair.MethodsTo increase the burden of spontaneous DNA damage, we generated mice with cardiomyocyte‐restricted inactivation of DNA repair endonuclease XPG (αMHC‐Xpgc/−). To induce physiological left ventricular (LV) hypertrophy, mice were exposed to 11 weeks of voluntary wheel running. Subsequently, LV geometry, function and structure were studied at age 16 weeks.ResultsCardiomyocyte‐restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction, demonstrated by decreases in fractional shortening, LVdP/dtP40 and LVdP/dtmin and increases in LV end‐diastolic lumen diameter (LVEDD) and relaxation time constant tau compared to WT (Table). In addition, expression level of hypertrophy maker gene β‐myosin heavy chain (β‐MHC) was elevated. Physical activity has been shown to be beneficial for maintaining and improving cardiac function in mice after myocardial infarction (de Waard et al. Circ Res, 2007;100:1097). In contrast, exercise failed to ameliorate LV remodeling and dysfunction in αMHC‐Xpgc/−, as it produced further increases in LVEDD, tau and β‐MHC compared to sedentary αMHC‐Xpgc/− (Table). Moreover, myocardial collagen content and the number of γH2A. X positive nuclei, a marker for DNA damage, were increased, suggesting that αMHC‐Xpgc/− showed increased susceptibility to exercise.ConclusionCardiomyocyte‐restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to exercise training. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only during basal conditions, but also in response to a physiological stimulus.Support or Funding InformationSupported by a NHF Grant 2007B024 and CVON‐ARENA (CVON2011‐11).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The demanding grey zone: Sport indices by cardiac magnetic resonance imaging differentiate hypertrophic cardiomyopathy from athlete's heart.

BackgroundWe aimed to characterize gender specific left ventricular hypertrophy using a novel, accurate and less time demanding cardiac magnetic resonance (CMR) quantification method to differentiate physiological hypertrophy and hypertrophic cardiomyopathy based on a large population of highly trained athletes and hypertrophic cardiomyopathy patients.MethodsElite athletes (n = 150,>18 training hours/week), HCM patients (n = 194) and athletes with hypertrophic cardiomyopathy (n = 10) were examined by CMR. CMR based sport indices such as maximal end-diastolic wall thickness to left ventricular end-diastolic volume index ratio (EDWT/LVEDVi) and left ventricular mass to left ventricular end-diastolic volume ratio (LVM/LVEDV) were calculated, established using both conventional and threshold-based quantification method.ResultsWhereas 47.5% of male athletes, only 4.1% of female athletes were in the grey zone of hypertrophy (EDWT 13-16mm). EDWT/LVEDVi discriminated between physiological and pathological left ventricular hypertrophy with excellent diagnostic accuracy (AUCCQ:0.998, AUCTQ:0.999). Cut-off value for LVM/LVEDVCQ<0.82 mm×m2/ml and for EDWT/LVEDViTQ<1.27 discriminated between physiological and pathological left ventricular hypertrophy with a sensitivity of 77.8% and 89.2%, a specificity of 86.7% and 91.3%, respectively. LVM/LVEDV evaluated using threshold-based quantification performed significantly better than conventional quantification even in the male subgroup with EDWT between 13-16mm (p<0.001).ConclusionsAlmost 50% of male highly trained athletes can reach EDWT of 13 mm. CMR based sport indices provide an important tool to distinguish hypertrophic cardiomyopathy from athlete’s heart, especially in highly trained athletes in the grey zone of hypertrophy.

Alteration in cardiac PI3K/Akt/mTOR and ERK signaling pathways with the use of growth hormone and swimming, and the roles of miR21 and miR133.

Athletes misuse recombinant human growth hormone (r-hGH) to enhance their performance. Although r-hGH is known to increase cardiac hypertrophy, the underlying molecular mechanism remains unclear. The aim of the present study was to investigate the role of r-hGH in cardiac intracellular signaling pathways and of miR-21 and miR-133 expression in rat hearts during exercise. A total of 36 adult male Sprague-Dawley rats were divided into sedentary control (SC, n=9), swimming exercise (SE, n=8), r-hGH (GH, n=10) and swimming exercise plus r-hGH (SE-GH, n=9) groups. The exercise groups completed a 1-h swimming exercise 5 times a week for 8 weeks. Subcutaneous r-hGH was administered as 0.3 mg/kg/day. Phosphoinositide-3-kinase (PI3K), serine/threonine protein kinase 1 (AKT1), extracellular signal-regulated kinase (ERK), microRNA (miR)-21 and miR-133 expression was evaluated in ventricular muscle by real-time quantitative polymerase chain reaction. Protein expression of PI3K, AKT1, ERK and mechanistic target of rapamycin (mTOR) was also assessed by immunohistochemistry. Statistical differences were analyzed by two-way ANOVA. PI3K and AKT1 expression and the gene and protein levels was notably increased in the SE-GH group compared with in SC ventricular tissues (P<0.05). mTOR protein expression was higher in the GH, SE and SE-GH groups compared with in the SC group (P<0.05, <0.05 and <0.001, respectively). ERK gene/protein expression was similar across all groups. miR-21 and miR-133 levels in ventricular muscle were higher in the SE and GH groups than those in the SC group. In summary, growth hormone application coupled with swimming exercise appeared to affect the PI3K/AKT/mTOR signaling pathway in the left ventricular tissue of rats; however, ERK signaling pathway appeared inactive in physiological left ventricular hypertrophy caused by swimming and GH administration over 8 weeks. Furthermore, GH treatment resulted in increased miR-21 and miR-133 expression. Future study by our group will aim to assess the effects of higher dose GH treatment.

Left Ventricular Hypertrophy in Athletes: Differentiating Physiology From Pathology.

The changes that occur in athlete's heart are influenced by a number of factors including age, gender, ethnicity and the type of cardiovascular training. It is therefore important that the clinician is able to integrate all of these factors when assessing athletes to be able to guide investigations appropriately and to distinguish pathology from physiology. This review discusses the potential diagnostic conundrums when trying to differentiate physiological left ventricular hypertrophy from pathological hypertrophic cardiomyopathy in athletes. The mechanism of physiological and pathological hypertrophy is discussed together with history, clinical and investigational findings that can help to identify pathology. Athletes with hypertrophic cardiomyopathy are more likely to have non-concentric left ventricular hypertrophy (LVH), an elevated relative wall thickness, lateral ECG changes and a smaller LV cavity than athletes with physiological LVH. Certain diastolic echocardiographic parameters when used as part of an algorithm (e'; E/E'; E/A) can help to distinguish physiology from pathology, and there is evidence that assessment of global longitudinal strain during exercise echocardiography may be of use in the future. Cardiac MRI is an important imaging modality that can have an additive effect over echocardiography in the diagnosis of cardiomyopathy. Late gadolinium enhancement is a recognised advantage for cardiac magnetic resonance to allow detection of fibrosis in hypertrophic cardiomyopathy. T1 mapping and extracellular volume quantification may be a tool for the future to help distinguish athlete's heart from HCM. Cardiac adaptation to exercise and training in athletes, the athlete's heart causes electrophysiological and geometric changes that may mimic mild phenotypes of a pathological cardiomyopathy. This review article summarises a systematic approach to the assessment of left ventricular hypertrophy in athletes and describes pertinent clinical and investigation findings that can help to differentiate physiology from pathology.

Role of Doppler Diastolic Parameters in Differentiating Physiological Left Ventricular Hypertrophy from Hypertrophic Cardiomyopathy

The association between athletic participation and alteration in diastolic function is not well established. The aims of this study were to determine the spectrum of Doppler parameters of left ventricular (LV) diastolic function in a large cohort of healthy athletes and to quantify the overlap between physiologic LV hypertrophy and hypertrophic cardiomyopathy (HCM). A retrospective analysis of indices of LV diastolic function was performed in 1,510 healthy athletes (mean age, 22±5years; range, 13-33years; 72% men). The results were compared with those from 58 young patients with HCM. Septal E' < 7cm/sec and lateral E' < 10cm/sec were found in five (0.3%) and eight (0.5%) athletes, respectively. Septal E' was >14.6cm/sec in 170 (11%) and lateral E' was >19.9cm/sec in 430 (28%) athletes. Athletes aged >25years showed lower E' velocities compared with younger athletes (mean septal E', 11.8±6.1 vs 12.9±5.9cm/sec [P<.001]; mean lateral E', 17.1±3.6 vs 19.3±4.1cm/sec [P<.001]). Athletes with high indexed LV end-diastolic diameters (>32mm/m2) exhibited lower septal E' compared with athletes with normal indexed LV end-diastolic diameters (mean septal E', 11.9±6 vs 12.7±6cm/sec; P=.002). Septal E' < 10cm/sec and lateral E' < 12cm/sec showed the best accuracy in differentiating between HCM and athlete's heart. Reduced septal and lateral E' are rarely observed in young elite athletes. Tissue Doppler velocities tend to decrease with increasing age and LV size, and values representative of supernormal diastolic function are found in less than one-third of young athletes. Cutoff thresholds for Doppler parameters of diastolic function should be corrected for multiple demographic and clinical variables to differentiate cardiac adaptation to exercise from HCM in young individuals.

133 Cardiopulmonary exercise testing: does ethnicity matter?

IntroductionHypertrophic cardiomyopathy (HCM) is the largest cause of sudden cardiac death in athletes. Differentiation between HCM and athletic cardiac adaptation is not always straightforward. Cardiopulmonary exercise testing (CPET) is useful...

Left ventricular dyssynchrony and 2D and 3D global longitudinal strain for differentiating physiological and pathological left ventricular hypertrophy

Diagnosis of hypertrophic cardiomyopathy (HCM) in athletes can be challenging. To ascertain parameters that differentiate patients with HCM from athletes with moderate left ventricular (LV) hypertrophy (LVH 13-15mm). We retrospectively included 100 men: 50 elite rugby players (25 with moderate LVH and 25 with no LVH), 25 patients with HCM and moderate LVH and 25 controls. LV dyssynchrony was defined as the standard deviation of time to peak 2D longitudinal strain (16-segment model) and global strain components were computed from two- (2D) and three-dimensional (3D) speckle tracking. 2D global longitudinal strain (GLS) (18±2% vs. 19±2%) and various 3D strain components were similar in athletes with moderate LVH and controls, while LV volumes and dyssynchrony (39±8 vs. 31±9ms; P<0.001) were greater in athletes with moderate LVH. The accuracy for differentiating patients with HCM from athletes ranged between 0.57 and 0.92 for various markers, with the best obtained for LV dyssynchrony (AUC=0.92;>48ms had sensitivity=83%, specificity=89%). Binary logistic regression showed that accuracy was improved when LV dyssynchrony was combined with 2D GLS. HCM was excluded when 2D GLS was preserved (>18%) and there was no LV dyssynchrony (>48ms) and only patients with HCM had reduced longitudinal strain and LV dyssynchrony. LV dyssynchrony combined with GLS can be used to differentiate athletes with moderate LVH from patients with HCM.