We compared cardiovascular magnetic resonance segmental native T1 against T2* values for the detection of myocardial iron overload (MIO) in thalassaemia major and we evaluated the clinical correlates of native T1 measurements.We considered 146 patients  consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network.T1 and T2* values were obtained in the 16 left ventricular (LV) segments. LV function parameters were quantified by cine images. Post-contrast late gadolinium enhancement (LGE) and T1 images were acquired.64.1% of segments had normal T2* and T1 values while 10.1% had pathologic T2* and T1 values. In 526 (23.0%) segments, there was a pathologic T1 and a normal T2* value while 65 (2.8%) segments had a pathologic T2* value but a normal T1 and an extracellular volume (ECV) ≥ 25% was detected in 16 of 19 segments where ECV was quantified.Global native T1 was independent from gender or LV function but decreased with increasing age. Patients with replacement myocardial fibrosis had significantly lower native global T1. Patients with cardiac complications had significantly lower native global T1.The combined use of both segmental native T1 and T2* values could improve the sensitivity for detecting MIO. Native T1 is associated with cardiac complications in thalassaemia major. Iron-induced cardiomyopathy is the leading cause of death in β-thalassaemia major (β-TM) patients . MyocardTo date, cardiovascular magnetic resonance (CMR) is the only non-invasive technique for quantification of MIO. The presence of myocardial iron deposits causes microscopic magnetic field inhomogeneities and results in a reduction in T1, T2 and T2* relaxation times . The T2*In vivo mapping of the myocardial T1 relaxation time has been proposed as a possible approach to overcome this limitation. A significant correlation between mid-septum native T1 and T2* values has been detected in patients with β-TM and other haemoglobinopathies –18.No literature data are available about the association between native T1 and T2* using a segmental approach including the entire left ventricle (LV). As previously demonstrated for the T2* technique, the segmental approach is more sensitive, allowing to detect MIO in the various cardiac segments before it occurs at the septal level . This apTo date, no study has evaluated whether T1 measurements quantifying MIO are influenced by age, gender, or myocardial fibrosis. Of note, replacement myocardial fibrosis detected by late gadolinium enhancement (LGE) CMR is common in β-TM patients  and it iWe sought to assess the relationship between native T1 and T2* values using a segmental approach, as well as the association between global T1 measurements, demographics, and cardiac involvement.We considered 146 β-TM patients , consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassaemia (E-MIOT) project, an Italian network constituted by 66 thalassaemia centres and 11 validated CMR sites , 25 sharThe study complied with the Declaration of Helsinki and was approved by the local ethical committee. All patients gave written informed consent.CMR exams were performed in the reference CMR center of the E-MIOT Network (Pisa) using a 1.5 T CMR scanner . A 30-element cardiac phased-array receiver surface coil with breath-holding and electrocardiographic (ECG)-gating was used.For T1 mapping, three parallel short-axis slices  of the LV were acquired in end-diastole using a modified Look-Locker inversion recovery (MOLLI) sequence  with a 3®), have been already described [T2* multiecho images were acquired in the same 3 slice locations used for T1 mapping by a multi-echo gradient-echo T2* sequence (10 echo times-TEs). Sequence parameters and T2* images analysis, performed using a custom-written and validated software  [Balanced steady-state free precession cine images were acquired in sequential 8-mm short-axis slices from the atrio-ventricular ring to the apex to quantify LV function parameters in a standard way using MASSerlands) . LV volu®; Bayer Healthcare; Berlin, Germany) intravenous administration (0.2 mmoL/kg). LGE images were not acquired in patients with an estimated glomerular filtration rate < 30 mL/min/1.73 m2 and in patients who declined contrast. LGE was considered present when visualized in two different views [To detect the presence of replacement myocardial fibrosis, LGE short-axis, vertical, horizontal, and oblique long-axis images were acquired 10–18 min after gadobutrol  on data acquired on 80 healthy subjects. Since in healthy subjects T1 values are influenced by gender, gender-specific segmental thresholds were derived.Heart failure (HF) was diagnosed by clinicians based on symptoms, signs and instrumental findings . All arrTo evaluate the intra-observer reproducibility, native T1 images from 20 patients were re-analyzed by the same operator after 4 weeks. To evaluate the inter-observer reproducibility, the same images were blindly analyzed by a second operator. The coefficient of variation (CoV) was calculated as the ratio of the SD to the mean, multiplied by 100. The intraclass correlation coefficient (ICC) was obtained from a two-way random effects model with measures of absolute agreement. The Bland–Altman technique was used to plot the absolute difference versus the average values between the two datasets. Bias was the mean of the difference between the two sets of values and agreement was the mean ± 1.96 SDs.All data were analyzed using SPSS .Continuous variables were described as mean ± SD and categorical variables were expressed as frequencies and percentages.The Kolomogorov-Smirnov test showed a non-normal distribution for T1 values.2 testing was performed for non-continuous variables.The comparison of T1 values between two groups was made by the Wilcoxon rank sum test. χCorrelation analysis was performed using the Spearman’s test.Logistic regression was used to evaluate the odds ratio (OR) with 95% confidence intervals (CI). The OR was used to compare the odds for two groups.To determine the best cut-off of T1 or T2* values for discriminating the presence of a specific condition, the maximum sum of sensitivity and specificity was calculated from receiver-operating characteristic (ROC) curve analysis.A 2-tailed P < 0.05 was considered statistically significant.Patients’ demographic and clinical characteristics are summarized in Table Mean global heart T1 value was 952 ± 99 ms (range 494–1170 ms) while mean global heart T2* value was 37.4 ± 9.3 ms (range 5.2–37.4 ms).Figure A significant correlation was detected between global heart and mid-septum T1 values . Out of the 70 patients with a reduced global heart T1 value , 58 (82.0%) had also a reduced mid-septum T1 value  while 12 (17.1%) had a normal mid-septum T1 value. Furthermore, out of the 85 patients with a normal mid-septum T1 value, 44 (51.8%) showed a pathological T1 value in at least one of the remaining 14 segments. For three patients a reduced mid-septum T1 value was detected in presence of a normal global heart T1 value, but all of them had also other two segments with reduced T1 value.For T2* a significant correlation was detected between global heart and mid-septum values . Four patients had a normal mid-septum T2* value in presence of a reduced global heart T2* value and out of the 127 patients with a normal mid-septum T2* value, 35 (27.6%) showed a pathological T1 value in at least one of the remaining 14 segments.The results of the intra- and inter-observer variability analysis for segmental and global T1 values are indicated in Table T1 images showed more pronounced motion artifacts and lower contrast-to-noise-ratio, determining the exclusion of 49/2336 (2.1%) segments. No segments were excluded in T2* images. Globally 2287 segmental T1 and T2* values were considered.Figure A significant correlation was detected between global heart T1 and T2* values . Out of the 22 (15.1%) patients with a pathologic global heart T2* value (< 32 ms), two had a normal T1. Fifty (34.2%) patients had a pathologic global T1 in the presence of a normal global T2*.Myocardial global T1 was comparable between males and females  while they showed a weak inverse correlation with age .A significant inverse correlation was detected between global T1 and serum ferritin levels .No correlation was detected between global T1 and LV volume indexes, mass index, or ejection fraction.Abnormal LV motion  was found in 14 (9.6%) patients: 13 hypokinetic and one dyskinetic. Patients with abnormal LV motion   had significantly lower global T1 than patients without LV motion abnormalities  . At ROC curve analysis, a global T1 ≤ 865 ms predicted the presence of LV motion abnormalities with a sensitivity of 42.9% and a specificity of 90.2% (P = 0.049). The area under the curve (AUC) was 0.66 .LGE images were acquired in 88 60.3%) patients; replacement myocardial fibrosis was detected in 36 (40.9%) patients. Two patients showed an ischemic pattern. Among the patients with LGE, 72.2% had two or more foci of fibrosis. Patients with replacement myocardial fibrosis had significantly lower global T1   and 105 (7.5%) were positive. Segments with LGE had significantly lower T1 than segments LGE-negative .Nineteen patients had an history of cardiac complications: 11 HF and 8 arrhythmias (7 supraventricular and 1 ventricular). Patients with cardiac complications had significantly lower global T1  . The AUC was 0.77 . The ROC curve did not reveal a global heart T2* threshold below which the probability of detecting a positive history of cardiac complications increases significantly with satisfying sensitivity and specificity . The Delong’s test showed a significant difference among the AUCs (P = 0.005) Fig. b.The optimal cut-off for the mid-septum T1 value was 957 ms (P < 0.001) and the AUC was 0.70 . No significant difference (P = 0.449) was obtained between the AUCs obtained for global and mid-septum T1.For eight patients, the cardiac complication was still active at the time of the CMR . These patients had a lower T1 than the group of patients without history of cardiac complications or with resolved cardiac complications at the time of CMR  but comparable global heart T2* values .To our knowledge, this is the first report relating native T1 to T2* values by a segmental approach including the entire LV wall in haemochromatotic patients. The segmental approach allows to identify a heterogeneous and early iron distribution, that would remain otherwise unexplored with a single measurement in the mid-ventricular septum , 19, 34.The robustness of the T2* segmental approach had been previously established by proper validation that documented good intra- and inter-observer, inter-study and inter-scanner reproducibility, however decreasing for higher T2* values , 24. TheAn association between mid-septum T1 and T2* values at 1.5 T has been previously shown in relatively large cohorts of β-TM patients –17, and In the present study, T2* and T1 showed a good correlation in identifying iron by a segmental approach, with 74% concordance. In 33 patients, T1 mapping could not detect iron in one or more segments, probably due to the presence of diffuse fibrosis, which is known to increase the native T1 . In factThe second objective of our study was to correlate global T1 measurements with demographics, CMR findings, and cardiac complications.In healthy subjects, native T1 is influenced by gender, with women having a higher value . In β-TMWe did not detect any correlation between native T1 and LV systolic function, volumes, or mass, probably because the majority of our patients had normal or mild abnormal values of these parameters, thanks to a good transfusional regimen. Conversely, although not frequent, LV movement abnormalities were associated with low native T1.TM patients with replacement myocardial fibrosis had significantly lower T1. The presence of replacement myocardial fibrosis detected by the LGE technique was shown to significantly increase native T1 , even inFinally, we here demonstrated for the first time an association between decreased native global T1 and a history of cardiac complications and we introduced a threshhold of 931 ms for the prediction of cardiac complications with satisfying sensitivity and specificity. Global myocardial T2* was similar among patients without and with cardiac complications. Likely in our population of well treated patients, generally not heavily loaded at the cardiac level, T1 emerge as a more sensitive marker of cardiac complications, stronger than global T2*. The comparison of cardiac T1 values between patients without and with active cardiac complications remained significant despite the low number of patients with active cardiac complications and despite the active complications were represented by supraventricular arrhythmias in 75% of the cases. MIO was shown to contribute less to the development of supraventricular arrhythmias than to HF , 12, 29.Our findings suggest that, due to its added diagnostic value, native T1 should be included in the routine CMR assessment of β-TM patients, where available and after the definition of reference ranges for T1 values in healthy human myocardium. Such a more sensitive approach in quantifying iron could support clinicians in earlier adjustment of chelation therapy and possibly further improve prognosis in β-TM.Altough the relaxation rates (R2* and R1) are proportional to the tissue iron content, we used their inverses (T2* and T1), since they are commonly adopted in the clinical practice, however an appropriate statistical approach has been used.White blood sequences were used for T2* assessment, although black blood sequences are more accurate and robust .Conversely to the T2* technique , 10, T1 Multicenter studies are needed to test the transferability for the T1 mapping as robust and useful complementary tool to T2* in the clinical practice and to verify the results in populations with lower prevalence of HCV infection in which a lower frequency of myocardial fibrosis may be attended.This is a cross-sectional study and prospective studies are recommended to evaluate the predictive value of native T1 for cardiac outcomes in β-TM.Native T1 is less specific than T2* mapping for MIO detection, given that myocardial fat and diffuse fibrosis can influence T1 values. Conversely, native T1 by a segmental approach can improve the sensitivity in detecting myocardial iron loading and is associated with cardiac complications in β-TM. The combined use of both T1 and T2* mapping by a segmental approach could therefore improve the detection of mild iron loading, potentially supporting clinicians in appropriately and timely modifying chelation therapy.


Four patients suffered from malignant tachyarrhythmia and recurrent syncope after TTS. Except for the CPVT patient and one LQTS 1 patient, all other cases underwent subcutaneous ICD implantation. An event recorder of the CPVT patient after starting beta-blocker did not detect arrhythmias. The diagnosis of primary electrical disease was in 80% of cases unmasked on a TTS event. This diagnosis triggered a family clinical and genetic screening confirming the diagnosis of primary electrical disease. A subsequent literature review identified five cases as the following: a congenital atrioventricular block (n = 1), a Jervell and Lange-Nielsen Syndrome (n = 1), and a family LQTS in the absence of a mutation (n = 2), LQTS 2 (n = 1). A primary electrical disease should be suspected in young and old TTS patients with a family history of sudden cardiac death. In suspected cases, e.g., ongoing QT interval prolongation, despite recovery of left ventricular ejection fraction a family screening is recommended.The pathophysiology of Takotsubo Syndrome (TTS) is not completely understood and the trigger of sudden cardiac death (SCD) in TTS is not clear either. We therefore sought to find an association between TTS and primary electrical diseases. A total of 148 TTS patients were analyzed between 2003 and 2017 in a bi-centric manner. Additionally, a literature review was performed. The patients were included in an ongoing retrospective cohort database. The coexistence of TTS and primary electrical diseases was confirmed in five cases as the following: catecholaminergic polymorphic ventricular tachycardia  ( Takotsubo Syndrome (TTS) is a reversible acute heart failure caused by a cardiac dysfunction and wall motion abnormalities mimicking acute coronary syndrome. Recently published data sorted TTS into four forms: the apical, the midventricular, and the rarely described basal and focal forms ,2,3. DifThe purpose of this retrospective study was to detect a possible association between congenital channelopathy in the presence of TTS in a bi-centric study as well as a literature review of published cases.A cohort of 148 patients presenting with TTS was reviewed and included in an ongoing retrospective cohort database from 2003 to 2017. They were part of the daily patient collective of the University Medical Centre Mannheim and the University Medical Centre Frankfurt. Additionally, a subsequent literature search using PubMed and the MeSH terms “Takotsubo” and “Congenital” identified further cases.Patients were presenting with symptoms of an acute coronary syndrome as chest pain or dyspnea, including electrocardiographic changes and the release of troponin and other myocardial enzymes, in the absence of significant obstructive coronary artery disease and fulfilled the Mayo Clinic criteria for TTS .All patients underwent coronary angiography to exclude a significant obstructive coronary artery disease. Demographics; symptoms on presentation; electrocardiographic and transthoracic echocardiography findings; and cardiac enzymes including creatine, troponin I, and creatine phosphokinase were recorded during the hospital admission. In selected cases, a cardiac magnetic resonance tomography (CMRI) was performed. Myocarditis and pheochromocytoma were excluded before reaching a diagnosis of TTS, as described previously .The angiograms, echocardiograms, and ECGs were reviewed by two experienced independent cardiologists to evaluate the diagnosis of TTS. The study protocol was approved by the Ethics Committee of University Medical Centre Mannheim . All methods were performed in accordance with the relevant guidelines and regulations.In-hospital events, arrhythmias, cardiac rupture, thromboembolic events, pulmonary congestion with use of non-invasive positive-pressure ventilation, intubation, use of a temporary pacemaker, use of inotropic agents, and in-hospital death were assessed based on chart review. If medical records, treating physicians, or relatives were unable to provide further information concerning the circumstances of death, it was defined as death due to unknown cause.Data are expressed as mean values ± standard deviation for continuous variables with a normal distribution, median (interquartile range) for continuous variables with a non-normal distribution, and percentages for categorical variables.p-values < 0.05 (two-tailed) were considered statistically significant.Statistical analysis was performed using SPSS 23.0 in all analyses; Among 148 TTS cases, five patients suffered from different channelopathies.An 18-year-old female patient was admitted for rhinoplasty. Her family history was associated with unexplained SCD of her aunt at 36 years of age, and the patient had 10 episodes of unexplained syncope during physical stress. General anesthesia was performed using propofol and remifentanil. However, after that, the patient developed a systolic blood pressure <70 mmHg associated with bidirectional tachycardia D betweenA 72-year-old woman was admitted for a nasal septoplasty. One day after the surgery, the patient complained about chest pain. Cardiac enzyme levels were elevated. A coronary angiography was performed, and an acute coronary syndrome was invasively ruled out. However, subsequent ventriculography and transthoracic echocardiography showed an apical ballooning and LQTS (QTc 661 ms) in her 12-lead-ECG A, consisA 65 year-old woman was admitted to the hospital due to dyspnea. She has a history of chronic obstructive pulmonary disease. Due to elevated cardiac enzymes, a coronary angiography was performed and excluded coronary artery disease. However, laevo-cardiography and echocardiography showed a midventricular TTS form with QTc interval prolongation (660 ms). Metoprolol was started. However, due to persistent QTc prolongation after recovery of LVEF, a family screening was started to exclude congenital long QT syndrome. Sudden cardiac death was documented B. A furtA 17-year-old girl attended a concert and was successfully resuscitated in the field from cardiac arrest due to ventricular fibrillation, leading to emergency hospital admission. The patient suffered from recurrent syncope. Her mother was diagnosed with an LQTS 2 several years ago. In the acute setting, coronary artery disease was ruled out invasively. An additionally performed ventriculography demonstrated an apical TTS form and impaired LVEF of 30%. The ECG showed significant QT prolongation (QTc = 500 ms). The patient was treated by a beta-blocker and was fitted with a wearable cardioverter defibrillator (WCD) after the intensive-care unit (ICU) stays. Three months later, left ventricular function was normalized. A subcutaneous ICD was implanted for secondary prevention.A 22-year-old patient was admitted to the hospital due to out-of-hospital cardiac arrest (OHCA) because of ventricular fibrillation (VF). An LQTS was diagnosed four years ago. An acutely performed coronary angiography excluded a coronary artery disease. However, an echocardiography documented a highly reduced EF with apical and midventricular wall motion abnormality. In the ICU, recurrent ventricular tachyarrhythmias were documented C. A cardOur literature research revealed five further TTS cases with a coincident primary electrical disease . Mahida Another 37-year-old  patient Additionally, two cases have been reported with a coincidence of channelopathy and TTS.A 55-year-old female patient was diagnosed with TTS and LQTS. The patient was numb, and a medical history analysis presented more cases of family deafness and LQTS consistent with Jervell and Lange-Nielsen Syndrome . A 42-yeWedekind and colleagues reported a case of a fatal combination of TTS, hypertrophic cardiomyopathy, and congenital LQTS. An 81-year-old female was diagnosed with TTS triggered by an emotional stress event after receiving the message of SCD of her 54-year-old son. She developed recurrent Torsade de Pointes and ventricular tachycardia. Because of the pronounced QT interval prolongation in this patient, ECG recordings during previous hospital stays revealed an LQTS. In the family screening, the living daughter was clearly diagnosed with LQTS (QTc 520 ms).We performed a retrospective clinical investigation in 148 TTS patients and a subsequent literature review and showed that (i) the coincidence of TTS and primary electrical diseases is not uncommon; (ii) the pathophysiology of LQTS in TTS might be multifactorial; and (iii) TTS with a concomitant primary electrical disease might increase the risk of ventricular arrhythmias.In unclear cases of myocardial infarction with non-obstructed coronary arteries (MINOCA), TTS diagnosis can be assessed by CMRI. Data have shown that patients with MINOCA are at high risk of major adverse cardiac events (MACE) regardless of the underlying cause of MINOCA. However, patients with a diagnosis of acute myocardial infarction according to CMRI are at the highest risk of MACE .In cases with persistent LQTS in TTS despite normalization of LVEF, a congenital LQTS should be evaluated. Here, we describe a case of two older patients with persistent LQTS despite the recovery of EF. In addition, two young patients with a family history of LQTS suffered from TTS. Genetic and family screening confirmed a family congenital channelopathy. The literature review confirmed our observation. Further cases of an old TTS patient and two young patients have unmasked the diagnosis of family LQTS.LQTS is a known dominator of tachyarrhythmias. The presence of QT-prolonging drugs, electrolyte imbalances, and bradycardia provoke acquired LQTS ,17,18. HPatients with TTS release intense catecholamine levels, which lead to myocardial stunning, coronary vasospasm, and oxidative stress. The catecholamine-mediated myocardial toxicity can be seen as repolarization abnormalities in standard 12-lead ECG, including T-wave inversions and QT prolongation . Those c++-handling [In the current study, we focus on a second cause of ECG changes in TTS. Since some cases are triggered by primary electrical disease, it is not excluded that a significant part of TTS patients has some LQTS-associated genes. Primary channelopathies and TTS might delay cardiac repolarization. TTS was shown to be associated with altered intracellular Cahandling . It can A strong correlation between myocardial edema and the extent of repolarization abnormalities that are often associated with a long QT interval in patients with TTS has been reported in TTS cohorts ,21. FurtLife-threatening arrhythmias including atrioventricular-block, ventricular tachycardia, and ventricular fibrillation have been reported in up to 14% of TTS cases, mainly in the setting of QTc interval prolongation ,10. TTS The medical treatment of TTS remains challenging. Data have shown that the use of beta-blockers might not be helpful in TTS patients . HoweverA recently published literature review showed presence of TTS among patients who are suffering from COVID-19 with only a predominance of females and a high rate of critical illness in these patients . SeveralThere are some limitations of this study that need to be mentioned. First, we report a very small number of TTS cases with co-incidence of primary electrical diseases. The described institutional database consists of 148 patients, and most data were obtained by a retrospective bi-center observation with confined event rates. Only TTS patients with suspected congenital channelopathy have received genetic and family screenings. Therefore, it is not excluded that other cases of inherited channelopathies  are underestimated in TTS patients due to historical data about acquired LQTS in TTS patients.The results of this study may show that TTS could be associated with repolarization abnormalities including QT prolongation. However, they may explain that LQTS is not an acquired syndrome in TTS and could be a primary trigger of TTS. Further studies are needed to determine its pathophysiological significance and to develop multivariate risk stratification for life-threatening arrhythmias in TTS. In the case of ongoing QTc prolongation months after the TTS event, malignant arrhythmia, and/or history of sudden cardiac death in family, screening for QTc prolonging genes should be completed.


The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches. We will show that despite many approaches having targeted individual/single components of E–C coupling to date, all have shown no benefit and/or differing levels of promise. This suggests a complexity to the current simplicity of thought regarding the treatment of heart failure.This review article will cover the origins of several schools of thought regarding E–C coupling in the failing heart and the treatment of heart failure . We will2+ indicator that can be used in multicellular preparations i, markers of myocardial energy supply, and connective tissue content were quantified. Although weanling animals with POH showed a similar degree of hypertrophy to that found in juvenile animals with POH, there were differences in peak twitch force despite there being no difference in peak [Ca2+]i. Connective tissue content, however, showed significant differences. In weanling animals with POH, connective tissue content was 10 ± 2% compared to 24.0 ± 6.8% in juvenile animals with POH (p < 0.001), which might have contributed to the lower peak twitch force in juvenile animals. Despite a lack of change in connective tissue content or resting [Ca2+]i in weanling animals, passive stiffness in muscles was increased. Lactate dehydrogenase was significantly higher (38%) in weanling animals. However, total creatine kinase activity and total creatine content were significantly less (22%) in hearts from juvenile animals. This study demonstrated that despite having similar levels of hypertrophy, there can be differences in the remodeling of the extracellular matrix (increased fibrosis) as well as molecular remodeling (decrease in the creatine kinase system)  and a prolonged diastolic relaxation. These abnormalities are more pronounced at higher frequencies of stimulation and may be caused by an altered Ca2+ resequestration into the SR. SERCA activity has been reported to be positively correlated with diastolic force. Diastolic force has an inverse relationship with the SERCA activity in failing myocardium. These findings suggested that a reduction in SERCA activity could contribute to both an impairment in systolic as well as diastolic function in failing human hearts [Two of the most significant characteristics of failing human myocardium that have been reported are an increase in diastolic [Can hearts .2+]i availability and myofilament contractile activation is cross-bridge cycling dynamics  might be beneficial in the treatment of heart failure. Studies on isolated muscles from failing human hearts demonstrated a decrease in inotropic response to milrinone . In ordeholidays .2+]i and enhancing inotropy/myocardial contractility in heart failure patients. A simple increase in intracellular Ca2+ was being shown to be clinically detrimental , which may explain in part the failure of the gene therapy trial (CUPID) using SERCA2a in heart failure patients i and SR Ca2+ release were not the sole contributors to heart failure. A novel mutation in TnC was also reported that further strengthened this school of thought  resulted in a further rightward shift in non-failing human myocardium, but did not further shift the Ca2+-force relationship in fibers from failing hearts. Importantly, cyclic guanosine monophosphate (cGMP) resulted in a greater decrease in myofilament sensitivity in fibers from failing hearts. From these studies, it was suggested that not only changes at the level of the thick myofilaments, as previously reported by Leinwand and Bristow i, and there was a change in the Hill coefficient (myofilament cooperativity). These findings indicated that there was a decrease in myofilament Ca2+ sensitivity and a change in cooperativity among thin myofilament proteins most likely reflecting phosphorylation of thin filament regulatory proteins by PKC. Both TnT and TnI have at least two phosphorylation sites. In heart failure tissue, there are two TnT isoforms. These findings might reflect the effect on relative states of phosphorylation of two TnT isoforms. PKC activation, which decreased SR Ca2+ release while decreasing the Ca2+ responsiveness of the myofilaments with a change in cooperativity among thin myofilament proteins, might be a future approach to the treatment of heart failure and Ca2+ regulation in the failing heart. However, the impact of PKC stimulation on vascular smooth muscle remains unclear and must be considered before possible future clinical development  and SR Ca2+ release are key contributors to the pathophysiology of heart failure and possible targets for therapeutic intervention, there is a dynamic state that occurs in the failing heart, especially when blood circulation is impaired and when increases in heart rate can induce a hypoxic milieu [Despite indications that changes at the level of the thick and thin myofilaments and diastolic [Cac milieu ,190,191.c milieu ,193,194.c milieu ,195. Carc milieu ,199,200)O-linked N-acetylglucosamine modification [2+ current, and RyR Ca2+ leak, which facilitate the progression of the above-mentioned diseases [Calcium/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase that has emerged as a key regulator of cardiac physiology and pathology ,203,204.fication ,206. Excfication ,210,211.diseases ,212. Thediseases ,214. Bendiseases ,216,217.diseases . One readiseases . Future A main upstream regulator of CaMKII is the oxidation at M281/282 by reactive oxygen species (ROS) ,220,221.2+ cycling protein SERCA2a [Despite progress in the clinical management of heart failure, it continues to be associated with a high rate of mortality and morbidity worldwide ,227,228. SERCA2a ,234,235, SERCA2a ,239,240.


Twenty (42%) patients had a single right ventricle (SRV). In single left ventricle (SLV), GCS was higher (p < 0.001), but GLS was lower (p = 0.04) than in SRV. GCS correlated positively with EDV (p = 0.005), ESV (p < 0.001), and EF (p ≤ 0.0001). GLS correlated positively with EF (p = 0.002), but not with ventricular volumes. Impaired GCS correlated with decreased ventricular function (p = 0.03) and atrioventricular valve regurgitation (p = 0.04) at echocardiography, direct atriopulmonary connection (p = 0.02), post-operative complications (p = 0.05), and presence of a rudimentary ventricle (p = 0.01). A reduced GCS was associated with increased NT-pro-BNP (p = 0.05). Myocardial deformation can be measured by CMR-FT in Fontan patients. SLVs have higher GCS, but lower GLS than SRVs. GCS correlates with ventricular volumes and EF, whereas GLS correlates with EF only. Myocardial deformation shows a relationship with several clinical parameters and NT-pro-BNP.Cardiac MR (CMR) is a standard modality for assessing ventricular function of single ventricles. CMR feature-tracking (CMR-FT) is a novel application enabling strain measurement on cine MR images and is used in patients with congenital heart diseases. We sought to assess the feasibility of CMR-FT in Fontan patients and analyze the correlation between CMR-FT strain values and conventional CMR volumetric parameters, clinical findings, and biomarkers. Global circumferential (GCS) and longitudinal (GLS) strain were retrospectively measured by CMR-FT on Steady-State Free Precession cine images. Data regarding post-operative course at Fontan operation, and medication, exercise capacity, invasive hemodynamics, and blood biomarkers at a time interval ± 6 months from CMR were collected. Forty-seven patients underwent CMR 11 ± 6 years after the Fontan operation; age at CMR was 15 ± 7 years. End-diastolic volume (EDV) of the SV was 93 ± 37 ml/m Treatment of patients with a single ventricle (SV) consists of a staged procedure, the last step being the Fontan operation . Thanks In Fontan patients echocardiography presents some important limitations due to the abnormal geometry of the SV and to a frequently limited acoustic window , 5. CardThe aim of this study was to assess the feasibility of CMR-FT in Fontan patients and to evaluate potential correlation between strain values measured by CMR-FT and clinical data such as patient characteristics, post-operative complications, hemodynamic measures, and blood biomarkers.n = 3) and missing informed consent (n = 3). Electronic records of the patients were reviewed regarding medical history and clinical data at follow-up, i.e., in a time interval of ± 6 months from the CMR examination. These included post-surgical complications, medication, blood biomarkers, exercise capacity and hemodynamic parameters invasively acquired during cardiac catheterization, if available. Echocardiographic reports were reviewed for ventricular function and presence of atrioventricular valve regurgitation (AVVR). Global ventricular contraction was qualitatively described in three categories: normal = 1, moderately decreased = 2, clearly impaired = 3. The degree of AVVR was graded I  to IV (severe).All Fontan patients who underwent a CMR examination in our institution between January 2014 and October 2018 were retrospectively reviewed. Exclusion criteria were insufficient image quality  using a 32-channel phased array cardiac coil. For measuring ventricular function, steady-state free precession (SSFP) cine images were acquired in a horizontal and vertical long-axis plane, as well in a short-axis plane covering the entire single ventricle. The SSFP parameters were as follows: retrospective cardiac gating, 40 phases/cardiac cycle, TE 1.5–1.8 ms, TR 2.8–3.1 ms, flip angle 45°, bandwidth 125 kHz, matrix 224 × 224, number of excitations 1, field of view 250–350, views per segment 4–10 according to heart rate. In-plane resolution was 1–1.5 mm and, true temporal resolution was < 25 ms.Myocardial strain was measured by applying feature tracking on SSFP cine images during post-processing with a dedicated software . Circumferential strain (CS) was measured on short-axis images and longitudinal strain (LS) was measured on long-axis images. The endocardial borders of the SV were first segmented manually in the end-diastolic phase and subsequently expanded to all phases using an automatic border detection algorithm. The endocardial borders were checked for adequacy in all cardiac phases and manually corrected if necessary. The software provided endocardial peak systolic strain.Measurement of radial strain has previously not been recommended due to inaccuracy and variability of the measurements . Measuret tests; Levene’s test for equality of variance was used to analyze if the variance in the two groups was significantly different. Differences in categorical data were evaluated with contingency tables and χ2 tests. The correlation among continuous variables was tested using Pearson’s correlations. Intraobserver variability was tested by repeating CMR-FT analysis in all patients by the same observer at a time interval of 3 months. Inter-observer variability was assessed by repeating strain measurements in 10 patients by two observers blinded to each other. Repeatability of CMR-FT measurements was then expressed with intraclass correlation coefficient. Statistical significance was defined by values of p < 0.05. As values of NT-pro-BNP were markedly skewed, a logarithmic transformation was performed and used in all statistical tests involving this parameter.Continuous variables are expressed as mean ± SD, categorical variables in counts and percentages. Groups were compared using unpaired Statistical analysis was performed with the software SPSS 25.0.0 .The study protocol was approved by the local ethics authorities (KEK-ZH-Nr.2017-00566) and adheres to the declaration of Helsinki (version 2013).A total of 47 patients  fulfilled the inclusion criteria and were enrolled in the study. CMR was performed at a mean age of 15 ± 7 years, weight 50 ± 22 kg, and height 150 ± 22 cm. The time interval between the Fontan operation and CMR was 11.6 ± 6.2 years. Diagnoses consisted of Hypoplastic Left Heart Syndrome (HLHS) in 15 (32%), Double Inlet Left Ventricle in 13 (27%), Pulmonary Atresia in 10 (21%), Double Outlet Right Ventricle in 4 (8%), Tricuspid Atresia in 3 (6%), and Double Inlet Right Ventricle and Ebstein Anomaly in one patient each (2%). The first surgical palliation consisted of a shunt in 30 (65%) and pulmonary banding in 14 patients (30%). A Norwood procedure was performed in 14 patients (30%). Six patients (13%) with HLHS were first palliated with a hybrid approach, consisting of a bilateral pulmonary banding and ductus stenting). As next step 31 (66%) patients underwent a cavopulmonary connection, 7 (15%) received a hemi-Fontan procedure, 6 (13%) a comprehensive stage I–II. Type of surgery at stage II was unknown in 3 patients (6%).2) of 82 ± 5%. A total cavopulmonary connection was created in 44 (94%) patients, consisting of 41 (87%) extracardiac conduits and 3 (6%) lateral tunnels. A fenestration was made in 22 of the 44 cases (50%). The remaining 3 (6%) patients received a direct atriopulmonary connection. Hospitalization length was 23 ± 10 days. At least one complication occurred in 19 (40%) patients; including chylothorax in 6 (13%), diaphragmatic paralysis in 6 (13%), thromboembolic event in 1 (2%), arrhythmia  in 2 (4%), significant bleeding in 1 (2%), and prolonged effusions in 2 (4%).The Fontan operation was eventually performed at the age of 37 ± 17 months, a weight of 14 ± 3 kg, and a transcutaneous oxygen saturation (SpOp = 0.02) and presented a lower global contractility (p = 0.05). In 28 (60%) cases, a rudimentary second ventricle was visible. In 5 (11%) cases a Fontan fenestration was still present at time of CMR. Short-axis images could be acquired in all 47 patients, while long-axis images were available in 37 patients. Insufficient image quality was observed in 3/47 short-axis images and 4/37 the long-axis images. Thus, GCS measurements were performed in 44 patients, GLS in 33 patients.The results of ventricular volumes and function as well as global strain values measured by CMR-FT are shown in Table Mean total GCS was − 22.2 ± 3.4%. Total global longitudinal strain (GLS) was − 16.3 ± 4.3%. GLS was better  in SRV than in SLV, while GCS was better in SLV  for GCS and 0.95 (0.87–0.97) for GLS. Inter-observer reproducibility presented an intraclass correlation coefficient for GCS of 0.88 (0.80–0.97), for GLS of 0.97 (0.88–0.99).Clinical follow-up data were available at a time interval of ± 4 ± 4.8 months from CMR in 43 patients. Twenty-two patients (45%) were in functional class NYHA I, 16 (34%) in NYHA class II, 3 (6%) in NYHA class III, and one in NYHA class IV. Five patients (11%) presented with a diaphragmatic paralysis, 2 (4%) with a scoliosis, one (2%) with protein losing enteropathy, and one (2%) with plastic bronchitis. Cardiac medication was taken by 14 patients (30%) and included diuretics in 11 (13%), ACE inhibitors in 5 (11%), and beta-blockers in 2 (4%). Echocardiography showed a normal ventricular function (grade 1) in 26 (55%), a moderately impaired function (grade 2) in 14 (30%), and a severely impaired function (grade 3) in 4 (9%) cases. Sinus rhythm was present in 37 (79%), a junctional or atrial rhythm in 9 (19%) patients.Hemodynamic cardiac catheterization data were available in 10 patients . In the overall group mean pulmonary artery pressure was 15 ± 3 mmHg, pulmonary capillary wedge pressure 12 ± 2 mmHg, and end-diastolic ventricular pressure 11 ± 2 mmHg.2) was 25 ± 10 ml/kg/min. Heart rate was elevated at rest (100 ± 16 bpm) and increased well during exercise (170 ± 21 bpm). Mean SpO2 at rest was 92 ± 1.8% and declined at peak exercise by an average of 5%.Cardiopulmonary exercise test data were available in 14 patients (30%); mean peak oxygen consumption (peakVOBlood biomarkers were available in 26 patients (55%) . Mean total protein was 69 ± 10 g/l, albumin 45 ± 7 g/dl, creatinine 56 ± 18 μmol/l, NT-pro-BNP 231 (1160) ng/l, and alanine aminotransferase 33 ± 11 IU/l. All parameters were within normal ranges.Myocardial deformation correlated well with ventricular volumes and contractility independently from ventricular morphology Table . Positivp = 0.01), an atriopulmonary connection (p = 0.02), post-surgical complications (p = 0.05), previous chylothorax (p = 0.03), echocardiographically reduced ventricular function (p = 0.003), and significant AVVR (p = 0.04). In contrast, GLS did not correlate with any clinical parameters.GCS values were worse (= higher) in patients with a rudimentary ventricle  in comparison to the reference CMR-FT strain values for the LV in healthy pediatric subjects, reported as − 24 ± 2.4% for GCS and − 15.5 ± 1.9% for GLS . In contThe different myofiber architecture between the SLV and SRV is a valuable explanation for the differences observed in the myocardial deformation of the SVs with better  GLS in SRV patients and better GCS in SLV patients. The RV presents with a predominant layer of longitudinally oriented fibers that lead to a strong longitudinal contraction , 23, 24.The correlation between strain and ventricular volumes and ejection fraction is quite intuitive and indicates the strong intrinsic relationship between myocardial mechanics and ejection of blood , 11.Regarding ventricular volumes, we have observed that GCS decreases  when the SV enlarges; in contrast values of GLS are not changing with ventricular size. Ghelani et al. reported a similar observation in their Fontan cohort . VentricEven though other studies have reported the use and feasibility of CMR-FT in Fontan patients Table , we are Additional factors associated with decreased GCS were palliation with an atriopulmonary connection and post-operative chylothorax. It is well known that one of the possible causes for chylothorax in Fontan patients is an abnormally increased systemic venous pressure; suboptimal hemodynamics with elevated filling pressures after the Fontan operation may have a negative influence on myocardial deformation.The retrospective design of this study is its most important limitation. The study population may present with a selection bias, since not all Fontan patients at our institution received a routine CMR examination in the past. The small number of available clinical follow-up data impeded a robust statistical analysis for risk factors. Our results give some suggestions about the potential clinical implications of CMR-FT, but its real prognostic value needs to be assessed in larger and prospective follow-up studies. As normal values for CMR-FT measurements in SVs are not available, CMR-FT may be more useful for serial evaluation of each patient during follow-up, by using each patient as his own control. Ghelani et al. have reported composite imaging parameters, echocardiographic and CMR data, as strong predictor for outcome in Fontan patients . Our resCMR-FT enables reproducible measurements of global myocardial strain in Fontan patients. Strain values correlate with ventricular volume, EF, NT-Pro-BNP as biomarkers for cardiac failure, post-operative chylothorax, and reduced contractility and AVVR at echocardiography. SRVs have better GLS but worse GCS than SLVs.These preliminary data suggest a potential relationship between imaging parameters and clinical markers for prognosis and may help designing future prospective CMR follow-up studies. As CMR-FT analysis does not prolong the duration of examination, we advocate to add FT to every CMR performed in Fontan patients.


Purpose: To explore the utility of phosphorus magnetic resonance spectroscopy (31P MRS) in identifying anthracycline-induced cardiac toxicity in patients with breast cancer.Methods: Twenty patients with newly diagnosed breast cancer receiving anthracycline-based chemotherapy had cardiac magnetic resonance assessment of left ventricular ejection fraction (LVEF) and 31P MRS to determine myocardial Phosphocreatine/Adenosine Triphosphate Ratio (PCr/ATP) at three time points: pre-, mid-, and end-chemotherapy. Plasma high sensitivity cardiac troponin-I (cTn-I) tests and electrocardiograms were also performed at these same time points.Results: Phosphocreatine/Adenosine Triphosphate did not change significantly between pre- and mid-chemo  and pre- and end-chemo . Mean LVEF reduced significantly by 5.1% between pre- and end-chemo . Change in PCr/ATP ratios from pre- to end-chemo correlated inversely with changes in LVEF over the same period . Plasma cTn-I increased progressively during chemotherapy from pre- to mid-chemo  and from mid- to end-chemo .Conclusions: In this small cohort pilot study, we did not observe a clear change in mean PCr/ATP values during chemotherapy despite evidence of increased plasma cardiac biomarkers and reduced LVEF. Future similar studies should be adequately powered to take account of patient drop-out and variable changes in PCr/ATP and could include T1 and T2 mapping. Anthracyclines are widely used in the treatment of breast cancer and are well-recognized to carry increased risk of cardiotoxicity –3. This Left Ventricular Ejection Fraction (LVEF), assessed by a variety of imaging methods, is recognized as insensitive for the detection of early anthracycline-induced cardiomyopathy . The wid31P-MRS) acquired using a clinical 3T MR system to identify early anthracycline-induced cardiac toxicity and baseline predisposition to cardiac injury. This technique measures the phosphocreatine/adenosine triphosphate concentration ratio (PCr/ATP), which reflects cardiac cellular energetics. The normal range of PCr/ATP is approximately 1.8–2.2, whereas decreased PCr/ATP is associated with a drop in available energy reserve in the heart, associated with many forms of heart failure  have also been applied. To our knowledge PCr/ATP has not previously been used sequentially to assess cardiac injury in breast cancer patients before, during, and after chemotherapy.This study was approved by the South East Scotland Research Ethics Committee (14/SS/1041) and all participants gave full written informed consent.3), cyclophosphamide], or three cycles of FEC  followed by three cycles of Docetaxel (FEC-T). Four patients had a history of hypertension: two treated with ramipril and two with bendroflumethiazide  and was designed flexibly to allow for the oncology team to defer or postpone the next chemo-treatment for clinical reasons including chemotherapy-related side effects including nausea, fatigue, and general malaise.31P MRS as described for patients. Phosphocreatine/Adenosine Triphosphate Ratios and left ventricular ejection fraction were calculated for each volunteer. Scanning was repeated for three of these normal subjects to assess repeatability of measurements. The maximum difference between repeated PCr/ATP measurements and repeated LVEF measurements for volunteers defined the cut-off above which a real change could be assumed to occur in patients between pre- to mid-chemotherapy, mid- to end-chemotherapy, and pre- to end-chemotherapy. Volunteers did not undergo ECG or plasma troponin measurements and did not undergo sequential repeat MR scans.Thirteen healthy volunteers  with no background medical conditions and on no medications underwent a single MRI imaging protocol and a single STAT Troponin I assay; Abbott Laboratories). This assay has a limit of detection of 1.2 ng/L, with a coefficient of variation of 23% at the limit of detection (1.2 ng/L) and <10% at 6 ng/L .Participants attended the Edinburgh Imaging QMRI facility at three time points: pre-, mid-, and end-chemotherapy. Mid-chemotherapy was defined as between cycles 3 and 4 and end-chemotherapy was within 27 ± 19 days of completing cycle 6. On each occasion participants were positioned head first supine in a 3T Verio MR scanner  between anterior and posterior parts of an 8-element cardiac 31P MRS protocol used for this study has been described in detail elsewhere . A flip angle (α) of 30° was applied to the mid-septum of the myocardium. Voxels were carefully planned so that one full voxel was aligned with the mid-septum. 31P MRS acquisition was not ECG gated.The lsewhere . In brie31P spectra was carried out using a custom Matlab implementation of AMARES . Two independent operators subsequently calculated the LVEF from these images using QMass® software . This was carried out for images acquired at each time point.A series of Cardiac Magnetic Resonance (CMR) cine images were acquired from base to apex in the short axis plane using the system's integrated body coil  supervising Trastuzumab trials which defined cardiotoxicity as a decrease in LVEF of 5 points to <55% symptoms .A 12-lead ECG was acquired at each of the three time points immediately prior to each MRI scan. These were reported by a Cardiologist and any abnormalities grouped by ST segment change, left ventricular hypertrophy and changes in the QT interval.t-tests or one-way ANOVA as appropriate. Associations between various parameters were assessed using Pearson's Coefficient. Significance was accepted at p ≤ 0.05.All statistical analysis was carried out using Minitab 17 Statistical Software , State College, PA: Minitab, Inc.). Data were analyzed using paired Student's n = 13). In three healthy volunteers with repeat measurements of PCr/ATP the difference in values between scans were 0.58, 0.53, and 0.20. This was consistent with other published work suggesting that a change in PCr/ATP of 0.5, with 95% confidence, could be detected with a sample size of nine patients using a similar protocol as that used in patients with heart failure  and median body mass index 28 (range 23–36). Six patients (30%) received FEC80, fourteen (70%) received FEC-T chemotherapy, and eighteen (90%) received radiotherapy. Two patients treated with the FEC-T received Trastuzumab from the mid-chemo time point. Ten patients had left sided tumors and one had left and right sided tumors. Nine participants were post-menopausal.All participants attended their pre-chemotherapy MRI scan while five were unable to attend the mid-chemotherapy scan due to inter-current illness and one was unable to attend the final end-chemotherapy MRI scan.The mean LVEF for healthy volunteers was 63.6 ± 4.5% with range 57.6–74.3%. Differences in repeated measurements of LVEF for three volunteers were 0.5, 0.6, and −0.5%, indicating a very high degree of repeatability.Left ventricular ejection fraction was calculated for all 20 participants prior to chemotherapy, 15 at mid-chemotherapy, and 19 at end-chemotherapy.p = 0.02). There was no significant difference in LVEF between patients receiving FEC80 (n = 5) and those receiving FEC-T (n = 12) at mid  or end-chemo time-points . Left ventricular mass did not change significantly between pre-chemo and end-chemo .The mean (± standard deviation) LVEF at pre-, mid-, and end-chemotherapy was 61.6 ± 4.4, 60.5 ± 5.2, and 56.3 ± 8.1% respectively . There wIn total, six patients experienced a significant decrease in LVEF according to agreed criteria . Three s31P MR spectra were successfully acquired for 19 breast cancer patients pre-chemotherapy, 11 at mid-chemotherapy, and 17 end-chemotherapy. Missing scans were due to inter-current illness or technical issues for one participant at the pre-chemotherapy scan, four mid-chemotherapy, and two end-chemotherapy. An example patient 31P spectrum is shown in p = 0.11).r = −0.68, p = 0.04). The mean change in the PCr/ATP ratio at mid- and at end-chemotherapy relative to the mean baseline value is plotted in For the patient cohort there was no significant difference in mean sequential values for PCr/ATP ratio comparing pre-, mid-, and end-chemotherapy time-points. However, there was a significant negative correlation between the change in PCr/ATP from pre- to mid-chemotherapy and the subsequent change in PCr/ATP from mid- to end chemotherapy  none of these values exceeded the ACS threshold (16 ng/L). By end-chemo there was a further significant increase in mean plasma cTn-I  with six cTn-I values above the ACS threshold. These six patients, and a further three patients with borderline normal cTnI levels at end-chemo, were invited back 2–3 months after end of chemotherapy for longer term follow-up with repeat blood cTn-I. In all cases cTn-I had returned to normal level .Plasma cardiac cTn-I-I levels (ng/L) were low-normal (<5 ng/L) in all patients at baseline prior to starting chemotherapy and increased progressively by mid-chemo with a further rise at the time of the last chemo cycle . The thrpatients . In our p = 0.12) or at end-chemo in patients receiving FEC80 compared to those receiving FEC-T . As expected, the side of the cancer had no impact on cTn-I levels at any of the time points studied .The specific type of chemotherapy regime had no impact on cTn-I levels. At mid-chemotherapy cTn-I was not significantly higher in patients receiving FEC-T compared to FEC80  with most of this increase occurring between baseline and mid-chemo. Overall, no patient showed an increase of QTc of >60 ms or a QTc above 500 ms.There were no significant changes in PR interval or QRS duration during chemotherapy. There was a small but significant increase in the corrected QT interval (QTc) from 422 ± 15 to 438 ± 13 ms . There was no apparent association between cTn-I and LVEF or PCr/ATP any of the time points. There was also no association found between changes in the corrected QT interval in the electrocardiogram and changes in cTn-I or changes in the QT interval and changes in LVEF. There was no apparent effect of trastuzumab treatment on cTn-I levels.A significant negative correlation was found between the change in PCr/ATP ratio and the change in LVEF from pre-chemo to end-chemo  resulting from mitochondrial damage associated with elevated intracellular iron  where low PCr/ATP ratios were associated with reduced LVEF , 29 and patients  switched31P-MRS scans could be significantly improved by using higher magnetic field strengths (7T)  , 31.31P MRS in assessing cardiac energetics of breast cancer patients undergoing chemotherapy in a pilot cohort. Our findings have highlighted the challenges of serial cardiac imaging studies during complex chemotherapy regimens and outlined a pathway by which this technique could be further explored to establish its potential for detection of cardiac energetics during chemotherapy. Future studies should take account of a potentially high level of patient drop-out, background factors that could influence cardiac PCr/ATP ratio, such as age, physical fitness, and regular medications, and should seek to improve sensitivity using 7T MRI. Future studies could include assessment of Trastuzumab on 31P MR myocardial imaging and changes in T1 and T2 mapping.This study investigated The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Lothian Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.GM, SS, OO, and MD conceived and designed the study and wrote the ethics application. OO, HM, and LH recruited patients, collated clinical data, and collected bloods for troponin. GM, SS, CR, AC, WC, and SM performed and reported the scans. MD, OO, GM, and SS wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


RLS was impaired in all 6 wall-regions in LAD infarctions in both the sub-acute and chronic phase, while LCx and RCA infarctions had preserved RLS in remote myocardium at both time points. Global longitudinal strain is impaired sub-acutely after STEMI and improvement is seen in the chronic phase, although not reaching normal levels. Global longitudinal strain is only moderately determined by infarct size. Regional longitudinal strain is most impaired in the infarcted region, and LAD infarctions have effects on the whole heart. This could explain why LAD infarcts are more serious than the other culprit vessel infarctions and more often cause heart failure.To assess (1) global longitudinal strain (GLS) by feature tracking cardiac magnetic resonance (CMR) in the sub-acute and chronic phases after ST-elevation infarction (STEMI) and compare to GLS in healthy controls, and (2) the evolution of GLS and regional longitudinal strain (RLS) over time, and their relationship to infarct location and size. Seventy-seven patients from the CHILL-MI-trial (NCT01379261) who underwent CMR 2–6 days and 6 months after STEMI and 27 healthy controls were included for comparison. Steady state free precession (SSFP) long-axis cine images were obtained for GLS and RLS, and late gadolinium enhancement (LGE) images were obtained for infarct size quantifications. GLS was impaired in the sub-acute (− 11.8 ± 3.0%) and chronic phases (− 14.3 ± 2.9%) compared to normal GLS in controls . GLS improved from sub-acute to chronic phase (p < 0.001). GLS was to some extent determined by infarct size (sub-acute: r Survival rates after ST-elevation myocardial infarction (STEMI) have improved substantially over the last decades, however both morbidity and mortality remain high –3. Left Echocardiography is the first-line modality to assess cardiac function and strain , and GLSGLS has been studied in the acute phase and at follow up in patients with STEMI using echocardiography , 22 and We have previously shown that atrioventricular plane displacement is decreased in both the sub-acute and chronic phases after STEMI, resulting in a decreased longitudinal contribution to stroke volume in both phases –26. WhilTherefore, the aims of this study were: (1) to assess GLS with FT-CMR 2–6 days (sub-acute phase) and 6 months (chronic phase) after STEMI compared with healthy controls, and (2) to investigate the evolution of GLS and regional longitudinal strain (RLS) over time, and their relationship to infarct location and size assessed by CMR.Patients from the multi-centre cardio-protection trial CHILL-MI  constituted the study population for this study . In shorPatients underwent CMR at one of multiple European centres using two different vendors: Philips Healthcare  or Siemens AG . Steady state free precession (SSFP) cine images in short-axis view (base to apex) and in 2-, 3- and 4-chamber long-axis views were acquired. Typical image parameters: 20–30 time frames per cardiac cycle, retrospectively ECG gated, 8 mm slice thickness (no gap) with in-plane resolution 1.5 × 1.5 mm covering the entire left ventricle.Late gadolinium enhancement (LGE) images were acquired 15–20 min after gadolinium-based contrast agent (0.2 mmol/kg) injection in the corresponding short- and long-axis view as for the SSFP cine imaging. All images were obtained at end-expiratory breath-hold with patients in supine position. Typical image parameters: prospective ECG gating with 8 mm slice thickness (no gap) with in-plane resolution was 1.5 × 1.5 mm. Inversion time was chosen to null remote myocardium .All CMR image analysis was performed using a freely available software for baseline data and infarct size  [Short-axis LGE images were used to quantify infarct size with a previously validated semi-automatic method using an automatic threshold computation followed by post processing to remove spurious infarct regions and a weighted summation to account for partial volume effects , where tPeak longitudinal strain was analysed both for GLS and RLS in the three long-axis  cine SSFP images using feature tracking Fig. . DelineaAll images were surveyed by one experienced reader (HS) and adjusted by a second expert reader (EO) as adjudicator when needed. If tracking was still inadequate, segments of this view was excluded, and the two remaining views were used for calculations.Longitudinal strain values were extracted both as an average of the whole LV (GLS) and in 17 LV segments based on American Heart Association’s segmentation model . RLS wasanterior, anterolateral, inferolateral, inferior, inferoseptal and anteroseptal wall. Apical segments and the apex (segment 17) were excluded for RLS comparisons as LAD infarctions often has a “wrap around” infarction with larger involvement of apical segments compared to LCx and RCA infarctions.When assessing RLS, the segments were grouped into six anatomical wall regions: Continuous data was expressed as mean ± SD. Categorical data was expressed in absolute numbers and proportion in percentage. Student’s t-test and Fisher’s Exact test were used for comparison between all patients and controls. Comparisons between the sub-acute and chronic phase for all patients were made with paired Student’s t-test. Coefficient of determination was calculated from Pearson’s correlation. Subgroup analyses by culprit vessel was—owing to non-normal distribution assessed by histograms—performed with Mann–Whitney U-test for comparison to controls, Wilcoxon Signed Ranks Test for comparison between the sub-acute and chronic phase and Kruskal–Wallis for multiple comparisons with Bonferroni’s correction for multiple tests. Results with a two-sided p-value < 0.05 were considered statistically significant.Statistical analyses were performed using SPSS  and GraphPad Prism . Radar charts were made in Microsoft Excel 2015.en par with the healthy controls.Seventy-seven patients 58.2 ± 10.2 years) and 27 age matched controls (60.7 ± 10.7 years) were included. At admission, none had prior myocardial infarction, percutaneous coronary intervention, coronary artery by-pass graft, or congested heart failure. One (1%) had prior stroke, 8 (10%) had known diabetes mellitus, 10 (13%) had medication for hyperlipidaemia, and 20 (26%) had antihypertensive medication. Twenty-seven (35%) had other significant lesions than the culprit lesion. Data on medical therapy at follow-up was not available in this study. Patients were divided into groups according to culprit vessel . Figure 0.2 yearsFour of 2172 segments were excluded owing to inadequate tracking. Table GLS was reduced both in the sub-acute and chronic phases compared to controls (p < 0.001 for both). GLS and EF improved from the sub-acute to the chronic phase (p < 0.001) Fig. .2 = 0.2, p < 0.001 for both) after STEMI and between endocardial extent and transmurality of infarction and EF in both phases . There was, however, no significant coefficient of determination between endocardial extent or transmurality of infarction and GLS in the sub-acute phase .IS and GLS had a modest, but significant coefficient of determination in both the sub-acute and chronic phases after STEMI as well as between IS and EF Fig. . LikewisThere was no difference in GLS in the sub-acute phase between patients with or without diabetes (p = 0.4), with or without antihypertensive medication (p = 0.08), or with or without lipid lowering medication (p = 0.2) at admission. Patients with other significant lesions than culprit lesion had lower GLS than those with only one lesion in the sub-acute phase , while there was no difference in GLS the chronic phase between the groups .In patients with LAD infarction, RLS was impaired in all six wall regions both in the sub-acute and chronic phases after STEMI compared to controls, with a significant improvement in the chronic phase in all regions Table , Fig. 5.In the sub-acute phase, patients with LAD infarction had lower RLS in the anterior, anteroseptal and inferoseptal walls than patients with RCA or LCx infarction , while there was no difference between RCA and LCx infarctions in these areas . In the inferior wall region, patients with LAD infarctions had worse RLS than patients with LCx infarctions (p = 0.02) and no difference was seen between patients with LAD and RCA infarctions (p = 0.1) or between RCA and LCx infarctions (p = 0.5). In the anterolateral and inferolateral wall, RLS did not differ between site of infarction .In the chronic phase, patients with LAD infarctions still had lower RLS than both patients with LCx and RCA infarctions in the anterior  and anteroseptal walls . In the inferoseptal wall, RLS was worse after infarction in the LAD than in the LCx (p = 0.007) but no significant difference remained compared to RCA infarctions (p = 0.08). No difference was seen in RLS between culprit vessels in the anterolateral (p = 0.7), inferolateral (p = 1.0) or inferior walls (p = 0.6).The main result of this study was that left ventricular GLS was impaired to a greater degree after a STEMI in the LAD territory compared to LCx and RCA territory. This may in part be explained by the larger IS for the LAD-infarction. In LAD-infarction, RLS is similarly impaired in infarcted and remote myocardium, even in the chronic phase. In contrast, LCx and RCA infarction show larger impairment of RLS in the infarcted territory compared to remote. GLS is, as expected, impaired in the sub-acute phase after STEMI compared to healthy controls, and ameliorates in the first six months, but not to the level of the controls. Further, GLS was moderately associated to IS in both the sub-acute and chronic phase, while GLS was only associated with endocardial extent of infarction in the chronic phase, and not in the sub-acute phase.GLS from FT-CMR within the first week after admission has been shown to be a strong and independent predictor of major adverse cardiac events in patients with STEMI . Our fin. used a standard deviation method for infarct assessment. Simple thresholds have shown varying results and we used a weighted intensity algorithm validated in patients and experimentally with low bias of infarct quantification [The evenly distributed decrease in RLS in patients with LAD infarctions could have many potential reasons and underlying mechanisms. First, it could be due to a larger IS seen in the patients with LAD compared to patients with LCx and RCA infarctions. On the other hand, we found only a modest association of GLS and IS, why IS alone cannot explain the decreased GLS and RLS. Secondly, longitudinal strain is preload-dependent and as post-infarction remodeling is altering the preload , IS coulfication .The results from RLS are in concordance to our findings of altered regional atrioventricular plane displacement . The resThere were some limitations to our study. First, feature tracking CMR strain is still under development and normal values are not generally applicable for all tracking algorithms. Strain values can differ among the different vendors , and theGlobal longitudinal strain is impaired sub-acutely after STEMI and improvement is seen in the chronic phase, although not reaching normal levels. Global longitudinal strain is only moderately depending on infarct size, indicating that other factors are important for ventricular function after STEMI. Even though regional longitudinal strain is most impaired in the infarcted region, remote regions can be significantly impaired in LAD infarctions, making the identification of culprit vessel from analysis of regional longitudinal strain difficult. Moreover, as LAD infarctions affect the whole heart, this could explain why LAD infarcts are more detrimental than the other culprit vessel infarctions and more often cause heart failure.


Introduction: This cardiovascular magnetic resonance (CMR) study aims to determine whether changes in systemic vascular resistance (SVR), obtained from CMR flow sequences, might explain the significant long-term changes in left ventricular (LV) ejection fraction (EF) observed in subjects with no cardiac disease history.Methods: Cohort subjects without any known cardiac disease but with high rates of hypertension and obesity, underwent CMR with phase-contrast sequences both at baseline and at a median follow-up of 5.2 years. Longitudinal changes in EF were analyzed for any concomitant changes in blood pressure and vascular function, notably the indexed SVR given by the formula: mean brachial blood pressure / cardiac output x body surface area.Results: A total of 118 subjects  were included, 26% had hypertension, and 52% were obese. Eighteen (15%) had significant EF variations between baseline and follow-up (7 increased EF and 11 decreased EF). Longitudinal changes in EF were inversely related to concomitant changes in mean and diastolic blood pressures  and much more significantly to SVR (p < 0.001). On average, these SVR changes were −8.08 ± 9.21 and +8.14 ± 8.28 mmHg.min.m2.L−1, respectively, in subjects with significant increases and decreases in EF, and 3.32 ± 7.53 mmHg.min.m2.L−1 in subjects with a stable EF .Conclusions: Significant EF variations are not uncommon during the long-term CMR follow-up of populations with no evident health issues except for uncomplicated hypertension and obesity. However, most of these variations are linked to SVR changes and may therefore be unrelated to any intrinsic change in LV contractility. This underscores the benefits of specifically assessing LV afterload when EF is monitored in populations at risk of vascular dysfunction.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT01716819 and NCT02430805. The left ventricular (LV) ejection fraction (EF) remains extensively used to quantify LV systolic performance , with caNowadays LV afterload is assessed more specifically and non-invasively by combining the information from brachial BP to the stroke volume values provided by CMR flow-velocity sequences –14. ThisA previously published CMR study showed that EF and SVR measurements were interdependent in the months following an acute myocardial infarction (MI), with the increase in EF associated with a concomitant decrease in SVR under a post-MI vasodilating medical regimen . It is hThe current CMR-based study aims to determine whether longitudinal changes in LV afterload and particularly in SVR, might explain the significant EF changes observed over time in subjects with no evident health issues except for uncomplicated hypertension and obesity.Subjects evaluated in the current study did not have any medical history of cardiac disease. Cardiovascular monitoring was performed using the same CMR protocol with subjects pooled from two different cohorts:ClinicalTrials.gov NCT01716819).(1) The “Role of the Renin-Angiotensin Aldosterone System in the Mechanisms of Transition to Heart Failure in Abdominal Obesity (R2C2-II)” cohort has already been described elsewhere , 14, 15.ClinicalTrials.gov NCT02430805).(2) The “Predisposition and Transition Mechanisms from Arterial Hypertension to Heart Failure (Hypercare)” family-based study included 58 subjects younger than 60 years of age, with uncomplicated hypertension or a history of familial hypertension. This longitudinal study, which included CMR investigations at baseline and at 4 years, has already been described elsewhere   –15. An aA steady-state free precession pulse sequence and dedicated software  were used to measure LV end-diastolic volume, end-diastolic mass, and EF in contiguous short-axis. The concentric remodeling (CR) index was defined as LV mass/end-diastolic volume ratio –15.Cardiac output was determined using a velocity-encoded phase-contrast gradient-echo sequence on a slice positioned perpendicularly to the ascending aorta –15. StroValues of cardiac output and stroke volume were used to estimate systemic vascular resistance (SVR: mean pressure/cardiac output) –19, effeAs already detailed elsewhere, abnormally high values of SVR, LV mass and concentric remodeling index were defined as the upper limits of the 95% confidence intervals observed in a healthy non-obese middle-aged population investigated using the same CMR methodology . A signip-values <0.05 to enter variables and >0.10 to remove variables . Continuous variables are expressed as mean and standard deviations (SD) and categorical variables as numbers and percentages . Paired ariables .−2.The study population consisted of a total of 118 subjects. As detailed in n = 31, 26%). CMR did not detect any significant cardiac abnormalities, except that 5 subjects had an EF below the 50% level (EF ranging from 43 to 47%), 3 and 17 subjects, respectively, had a higher-than-normal LV mass and CR index.Based on the inclusion criteria, none of these 118 subjects had any history of cardiovascular disease except for uncomplicated hypertension , provided evidence of significant increases in body weight, body mass index, diastolic BP and SVR, compared to baseline .p = 0.01). All were male with no specific differences in baseline characteristics compared to other male study subjects.Only 4 subjects (3%) had <50% EF at follow-up, but 18 (15%) had significant EF variations between baseline and follow-up (7 increased EF and 11 decreased EF). The 4 patients with <50% EF at follow-up exhibited a significant EF deterioration during follow-up (−7.8 ± 6.0%), compared to the other patients  and diastolic BP (p = 0.027).As detailed in p < 0.001; This predictive value of BP-changes was however much lower than that provided by the baseline-to-follow-up changes in effective arterial elastance (Ea) and in SVR . The remaining subjects with stable EFs had no significant baseline-to-follow-up changes in SVR (SVR difference in this group: 3.32 ± 7.53 mmHg.min.m2.L−1) (As illustrated in .m2.L−1) .p = 0.013).Finally, the percentage value of significant EF variations over time (>8%), initially observed in the overall study population (15.3%), was significantly lower after EF-changes had been adjusted for SVR-changes and baseline EF using equations shown in In a population with no history of cardiac disease but including hypertensive and obese subjects, the present CMR study shows that significant long-term EF variations are not uncommon, affecting some 15% of the study population. These variations correlate to SVR changes and may thus be unrelated to any intrinsic changes in LV contractility.SVR is the main component of the LV afterload and reflects the opposing resistance of the microcirculation that must be overcome by the LV to eject blood. In the current study population, mean SVR increased over time , consistThe interdependence of the EF on cardiac loading conditions is well-established. Despite this limitation, EF remains extensively used to quantify LV systolic performance . The curWe also measured more specific functional arterial parameters from conventional CMR flow sequences. These allowed to determine aortic stroke volume, independently of other CMR sequences used to assess LV function, and more accurately than Doppler-based techniques . CombiniA significant decrease in SVR has already been shown to be the predominant mechanism by which the EF increases during exercise in heart disease patients , and durIt may additionally be pointed out that the EF variations were unrelated to the concomitant changes in LV end-diastolic volume , an indiIt is also worth mentioning that in addition to the SVR changes, the baseline EF level was an independent predictor of EF variations over time. The impact of baseline EF could at least partly be attributed to a regression to the mean - i.e., a statistic phenomenon that implies that a sample point of a random variable, which is distant from the mean value on a first measurement, has a high probability of being closer to the mean value on a second measurement. This point is further detailed and illustrated in The current study defined a significant EF variation using an absolute threshold of 8% which corresponds to the results of a reproducibility analysis previously reported by our team using the same CMR methodology . The thrThe current longitudinal CMR study of a cohort including hypertensive and obese subjects shows that significant long-term variations in EF are not uncommon, but that most of these variations are potentially driven by changes in SVR rather than changes in LV contractility. Although a causative relationship is only suggested and remains to be proven, this observation underscores the benefits of specifically assessing LV afterload when EF is monitored in populations at risk of vascular dysfunction.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comité de Protection des Personnes se prêtant à la recherche biomédicale (CPP) - Est. The patients/participants provided their written informed consent to participate in this study.DM, NG, ZL, and P-YM: analysis and interpretation of the data. DM, NG, MB, FZ, PR, and P-YM: writing or revision of the manuscript. OH, LF, EM, M-PN, and NP: study implementation and management of the included subjects. All authors contributed to the article and approved the submitted version.This study was funded by a National Health Ministry  and the 6th framework program of the European Commission .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Elite athletes have been the subject of great interest, but athletes at an intermediate level of physical activity have received less attention in respect to the presence of cardiac enlargement and/or hypertrophy. We hypothesized that playing football, often defined as demanding less endurance components than running or cycling, would still induce remodelling similar to sports with a dominating endurance component.p < 0.001.23 male football players, age 25+/− 3.9 yrs. underwent exercise testing, 2D- and 3D- echocardiography and cardiac magnetic resonance (CMR). The results were compared with a control group of engineering students of similar age. The athletes exercised 12 h/week and the control subjects 1 h/week, p < 0.001) as well as higher calculated maximal oxygen consumption,  compared to the sedentary group. All left ventricular (LV) volumes assessed by 3DEcho and CMR, as well as CMR left atrial (LA) volume were significantly higher in the athletes . LVEF and RVEF, LV strain by CMR or by echo did not differentiate athletes from sedentary participants. Right ventricular (RV) longitudinal strain, LA and right atrial (RA) strain by CMR all showed similar results in the two groups.The football players achieved a significantly higher maximal load at the exercise test (380 W vs 300 W, Moderately trained intermediate level football players showed anatomical but not functional cardiac remodelling compared to sedentary males.The online version contains supplementary material available at 10.1186/s12947-021-00263-0. Various sports are categorized in terms of the size of the endurance component of exercise [Athlete’s heart, defined as a physiological cardiac adaptation to exercise , has beeexercise . Playingexercise , 9. Most+ 3.9 yrs., (range 18–31) were recruited from their preparticipation health screening at the beginning of the football season and were offered a comprehensive cardiac evaluation. The control group consisted of 16 male engineering students of matching age, 23 + 3.2 yrs. (range 19–31), recruited from the local University. Inclusion criterion for both groups was absence of a history of cardiac or other chronic diseases, and in addition for the control group, absence of exercise on a regular basis (cut-off less than 2 h/week). Both groups completed a questionnaire regarding background factors and smoking habits. For additional basic demographics, see Table 23 male football players, age 25 ., range 8–31 wereEach participant underwent two-dimensional echocardiography (2DEcho), three-dimensional echocardiography (3DEcho), exercise testing (CPET), and CMR, all within the same day. Immediately after the 2DEcho exam, volumetric analysis by 3DEcho was performed. 3D volumes were acquired without echo contrast agent. Echocardiography always preceded the exercise test while CMR, if occurring after exercise, always was preceded by at least 20 min of rest.2 max using the values measured during the last 60s of exercise and expressed the results in terms of mL * min− 1 and mL * kg− 1 * min − 1. We considered the participants to have achieved maximal exercise capacity if the respiratory exchange ratio was > 1 continuously for 3 min or longer, which was attained by all athletes. The control group performed a similar exercise protocol. Since for their part, VO2 max could not be measured, it was calculated from the attained exercise level and the peak heartrate [calculated VO2 max in order to use the same method for athletes and controls. The only presentation of the measured VO2 max is in Additional file The athletes performed a maximum CPET in a seated position on a cycle ergometer CASE Stress Test System 6.61  . Cyclingeartrate , Table 1Standard transthoracic echocardiography was performed according to then current guidelines using a Vivid 7 scanner  with a 3.5 MHz M5S ultrasound probe for 2DEcho and a 3 V-D transducer for the acquisition of 3D images . Two-dimLV global longitudinal strain (LVGLS) was analysed from three apical views  using speckle tracking. LA strain was calculated on a global level, based on the relative reduction of the LA circumference in the 4Ch view .Right ventricular (RV) end-diastolic dimension (RVEDd) was measured in the focused four-chamber view at the base of the RV and fractional area change (RVFAC) was calculated after delineation of the cavity in end-diastole and end-systole. Systolic displacement of the RV tricuspid annulus (TAPSE) was measured using M-mode positioned in the lateral annulus. Right atrial area was measured in the modified apical 4-Ch view and RA strain was calculated based on the relative reduction of the RA circumference.A pulsed-wave Doppler with a sample volume of 5 mm was recorded at the tip of the mitral leaflets in the apical 4Ch-view and the early (E) and late (A) diastolic blood flow velocities were registered and measured. Tissue Doppler early diastolic velocity was recorded at the base of the LV septum and lateral wall in the apical 4Ch-view, and a mean of the two velocities was calculated (e´). The E/e´-ratio was calculated as part of the evaluation of LV diastolic function . Body su4D-volumes of the left ventricle and the left atrium (LA) were obtained from an apical probe position. Four consecutive electrocardiographically gated beats were acquired during apnea. We analyzed the data with 4D-Auto-LVQ included in the Echopac software which also provides measurements of sphericity . AdditioCMR was performed on a 1.5 T scanner  equipped with a 6-element phased array body matrix coil combined with 6-elements in the spine coil. Retrospectively ECG-gated images were acquired in supine position during repeated breath-holds. For cine imaging, a turbo- FLASH (fast low angle shot) sequence was used and after scout images, long-axis slices in the 4Ch-, 2Ch- and apical long-axis views were acquired as well as multiple parallel short-axis views, covering both ventricles from base to apex. No gadolinium contrast was given.Analysis was performed on a workstation equipped with Segment v2.0 R5201 semiautomatic software for cardiac volumetric analysis . Volumesp < 0.05 was considered significant. Multiple logistic regression with backward deletion was performed for the interaction between LVEDV, RVEDV and LAESV by CMR. ICC was calculated with Medcalc® , all other statistics used Statistica v. 13 .Continuous variables are presented as median and interquartile range, categorical data as frequencies. Due to the skewed distribution in some of the data points, the non-parametric Mann-Whitney U-test was used for all statistical comparisons of continuous variables between the groups. Differences between proportions were calculated with the Chi-2-test. A probability level of < 0.01 was assumed statistically significant for descriptive data with many comparisons, but for testing the main hypothesis, Interobserver variability was determined for 3D-LVEDV by echo and for LVEDV as well as for RV-strain by CMR using the intraclass correlation coefficient and according to Dahlberg .p = 0.329, p = 0.128 and p = 0.061 respectively). This also applies to body mass index  and body surface area . In agreement with the inclusion criteria, the control subjects exercised only 1 h per week vs the athletes 12 h/week, p < 0.001. The controls had a higher heart rate at rest before the exercise test , and during echocardiography (see Tables p = 0.612).Descriptive data of the study population are reported in Table The football players had a higher frequency of family risk factors for cardiovascular disease such as diabetes and hypertension, but no one of the participants had any known history of hypertension, diabetes, valve disease or other cardiovascular disease. Two of the football players and four of the control subjects reported using bronchodilators to combat asthma. No one in this study was an active smoker, but three of the football players were using chewing tobacco/snuff.p = 0.20) or QRS axis , but six of the football players compared to two in the control group fulfilled the Sokolov-Lyon criteria for left ventricular hypertrophy.All subjects were in sinus rhythm. There was no significant difference between the two groups regarding QRS duration  as well as higher calculated VO2 max  compared to the sedentary group, but peak heart rate did not differ between groups . In the football players, calculated VO2 max was lower than measured, mean difference − 0.3 + 0.3 l/min, p < 0.001, regression equation: calculated VO2 max * kg− 1 *min− 1 = 0.95x − 1.254, r = 0.79, R2 = 0.63  were significantly higher in the athletes. The shape of the LV expressed as the 3DEcho sphericity index, differed significantly between the two groups, being higher in the athletes, 0.45 vs. 0.33, p < 0.001, indicating a more spherical end-diastolic shape. However, CMR could not confirm this finding. LVM and relative wall thickness (RWTd by 2DEcho) were higher in the athletes  while the LVM-to-volume ratio was borderline higher, 0.50 g/mL vs. 0.47 g/mL, p = 0.032. Three of the football players had an end-diastolic septal thickness on echo of 12 mm, but no one in the sedentary group. No study person had a calculated LVM, as assessed by CMR, higher than the recommended upper level of normal, 184 g or 91 g * m− 2 [− 2 on 2DEcho which is the upper limit of reference for LVM by linear measurements [All LV volumes  assessed by 3DEcho and CMR . There was no difference in the left-to-right end-diastolic ventricular volume ratio between the groups . In univariate analysis adjusted for age and height, all three o f LVEDV, RVEDV and LAESV by CMR correlated significantly with calculated VO2 max. In multivariate analysis, only LVEDV remained significant indicating a high interdependence between these volumes.RV end-diastolic and end-systolic volumes and stroke volume were larger in the athletes, Table p = 0.569, p = 0.529 and p = 0.009). Mean values for 2DEcho, 3DEcho and CMR LVEF, CMR RVEF and 2DEcho FAC were not significantly different for the athletes compared to the controls. Furthermore, LV strain by CMR in the longitudinal or circumferential directions, longitudinal LV strain by 2DEcho or RV longitudinal strain did not differentiate athletes from sedentary participants, Table Strain parameters, EF and AVPD for the LV and the RV are reported in Tables p = 0.009  and with CMR-LVGCS, R = 0.12, p = 0.48.Calculated maximal oxygen uptake in the combined group correlated linearly with 3DEcho-LVEDV and CMR-LVEDV, R = 0.78 and R = 0.72, Fig. LVEDV by 3DEcho calculated by two observers showed for all participants a mean value of 176 mL and a coefficient of variation (COV) 8.15% according to Dahlberg . LVEDV bIn this moderately trained group of football players, we found anatomical remodelling of the left and right ventricle as well as of the left and right atrium. Ventricular function parameters, such as EF, AV-plane displacement, longitudinal strain (echo) or circumferential strain (CMR) did not differ significantly between the football players and controls.2 max [The volume load of endurance exercise is a stimulus to the excentric hypertrophy seen in sports with a high dynamic component , 27. Pre2 max . Earlier2 max  which we2 max in football players, a relationship between the competitive level of the athletes and VO2 max was found [2 max was 49 mL/kg/min. In a large Scandinavian study, Norwegian male football players from the elite and first division league, underwent echocardiography, focusing on dimensions [2 max in football players was 56 mL/kg/min, LV dimensions and mass were elevated compared to controls, E-velocity or E/A ratio did not differ, neither did the myocardial performance index.As the training literature so far has focused mainly on elite athletes, we found it of interest to elucidate the type and extent of cardiac adaptation seen in moderately trained football players which constitute a rather large athletic population in many countries. In a meta-analysis of studies measuring VOas found . Elite fas found . The foomensions . Systolimensions . AverageIn the present study we used both echocardiography and CMR to characterize remodelling, with principally similar differences between athletes and controls, although the dimensions and volumes were not numerically equal. Echocardiography has in previous studies consistently shown lower ventricular volumes than CMR and cardiac CT, which has been regarded to be due to a tendency to favour inclusion of trabeculae in the thickness of the LV wall , 35. SinSystolic functional measurements, i.e. ejection fraction, GLS (2DEcho) and GCS (CMR) did not differ between the athletes and their controls in the present study. Measurement of tissue velocity using pulsed Tissue Doppler as well as deformation analysis (strain) based on speckle tracking have been shown to be more sensitive for subtle changes in LV and RV systolic function than ejection fraction, also in athletes , 37. How2 max 49 mL/kg/min which was significantly higher than in an untrained control group. The football players had significantly larger heart chamber dimensions and higher LV mass than controls. Systolic ventricular function parameters did not differ significantly between athletes and controls. Whether the type of athletic activity or the training dose is the main explanation to this remains to be proven. It has been suggested that an improved diastolic LV function is related to changes in systolic function parameters in endurance athletes. This is, however, also difficult to evaluate since many diastolic function measures are heart rate dependent which is seldom sufficiently taken into account.To summarize, football players on a moderate competitional level, training on average 12 h/week  had an average VOOur data provide information about the degree of cardiac enlargement that may occur in moderately trained football players, which may be valuable when evaluating athletes with suspected heart disease or screened by echocardiography or CMR. It is important to measure the aerobic capacity of the athletes for an optimal definition of normality.2 max was measured in the athletes to characterize their aerobic capacity, but for comparisons between athletes and control subjects, the calculated VO2 max was used in both groups.VOEven moderate physical training such as practiced in an intermediate level football team, induces cardiac anatomical but not functional remodelling. Oxygen uptake should be taken into consideration when assessing cardiac size even in moderately trained individuals. This study adds valuable insight into training effects in athletes at an intermediate training level, as defined from oxygen uptake measurements.Additional file 1. Computation of regression equation between measured VO2max and calculated VO2max, developed in the group of athletes.Additional file 2. Segmentation and calculation of volumes and ejection fraction based on 3D echocardiography volume in an athlete. Note the large LVEDV and the higher sphericity value compared to the control in Additional file Additional file 3. Segmentation and calculation of volumes and ejection fraction based on 3D echocardiography volume in a control participant. Note lower LVEDV than for the athlete in Additional file Additional file 4. Supervised automatic segmentation of left ventricular MR slices for volumes, ejection fraction and left ventricular mass, using Segment. Cineloop shows tracking of the endo- and epicardium over the cardiac cycle.Additional file 5. Automatic segmentation and calculation of circumferential LV strain using feature tracking in the 2D-Cardiac Performance Analysis software. Cine-loop shows tracking of the endo- and epicardium over the cardiac cycle.Additional file 6. Tracking and calculation of RV global longitudinal and wall strain using feature tracking in Segment. Note the much higher GLS value in the RV free wall compared to the septum.