Herceptin (trastuzumab) is a recombinant, humanized, monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) and is used in the treatment of HER2-positive breast and gastric cancers. However, it carries a risk of cardiotoxicity, manifesting as left ventricular (LV) systolic dysfunction, conventionally assessed for by transthoracic echocardiography. Clinical surveillance of cardiac function and discontinuation of trastuzumab at an early stage of LV systolic dysfunction allow for the timely initiation of heart failure drug therapies that can result in the rapid recovery of cardiac function in most patients. Often considered the reference standard for the noninvasive assessment of cardiac volume and function, cardiac magnetic resonance (CMR) imaging has superior reproducibility and accuracy compared to other noninvasive imaging modalities. However, due to limited availability, it is not routinely used in the serial assessment of cardiac function in patients receiving trastuzumab. In this article, we review the diagnostic and prognostic role of CMR in trastuzumab-mediated cardiotoxicity. Herceptin (trastuzumab) is a recombinant, humanized, monoclonal antibody directed against the extracellular domain IV of the human epidermal growth factor receptor 2 (HER2) and is indicated for the treatment of HER2-positive breast and gastric cancers –3. HER2 Although the chemotherapeutic mechanisms of trastuzumab are well characterised, the molecular aspects of trastuzumab-induced cardiotoxicity, recognised since its phase III trial , remain Consequently, a distinct multidisciplinary clinical subspecialty, cardio-oncology, has emerged with the aim of preventing, monitoring, and treating cancer therapeutics-related cardiac dysfunction (CTRCD) . In currThe assessment of cardiac function before, during, and after therapy is essential for all cancer patients undergoing potentially cardiotoxic therapy . Whilst Multigated acquisition (MUGA) scanning was once a commonly used method for serial evaluation of cardiotoxicity. Despite low inter- and intra-observer variability, such methodology may be rendered obsolete in modern times due to low sensitivity to subtle changes and radiation exposure  Table 1Table 1.P=0.001) and overall survival  [The superior accuracy and lower variability of CMR lend it clinical significance not only for the timely diagnosis of CTRCD, via detection of true positives cases, but also for its ability to avoid false negatives, thereby preventing unnecessary treatment interruptions. This is evident from a retrospective cohort study of 369 patients receiving trastuzumab therapy for breast cancer where trastuzumab was withheld for at least 4 weeks in patients who had experienced a decline in LVEF ≥16%, or decline ≥10% whilst below normal LVEF limits . This tr< 0.001) .In the absence of randomized prospective studies directly comparing patient outcomes from CMR and TTE derived LVEF, guidance from the British Society for Echocardiography (BSE) and British Cardio-Oncology Society (BCOS) recognises the addition of recent pilot data on the safe use of trastuzumab in patients with asymptomatic reductions in TTE-derived LVEF down to 40% , 29, 30.While LVEF has historically been used as a standard measure of systolic function, there is increasing interest in the use of more sensitive markers that can detect “subclinical” signs of LV dysfunction that can aid earlier initiation of cardioprotective therapy. The extent of myocardial deformation which occurs following application of contractile and relaxation forces can be quantified as strain, defined as the percent change in myocardial length from the relaxed to the contractile state. This deformation represents a fundamental property of the tissue  and therMost myocardial strain studies in patients receiving trastuzumab have used GLS derived from 2D speckle tracking echocardiography (STE). A meta-analysis of 9 studies found reduced GLS to be associated with a higher CTRCD risk  . HoweverMyocardial strain quantification is also feasible with CMR and is traditionally performed with one of many dedicated “tagging” sequences , harmonic phase (HARP), displacement encoding (DENSE), and strain encoding (SENC). These sequences magnetise temporary tags into the myocardium which are prominent during systole and fade during diastole. These tags can be tracked throughout the cardiac cycle to highlight myocardial movement. CMR-tagging derived GLS and GCS have been noted to be worse (less negative) than STE derived strain in a study of 46 cancer survivors exposed to anthracycline therapy with normal range LVEF, suggesting CMR to be more sensitive to subclinical LV dysfunction compared to TTE . LookingThe main disadvantage of dedicated deformation CMR sequences is their time-consuming nature. To overcome this, it is possible to derive strain from feature-tracking of steady-state free precession (SSFP) cine images, with important distinctions being made between 2D  and 3D derived strain values . WhereasA large meta-analysis comprising 65 studies and 2888 patients compared the most used noninvasive imaging modalities to the reference standard CMR in the last two decades . The finCardiotoxicity is a broad term that refers to any direct untoward toxic effects on cardiac structure and function or the acceleration of cardiovascular disease (CVD) among patients with cardiovascular risk factors or preexisting CVD as a result of cancer therapy . A univeMore recently, the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE) defined cardiotoxicity as ≥10% decline in LVEF to a final LVEF <53% by echocardiography, multigated acquisition scan (MUGA), and cardiac magnetic resonance imaging (CMR), as well as being the first reported guidelines to include global longitudinal strain (GLS) reduction defined as >15% , 19. TheTrastuzumab has demonstrated effectiveness when used either as monotherapy or in combination with other substances . HoweverIn vivo work in HER2-deleted mice showed interruption to the HER2 signalling pathway resulted in the spontaneous development of dilated cardiomyopathy [The mechanisms of trastuzumab-induced cardiotoxicity remain to be definitively identified. Limited data from myocardial biopsies reveal rather different mechanisms between trastuzumab and anthracycline, and the prompt recovery of trastuzumab-induced toxicity upon treatment discontinuation further supports this . Differemyopathy , supportmyopathy . Presentmyopathy . In patiIn contrast to anthracycline, the clinical outcome for trastuzumab-induced cardiotoxicity is generally considered to be more favourable since LV dysfunction appears largely reversible upon the discontinuation of trastuzumab, and the inclusion of standard cardioprotective therapy seems to accelerate the recovery process . A rightTrastuzumab-mediated cardiotoxicity is generally considered to not cause ultrastructural changes, though benign ultrastructural changes were observed from endomyocardial biopsy samples in a trial by Ewer and Ewer . It shouAdditionally, an earlier trial comprising 160 patients by Fallah-Rad et al.  identifiRelatively little is currently known about the long-term prognosis of trastuzumab-induced cardiotoxicity. To our knowledge, CMR studies to date have seldom followed up patients beyond 18 months. From the available data , 72, 73,P < 0.001).One long-term study aimed to determine whether trastuzumab-induced cardiotoxicity recovers and explore any association with long-term cardiopulmonary dysfunction in survivors of HER2+ breast cancer . The triA large meta-analysis of randomized and cohort studies of over 29,000 women with breast cancer observed the frequency of severe cardiotoxicity up to 3 years following trastuzumab initiation . Among tBased on these findings, the consensus is that trastuzumab-mediated cardiotoxicity is largely reversible, or at least partially reversible, particularly from a functional standpoint. Though the true prevalence and extent of reversibility is debatable, late toxicity remains a possibility. With the toxicity profile of trastuzumab yet to be fully established, treatment necessitates close monitoring, and in the face of new, emerging data, such issues warrant revisiting.An important limitation to these studies, from the CMR perspective, other than the small sample sizes, is the lack of CMR imaging for evaluating cardiotoxicity, whilst cardiac biomarkers, myocardial biopsy (in some cases), and echocardiography, or other imaging modalities, were adopted instead. Large, prospective CMR-studies are warranted to enable a more definitive conclusion on the diagnostic and prognostic role of trastuzumab-induced cardiotoxicity. Collectively, these studies highlight the potential need for the utilisation of cardiac MRI in the early detection of subclinical cardiotoxicity, as well its extended toxicity profile.Establishing a validated risk stratification tool to distinguish patients that are at increased risk of developing cardiotoxicity to those of lower risk may be necessary so that monitoring by and utilisation of CMR can be reserved for those at higher risk. From the present data, a multitude of risk factors are associated with increased risk of trastuzumab-treated cardiac events, including age (2.31% in <50 years to 4.91% in >60 years 95% CI 3.22–6.94), postmenopausal status (0.013 OR: 4.39 CI: 1.28–15.02), smoking status , body mass index ≥25 , hypertension , dyslipidaemia , diabetes , and previous positive cardiac history  , 73. A sChemotherapy associated myocardial oedema, diffuse interstitial fibrosis (collagen deposition in the absence of myocyte loss), and coarse replacement fibrosis (collagen deposition in the presence of myocyte necrosis) can be uniquely imaged with CMR based T2 mapping, T1 mapping, and late-gadolinium enhancement (LGE) sequences, respectively  Table 4Table 4. In the 2016 ESC position paper, there was recognition of the value of CMR for the following: evaluating cardiac structure and function, identifying the cause of LV dysfunction, and distinguishing left and right ventricular function in difficult cases where other imaging modalities are unsuccessful , 101. WhCMR is demonstrably superior to echo-based imaging of left ventricular function, whether by assessment of LVEF or strain, offering greater sensitivity and specificity in the detection of cardiotoxicity in patients receiving trastuzumab. Furthermore, it offers the ability to assess for myocardial oedema, diffuse interstitial fibrosis, or replacement fibrosis. It also carries some limitations. Thus, currently published normal LVEF reference ranges show an overlap of normal ranges. Application of CMR to patients would require a baseline CMR and regular surveillance scans with associated healthcare costs and requires gadolinium administration.There are several important lines of enquiry to guide future research. Firstly, whether CMR-based detection of cardiotoxicity as assessed by LVEF and strain leads to improved outcomes compared to their detection by echo remains to be determined. Secondly, whether CMR-based identification of oedema and fibrosis, particularly the type and distribution of the latter, leads to improved risk stratification in trastuzumab cardiotoxicity is unknown. Thirdly, can CMR offer detection of features that would suggest a greater likelihood of recovery from cardiotoxicity by tissue characterisation findings? Given the greater availability of echocardiography than CMR, these three questions are central to further research into the optimum detection, follow-up, and surveillance of cardiotoxicity in trastuzumab patients. In the interim, we agree on the current echo-based methodology of current guidance, with the use of CMR where echo images are poor despite left ventricular opacification with echo contrast agents.


Negative correlations of gal-3 concentration were also observed in relation to the volume and contractility of the left ventricle. The concentration of gal-3 significantly negatively correlates with the size, systolic function, and compliance of the LA wall in patients with persistent AF. Determining gal-3 concentration in patients with persistent AF may help in the assessment of remodeling of the LA wall.Galectin-3  is a fibrosis marker and may play a role in fibrosis of the left atrium (LA). Left atrial wall fibrosis may influence the transition from paroxysmal to non-paroxysmal atrial fibrillation (AF). In this study, we assessed the correlation of gal-3 concentration with the main echocardio-graphic parameters evaluating dimensions, volume, compliance, and left atrial contractility during AF and after successful electrical cardioversion (DCCV). The study included 63 patients with left atrial enlargement who qualified for DCCV due to persistent AF. The procedure recovered sinus rhythm in 43 (68.3%) patients. The concentration of gal-3 was negatively correlated with the echocardiographic parameters of LA including dimensions (LA length pre, rho = −0.38;  Atrial fibrillation (AF) is the most common persistent supraventricular tachyarrhythmia . It is aMany biomarkers to assess the risk of AF recurrence or thromboembolic events after direct current cardioversion (DCCV) or ablation are currently being investigated. One of the biomarkers introduced in the clinic relatively recently and used in the assessment of patients with heart failure and AF is galectin-3 . Biochemically, it is a protein with a molecular weight of 35 KDa. It is encoded by a single gene: LGALS3, located in position q21-q22 on chromosome 14 ,14. LikeSo far, data presented showing the prognostic value of gal-3 in the prognosis of maintaining sinus rhythm (SR) after DCCV or ablation in patients with persistent and paroxysmal AF have been inconclusive ,30,31,32In this study, we present the analysis of the correlation of gal-3 levels with traditional and new echocardiographic parameters describing the degree of left atrial structural and mechanical remodeling in patients with persistent AF and left atrial enlargement qualified for DCCV.The study protocol was approved by the Institutional Review Board of the Swietokrzyskie Medical Chamber. We included patients with persistent AF, who qualified for DCCV between February 2016 and August 2018. The inclusion criteria were as follows: symptomatic, persistent AF for 7 or more days; ejection fraction of left ventricle (LV) during AF > 50%; and appropriate anticoagulation  for 3 or more weeks before DCCV. The exclusion criteria were: age below 18 years; no consent to participate in the study; no consent for DCCV; receiving poor quality echocardiograms; moderate or severe valve regurgitation or valve aortic stenosis; existence of valvular prosthesis; existence of thrombus in the left atrial appendage; acute myocardial infarction; acute decompensation of heart failure; a history of pulmonary vein isolation, anemia with hemoglobin of 6.9 mmol/L or less, dysthyroidism, acute infection, immune conditions, and neoplastic disease. Clinical data collection took place immediately before DCCV. Echocardiographic images were performed immediately prior to DCCV and on the next day during SR. Blood samples were drawn directly before DCCV.2DS2-VASc and HAS-BLED scores were calculated as claimed by the current European guidelines on AF management [Baseline clinical assessment comprised age, sex, body mass index (BMI), smoking status, body surface area , diabetes mellitus, hypertension, dyslipidemia, dysthyroidism, heart failure, coronary artery disease, history of stroke or transient ischemic attack, obstructive pulmonary disease, renal disease, EHRA (European Heart Rhythm Association) score, and data about pharmacological treatment. Diagnosis of coronary artery disease was based on a history of myocardial infarction, percutaneous coronary intervention, or aortocoronary bypass grafting. The glomerular filtration rate was calculated using the Cockcroft–Gault equation. The CHAnagement .All electrical DCCV were performed with anesthesiologic assistance under general anesthesia as previously described .Transthoracic echocardiography was performed according to current guidelines using a Vivid S6 ultrasound machine  supplied with an M4S RS probe ,37. TranThe left ventricular volume and ejection fraction were measured using Simpson’s method. The right atrial area was measured from the apical four-chamber view at the end systole (RAAs) and end diastole (RAAd) on the frame of tricuspid valve closure. Transmitral pulsed Doppler was recorded from the apical four-chamber view with sample volume of 2 mm placed between the tips of the mitral leaflets. Pulsed tissue Doppler imaging of the mitral annulus motion was performed from the apical four-chamber view with a 5 mm sample volume at the lateral and septal basal regions. The s’ mean, e’ mean and a’ mean were retrieved as averages from septal and lateral measurements. The measurements obtained during AF were averaged from five consecutive beats. Speckle tracking echocardiography was used to analyze left atrial deformation. The measurements of the left atrial global longitudinal strain were taken in the four-chamber and two-chamber projections. Subsequently, the average of both projections was calculated according to the recommendations of the European Association of Cardiovascular Imaging (EACVI) consensus document . The lefE. coli expressed recombinant human gal-3 and antibodies raised against the recombinant protein.Blood samples were drawn from the cubital vein before DCCV after overnight fasting and rest, while the patient was sitting. Following centrifugation, blood serum was snap-frozen and stored at −70 °C. The concentrations of gal-3 were determined in the samples using Quantikine Human Galectin-3 immunoassay  in August 2018. The Quantikine Human Galectin-3 Immunoassay is a 4.5 h solid phase ELISA designed to measure gal-3 levels in serum. It contains p < 0.05. Statistical analyses were performed with STATISTICA 13.3 software .Results were presented as means ± standard deviations or counts and percentages. For quantitative features, the distributions were checked using the Shapiro-Wilk test. The Spearman rank correlation coefficient was used to study associations between gal-3 and echocardiographic parameters. The use of this test was dictated by the lack of normal distribution for the gal-3 variable. Statistical significance was set at The clinical and echocardiographic characteristics are presented in 2, assessed during AF before DCCV. The relatively low effectiveness of DCCV was caused by the selection of patients with left atrial structural remodeling.All examined patients had normal left ventricular contraction function. The characteristics of the study group show a tendency to elevated left ventricular filling pressure, assessed by measuring E/e’ and E/A in patients for whom DCCV was successful, and recovery of SR was achieved.In our study group, all patients had developed left atrial structural remodeling expressed as LAVI > 34 mL/mp = 0.003) and left atrial volume  were significantly negatively correlated with the concentration of gal-3 (p = 0.01), LA length , LA transverse  and left atrial volumes LAV  and LAVI   .p = 0.033). Left atrial strain  and strain rate in contraction phase assessed after successful DCCV were also negatively correlated with gal-3 levels   was also negatively correlated with the gal-3 concentration. Left atrial contractility, assessed by tissue Doppler measuring the a’ lat post wave after successful DCCV, showed a negative correlation with the level of gal-3  .p = 0.032; LASr 2c post, rho = −0.35; p = 0.031; LASr mean post, rho = −0.33; p = 0.042; pLASRr 2c post, rho = −0.33; p = 0.042)  and after  effective DCCV and left ventricular contractility assessed by measuring the s’ lat post wave using tissue Doppler   . Negativ= 0.016) .In our study, we showed that gal-3 level negatively correlates with the size of the LA cavity, one of the main echocardiographic parameters assessing atrial structural remodeling. In our group, patients with higher concentrations of gal-3 had a smaller-sized LA, which suggests that left atrial fibrosis may lead to a reduction in its dimensions and volume. This correlation was visible in the left atrial measurements taken during AF and in the measurements obtained after the SR had been restored following successful DCCV. In addition, we demonstrated that gal-3 concentration is negatively correlated with the left atrial reservoir strain assessed during SR, a parameter that assesses left atrial compliance. It follows that the higher the concentration of the fibrosis marker, the lower the left atrial compliance. This may indicate a decrease in the number of stretchable components, i.e., muscle tissue, and an increase in non-stretchable components, i.e., fibrous tissue in the left atrial wall. Negative correlations of gal-3 levels with contractility strain and the a’ wave of the lateral part of the mitral annulus assessed during SR after effective DCCV, which were the parameters assessing the left atrial contractility, also indicate the reduction of muscle tissue in the left atrial wall. These data suggest that the high concentration of gal-3 in patients with AF may indirectly indicate advanced left atrial fibrosis.So far, the assessment of left atrial structural remodeling has been based mainly on assessing the dimensions of this heart cavity via echocardiographic examination. The results of our study suggest that gal-3 could be used to assess the left atrial structural remodeling at the cellular level.In the studied group of patients, we also noted a negative correlation of gal-3 level with the volume of the LV, which additionally suggests that fibrosis may lead to a reduction in the dimensions of the LV, which is also emphasized by the observation of the effect of gal-3 concentration on the reduction of dimensions and volume of the LA. A negative correlation of gal-3 concentration was also noted when measuring the s’ wave of the lateral part of the mitral annulus, which indicates that fibrosis may reduce the left ventricular contractility in the same way as we described it in relation to the left atrial contractility. There is extensive literature on galectins as particles that play a key role in chronic inflammation, apoptosis, immune response, cancer, atherosclerosis, microbial infections, leukemia, multiple myeloma, pulmonary fibrosis, and viral infections . ReportsOur study was single center and performed on a small group of patients. The data on AF duration were obtained retrospectively from patient reports. When interpreting our results, one should remember that echocardiography is a subjective method that is highly operator-dependent and requires experience and skill. Therefore, in our study, all echocardiographic examinations were performed by one experienced operator. All DCCV procedures were performed in the antero-lateral position, without changing the paddle position in the case of DCCV failure. This might have influenced the success rate. We did not perform control measurements of gal-3 in patients whose SR was maintained; consequently, we cannot assess the diagnostic value of gal-3 for reverse remodeling.The concentration of gal-3 significantly negatively correlates with the size, systolic function, and compliance of the left atrial wall in patients with persistent AF. The concentration of gal-3 negatively correlates with the size and systolic function of the LV in patients with persistent AF. The assessment of gal-3 concentration in patients with persistent AF may help in the assessment of left atrial remodeling.Patients who will be treated with galectin inhibitors should be monitored echo-cardio-graphically for changes in the size and function of the LA and LV. Further studies should assess the usefulness of fibrosis markers in predicting outcomes in patients with AF.


However, echo provided significantly lower values for left ventricular volume (p < 0.0001). The echo LA Vol of all the subjects correlated well with that measured by MRI . When comparing the two methods, significant positive correlations of EDV  and ESV  were found, with a negative bias for values determined using echo. For a subgroup of participants with ventricular volumes smaller than 49.50 mL, this bias was missing, thus in this case echocardiography could be used as an alternative for MRI. Conclusion: Good correlation and reduced bias were observed for LA Vol and EF determined by echo as compared to cardiac MRI in a mixed cohort of patients with AF and healthy volunteers. For the determination of volume values below 49.50 mL, an excellent correlation was observed between values obtained using echo and MRI, with comparatively reduced bias for the volumes determined by echo. Therefore, in certain cases, echocardiography could be used as a less expensive, less time-consuming, and contraindication free alternative to MRI for cardiac volume determination.Aims: We aimed to compare cardiac volumes measured with echocardiography (echo) and cardiac magnetic resonance imaging (MRI) in a mixed cohort of healthy controls (controls) and patients with atrial fibrillation (AF). Materials and methods: In total, 123 subjects were included in our study; 99 full datasets were analyzed. All the participants underwent clinical evaluation, EKG, echo, and cardiac MRI acquisition. Participants with full clinical data were grouped into 63 AF patients and 36 controls for calculation of left atrial volume (LA Vol) and 51 AF patients and 30 controls for calculation of left ventricular end-diastolic volume (LV EDV), end-systolic volume (ESV), and LV ejection fraction (LV EF). Results: No significant differences in LA Vol were observed ( Cardiac volumes and functions are landmark parameters used in the clinical diagnosis, prognosis, and treatment of cardiovascular disease ,2,3,4,5.Currently, two of the most frequently used techniques in this field are echocardiography and cardiovascular magnetic resonance imaging (MRI). For both methods, rigorous scientific recommendations to accurately quantify cardiac chamber parameters have been elaborated and made available to clinicians ,12. In cIn terms of direct comparisons of cardiac parameter values obtained using echocardiography with those obtained by cardiac MRI, numerous earlier studies have found that echocardiography tends to underestimate cardiac volumes as compared to MRI ,29,30,31Patients with atrial fibrillation (AF) and healthy volunteers were recruited to participate in our clinical study. Our study  complied with the Helsinki Declaration, obtained ethical approval from the local Ethics committee of the County Clinical Emergency Hospital of Cluj-Napoca (Nr. 20117/04.10.2016) and recruited participants between 2017 and 2020. All participants gave their written informed consent to participate in the study. Inclusion criteria were age between 20–80 years, weight 50–120 kg. For the included AF patients, a diagnosis of persistent, permanent, or paroxysmal AF, not more than three months from conversion with constant chronical medication and an optimal echocardiographic window was mandatory. Exclusion criteria for healthy volunteers were the presence of cardiovascular diseases, hypertension, or diabetes. Whereas, for AF patients, exclusion criteria were other known cardiac or chronic diseases; patients under other chronic anti-inflammatory, oncology or study treatment; contraindication for cardiac MRI: prosthesis, pace-maker, metallic particles, pregnancy, known allergies and altered renal function (creatinine clearance < 40 mL/min determined after Cockcroft-Gault). All the participants underwent full cardiologic evaluation including ECG and echocardiography.Complete echocardiographic evaluations were performed with a Philips Affiniti 50 ultrasound device with a Philips S4-2 Cardiac Sector Probe transducer. From the apical 4-chamber and 2-chamber acoustic windows, two-dimensional images of the LA and LV were traced to calculate end-diastolic and end-systolic volumes  using the ellipsoid model . EF and The subjects fulfilling the previously presented inclusion criteria were considered suitable for cardiac MRI measurements. All subjects were imaged with a 3T whole-body MRI system  using a dedicated body coil for signal reception.To avoid postprocessing differences between echocardiography and MRI techniques, the values for LA Vol, EDV, and ESV determined by MRI were calculated using the same method as for echocardiography, namely using the ellipsoid model . LA dimeLVEF was measured by manual planimetry of the left ventricular endocardium in short axis cine images at end-systole and end-diastole. At the basal slice, the ventricular cavity was differentiated from the atrium by the presence of ventricular myocardium and was confirmed on a co-registered long-axis image. Papillary muscles were regarded as part of the ventricular cavity. These quantitative CMR measurements were performed by a junior radiologist (LP) and validated by a senior radiologist (SM). LV EF was manually calculated based on the EDV and ESV measurements, according to the formula:The MRI acquisitions were performed within 10 days of echocardiography and cardiac evaluation, with a mean of 4 days. Cardiac MRI required synchronous cardiac gating with EKG and breath-holding techniques to overcome motion artifacts. Following acquisition, data were stored and analyzed offline using the workstation of the instrument. The cardiac MRI protocol consisted of dark blood sequences (Black Blood SSFSE), FIESTA cine sequences , and post-contrast sequences: rest perfusion (FGRE Time Course), angiography imaging (Aorta CEMRA Asset) and LGE/MDE images  in three different planes: short axis, four-chamber and two-chamber view. The MDE/LGE sequences were acquired with a time delay of 10 min after gadolinium injection , showing contrast between normal myocardium (dark) and abnormal myocardium (hyperenhancement). 3D HEART sequence  was also acquired and used to assess coronary abnormalities.The participants were monitored constantly during the examination, and no immediate adverse effects were reported. The results and all data were exported and stored as DICOM files.t-test, Wilcoxon ranking. Correlation coefficients were calculated using non-parametric Spearman correlation. Differences between the gender distributions inside the groups were tested using Fisher’s exact test. p values provided are two-sided; p < 0.05 was considered statistically significant. Bland-Altman analysis was used to assess the agreement between echocardiography and MRI. The age- and body-surface area (BSA)-related differences between healthy controls and AF patients were tested using a non-parametric and unpaired Student’s t-test, (Mann-Whitney U test). Statistical analyses were performed using GraphPad Prism .The normality of data distribution was tested using Anderson-Darling, D’Agostino Pearson, Shapiro-Wilk and Kolmogorov-Smirnov tests. The echocardiographic and MRI data did not pass the normality tests. Thus, the variables are represented as median and interquartile range (IQR). Age and BSA passed the normality tests, and they are presented as mean ± standard deviation (SD), together with their range. Comparisons between MRI and echocardiographic measurements of LV volumes, LA volumes, and EF were performed using non-parametric and paired Student’s In total, 123 subjects gave written informed consent to participate in this study. The study outline is presented in n = 63 AF patients and n = 36 healthy controls.Out of the total number, two patients were excluded because of poor quality or limited echocardiographic window. After general cardiologic evaluation and echocardiographic analysis, 121 participants were recruited for cardiac MRI measurements. Twenty-two subjects were excluded from the study/analysis for various reasons . After all procedures, 99 subjects were included in the database with full data. They were distributed into two groups: n = 99 (36 Controls and 63 AF patients).n = 6 Controls and n = 12 AF patients, full LV Vol data were missing due to data storage and archiving problems. Therefore, the cohort for LV Vol included in the study had a total of n = 81 subjects . However, the echocardiographic examination resulted in significantly lower values of the LV Vol than the cardiac MRI (p < 0.0001). The value of EDV for all subjects measured by echocardiography was 90.1 (77.65–102.5) mL, while the same parameter measured by cardiac MRI reached the value of 130.5 (113.9–160.6) mL. The same trend was observed for both groups: Control (94.75 (80.3–103.2) mL measured by echocardiography vs. 128.8 (106.8–159.9) mL measured by cardiac MRI) and AF patients (88.6 (77.4–100.9) mL measured by echocardiography vs. 135.6 (114.4–162.1) mL measured by cardiac MRI). The results were similar for ESV but presented smaller differences between the two techniques. The ESV value from echocardiography was 39.3 (30.95–44.55) mL for all subjects, 36.25 (28.4–41.65) mL for controls, and 36.3 (31.6–47.4) mL for AF patients, while the cardiac MRI resulted in mean values for ESV of 52.4 (36.9–69.7) mL for all subjects (p < 0.0001), 44.2 (35.1–54.7) mL for Controls (p = 0.0015), and 60.1 (44.31–76.7) mL for AF patients (p < 0.0001). Although the values for EF were similar for all subjects (p = 0.10) and the AF patients group (p = 0.93) regardless of the measurement technique, the values for the controls group measured by echocardiography were significantly lower (61.05 (57.63–66.7)%) than those from cardiac MRI (65.6 (61.9–71.6)%, p = 0.003).There was no significant difference between LA Vol measured by echocardiography and the values obtained by cardiac MRI , and the bias of the echo LA Vol measurements was close to 0 (−0.88 mL) with the 95% confidence interval (CI) of −46.86 to 45.09 mL. Good correlations between the echo LA Vol and cardiac MRI LA Vol values were observed both for Controls  and AF patients . The values with low bias were −4.10 mL for Controls with 95% CI: −31.00 to 22.81 mL and 0.96 mL for AF patients with 95% CI: −52.86 to 54.76 mL.The echo LA Vol of all subjects correlated with the cardiac MRI LA Vol , with a bias of −40.12 mL  and all the subjects . The obtained echocardiographic values were lower than the cardiac MRI values, with 52.40 mL for AF patients and 47.85 mL for all subjects. Although the echocardiographic values significantly correlated with cardiac MRI, a bias was present, with the latter resulting in higher values for EDV.The correlation was weaker, though significant, for AF patients , controls (bias of −8.17 mL), and AF patients (bias of −25.07 mL).We set an error threshold in measurements of 5% from the actual value, and we searched for the highest value of ESV for which echo measurements did not exceed this error. When we analyzed a subgroup of subjects with volumes smaller than a fixed value  there was good overlap between the two methods, a bias of −2.41 with −18.91 to 14.10 mL agreement limit . This thEcho EF significantly correlated with EF values determined by cardiac MRI . The Spep = 0.01) and AF patients (r = 0.56 and p < 0.0001). The underestimation of echo EF values reached a value of 4.69% (95% CI: −19.30% to 10.01%) for controls, whereas for AF patients, echocardiographic measurements showed higher values than cardiac MRI examination with a 0.39% positive bias (95% CI: −20.61% to 21.38%).The same trend maintained for controls (r = 0.46 and p < 0.0001) and the low bias (−0.88) show the potential of echocardiography for measuring LA Vol. Significant correlation was observed both in Controls  and AF patients .Large values of LA Vol are a sign of chronicity in diastolic dysfunction, which is correlated with AF and stroke. A rapid and easy method for LA Vol determination is useful in decreasing the overall mortality after myocardial infarction ,12. In oThere was a small variability between the approximation methods used in echocardiography for volume measurements ,36. LA VAs previously reported, the LV Vol is underestimated by echocardiography . SimilarThe bias and limits of agreement for LV Vol and LV EF were higher for the AF patients group compared to the Controls because of the assumption of ellipsoid geometry of the LV, which does not apply in a variety of cardiac pathologies . It can p = 0.0007), and the bias was reduced from −18.81 mL for all values to −3.30 mL for ESV < 49.50 mL , echocardiography correlated with MRI . Howevep < 0.0001) and a low negative bias was also observed in our study (bias of −1.49). The mean relative absolute error when compared with MRI reached a value of 14.90%. EF measured by echocardiography did correlate with the MRI values for healthy controls (r = 0.46 p = 0.01) and AF patients , with the mean differences between the two techniques being low in both groups (−4.69 for controls and 0.39 for patients).Echocardiographic determination of LVEF has previously been shown to offer good results when compared to the previous gold standard, radionuclide angiography , and witCorrelation between echocardiography and MRI measurements of cardiac volumes have previously been reported. Hoffmann et al. showed the necessity of contrast application in LV function measurements to lower the bias from 11 for unenhanced echo to 9.2 for enhanced echo . Our resOur results were based on a cohort of well-characterized AF patients and controls, as they were included in our clinical study after full cardiological evaluation and according to strict criteria (see Methods); therefore, our results cannot be extrapolated to other types of severe cardiac dysfunctions or genetic malformations.A good correlation and reduced bias were observed for LA Vol and EF determined by echocardiography as compared to the gold standard, cardiac MRI, in patients with atrial fibrillation and healthy volunteers. A bias associated with larger LV Vol was observed. However, for volumes lower than 49.5 mL, echocardiography could be used as a less expensive, less time-consuming alternative for cardiac MRI in ESV volume determination. Moreover, this opens the possibility for LV volume determination for patients with MRI contraindications.


Distinguishing hypertrophic cardiomyopathy (HCM) from left ventricular hypertrophy (LVH) due to systematic training  from morphologic assessment remains challenging. The purpose of this study was to examine the role of T2 mapping and deformation imaging obtained by cardiovascular magnetic resonance (CMR) to discriminate AH from HCM with (HOCM) or without outflow tract obstruction (HNCM).Thirty-three patients with HOCM, 9 with HNCM, 13 strength-trained athletes as well as individual age- and gender-matched controls received CMR. For T2 mapping, GRASE-derived multi-echo images were obtained and analyzed using dedicated software. Besides T2 mapping analyses, left ventricular (LV) dimensional and functional parameters were obtained including LV mass per body surface area (LVMi), interventricular septum thickness (IVS), and global longitudinal strain (GLS).While LVMi was not significantly different, IVS was thickened in HOCM patients compared to athlete’s. Absolute values of GLS were significantly increased in patients with HOCM/HNCM compared to AH. Median T2 values were elevated compared to controls except in athlete’s heart. ROC analysis revealed T2 values (AUC 0.78) and GLS (AUC 0.91) as good parameters to discriminate AH from overall HNCM/HOCM.Discrimination of pathologic from non-pathologic LVH has implications for risk assessment of competitive sports in athletes. Multiparametric CMR with parametric T2 mapping and deformation imaging may add information to distinguish AH from LVH due to HCM.• Structural analyses using T2 mapping cardiovascular magnetic resonance imaging (CMR) may help to further distinguish myocardial diseases.To differentiate pathologic from non-pathologic left ventricular hypertrophy, CMR including T2 mapping was obtained in patients with hypertrophic obstructive/non-obstructive cardiomyopathy (HOCM/HNCM) as well as in strength-trained athletes.•  Elevated median T2 values in HOCM/HNCM compared with athlete’s may add information to distinguish athlete’s heart from pathologic left ventricular hypertrophy.•  Hypertrophic cardiomyopathy (HCM) has implications on risk assessment of competitive athletes due to cardiovascular complications including sudden cardiac death or arrhythmias . As the The American and European guidelines recommend the exclusion of athletes with HCM from competitive sports with the exception of low-intensity activity , 4, 7, 9Besides clinical history, physical examination, and 12-lead electrocardiogram (ECG), transthoracic echocardiography (TTE) with a focus on morphologic and functional parameters is regularly performed in athlete assessment –9. For cIn cases of uncertainty, cardiovascular magnetic resonance (CMR) is recommended as an additional imaging approach due to its reproducibility as well as its ability for the characterization of myocardial structure, e.g., by using contrast agents . StandarIn this context, T2 values have been shown to increase diagnostic accuracy in myocarditis as they detect extracellular fluid imbalances . For LVHThe study was conducted in accordance to the Declaration of Helsinki and approved by the local ethics committee (application number 4307). Written informed consent was waived by the Institutional Review Board. Athletes gave their written informed consent.Thirty-three patients with HOCM , 9 patients with HNCM  and 13 strength-trained, healthy athletes with a minimum of 120 kg weightlift in the bench press  received CMR. There was no history of cardiovascular diseases or a previous pathologic ECG in athletes. The inclusion criteria for HOCM and HNCM were based on the 2014 ESC Guidelines [A group of age-, gender-, and comorbidity-matched volunteers to the different types of LVH, but no LVH itself, served as controls. Controls were ethnicity-matched as well. Volunteers were screened and included during routine cardiology consultations.3, EPI factor 3, parallel imaging with an acceleration factor of 2).CMR was performed on a 1.5-T MRI-system  using a 32-channel phased array coil. After scout and reference scans, a gradient-spin echo (GRASE) sequence for T2 mapping was acquired as described previously . Briefly3, 35 phases, breath-hold).Further functional and structural assessment was determined by cine steady-state free precession (SSFP) images in standard long-axis geometries  as well as in short-axis orientation with full ventricle coverage from basis to apex  and right ventricular (RV) dimensional and functional parameters .cc) from the short-axis stack. Endocardial contours were applied followed by subsequent software-driven automatic tracking. Quality adjustment was performed and contours were amended manually if necessary.Myocardial feature tracking was performed offline using the Image-Arena software  . Cine imGRASE images for local T2 value generation were post-processed using software based on the LabView environment  . Endo- aStatistical analysis was performed using SPSS 25.0 (SPSS Inc.). Unless otherwise stated, quantitative data are reported as mean ± SD. Normal distribution was tested using the Shapiro-Wilk test.H test with post hoc Bonferroni correction for not normally distributed data. Data between the LVH groups and their respective controls were analyzed by 2-sided unpaired Student’s t tests for normally distributed data and the Mann-Whitney U test for not normally distributed data. Fisher’s exact test was used to examine significant differences between nominal classifications.Continuous data were analyzed using analysis of variance (ANOVA) with the post hoc Bonferroni analysis to examine differences between the LVH groups for normally distributed data and the Kruskal-Wallis P values below 0.05 were considered statistically significant.Receiver operating characteristics (ROC) were used to generate cutoff values to define sensitivity and specificity for the diagnosis of AH. p = 0.608) whereas patients with HOCM were significantly older according to post hoc testing (p < 0.01 to AH). Concomitant to an elevated left ventricular end-diastolic pressure, patients with HOCM and HNCM displayed a considerable amount of dyspnea in the New York Heart Association (NYHA) class III–IV .The demographic and clinical characteristics of patients and controls are summarized in Table p < 0.05 all). Hypertrophy was predominantly localized in septal segments  with a significantly thickened IVS in HOCM in the post hoc Bonferroni correction, but no difference between HNCM and AH.Table p = 0.067).Late gadolinium enhancement (LGE) was detected in 18 patients  of the HOCM/HNCM group. No myocardial scarring was seen in the 6 athletes who received contrast agent. LGE expression was not significantly different in Fisher’s exact test comparing HOCM/HNCM with AH  and between AH and their controls (p = 0.033). Accompanying the results for LVEF, absolute GLS was significantly elevated in patients with HOCM/HNCM compared with AH  (Table p = 0.025 for HOCM and p < 0.001 for AH). There was no difference in SRcc between the different study cohorts. GLS and SRcc of one HOCM subject had to be excluded due to poor image data, but no further data points of the other groups.Left ventricular ejection fraction (LVEF) was significantly elevated in HOCM/HNCM compared with AH (AH vs. HOCM or HNCM: n) Table . GLS of N = 25 due to poor image quality of 8 subjects) and HNCM (N = 9) compared with AH  .As shown in Fig. p = 0.001; control HNCM: 56.3 ± 4.0 ms, p = 0.011). AH showed no difference from their respective controls (control AH: 55.5 ± 3.5 ms).Compared with their normal control groups, T2 values were significantly increased in LVH due to HOCM and HNCM . This was most pronounced in segment 2 using the post hoc Bonferroni correction  .In segmental analysis, the difference of T2 values was most indicated for the anterior and anteroseptal basal IVS , HR , and age . GLS showed a weak correlation to age , but none to LVMi . In addition, there was no impact of gender on T2 values (p = 0.056) or GLS (p = 0.328).To account for a dependency of GLS and T2 values to cofactors, Pearsons correlation was performed that showed a weak, but significant, correlation of T2 values to LVMi , IVS (p = 0.007), LVEDV (p = 0.007), GLS (p = 0.002), and T2 values (p = 0.007) were significant for the differentiation of AH from overall HCM. Multivariate analyses were not performed due to a potential overfit of the model as given by the low number of athletes and HNCM patients.In further univariate regression analysis, LVEF  was not significantly different. An explanation for this might be a heterogeneous course of HCM with a varying degree of diastolic dysfunction [cc changes. This is underlined by other measures of diastolic function in the HOCM/HNCM group that indicate diastolic function, e.g., the different NYHA class. Normal SRcc values in athletes are in line with a previous CMR tagging study [cc to report diastolic function is given by its good reproducibility, especially in other entities of LVH, and its good correlation to measures of diastolic function from TTE [For feature tracking using CMR, there is no existing literature about the comparison of different LVH entities. As has been shown by TTE, diastolic parameters  are good discriminators of HNCM and AH with the diastolic function being significantly more affected in HNCM , 22. Thifunction , 24. In ng study . The reafrom TTE –28.Surprisingly, GLS was significantly decreased in AH compared to controls and the HCM cohort. Concerning GLS in AH, controversial literature exists. On the one hand, GLS values were decreased or equal in patients with HOCM/HCNM and AH, but within the same range as in the current study , 30, on Previous studies have highlighted the value of parametric mapping to distinguish different forms of cardiovascular diseases without the use of contrast agents. While T1 mapping is more likely to display diffuse myocardial fibrosis and local scarring, T2 mapping is subjected to display myocardial or interstitial water content , 33. DatA possible explanation for the differences in T2 values might be found on a structural level. “Pathologic” LVH of HOCM/HNCM has been characterized by parallel addition of new sarcomeres, myofiber disarray, myocyte degeneration, and diffuse myocardial replacement fibrosis, e.g., due to small-vessel disease with relative ischemia –39. FurtAge- and gender-related differences have already been reported as influencing factors on T2 values in healthy volunteers . In our However, one should point out the overlap of T2 values between the different cohorts that may be triggered due to dynamic histopathological states of HOCM/HNCM with a varying degree of edema, cell death, fiber disarray, and myocardial scarring  as well In addition, no difference could be seen in the LGE expression between the HOCM/HNCM and AH groups. This is likely due to the low number of athletes receiving contrast agent. LGE is still assumed as an essential component to differentiate the LVH groups, although focal fibrosis has been described at the insertion points of the right ventricle in athletes .This is a single-center study and due to the small sample size, statistical analysis could have been hampered, especially for the small groups of HNCM and AH, which can be seen on the discrete data points of Fig. Our CMR protocol did not include systematic T1 mapping for completion of parametric mapping, since there is already convincing data of T1 values and AH , 49.Athletes were recruited if they participated in physical strength training with a minimum weight lift of 120 kg in bench pressing. Despite explicitly neglecting the use of performance-enhancing substances such as steroids, we still could not control for substance abuse by blood sampling. It has been reported that those substances may have an impact on cardiovascular function and fibrosis , 51. DueAs we did not perform further testing such as catheterization, HNCM and other cardiovascular diseases could not be ruled out with absolute certainty for the athlete’s group. Based on the clinical history and cardiovascular symptoms, relevant cardiac diseases were excluded.Multiparametric CMR with parametric mapping identified preserved T2 values and reduced GLS of AH in comparison with elevated T2 values and preserved GLS in HCM. As the ability to differentiate between pathologic and non-pathologic LVH has implications for risk assessment and exclusion of competitive sports in athletes, this could be of importance as T2 mapping and GLS, besides other functional and dimensional LV parameters, can help to distinguish AH from HCM.


Introduction: Pompe disease is caused by deficiency of the lysosomal enzyme acid α-glucosidase, which results in cardiac and muscular complications that can jeopardize perioperative outcomes. We report a 4-month-old infant with Pompe disease receiving cheiloplasty under general anesthesia with the aid of peripheral nerve blocks and intensive hemodynamic monitoring.Case Description: This case report describes a 4-month-old full-term Taiwanese female infant who presented with left unilateral cleft lip and palate in the prenatal examination. She was diagnosed with infantile-onset Pompe disease after acidic α-glucosidase (GAA) gene sequencing. She also received enzyme replacement therapy (ERT) 15 days after birth and regular ERT every other week. Cheiloplasty was performed under general anesthesia uneventfully, and peripheral nerve blocks were adopted for analgesia. Intensive hemodynamic monitoring using electrical cardiometry technology (ICON®) and pulse contour analysis (FloTrac system) were applied during the operation. No adverse effects were observed, and the wound healed well. Therefore, the patient was discharged 4 days after surgery.Conclusion: With the availability of ERT, severe organ dysfunction in infantile-onset Pompe disease patients is no longer common. However, moderate cardiac depression can still occur while increasing inspiratory pressure and deepening the anesthesia level despite a normal preoperative echocardiogram report. Therefore, careful, gradual titration is desirable. Furthermore, electrical cardiometry can detect hemodynamic changes more instantaneously and reliably than pulse contour analysis. In addition, we suggest taking advantage of the peripheral nerve block as a part of balanced anesthesia to alleviate the cardiac suppression caused by general anesthesia. Pompe disease, an autosomal recessive disorder, is caused by deficiency of the lysosomal enzyme acid α-glucosidase, which metabolizes glycogen in lysosomes , 2. Glyc®) and pulse contour analysis (FloTrac system) intraoperatively. This study was approved by the Taipei Medical University Joint Institutional Review Board (N202104013). We have obtained the written informed consent from her parents. De-identification was done according to Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule safe harbor method.Here, we report a female infant with infantile-onset Pompe disease who underwent cheiloplasty under general anesthesia and peripheral nerve blocks. In addition, we applied intensive hemodynamic monitoring using electrical cardiometry technology  (*29) and c.1935C>A (p.Asp645Glu). One heterogenous pseudodeficiency mutation, p.Gly576Ser, was also noticed. Her cross-reactive immunological material (CRIM) status was positive linked to c.1935C>A (p.Asp645Glu). All above findings indicated the diagnosis of Pompe disease. She received regular ERT at an initial dosage of 20 mg/kg intravenous infusion every other week beginning at 15 days old until 2 days before surgery. Preoperative echocardiography revealed preserved LV systolic function with minimal tricuspid regurgitation. Patent ductus arteriosus (PDA) and patent foramen ovale (PFO) were closed. LVMI was 65.5 g/m2.7, which was in the 75th percentile for her age (<6 months old)  (Insp): 13 cm H2O, positive end-expiratory pressure (PEEP): 0 cm H2O, respiratory rate (RR): 30 breaths per minute, and inspiratory-to-expiratory time (I:E ratio): 1:1.5. Our goal was to maintain mean arterial pressure (MAP) above 45 mmHg and heart rate (HR) between 90 and 160 bpm. We focused on five parameters of ICON®: index of contractility (ICON), systolic time ratio (STR), thoracic fluid content (TFC), stroke volume variation (SVV), and systemic vascular resistance (SVR). We focused on three parameters of FloTrac: cardiac output (CO), SVV, and SVR. We compared CO, SVV, and SVR between these two hemodynamic monitors   were appmonitors . Due to monitors , the dat® changed accordingly. ICON and SVR dropped gradually in 1 min, whereas CO increased. However, 3 min later, the decline in ICON and SVR was significant. CO remained at the same level, causing a decrease in arterial blood pressure. Therefore, we cautiously decreased the inhalational gas concentration. Detailed changes in ICON, SVR, and CO are displayed in Insp from 13 to 15 cm H2O. Arterial blood pressure dropped soon after. This combined with the observation that SVV was occasionally above the normal range suggested fluid deficiency; therefore, we prescribed bolus normal saline (3 mL) with no apparent improvement. The ventilator setting was adjusted back to the initial setting, and the inhalational gas concentration was slowly titrated to 0.6 MAC. Eighty minutes after anesthesia induction, we also increased the normal saline infusion rate, as SVV was above the normal range and TFC was low; however, MAP was stable and in the normal range. No additional analgesic agent was prescribed during maintenance. At the end of surgery, we prescribed neostigmine 0.125 mg and glycopyrrolate 0.025 mg as neuromuscular blocking agent reverse medication before extubation. Extubation was uneventful with normal respiratory function. She was discharged 4 days later without adverse events.During early maintenance, we titrated the inhalational gas concentration from 0.7 to 1.0 minimal alveolar concentration (MAC) before the skin incision, and we observed that the hemodynamic parameters on ICONAfter 3 months of follow-up, the patient was able to roll over, lie prone on the forearms, and reach out for objects, and she had a social smile. However, she could not maintain a sitting position unassisted, indicating slower development potentially than other infants of the same age. In addition, mild hypotonia was still observed compared with other infants. The girl infant also underwent another surgery in our hospital several months later. Unlike the previous surgery, she was more tolerant of inhalational gas concentration titration, which may represent improved cardiac function under regular ERT. After receiving ERT treatment for half a year, her anti-alglucosidase-α antibody revealed positive. Therefore, hydrocortisone was added in the following ERT courses. Her anti-alglucosidase alfa antibody will be followed in the next few months to see if additional immunosuppressive agents are needed.® as an intensive hemodynamic monitoring method. Few facilities will or are able to perform stress test for cardiac function assessment for infants. As mentioned in our study, these patients might have a normal static cardiac echocardiography report, but are not normal enough to face stress from surgery and general anesthesia. In previous studies, Sanders et al. , and the results showed that ICON® use was effective intraoperatively. However, due to inadequate sample sizes, more comparative studies are required to provide accurate data and evidence in infants. Third, peripheral nerve blocks were employed as a part of combined anesthesia to provide ideal analgesic effects. Utilizing peripheral nerve block in patients undergoing cleft lip and palate can prevent the patients from complications of respiratory depression and airway obstruction, which is induced by opioid  .®, using keywords of Pompe disease and anesthesia. Reference lists were also manually searched to include all the related studies. In these studies, most underwent a short procedure. Thirteen patients underwent central venous catheter insertion or muscle biopsy, and the remaining three patients underwent elective intubation, bronchoscopy, and bilateral inguinal hernia repair. Only 2 of the 16 patients received ERT, but bradycardia with wide QRS complexes and non-sustained ventricular tachycardia were still reported after induction and during the early phase of maintenance anesthesia, respectively. Among the 14 patients without ERT, 10 had complications such as bradycardia, torsade de pointes, ventricular fibrillation, and cardiac arrest. None of these patients involved intensive intraoperative hemodynamic monitoring methods.Previously reported cases of infantile-onset Pompe disease patients who received general anesthesia were listed in The cause of arrhythmia of infantile-onset Pompe disease patients may be due to the intracardiac accumulation of glycogen inducing progressive hypertrophic cardiomyopathy and diastolic dysfunction. Therefore, venous return is obstructed and cardiac output decreases. Besides, certain anesthetics cause significant decrease in systemic vascular resistance or diastolic blood pressure, which result in decreased coronary perfusion and arrhythmia . Early dIt might be possible for the Pompe disease girl infant to receive the surgery later, after receiving more courses of enzyme replacement therapy. However, many studies suggested to perform primary cleft lip repair between the ages of 3 and 6 months since it is proper timing, allows subsequent treatments to perform and also for better establishing lip competence , 21. Con2) if halogenated inhalational anesthetics was chosen. After anesthesia induction, we utilized peripheral nerve blocks as additional analgesia. Only two studies have reported on infantile-onset Pompe disease patients who underwent muscle biopsy using peripheral nerve blocks but were without endotracheal intubation , while a positive correlation between ICON and inhalational gas concentration was noted . However, We further analyzed the data of ICON, ventilator settings and the sevoflurane concentration using the Pearson correlation coefficient. A negative correlation between ICON and peak inspiratory pressure was observed (®: STR and ICON. STR equates to the pre-ejection period (PEP) divided by the left ventricular ejection time (LVET). Theoretically, low STR correlates with high ejection fraction. ICON represents the acceleration of the blood in the aorta. After analysis, we found that STR was related to ICON. Moreover, STR could react faster than ICON when a large variation occurred (We also noticed a correlation between two contractility parameters in ICON® in this case. Mahmoud et al. (Fluid is another factor influencing perfusion, and we monitored fluid status through the SVV and TFC parameters of ICONd et al.  reportedd et al. .Once Pompe disease is suspected, genetic screening, laboratory tests, electrocardiography, and image surveys should be conducted immediately. ERT should also be arranged as soon as the diagnosis has been made. Recent studies have revealed that with ERT intervention to prevent hypertrophic cardiomyopathy and a thorough preoperative evaluation, anesthesia management is much safer in infantile-onset Pompe disease patients , 17. A p® intraoperatively in infants. More comparative studies may be needed to prove its use and validity in infants. Second, ICON® depends on the theory of electrical bioimpedance cardiometry, which is interfered by electrocautery. In our case, ~10% of the data were of low quality and therefore excluded. Third, since the perioperative complication rate has dropped dramatically after the spread of ERT, cases with cardiac complications which we mentioned above were not fully comparable with current cases.Our study has some limitations. First, we lacked strong evidence to clarify and support the accuracy of ICON® may be considered, as the trend of hemodynamic parameters can facilitate the advanced identification of potential problems, especially STR. Future studies should focus on ICON® in infant perioperative monitoring to validate the safety and multiple parameters in this non-invasive hemodynamic monitoring method.The recent consensus suggests that early diagnosis and treatment with ERT can improve hemodynamic stability. However, with regular ERT, lower tolerance to anesthetic agents was still noted in this case. Peripheral nerve blocks can reduce the required dose of analgesic agents and make the processes of surgery and emergence safer and faster. For infants with existing cardiac pathophysiologic changes, ICON10.6084/m9.figshare.16955032.The raw data presented in the study are deposited in figshare repository. doi: The studies involving human participants were reviewed and approved by Taipei Medical University-Joint Institutional Review Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.M-CL and H-CT had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. D-MN helped us in acquisition of relevant data. All authors made substantial contributions to the study conception and acquisition of data, or analysis and interpretation of data, involved in drafting the article or revising it critically for important intellectual content, and approved the final version to be published.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.


Chagas disease (CD), with approximately 10,000 deaths annually, has become a worldwide health problem. Approximately 35% of cases may show cardiac manifestations such as arrhythmias and/or conduction disorders, heart failure, thromboembolic accidents, and sudden death. The Amazon region has long been considered a non-endemic area for CD; however, in the last decades, with an increase in the number of acute and chronic cases, disease evolution has received greater attention. Here, we report the successful implementation of a cardioverter-defibrillator for the prevention of sudden death in a patient with autochthonous Chagas cardiomyopathy in the Brazilian Amazon. Chagas disease (CD) is endemic in Latin America and has become a worldwide public health problem due to the increase in human migration. It was considered a neglected disease in 2005. One hundred and ten years after its discovery, the World Health Organization now estimates that 70 million people are at risk of acquiring the disease, 7 million people are infected, and 10,000 deaths are caused by the disease annually,This disease can manifest in two stages: an acute stage in an asymptomatic or a symptomatic form, and a chronic stage in indeterminate, cardiac, or digestive forms. Approximately 60% of infected individuals have the indeterminate form, 25% to 35% develop heart disease; of these, 10% may develop severe heart diseaseT. cruzi strains from those found in traditionally endemic areas,The Amazon region has long been considered a non-endemic area for CD; however, in recent decades, with an increase in the number of acute and chronic cases, this profile has changed. In the state of Amazonas, the first patient with serologically positive chronic disease was recorded in 1977Despite this, a few cases of CCM have been reported in the Amazon. The first reports of dilated cardiomyopathy with chagasic etiology in this region date back to 2003, with two fatal casesIn this study, we present a case report of successful cardioverter-defibrillator implantation for the prevention of sudden death in a patient with autochthonous CCM in the Brazilian Amazon. A 60-year-old man, a painter currently living in the state capital, Manaus but born in Autazes in the interior of Amazonas, where he lived until the age of 18, was diagnosed with Chagas disease in 2015 after an attempt to donate blood. He developed the cardiac form of the disease and presented with dilated cardiomyopathy with ventricular dysfunction. His left ventricular ejection fraction (LVEF) was 44% using the Simpson method. An apical aneurysm was observed, and a baseline 12-lead electrocardiogram (ECG) showed an abnormal sinus rhythm and changes in ventricular repolarization in the lower-lateral wall. On the 24-hour Holter recording, he presented 16,881 isolated, bigeminated, polymorphic ventricular arrhythmias.In 2018, cardiac magnetic resonance imaging was performed revealing increased cavity volumes and significant left ventricular dysfunction in addition to a late transmural enhancement in the inferior-medial-basal wall A. FurtheIn August 2019, he was admitted to the emergency department with tachycardic palpitations, cold sweats, and syncope. In the emergency room, monomorphic ventricular tachycardia without pulse was monitored and recorded on the ECG , which sSince the time of diagnosis of CD and CCM, the patient has been on medication optimized for heart failure: enalapril 20mg/day, carvedilol 50mg/day, and spironolactone 25mg/day. During the cardiorespiratory arrest episode with pulseless monomorphic ventricular tachycardia and after its reversal with defibrillation, the patient was referred for the implantation of an implantable cardioverter-defibrillator (ICD) as secondary prophylaxis for sudden death.After discharge from the hospital, he was referred for outpatient follow-up and was prescribed medication for heart failure in combination with 400 mg/day amiodarone in order to avoid arrhythmic storms. Twenty-four-hour Holter monitoring was performed again, which demonstrated the absence of ventricular arrhythmias. Approximately three months after ICD implantation, the patient presented with an ICD shock episode, documented by intracavitary electrogram during telemetric evaluation  and 2C.To date, there are few published records of the occurrence of chagasic cardiomyopathy in the Amazon region, in which, ventricular aneurysmsMarques et al. (2012)Although both early diagnosis and monitoring are important, the patient in this report already had myocardial fibrosis identified by cardiac magnetic resonance, with late myocardial enhancement. Malignant ventricular arrhythmias are more prevalent than other forms of heart disease in patients with CD, and sudden cardiac death is commonly observed in CD; therefore, this cardiomyopathy is a frequent indication for ICD implantationMyocardial fibrosis identified using cardiac magnetic resonance, with late myocardial enhancement serves as an important predictor of arrhythmias and sudden death in several ischemic and non-ischemic cardiomyopathies, such as hypertrophic cardiomyopathy and CD, and it should be considered for patient monitoring and assessment of severity and interventionsThe arrhythmogenic form of CD is an important cause of mortalityIn recent decades, the occurrences of acute and chronic cases of CD have increased significantly in regions where diagnostic and therapeutic resources are scarce. This case report reinforces the need for improvement of regional diagnostic resources, early identification of patients at greatest risk, and prevention of sudden death.


A 3-dimensional, robust, and sustained myocardial restoration by means of tissue engineering remains an experimental approach. Prolific protocols have been developed and tested in small and large animals, but, as clinical cardiac surgeons, we have not arrived at the privilege of utilizing any of them in our clinical practice. The question arises as to why this is. The heart is a unique organ, anatomically and functionally. It is not an easy target to replicate with current techniques, or even to support in its viability and function. Currently, available therapies fail to reverse the loss of functional cardiac tissue, the fundamental pathology remains unaddressed, and heart transplantation is an ultima ratio treatment option. Owing to the equivocal results of cell-based therapies, several strategies have been pursued to overcome the limitations of the current treatment options. Preclinical data, as well as first-in-human studies, conducted to-date have provided important insights into the understanding of injection-based approaches for myocardial restoration. In light of the available data, injectable biomaterials suitable for transcatheter delivery appear to have the highest translational potential. This article presents a current state-of-the-literature review in the field of hydrogel-based myocardial restoration therapy. This may constitute a somewhat nihilistic approach, from the mouth of an authority in cardiac surgery and heart failure treatment, yet holds more or less true to this day—simply taken from the perspective of clinical implementation—in the form of a comprehensive, recommended, if not guideline-supported, protocol: after 25 years into myocardial restoration attempts following myocardial injury, there has not been a single efficient, robust, and sustained impact on the injured heart muscle following ischemic insult. Approaches so far have encompassed various types of cells, cell products or derivatives, scaffolds of various physical conditions, as well as multiple administration routes. It would be beyond the scope of the present paper to revisit them all; however, in brief, they all hold promise and peril.Gerard Buckberg, with his seminal paper “The Helix and the Heart”, has awakened many aspired myocardial restorers to the fact that the heart is not a quiescent, homogenously built target, but rather is a highly asymmetric, anisotropic, and angiotropic organ, featuring an intricate architecture . Not oneVu et al. had postulated that the acute myocardial injury, known as infarct, triggers a cascade of events with severe cellular and functional impacts . This viThe prevailing dogma suggesting that adult mammalian cardiomyocytes are post-mitotic cells with no ability to renew has been recently overthrown by studies demonstrating a low level of proliferation, even in adult hearts . HoweverOver the last few decades, cell therapy has been applied in clinical myocardial restoration. Though the result is non-conclusive, some studies have shown the attenuation of ventricular remodeling. The ensuing hostile and inflammatory environment results in the rapid death of injected cells, or lack of integration thereof. It is incomprehensive, and the vast majority of studies have proven that injected cells do not organize in an integrated syncytium, which excites orchestrated contractility. Depending on the type of cells that are randomly injected, different complications occur . Solid sInjectable, hence minimally invasive, administrationAutologous material, not of stem cell nature, to be derived simply during treatmentA polytherapy approach to address concomitant aspects of the vicious circle of myocardial ischemia Easy adoption and clinical penetration in the horizon.There is an obvious need for a targeted, less invasive myocardial restoration treatment, which does not add too much stand-alone trauma to the patient and can be integrated into a viable clinical protocol, to be adopted by cardiologists as well. Arising from the above pain-points, we have long shifted our focus from stem cells to liquid compounds, with the following key value propositions:A literature search was performed electronically using the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines . We condThe inclusion criteria included any experimental cohort studies in which large animals or patients underwent an injectable delivery of hydrogel and/or hydrogel compound analogure for an effect analysis on ischemic heart disease. Furthermore, only studies published after the year 2000 were included to prevent using outdated data. Articles with hydrogel compound processing (lab experiment) and in-vitro experiments, small animal studies, and case reports were excluded. Additionally, any studies that were not written in the English language were excluded. Three authors  independently abstracted details of the study characteristics, the myocardial infarct (MI) creation, the hydrogel characteristics, the delivery method, and the outcomes measured. Data extracted, with respect to the infarct creation, hydrogel characteristics, and the delivery method, included: method of MI creation, the artery involved, the cell delivered via hydrogel or its analogues, the type of matrix, and the method of delivery to the myocardium. Data extracted, with respect to the outcomes measured, included: any data related to the functional and morphological outcomes of the heart. Outcomes were then grouped according to the modality they were measured with. All outcomes are expressed as the treatment group outcome when compared to the control group.The systematic search revealed a total of 28,704 papers. After 13,775 duplicates were excluded, 14,929 papers remained for screening. Based on the title and abstract, irrelevant articles were excluded, leaving 70 papers for full-text review. Out of these 70 papers, 69 could be retrieved. Following a full-text review of these papers, 19 papers remained for inclusion. Additional sources provided 2 papers that were added to the final pool, resulting in a total of 21 papers for inclusion into the present study . The chaOut of the 21 studies, 17 measured systolic function via LVEF and 4 via SV . YamamotThe ventricle size was frequently measured via ESV, EDV, wall thickness, and LV mass. The common modalities used to measure these parameters included: echocardiography, MRI, and immunohistochemistry. Out of the 21 studies, Giordano et al., 2013 , YamamotCardiac fibrosis was frequently quantified via scar size and the extent of fibrosis. These parameters were measured via immunohistochemistry, Masson’s trichrome stain, MRI, and computed tomography (CT). Out of the 21 studies, only 5 studies ,14,23,28The degree of angiogenesis was mainly quantified using blood vessel density via immunohistochemistry staining. Out of the 21 studies, only 11 ,27,28,30In the vast majority of cases, MI is a consequence of a vulnerable plaque rupture and a subsequent intracoronary thrombosis. The process initiates maladaptive changes in the myocardium, termed “cardiac remodeling“, which may result in the development of HF . The cliOwing to the intricate myocardial architecture and function, we believe that the triple approach  yields the best restorative effect. Some of the most promising therapeutic compounds are hydrogel-based biomaterials that can not only provide mechanical support for a failing heart, but can also serve as a vehicle for cells, growth factors, and drugs. Because of their potential for minimally invasive transcatheter delivery, injectable hydrogels appear to be one of the most promising types of compounds in terms of their potential clinical application. Several types of hydrogel-based approaches for cardiac tissue repair have been investigated to date. Each category of hydrogels has its advantages and disadvantages that can influence their potential clinical applicability. There are various types of hydrogels with different properties based on their origin , various mechanisms of cross-linking, etc.TM (ECM from the decellularized porcine myocardium) in patients with 1st STEMI treated by PCI within a period of post-intervention between 60 days and 3 years, and found MRI evidence of LV remodeling and a clinical improvement in the study subgroup. Based on the best evidence, we have observed a diverse range of compounds with none of the compositions showing clear superiority . There aOne of the most important aspects of hydrogel-based myocardial restoration therapy is the mode of delivery. In the context of the increasing role of minimally invasive techniques, a particular emphasis has been placed on shifting away from open heart surgery to catheter-based techniques. We doubt that any restoration method involving major surgical trauma can survive as a stand-alone treatment, as no patient, cardiologist, or surgeon will adopt it. Second, therapy may have to be chronic and repeated . The patient cannot undergo countless re-dos if the procedure is invasive. This has prompted researchers to develop new devices for pinpointing the delivery of therapeutic compounds into a desired area of the myocardium. As a result, catheter-based techniques for myocardial restoration therapy have evolved from simple intracoronary injections  to techniques with more efficient therapeutic retention. One of the examples is the TransAccess catheter system with fluoroscopic and intravascular ultrasound guidance, which was used for autologous skeletal myoblast delivery . CurrentLess Invasive procedures, coupled with injectable compounds, present a valid platform for a translational restoration protocol, which may be adopted by interventional cardiologists and heart surgeons. Polytherapeutic adjuvants, such as antioxidants, paracrine-active drugs, and anti-inflammatory substances, may be added to the protocols to ensure a sustained myocardial restoration effect.As discussed in the present paper, among all biomaterials currently used in cardiac tissue engineering, injectable hydrogels, with their potential for minimally invasive delivery and in-vivo breakdown into harmless derivatives, represent the most promising therapeutic option. However, the translational pathway from bench to bedside is challenging and still needs to be explored. It can be anticipated that in the next few decades the role of cell-vehicle compounds in the treatment of ischemic HF patients will expand, and injectable hydrogels will penetrate into the clinical arena to a higher extent.


The extent and significance in of cardiac remodeling in Fontan patients are unclear and were the subject of this study.This retrospective cohort study compared cardiovascular magnetic resonance (CMR) imaging markers of cardiac function, myocardial fibrosis, and hemodynamics in young Fontan patients to controls.2 vs 93 ml/m2, p < 0.001), and lower ejection fraction , circumferential , radial , and longitudinal strain . Compared to healthy controls, Fontan patients had higher extracellular volume fraction (ECV)  and native T1 . Patients with a dominant right ventricle demonstrated larger ventricles , lower EF , worse CS , and a trend towards higher ECV . Worse EF and CS correlated with longer cumulative bypass , cross-clamp  and circulatory arrest times . T1 correlated with aortopulmonary collateral (APC) flow  which, in the linear regression model, was independent of ventricular morphology (p = 0.9) and EDVI (p = 0.2). The composite outcome  was associated with increased native T1  and EDVI , as well as decreased EF  and worse CS . APC flow  was independently associated with the composite outcome, independent of ventricular morphology (HR 0.71 CI 0.30–1.69 p = 0.44) and T1 .Fifty-five Fontan patients and 44 healthy controls were included (median age 14 years (range 7–17 years) vs 13 years (range 4–14 years), p = 0.057). Fontan patients had a higher indexed end-diastolic ventricular volume (EDVI 129 ml/mPediatric Fontan patients have ventricular dysfunction, altered myocardial mechanics and increased fibrotic remodeling. Cumulative exposure to cardiopulmonary bypass and increased aortopulmonary collateral flow are associated with myocardial dysfunction and fibrosis. Cardiac dysfunction, fibrosis, and collateral flow are associated with adverse outcomes.The online version contains supplementary material available at 10.1186/s12968-021-00782-9. By early adulthood, up to 50% of patients with a Fontan circulation are in heart failure, , 2 a comThe aims of the present study were to investigate the degree of functional and fibrotic myocardial remodeling present in young Fontan patients, to unveil candidate etiologies for alterations in structure and contractility, and to describe their potential functional impact. We hypothesized that ventricular dysfunction and fibrotic myocardial remodelling are enhanced in the subgroup of Fontan patients with a dominant right ventricle (DRV).Fontan patients and control subjects who had received cardiovascular magnetic resonance (CMR) imaging between April 2014 and March 2018 were included in this retrospective cohort study. The study setting is a tertiary care hospital. If more than one CMR had been performed in the same patient, only the last CMR was included. Scans were excluded if non-diagnostic. Further, Fontan patients with two nearly equal sized ventricles were excluded to allow for a comparison between patients with DRV and dominant left ventricle (DLV). Patients referred for coronary artery imaging because of non-specific chest pain or for a family history of arrhythmogenic right ventricular cardiomyopathy were included as controls if their work-up, including CMR, was negative. Twenty-one Fontan patients and 24 healthy control subjects were previously reported . The priDemographic, surgical, and clinical data were retrieved from the patients’ medical records. Results from cardiac catheterization, echocardiography, and cardiopulmonary exercise testing were collected if the test had occurred within 12 months of CMR, without an interim intervention. ‘Failing Fontan circulation’ was defined by the presence of plastic bronchitis, protein-losing enteropathy, anasarca, or surgical take-down of the Fontan within 6 months of CMR. A composite outcome was used to assess the predictive value of CMR and included any of the following at or after the CMR, up until study completion: readmission for cardiac indication, cardiac reintervention, Fontan failure or any clinically significant arrhythmia. Of note, the former patients with Fontan failure were also included in the composite outcome. Significant atrioventricular valvar regurgitation (AVVR) was defined as at least moderate insufficiency by echocardiography.All examinations were conducted on a 1.5 T CMR system . The protocol included balanced steady-state free precession short-axis cine stacks for ventricular volumetry, as previously described . Phase cA single observer (MR) with several months of focused training and under the supervision of a single senior reader (LGW) for each case analyzed short axis cine stacks for ventricular volumes using commercially available software Qmass . In patients with a ventricular septal defect or a communication of the hypoplastic ventricle with the neo-aorta, the smaller chamber was included in the single ventricular contours. Blood flow volumes were quantified using Qflow . Aortopulmonary collateral (APC) flow was calculated as the difference between pulmonary venous and arterial flows, indexed to body surface area.T1 relaxometry analysis was performed by a single observer (CdL) with 10 years of CMR experience on the online motion-corrected source images, using’Qmap 2.2.36’ . Regions of interest (ROIs) were drawn in the freewall of the dominant ventricle, propagated to each of the eight source images and adjusted for motion , as previously described , 17. SegContinuous variables are presented as means ± standard deviations if normally distributed, otherwise as medians and ranges. For normally distributed continuous variables, two-tailed independent sample t-tests were used in conjunction with Levene’s Test of Equality of Variances. For non-normally distributed continuous variables Wilcox rank sum test was used. Univariate and multivariable regressions were performed to explore presence of linear relationships between measurements in the overall cohort. Correlations were assessed using Pearson’s correlation coefficient analysis for normally distributed continuous variables and Spearman rank-order test for non-normally distributed data. Intra- and interobserver variability of T1 and ECV was analyzed using Bland–Altman plots. P-values < 0.05 were considered statistically significant  had undergone cardiac catheterization within one year of CMR with a median interval of zero days (range 0–206 days). There was no difference in the central venous, atrial or ventricular end-diastolic pressure between DLV and DRV patients Table . EchocarCardiopulmonary exercise test results were available within one year of CMR in 28 of the 55 Fontan patients (51%), at a median of 87 days (range 0–365 days). There were no differences in the maximum oxygen consumption, anaerobic threshold or maximum work-load between DLV and DRV patients or between those with and without significant AVVR. There was no correlation between exercise parameters and myocardial strain, ejection fraction (EF), ventricular volumes, fibrosis markers, ESFS, or ESWS.2 versus 122 ± 36 ml/m2, p = 0.08).Ventricular volumes and myocardial function indices are provided in Table Worse EF and CS correlated with cumulative bypass , aortic cross clamp  and circulatory arrest  times. EDVI correlated with APC flow . There was a correlation between ECV and EDVI  that, in linear regression, was independent of APC flow  and ventricular morphology . As compared to controls, the Fontan cohort demonstrated evidence of intraventricular dyssynchrony with an increased standard deviation of the times to peak CS (p = 0.04).The VAC ratio was higher in Fontan patients as compared to controls subjects (p < 0.001) with a greater range and standard deviation. The DRV group demonstrated a higher VAC ratio (p = 0.015), Ees (p = 0.019) and ESWS (p = 0.006) as compared to the DLV group Table . PatientThere were no correlations between the haemodynamic or exercise data and wall or fibre stress, or VAC. Ees correlated with cumulative bypass , aortic cross clamp (R − 0.44 p = 0.001) and circulatory arrest times (R − 0.43 p = 0.001). VAC, ESWS and ESFS correlated inversely with EF  and correlated positively with CS .LGE was present in five if the 55 Fontan patients 10%) and in no controls. Myocardial T1 and ECV measurements demonstrated adequate reproducibility  which, in a linear regression model, was independent of ventricular morphology  and EDVi .We investigated the following two outcome surrogates: clinical Fontan failure concurrent to CMR and the composite outcome. Within six months of CMR, six of 55 Fontan patients (9%), four with a DRV and two with a DLV, had a failing Fontan physiology. The six patients with Fontan failure had decreased EF , global CS  and RS  and higher ECV  and T1 . Twenty-two of the 55 Fontan patients (40%) experienced the composite outcome . This model showed that APC flow  was independently associated with the composite outcome, independent of ventricular morphology (HR 0.71 CI 0.30–1.69 p = 0.44) and T1 .Fibrotic myocardial remodeling has been identified as an important culprit in the pathogenesis of ventricular dysfunction in acquired heart disease, but only preliminary results on its prevalence, extent, and impact on myocardial function are available for the single ventricle population –12. We pLGE has been associated with adverse outcomes in Fontan patients . In our In the present cohort, patients who experienced the composite outcome had increased fibrosis and decreased myocardial function, evidenced by worse EF and CS. In a series of older Fontan patients, Rathod et al. demonstrated that volume loading was independently associated with death or transplantation . SimilarOur morphological and functional results add to the growing body of evidence that patients with DRVs have worse ventricular function and, according to some studies, less favorable outcomes , 23, 24.The Fontan cohort had larger ventricular volumes as well as lower EF and strain in all domains as compared to controls, corroborating previous findings by both echocardiography and CMR , 9, 13. More recently, elevated ESWS and ESFS, which result in an imbalance between myocardial oxygen consumption and supply , have emVAC ratio is a novel parameter that can be measured invasively, using pressure volume loops , or non-Several study limitations warrant discussion. First, T1 relaxometry was consistently feasible only in the free wall and our assumption that the values are representative of the entire ventricular myocardium may be erroneous. Second, the control cohort was older than the Fontan group; for ethical reasons, younger children could not be recruited for a contrast-enhanced CMR study under general anaesthesia. However, one would expect a greater degree of myocardial fibrosis with increasing age and thus the older age of the control subjects would underestimate the significance of the fibrosis found in the Fontan population. Furthermore, the subgroup of patients with Fontan failure was small and related results need to be substantiated in a larger cohort. Lastly, two different gadolinium agents had been used, with potential impact on ECV. However, the influence of the type of gadolinium has been shown to be small .Our results point towards a preclinical adverse cardiac remodeling process which is evident even in young and comparatively healthy Fontan patients. A greater degree of aortopulmonary collateral flow is associated with higher myocardial fibrosis markers and adverse outcomes.Additional file 1: Figure S1. Bland-Altman plot for interobserver variability of ECV, with limits of agreement. There was good agreement and no statistically significant bias. Figure S2. Bland-Altman plot for interobserver variability of T1 with limits of agreement. There was good agreement and no statistically significant bias. Figure S3. Bland-Altman plot for intraobserver variability of T1 with limits of agreement. There was good agreement and no statistically significant bias. Figure S4. Bland and Altman plot for intraobserver variability of ECV with limits of agreement. There was good agreement and no statistically significant bias.