Interpretation of T2 values remains difficult due to limited comparability across hardware and software systems and the lack of validated measurement recommendations for the number and orientation of mandatory slices. Our aims were to provide a standardized comparison of intra- and inter-individual T2 values in the short and long axes and to investigate inter-scanner reproducibility.Ninety cardiovascular magnetic resonance (CMR) studies in 30 healthy subjects were performed with three identical 1.5 T CMR scanners (same hardware and software) using a balanced steady-state free precession (bSSFP) gradient echo sequence in three short axis (SAx) and three long axis (LAx) views. A commercially available T2 mapping software package of the latest generation with automatic in-line motion correction was used for acquisition. Regions of interest were manually drawn in each of the 16 myocardial segments according to the American Heart Association (AHA) model in three SAx and three LAx acquisitions. Analysis of inter-scanner, inter-segmental, intra-segmental, inter-regional and inter-level differences was performed.Inter-scanner reproducibility was high and the mean myocardial T2 value for all evaluated segments was 45.7 ± 3.4 ms. Significant inter-segmental variations of mean T2 values were found. Mean intra-segmental T2 values were comparable between LAx and SAx acquisitions in 72%. Significantly higher T2 values were found in apical segments and a significant disparity among different regions was found for SAx and LAx orientations.Standardized cardiac T2 mapping is highly reproducible on identical CMR systems. T2 values vary significantly between single heart segments, regions, levels, and axes in young, healthy subjects. Cardiovascular magnetic resonance (CMR) is widely used to investigate a variety of cardiac pathologies, from myocardial infarctions to non-ischemic cardiomyopathies –4. MyocaThe aim of this study was to provide a structured evaluation of inter-scanner reproducibility and of territorial disparity of T2 values according to the American Heart Association (AHA) model. For this purpose, T2 values in short axis (SAx) and long axis (LAx) were assessed on three identical 1.5 T CMR scanners from the same vendor, using a standardized acquisition protocol and a dedicated, commercially available software package of the latest generation with in-line motion correction and automated T2 map calculation.Thirty healthy subjects were included in this prospective study. All subjects were recruited through advertising for research studies. None had a history of cardiovascular disease or cardiac risk factors, including hypertension, hyperlipidemia, or diabetes. None were referred as a patient for a clinical CMR scan. Subjects older than 30 years of age or with known cardiovascular disease, previous cardiac surgery, or relative contraindications to CMR examination  were excluded. Institutional Review Board approval was obtained and all patients gave written informed consent.3. Scan time was 9 heartbeats. The data were fitted using a linear two-parameter model with logarithmic transformation. Motion correction was performed using a variational non-rigid registration algorithm, aligning all T2-prepared frames to the center frame [All T2 measurements were performed without contrast using a balanced steady-state free precession (bSSFP) sequence  on three identical 1.5 T CMR systems . The same technologist performed all three examinations in each patient on the same day using the same 16-channel phased array body coil. The sequence of CMR scanners was randomized for each patient. Patients were placed in a supine position, and images were acquired with electrocardiogram (ECG) gating. Commands were given to hold the breath at end-expiration, as this affords high reproducibility of the position of the diaphragm. Initially, scout images were acquired to adjust the long and short axis of the heart. Three cinematic LAx  and three SAx  views were acquired with a retrospectively ECG-gated segmented k-space bSSFP pulse sequence . Basal section was defined as a fixed distance of 2 cm to the mitral annulus in an end-diastolic four-chamber view. Mid-cavity and apical sections were defined in the same four-chamber view, each with a gap of 2 cm, as shown in Fig. er frame . OptimalCMR analysis was performed by two board-certified radiologists (observers 1 and 2), each with 8 years of experience in cardiovascular imaging, using dedicated server/client-based post-processing software . Both observers were blinded to all participants and other imaging data. A freehand region of interest (ROI) was manually drawn to encompass the largest possible area, carefully avoiding the adjacent blood pool or extra-cardiac structures, in each of the myocardial segments by observer 1 according to the AHA model in the three SAx (16 ROIs) and the three LAx (18 ROIs) acquisitions . In addition, inter-segmental differences were calculated for SAx and LAx together .To evaluate inter-regional differences, heart segments were vertically grouped into anterior , anteroseptal , inferoseptal , inferior , inferolateral , and anterolateral  regions , mid-cavity (segments 7–12), and apical (segments 13–16) levels. SAx and LAx segments were grouped separately to these levels.Both observers rated the image quality in all datasets and in each heart segment using a 3-point Likert scale: 1, insufficient image quality with major artifacts; 2, satisfactory image quality with minor artifacts; and 3, good image quality without artifacts.2-doped water , supported by the International Society for Magnetic Resonance in Medicine (ISMRM), was chosen for these acquisitions . It contter Fig. . We decip-values < 0.05. Statistical analysis was performed using the software package SPSS .The Kolmogorov–Smirnov test with Lilliefors correction was used to evaluate the data for normal distribution. Descriptive statistical data were provided as mean and single standard deviation. Non-parametric Friedman test was performed for inter-scanner evaluation of T2 values among the three different CMR scanners and for inter-segmental comparison, as normal distribution was not assumed by the Kolmogorov–Smirnov test. Post hoc analysis was performed using the Dunn-Bonferroni pairwise comparison test. Bland–Altman plots were used for visual comparison of T2 values for each CMR scanner. Furthermore, the non-parametric Wilcoxon rank-sum test was used for inter-region and inter-level comparisons. Inter-observer reproducibility was assessed using the Pearson correlation coefficient for the inter-observer data in the randomly chosen datasets of 10 subjects, and intra-observer reproducibility was assessed using the intraclass correlation coefficient. The Friedman test and Pearson correlation analysis were performed for the phantom measurements. Statistical significance was accepted for The study population consisted of 16 female and 14 male subjects with a mean age of 23 ± 4 years (range 19–29). The average heart rate during the examination was 65 ± 5 beats per minute (bpm).p <  0.001). The mean T2 value for all segments in SAx was 45.2 ± 3.3 ms, which was significantly lower than the T2 values in LAx . The mean intra-individual range of the T2 values  for all subjects was 15.7 ± 3.7 ms. The inter-individual range was 15.6 ms in a segment-based comparison. Only 5.8% of all measured T2 values were more than two standard deviations above or below the mean (6.4% in SAx and 5.2% in LAx segments). Box plots of segmental T2 values in SAx, LAx, and SAx/LAx combined are shown in Fig. A total of 102 segments per subject were analyzed: 16 segments in SAx and 18 segments in LAx at three different time points. A total of 3060 ROIs were drawn and the mean myocardial T2 value for all evaluated segments in all subjects  was 45.7 ± 3.4 ms. Male subjects had significantly lower T2 values (44.6 ± 2.7 ms) than female subjects , segment 14 in the four-chamber LAx , segment 6 in the four-chamber LAx , and segment 10 in the two-chamber LAx  differed significantly among the three time points. Agreement among the different scanners is shown in Bland–Altman plots  segments among the three different time points. However, segment 14 in the apical SAx  corresponding myocardial segment pairs in SAx and LAx views. Segment 11  and the apical segments 14 , 15 (inferior), and 16  differed significantly. A detailed statistical overview is provided in Table p <  0.001) across all segments. No discrepancies could be found in the pairwise comparisons in 77% of all segments in SAx (p > 0.05) and in 78% of all segments in LAx (p > 0.05). Inter-segment differences were slightly lower if calculated for SAx and LAx together .T2 values in SAx and LAx showed significant differences (p > 0.05). A detailed presentation of all post hoc test results is absent due to the high number of post hoc test situations (561).Of note, inter-segment variability of septal segments was higher than the average for both separate evaluation  and combined evaluation  vertically grouped SAx segments and in 8 of 15 53%) vertically grouped LAx segments. For details and descriptive data see Tables 7% vertic% verticap = 0.16 and p = 0.83, respectively). Apical T2 values in SAx and LAx were significantly higher than mid-cavity or basal values (both p <  0.001). A detailed overview is provided in Table Basal and mid-cavity T2 values in SAx and LAx were comparable  in all heart segments in all CMR examinations.p = 0.347), irrespective of the height of the T2 value. The inter-scanner Pearson correlation coefficient was 0.99 for all comparison constellations. Box plots are shown in Fig. No significant differences were found for the phantom measurements among the three CMR scanners  . Both inGender also contributes to the inter-individual differences. Healthy male subjects had significantly lower T2 values than healthy female subjects. This is in line with a previous report that also found higher T2 values for young female subjects . CardiacIn addition to individual factors, technical aspects influence the variability of T2 values. In contrast to our results, Baessler and colleagues found only moderate reproducibility of T2 values using three different acquisition techniques at three different time points on the same CMR system with subsequent manual image registration and manual motion correction . We sougSome limitations must be considered when interpreting the results of this study. First, the number of study participants is rather small. However, the total number of CMR examinations is high, thus providing a sufficient number of replicates for robust statistical analysis. Multi-center studies with a larger number of subjects and patients could help to validate our findings.Second, only young, healthy adult subjects were included in this study. Most patient populations are of higher age and might present with diverse medical history; thus, they might also have altered myocardial structures. Although the phantom measurements indicate that the robustness is not limited to a physiological range of T2 values, patients may be less compliant, more obese, and less capable of holding their breath than healthy subjects. However, these artifacts and problems are patient specific and should thus not be considered a technical limitation.A third limitation is that the results are only representative for one specific type of scanner, sequence, and software. Further research is needed to transfer this information to other scanner generations and vendors. Our standardized phantom measurements could serve as starting point here. Until the proposed studies are conducted, all other scanners still require institutional reference measurements for interpretation of T2 time values, as recommended by the SCMR.Cardiac T2 mapping on identical CMR systems is highly reproducible. However, local T2 values vary significantly between single heart segments, regions, levels, and axes in young, healthy subjects. Standardized acquisition and post-processing techniques can help to address this regional disparity of the healthy myocardium during clinical interpretation and could allow for comparison among clinical sites.


The relationship between adipocyte fatty acid-binding protein (AFABP) and cardiac remodelling has been reported in cross-sectional studies, although with conflicting results. Type 2 diabetes mellitus (T2DM) is associated with left ventricular (LV) hypertrophy and diastolic dysfunction, as well as elevated circulating AFABP levels. Here we investigated prospectively the association between AFABP with the longitudinal changes of cardiac remodelling and diastolic dysfunction in T2DM.Circulating AFABP levels were measured in 176 T2DM patients without cardiovascular diseases (CVD) at baseline. All participants received detailed transthoracic echocardiography both at baseline and after 1 year. Multivariable linear and Cox regression analyses were used to evaluate the associations of circulating AFABP levels with changes in echocardiography parameters and incident major adverse cardiovascular events (MACE), respectively.The median duration between baseline and follow-up echocardiography assessments was 28 months. Higher sex-specific AFABP quartiles at baseline were associated with increase in LV mass and worsening of average E/e′ . Multivariable linear regression demonstrated that AFABP in the highest quartile was independently associated with both increase in LV mass  and worsening of average E/e′ . Moreover, multivariable Cox regression analysis showed that elevated baseline circulating AFABP level independently predicted incident MACE  after adjustments for age, sex, body mass index, glycated haemoglobin, hypertension, dyslipidemia and presence of chronic kidney disease.Circulating AFABP level at baseline predicted the development of LV hypertrophy, diastolic dysfunction and MACE in T2DM patients without CVD. Type 2 diabetes mellitus (T2DM) is associated with left ventricular (LV) hypertrophy and diastolic dysfunction independent of underlying coronary artery disease (CAD) –3, and cFatty acid-binding protein has been linked with cardiovascular diseases , 6. AdipIn heart failure, AFABP positively correlated with N-terminal pro-brain natriuretic peptide (NT-proBNP) and clinical severity . In a prAll participants were recruited from the specialist medical clinics of Queen Mary Hospital, Hong Kong from July 2011 to August 2014. Participants who had T2DM but without CVD and severe structural heart disease were enrolled for baseline blood tests and echocardiography. Subsequently, they were invited for follow-up echocardiography after 1 year. The study was approved by the ethics committee of the West Cluster Hospital Authority of Hong Kong and all participants gave written informed consent prior to any study-related procedures. This study was part of the Chinese Diabetic Heart Study (CDATS) to evaluate the cardiovascular manifestations in Chinese T2DM patients, the pathophysiology behind and related potential therapies .2. Blood pressure was measured at the end of echocardiography examination after a 5-min rest. Fasting blood samples were obtained for measurements of glycated haemoglobin (HbA1c), glucose, lipid profile, serum creatinine (SCr) and stored in aliquots at -80 °C for further assay [Clinical measurements and blood sampling were obtained on the same day after an overnight fast for at least 8 h. Detailed medical and medication histories including smoking status, hypertension, dyslipidemia, use of anti-hypertensive and anti-diabetic medications were documented. Anthropometric parameters including body weight and height were measured, with body mass index (BMI) calculated in kg/mer assay . Estimater assay . Serum Aer assay , 28. TheDetailed transthoracic echocardiography examination was performed in all participants with commercially available echocardiography machines  by two cardiologists at baseline and follow-up. Images were obtained using a 3.5-MHz transducer and digitally stored into 3 cardiac cycles for offline analysis by EchoPAC version 108.1.5 . 20 participants were randomly selected to assess the intra- and inter-observer reproducibility in the measurements of echocardiography parameters, estimated by Bland–Altman and intra-class correlation coefficients. The agreement of intraobserver and interobserver variability was accepted  and LV posterior wall thickness at end-diastole (LVPWd) were measured using two-dimensional echocardiography guided M-mode approach based on current recommendations . LV mass2.In this study, the diagnosis of T2DM was based on criteria set out by the American Diabetes Association . Hypertest March 2020. The follow up of MACE started after the baseline visit of all patients. All clinical outcomes were retrieved from the electronic clinical management system of the Hospital Authority, Hong Kong, where all hospitalization and causes of mortality for each individual were documented in detail.MACE was defined as a composite of cardiovascular death, hospitalization for heart failure, non-fatal myocardial infarction and stroke developed as of 31https://www.IBM.com/SPSS), and a 2-sided P < 0.05 was considered statistically significant.In this study, categorical variables were presented as frequencies (proportions), where continuous variables with normal distribution were expressed as mean ± standard deviation. Skewed variables such as AFABP, TG and eGFR were presented as median (interquartile range), and were logarithmically transformed to obtain near normality before analysis. Since sexual dimorphism was known to be present in serum AFABP levels, patients were divided into four groups based on sex-specific AFABP quartiles as previously described , with eaA total of 265 T2DM patients were recruited in this study. After excluding those with history of severe valvular heart disease (n = 3), CAD (n = 16), heart failure (n = 3), stroke (n = 6), atrial fibrillation (n = 2), malignancy (n = 4) and poor echocardiographic images (n = 10) at baseline, 221 participants were enrolled for further evaluation with blood tests and invited for follow-up echocardiography. Participants who did not have follow-up echocardiography included those who developed new-onset heart failure (n = 2), severe valvular heart disease (n = 1), stroke (n = 1), CAD (n = 1), end-stage renal failure (n = 2), malignancy (n = 4), death (n = 3), lost to follow-up (n = 16), or declined the invitation (n = 15) after their baseline visit. Therefore, 176 participants returned for follow-up echocardiography after a median interval of 28 months, and were included in the analysis of this study.2 and their mean duration of diabetes was 17 ± 7 years. The prevalence of hypertension, dyslipidemia and CKD were 75.6%, 68.8% and 14.2%, respectively. Their median circulating AFABP levels at baseline were 29.59 (20.62–52.60) ng/mL in women and 19.22 (12.49–29.24) ng/mL in men. Participants with increasing AFABP quartile were significantly older, and had higher BMI and prevalence of hypertension, serum TG levels, and lower eGFR and HDL-C levels .Baseline clinical characteristics of these 176 participants are shown in Table At the time of follow-up echocardiography in these 176 participants, their blood pressure significantly improved, while their eGFR, LDL-C and TG levels decreased compared to baseline. Moreover, there was an increase in the use of gliptins, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) and statins at follow-up. However, their BMI, HbA1c, fasting glucose, HDL-C and the use of insulin, metformin and sulfonylureas were comparable between baseline and at follow-up. . Moreover, both their LV systolic and diastolic functions deteriorated, as reflected by the decrease in their LVEF, E/A ratio, e′ septal, e′ lateral and increase in their average E/e′ at follow-up   , which included 9 cardiovascular deaths, 3 hospitalizations for heart failure, 5 myocardial infarction and 1 stroke. The incidence of MACE was highest among participants with AFABP in the highest quartile (22.7%). Kaplan–Meier survival curve showed that participants with their AFABP in the highest quartile had the highest risk of developing MACE compared to those in the lower AFABP quartiles Fig. . HoweverOur study provides the first prospective evaluation of the relationship between circulating AFABP level and longitudinal changes in LV remodelling and diastolic function in patients with T2DM. The key finding of this study was that circulating AFABP level was not only associated with LV remodelling and diastolic dysfunction at baseline but also the longitudinal increase in LV mass and E/e′ ratio after a follow-up of 28 months. Moreover, we demonstrated that circulating AFABP level was an independent predictor of MACE in T2DM patients without CVD at baseline.Although previous studies have examined the association between circulating AFABP level with LV remodelling and diastolic dysfunction in various groups of patients –21, 33, A major strength of our study is the longitudinal echocardiography assessments using a prospective cohort of T2DM patients without CVD. Echocardiography is a readily available imaging modality that enables the detection of adverse LV remodelling and diastolic dysfunction in T2DM patients . PreviouIn addition, while previous studies have demonstrated that AFABP predicted MACE in patients with CAD , our stuAlthough we  and otheIt has been increasingly recognized that the presence of LV hypertrophy and diastolic dysfunction is common in patients with T2DM and is associated with adverse clinical outcomes. Nonetheless, the underlying mechanisms of adverse LV remodelling and myocardial dysfunction is uncertain and likely to be multifactorial. Our findings provide clinical evidence that an elevated circulating AFABP level is associated with the development of adverse LV remodelling, diastolic dysfunction and MACE in T2DM. It is therefore of great interest that targeting AFABP might be a potential strategy to prevent adverse LV remodelling, diastolic dysfunction and subsequent adverse events in patients with T2DM. Indeed, prior studies have reported that lifestyle modification with exercise , 56, omeOur study has several limitations. First, the sample size of this prospective study was underpower to estimate the correlation of AFABP with LV remodelling and myocardial dysfunction between BMI subgroups or sex-specific analyses. Second, advanced analysis method such as two-dimension speckle tracking or stress echocardiography could be applied to further confirm the association between AFABP and LV systolic dysfunction. Third, our study only included T2DM patients without existing CVD and future study is required to clarify the role of AFABP in cardiac remodelling and function in T2DM patients with concomitant CVD. Moreover, since only baseline circulating AFABP level was measured, the present study could not evaluate the association of longitudinal changes of circulating AFABP level with LV remodelling and myocardial dysfunction. Lastly, although sodium-glucose co-transporter 2 inhibitors (SGLT2i) has been associated with both changes in AFABP levels and reduction in risk of heart failure in T2DM patients, all of our participants were recruited before SGLT2i became available and hence the effects of SGLT2i in the relationship between AFABP and cardiac remodelling could not be evaluated.This prospective study demonstrated that baseline circulating AFABP level was independently associated with a longitudinal increase in LV mass, worsening of diastolic dysfunction and incident MACE among T2DM patients without coexisting CVD. Our findings provided important insights for the planning of future randomized trials that explore targeting AFABP as a potential therapeutic strategy to reduce LV remodelling, diastolic functional deterioration and subsequent adverse events in patients with T2DM.Additional file 1. Table S1. Intraobserver and interobserver reproducibility of echocardiography parameters. Table S2. Clinical characteristics and echocardiography parameters of participants at baseline and follow-up. Table S3. Univariate linear regression showing the variables associated with changes in echocardiography parameters. Table S4. Clinical characteristics of participants stratified by incident MACE.


High ischemic mitral regurgitation (IMR) recurrence rates continue to plague IMR repair with undersized ring annuloplasty. We have previously shown that pre-repair three-dimensional echocardiography (3DE) analysis is highly predictive of IMR recurrence. The objective of this study was to determine the quantitative change in 3DE annular and leaflet tethering parameters immediately after repair and to determine if intraoperative post-repair 3DE parameters would be able to predict IMR recurrence 6 months after repair.Intraoperative pre- and post-repair transesophageal real-time 3DE was performed in 35 patients undergoing undersized ring annuloplasty for IMR. An advanced modeling algorhythm was used to assess 3D annular geometry and regional leaflet tethering. IMR recurrence (≥ grade 2) was assessed with transthoracic echocardiography 6 months after repair.n = 9) and patients with non-recurrent IMR (n = 26). No intraoperative post-repair predictors of IMR recurrence could be identified.Annuloplasty significantly reduced septolateral diameter, commissural width, annular area, and tethering volume and significantly increased all segmental tethering angles (except A2). Intraoperative post-repair annular geometry and leaflet tethering did not differ significantly between patients with recurrent IMR  is highly predictive of recurrent IMR, whereas immediate post-repair 3D valve geometry (which does not completely reflect chronic left ventricular remodeling anymore) is not. Despite the general belief that undersized ring annuloplasty is the preferred surgical treatment strategy for all patients with ischemic mitral regurgitation (IMR), the durability of undersized ring annuloplasty is limited by the fact that recurrent IMR develops in 30% or more of patients in a few months after surgery , 2. IMR The literature on mitral valve (MV) geometry directly after annuloplasty is relatively sparse. 3DE valve analysis might give us more accurate insights into the quantitative effect of annuloplasty on mitral valve geometry. 2DE studies have shown that undersized annuloplasty may exacerbate leaflet tethering and that this may be a possible mechanism of recurrent IMR –9.We hypothesized that the degree of intraoperative post-repair mitral leaflet tethering would determine the risk of IMR recurrence after undersized ring annuloplasty. We have previously published the pre-repair 3DE and 2DE results of 50 patients with IMR who underwent repair , and to This study was approved by the Institutional Review Boards of the University of Pennsylvania, the University of Pittsburgh, and the Beth Israel Deaconess Medical Center. Written informed consent was obtained from all patients.Fifty patients with severe IMR underwent MV repair with an undersized annuloplasty ring. Pre- and immediate post-repair TEE was performed in all patients. Fifteen patients had intraoperative post-repair 3DE images of insufficient quality for modeling and were excluded. The remaining 35 patients were included for analysis. Table 8. Recurrent IMR 6 months after repair was defined as IMR ≥ grade 2.Two-dimensional (2D) transthoracic echocardiography was performed preoperatively and six months after repair. Images were acquired through a transthoracic apical four chamber view. Severity of IMR was determined semi quantitatively with color Doppler by assessing the area of the regurgitant jet as a percentage of left atrial area in the apical four chamber view. The following grading scale was used: grade 0, no IMR; grade 1, less than 20%; grade 2, 20 to 40%; grade 3, 40 to 60%; and grade 4, more than 60% Pre-repair real-time 3D TEE images were obtained after induction of anesthesia and prior to sternotomy. Post-repair images were obtained after MV repair and weaning off cardiopulmonary bypass. TEE images were obtained with a systolic blood pressure of at least 100 mmHg. IMR grade was 0 (no/trace) or 1 (only mild) in all patients after repair. TEE images were also obtained for 21 patients with normal mitral valves and LV function who underwent cardiac surgery for indications other than MV disease. Images were acquired through a mid-esophageal view using a Philips IE33  ultrasound system equipped with a 2- to 7-MHz X7-2t TEE matrix transducer. During 4 cardiac cycles the images were acquired with a volumetric frame rate of 17–30 Hz and an imaging depth of 12–16 cm. This way a full volume real-time 3DE data set could be obtained.The full volume 3D data set was exported to an Echo-View 5.4  software workstation. All analyses were performed in midsystole. Techniques of annular and leaflet segmentation have been described previously . The CarDetermination or calculation of septolateral diameter, intercommissural width, transverse diameter, annular area, annular circumference, tethering area, tethering volume, tethering index, posterior- and anterior tethering angle, and segmental (mean) tethering angles were described previously , 6.Mitral valve tethering index was calculated by dividing mitral valve tethering volume by mitral annular area. Tethering volume is strongly influenced by annular size and to correct for annular geometry we introduced the mitral valve tethering index .2 test or Fisher exact test (two-sided) as appropriate for categorical variables and the independent samples t-test or Mann-Whitney U test (two-sided) as appropriate for continuous variables. Within-group comparisons were performed using the paired samples t-test for continuous variables. Statistical significance was established at P < 0.05.All calculations were performed using IBM SPSS Statistics 23.0 . Continuous variables were expressed as mean ± standard deviation. Categorical variables were expressed as percentages. Comparisons between groups were performed using Pearson χA total of 9 patients (26%) experienced recurrent IMR 6 months after undersized annuloplasty. Based on these findings patients were divided in recurrent and non-recurrent IMR groups. Preoperative and intraoperative patient characteristics are presented in Table P < 0.05 for all variables). MV tethering volume was significantly reduced (P < 0.05), tethering index did not change significantly (P = 0.96). All segmental tethering angles significantly increased after annuloplasty, except for the A2 tethering angle. The posterior tethering angles (P1-P3) changed most (> 20°). Figure In Table  angles P-P3 changP < 0.05). All postoperative annular and tethering variables were not significantly different between recurrent and non-recurrent groups. Figure A comparison between the non-recurrent and recurrent IMR subgroups was made in Table Undersized annuloplasty is generally still considered the preferred surgical treatment strategy for IMR , 12, 13.This post-repair study clearly shows the immediate effect of undersized annuloplasty on 3D annular and leaflet geometry. Although MV tethering volume was significantly reduced after repair, which can be explained by the fact that the mitral annular area is extensively reduced by annuloplasty, leaflet tethering increases significantly in nearly all segments. An important finding in this study is the very high and significant increase in posterior leaflet tethering. This is in line with the results of previous 2DE studies and has been proposed as a possible mechanism of recurrent IMR , 8. Zhu Pre-repair leaflet tethering is basically a reflection of subvalvular remodeling in IMR and is a predictor of IMR recurrence in several studies , 14, 15.The one and two year outcomes of the CTSN trial showed that there was no difference in LV diameter after mitral valve repair versus replacement, nor in a composite endpoint of major adverse cardiac or cerebrovascular related events, functional status or quality of life , 16. IMRA substudy of the CTSN trial by Capoulade et al focused on a relatively new parameter, the LV end-systolic diameter to ring size ratio, which appeared to be a significant predictor for IMR recurrence . This “LOur previous studies have shown that pre-repair 3DE mitral valve modeling is highly predictive of IMR recurrence and that its predictive value is much higher than that of 2DE mitral parameters , 6. The n = 35) and follow-up was relatively short (6 months). Fifteen of the original 50 patients had intraoperative post-repair 3DE images of insufficient quality for modeling and were excluded. (2) The segmentation and modeling methodology of 3D TEE images requires time-consuming off-line analysis. Therefore, work is in progress to develop and validate an automated segmentation technique that will allow image processing and mitral leaflet segmentation in minutes rather than hours [There were several limitations in this study. (1) The number of patients was relatively small Undersized ring annuloplasty changes mitral geometry acutely, exacerbates leaflet tethering, and generally fixes IMR acutely, but it does not always fix the delicate underlying chronic problem of continued LV dilatation and remodeling. This may explain why pre-repair 3D valve geometry (which reflects chronic LV remodeling) is highly predictive of recurrent IMR, whereas immediate post-repair 3D valve geometry (which does not completely reflect chronic LV remodeling anymore) is not.


Non-invasive assessment of myocardial ischemia is challenging. Because the BOLD (Blood Oxygen Level Dependent) effect mainly relies on endogenous contrast to differentiate ischemic from non-ischemic tissue, BOLD has the potential to directly assess myocardial oxygenation.2*-weighting is easily achieved using triggered, mid-diastolic echo planar imaging (EPI), it can be sensitive to artifacts. However, by using a cine-EPI approach, it may be possible to use a lower effective TE (TEeff), thereby reducing artifacts but maintaining BOLD sensitivity by averaging several mid-diastolic phases during analysis.Though TTo demonstrate that a cine-EPI sequence can be used to detect adenosine-induced oxygenation changes in a stenosis dog model.We developed a cine EPI sequence with the goal of obtaining strong BOLD-weighted imaging but without significant image artifacts. Cine phases were acquired using prospective ECG-triggering, a breath hold (~12 s), a short echo train (4 echoes) with a segmented approach (8 lines/segment), and a bipolar readout. All studies were performed on a 1.5 T MAGNETOM Avanto  in canines (n = 4) with a balloon catheter fluoroscopically guided into the left circumflex or left anterior descending coronary artery, to create stenoses as validated by simultaneous fractional flow reserve.2; matrix = 123 × 128; thickness = 10 mm; temporal resolution = 49 ms; flip angle = 15°; TEeff = 15 ms.We obtained cine-EPI images in a mid-ventricular slice, before and during an adenosine infusion of 140 μg/kg for two minutes. We repeated this process twice, once with a mid-grade stenosis and once with a high-grade stenosis. At the end of the study, we injected gadolinium (Gd) via our intracoronary catheter and ran a perfusion scan to verify the territory affected by the stenosed artery. We then injected Gd intravenously and performed late enhancement (LE) to verify the absence of infarct. Sequence parameters for cine-EPI: FOV = 300 × 300 mm42, Circle Cardiovascular Imaging Inc., Canada). We used the intracoronary perfusion images to identify the affected and remote myocardium. By averaging 4 phases corresponding to mid-diastole, we measured mean signal intensity (meanSI) in the affected and remote territory during no stenosis and the two stenosis levels, when the subject was at rest and during adenosine infusion. For each territory, we calculated the adenosine response as a percent change in image meanSI going from rest to stress (%ΔSIaden) for each of the three stenosis levels . We then compared %ΔSIaden in a particular territory for the different stenosis levels using a matched pairs t-test (α = 0.05).We analyzed the data using a clinically validated software package  was 12.3% ± 3%, 11.7% ± 4%, and 11.3% ± 3% respectively. In the affected territory, the same measurements were 12.0% ± 1%, 8.6% ± 1%, and 1.2% ± 1%. Looking at each stenosis level, there was only a statistically significant difference between the two territories for the high-grade stenosis. Looking at each territory, there was no statistically significant difference between the %ΔSIaden observed for the different stenosis levels in the remote territory. For the affected myocardial territory, there was a statistically significant decrease in %ΔSIaden going from baseline to either stenosis level, as well as going from mid- to high-grade stenosis. No LE was observed.The results are summarized in the Figure eff than previously reported for EPI cardiac BOLD because we were able to signal average over several cardiac phases, which in turn reduced image artifacts. Cine-EPI shows promise for identifying regions of ischemia in CMR, simultaneous to functional assessment.We have shown that cine-EPI can accurately detect changes in adenosine response in myocardium affected by a high-grade stenosis. We could use a lower TE


Radiotherapy for breast cancer (BC) and its resulting cardiac exposure are associated with subclinical left ventricular dysfunction characterized by early decrease of global longitudinal strain (LS) measurement based on 2D speckle-tracking echocardiography. Recent software allows multi-layer and segmental analysis of strain, which may be of interest to quantify and locate the impact of cardiac exposure on myocardial function and potentially increase the early detection of radiation-induced cardiotoxicity. The aim of the study was to evaluate whether decrease in LS 6 months after radiotherapy is layer-specific and if it varies according to the left ventricular regional level and the coronary arterial territories.LS was measured at baseline before radiotherapy and 6 months post-radiotherapy. The LS was obtained for each myocardial layer , left ventricular regional level  and coronary artery territory (left anterior descending artery (LAD), circumflex artery, right coronary artery).p = 0.02), but only the relative decrease of LS in the endocardial layer was close to be significant . More precisely, the LS of the endocardial layer was significantly decreased for the most exposed parts of the left ventricle corresponding to the apical level  and LAD territory .The study included 64 left-sided BC patients. Mean age was 58 years, mean doses to the heart, the left ventricle and the LAD were respectively 3.0, 6.7 and 16.4 Gy. The absolute decrease of LS was significant for the three layers (endocardial: − 20.0 ± 3.2% to − 18.8 ± 3.8%; mid-myocardial: − 16.0 ± 2.7% to − 15.0 ± 3.1%; epicardial: − 12.3 ± 2.5% to − 11.4 ± 2.8%, all Six months post-radiotherapy, LS decreased predominantly in the endocardial layer of the most exposed part of the left ventricle. For precise evaluation of radiotherapy-induced cardiotoxicity and early left ventricular dysfunction, the endocardial layer-based LS might be the most sensitive parameter.NCT02605512, Registered 6 November 2015 - Retrospectively registered.ClinicalTrials.gov:  Radiotherapy (RT) is a major component of breast cancer treatment. Despite its benefits, it is now commonly accepted that breast cancer RT can be associated with long-term cardiac complications, including coronary artery diseases, due to the presence of cardiac tissues in the irradiation field –3. Long However, the left ventricular wall of the heart is composed of three myocardial layers: endocardial, mid-myocardial, and epicardial. Of these 3 layers, the endocardial layer is the most susceptible of ischemic injury  and poteCardiac exposure due to breast cancer RT is not homogeneous . HighestBased on the BACCARAT prospective cohort of left and right BC patients treated with 3D-CRT, we had presented a 6-month interim follow-up analysis on a secondary outcome measure defined by a decrease of global LS from baseline to 6 months after RT . In the n = 20) remaining 79 patients [The BACCARAT study initially included 118 female patients of the Clinic Pasteur Toulouse from October 2015 to December 2017, aged 40 to 75 years old, mainly with left unilateral BC, and in a smaller proportion with right-sided unilateral BC. All patients were treated with adjuvant 3D-CRT after breast conserving surgery or mastectomy, without chemotherapy. Five patients withdrew consent, 8 patients had abnormal LVEF before RT (LVEF < 45%) and 6 patients without available cardiac dosimetry were excluded. We excluded patients with echocardiographies for which the image quality was too low for a reliable assessment of longitudinal strain (patients . For thehttp://www.dosisoft.com/en/radiotherapy/planning-products.html), manual delineation was performed for the left ventricle (LV), the left anterior descending artery (LAD), the left circumflex artery (Cx) and the right coronary artery (RCA). Using the 3D dose matrix generated during treatment planning and the new delineated substructures, DVH for LV and coronary arteries were generated with ISOgray TPS by the dosimetric department of IRSN in collaboration with the Clinic Pasteur radiotherapy department. We thus obtained mean doses for the following cardiac structures: whole heart, left ventricle, left anterior descending artery, circumflex artery and right coronary artery.All patients were treated with 3D-CRT. The prescription dose was delivered over 5 weeks: either 50 Gy in 25 daily fractions of 2 Gy or 47 Gy in 20 daily fractions of 2.35 Gy. The methods to evaluate radiation doses in BACCARAT patients were presented elsewhere , 19, 23.Transthoracic echocardiography was performed at baseline before RT and 6 months after RT with ultrasound Acuson S2000 device , using a 3 MHz transducer. Image analysis was independently performed by a single blinded observer unaware of clinical data. Longitudinal strain (LS) measurement was evaluated using two-dimensional speckle tracking  using a t-test or Wilcoxon non-parametric test was used to compare continuous variables, adapted to paired samples for the comparison of echocardiographic variables before RT and 6 months after RT. Comparison of layer-specific LS at baseline and RT + 6 months were performed, mean relative change was evaluated (Mean = V6 – V0 / V0). Specific analysis of segmental strains values according to regional level or coronary arteries territorial areas was performed, and the evolution of LS in these levels from baseline to RT + 6 months was analyzed. We compared these evolutions according to the group of exposure . Given the exploratory nature of this work, we presented unadjusted p-values for comparisons, but in order to take into account multiple testing in these comparisons we also applied the Holm–Bonferroni method, a step-down procedure performed after conducting the multiple comparison tests. Finally, p-value < 0.05 was considered statistically significant. All statistical analysis was performed using SAS statistical software for Windows .Continuous variables are presented with mean and standard deviation or median and interquartile range values. Categorical values are presented with percentages. Student’s 2, respectively. Moreover, 8% of patients had diabetes, and 47% were current smokers. The mean dose received by the left ventricle was more than twice as high as the mean dose received by the whole heart . For coronary arteries exposure, the highest mean dose was found in the LAD (16.41 ± 7.41 Gy), while the lowest mean dose was found in the RCA (0.71 ± 0.37 Gy).Sixty-four left-sided breast cancer patients were included in the analysis. Baseline characteristics of the population are shown in Table p = 0.05) whereas for other layers, the mean relative change was slightly lower.Echocardiography parameters are displayed in Table p = 0.03). After Holm-Bonferroni method for multiple testing for 3 tests, this decrease did not reach statistical significance. While separating patients into two groups according to their exposure to the left ventricle (Table 3), the regional analysis showed that LS decreased significantly after RT at the apical level in the highly exposed group corresponding to the 22 patients with LV Dose >66th percentile = 8.6 Gy , which did not remain significant after multiple testing correction. More precisely, the segmental analysis of strain values  showed a decrease in all segments of the apical level, with significant deteriorations in the apical inferior segment (segment 15) and the mid-anteroseptal segment (segment 8), but not significant after Holm-Bonferroni method.Among the three regional left ventricular levels, a significant decrease of the LS was observed only in the apical level . While separating patients into two groups according to their exposure to the left ventricle (Table p = 0.05).The coronary arteries territorial analysis showed no significant decrease for the Cx and the RCA. However, an alteration of the LS was observed for the LAD territory , and this result remained significant after Holm-Bonferroni method for 2-tests comparisons. No significant difference could be observed in less exposed patients, corresponding to a decrease of LS from − 22.3% at V0 to − 19.5% at V6  [Several limitations should be mentioned. The first point is not specific of our study, but a general limitation of global LS to know how the changes in LS might translate into clinical cardiac outcome parameters . In the context of chemotherapy, it has been showed that there is a correlation and a predictive value of GLS decrease on the later presence of the outcome CTRCD (Cancer Therapeutics-Related Cardiac Dysfunction) defined by a decrease in LVEF of at least 10% to a value < 53% . Howeverecrease) . In the ecrease) , 31. Furecrease) , limitedecrease) . Our resWith a follow-up of 6 months after RT, LS decrease was predominantly in the endocardial myocardial layer and appeared to be localized in the most exposed part of the left ventricle. For precise evaluation of RT-induced cardiotoxicity and early left ventricular dysfunction, the endocardial layer-based LS might be the most sensitive parameter, in particular to evaluate the impact of radiation exposure during BC RT to the LAD. However, this exploratory analysis remains to be confirmed with larger studies and longer follow-up.


Growing interest lies in the assessment of the metabolic status of patients with a univentricular circulation after Fontan operation, especially in changes of amino acid metabolism. Using targeted metabolomic examinations, we investigated amino acid metabolism in a homogeneous adult Fontan-patient group with a dominant left ventricle, seeking biomarker patterns that might permit better understanding of Fontan pathophysiology and early detection of subtle ventricular or circulatory dysfunction. We compared serum amino acid levels  in 20 adult Fontan patients with a dominant left ventricle and those in age- and sex-matched biventricular controls. Serum concentrations of asymmetric dimethylarginine, methionine sulfoxide, glutamic acid, and trans-4-hydroxyproline and the methionine sulfoxide/methionine ratio (Met-SO/Met) were significantly higher and serum concentrations of asparagine, histidine, taurine, and threonine were significantly lower in patients than in controls. Met-SO/Met values exhibited a significant negative correlation with oxygen uptake during exercise. The alterations in amino acid metabolome that we found in Fontan patients suggest links between Fontan pathophysiology, altered cell energy metabolism, oxidative stress, and endothelial dysfunction like those found in biventricular patients with congestive heart failure. Studies of extended amino acid metabolism may allow better understanding of Fontan pathophysiology that will permit early detection of subtle ventricular or circulatory dysfunction in Fontan patients. Besides limited cardiac output, alterations that mark Fontan hemodynamics are passive flow to the lungs, chronically elevated venous pressures, and congestion. Unfortunately, the clinical use of traditional markers such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels for non-invasive diagnostics and monitoring in such patients is limited4. Thus, for early detection of cardiac and circulatory derangement and for evaluation and tailoring of treatment options, regular functional assessment of these patients is crucial, with complete clinical examination, electrocardiogram, imaging studies, determination of values for traditional laboratory markers, or exercise capacity testing. In adult biventricular patients, novel candidate biomarkers, in addition to natriuretic peptides and troponins, for congestive heart failure and vascular perturbations have been identified via metabolomics, the study of small organic molecules, their synthesis, and their breakdown6. Interest has grown recently in the metabolic status of Fontan patients: besides reported abnormalities in Fontan patients’ glucose metabolism7, to date their handling of lipids has been best studied, with important changes shown, especially in the cholesterol, lipoprotein, and phospholipid pathways, hinting at chronic low-level inflammation and at altered cell signalling and energy metabolism as are found in biventricular patients with congestive heart failure9. In the biventricular patient with heart failure, alterations occur especially in the handling of amino acids important in both myocardium protein turnover and energy metabolism10. Additionally, the Fontan-specific characteristic of chronically elevated venous pressure favors development of a protein losing enteropathy together with end-organ, especially liver, dysfunction2. Thus, study of the metabolism of amino acids also should be a promising field in Fontan patients. With the help of targeted metabolomic examinations we hence elected to investigate amino acid metabolism in a homogeneous adult Fontan-patient group with a dominant left ventricle, seeking biomarker patterns that might permit a better understanding of Fontan pathophysiology or early detection of ventricular or circulatory dysfunction.Ventricular dysfunction and circulatory failure with progressing end-organ impairment like renal or liver dysfunction are an important cause of morbidity and mortality in adults with complex congenital heart disease (CHD), especially in patients with single-ventricle types of CHD and Fontan circulation9. Table 2 at the anaerobic threshold and at maximum were significantly lower than in controls.After applying all inclusion and exclusion criteria, 20 adult Fontan patients with a systemic left ventricle were selected for the study , gamma glutamyl transferase and alanine aminotransferase activities, total bilirubin and creatinine concentrations , and international normalized ratio (INR) values and triglyceride and high density lipoprotein-cholesterol (HDL-C) concentrations (“triglycerides” and “HDL-C”) differed significantly between Fontan patients and controls Table .Table 2VSerum concentrations of 29 amino acids or biogenic amines and their derivatives were determined, with selected sums and ratios Table , Fig. 1.Among routine analytes, the variables hemoglobin, albumin, and triglycerides displayed significantly positive correlations with glutamic acid. Creatinine and triglycerides displayed significantly positive correlations with ADMA, as did the variables creatinine and total bilirubin with Met-SO. Hematocrit, hemoglobin, and INR as well as minimum and maximum oxygen saturations revealed significantly positive correlations with Met-SO/Met values, and oxygen uptake at the anaerobic threshold and maximum oxygen uptake displayed significantly negative correlations with Met-SO/Met values. Single significant correlations between isolated variables included positive correlation of albumin with ornithine and serine, of triglycerides with alpha aminoadipic acid, and of the oxygen uptake at the anaerobic threshold with threonine as well as negative correlations of alanine aminotransferase activity with taurine and of INR with serotonin. No further correlations were identified, especially none with CRP or NT-proBNP  cell energy metabolism and an elevated myocardial protein turnover as well as at oxidative stress and endothelial dysfunction, as found in biventricular patients with congestive heart failure.10. Decreased concentrations of taurine are described in patients with dilated cardiomyopathy and in golden retrievers with heart failure11, and many studies report a beneficial effect of taurine supplementation on myocardial function in patients with congestive heart failure12.Decreased serum concentrations of taurine, asparagine, and threonine and increased concentrations of glutamic acid and hydroxyproline in our Fontan patients indicate alterations in  cell energy metabolism and elevated myocardium protein turnover, as found in biventricular patients with congestive heart failure. Taurine is abundant in myocardial tissue, with a major function in regulation of the respiratory chain: the taurine-deficient heart suffers impaired respiratory chain function and diminished long chain fatty acid uptake by mitochondria, as found in patients with congestive heart failure13. Against the background of a switch in heart failure of preferred myocardial energy substrate from fatty acids to glucose and ketone bodies14, our findings hint at altered myocardial energy metabolism, indicating subtle ventricular dysfunction. This idea is supported by glutamic acid’s involvement in the synthesis of metabolites, e.g., by serving as a precursor for the biosynthesis of amino acids such as proline and arginine16. Indeed, increased serum levels of glutamic acid indicate increased protein turnover, as typical in adults with congestive heart failure or coronary heart disease18. The same is true for threonine, a major component of proteins, e.g., of collagen and immunoglobulins: We found decreased serum threonine levels, and decreased plasma levels are described in patients with chronic heart failure17. The increase that we observed in hydroxyproline, an analyte used to track collagen degradation, also reflects elevated protein turnover: Elevated urine and serum hydroxyproline levels are reported after muscle damage or in the bedridden and elderly20.Glutamic acid and asparagine also take part in central pathways of aerobic cell respiration and thereby of energy production. Via anaplerotic reactions, both amino acids are substantially involved in the tricarboxylic acid cyclei.e., under oxidative stress and during endothelial dysfunction, both of which are directly linked to heart failure: Nitrous oxide (NO) synthase (NOS) isoforms are expressed not only in endothelial cells but also in cardiomyocytes, and NO regulates cardiac function through vascular-dependent and -independent effects, with, in the healthy heart, a positive inotropic effect at low NO exposure and a negative one at higher exposure22. In heart failure, regulation of myocardial NO production and release breaks down, with excessive release, and peripheral and vascular endothelial NOS activity is lost, resulting in endothelial dysfunction with decreased NO bioavailability attributable to increased oxidative stress23. In the course of cardiac decompensation, NO likely influences several of the core features of cardiac failure, e.g., chamber dilation, defective b-adrenergic responsiveness, and calcium cycling22.Protein turnover also is elevated in  the presence of hyperreactive oxygen species, 26. ADMA values reportedly track enhanced cardiovascular risk with endothelial dysfunction28, positively correlating with age, mean arterial pressure, renovascular resistance, intimal media thickness, and peripheral arterial occlusive disease33, ADMA is additionally involved in further nitric oxide (NO)-dependent signalling processes, interfering with anti-thrombotic, anti-inflammatory, and anti-apoptotic actions21.That serum concentrations of ADMA were elevated also suggests that our Fontan patients were under oxidative stress, with altered endothelial function, consistent with subtle ventricular dysfunction. ADMA, a methyl derivate of arginine, is involved in NO-signalling and in pro- and antioxidant and -inflammatory processes. It is the major endogenous inhibitor of nitric oxide synthase (NOS). By displacing arginine, the normal NOS substrate, ADMA enhances oxidative stress by influencing NO-reactive oxygen species balance and disturbs vasodilation34. Increased Met-SO levels have been reported in vascular disease, cardiac ischemia, and in left ventricular diastolic dysfunction36. The negative correlation observed between Met-SO/Met values and oxygen uptake under exercise strikingly emphasizes the role of markers of oxidative stress as indicators for subtle ventricular dysfunction in our patients. Finally, our hypothesis that oxidative stress affects our patients is supported by the decreased level found of histidine, with its anti-oxidant and anti-inflammatory properties37, and by decreases in HDL-C40. A direct interplay of lipoprotein metabolism and markers for oxidative stress exists: lipoprotein disorders are associated with increased ADMA41.The increases in value for Met-SO and for the Met-SO/Met ratio as indicators of systemic oxidative stress also suggest that our patients are under oxidative stress and suffer from endothelial dysfunction. Reaction with oxygen species yields Met-SO, which activates endogenous antioxidant enzymes such as Met-SO reductase A and induces synthesis of glutathione, thereby counteracting oxidative stress and inflammation33. Thus we stress that our findings of altered amino acid serum levels might imply subtle rather than frank heart failure43, a hypothesis supported by the fact that we found no correlation of any of the metabolites with the traditional marker for heart failure, NT-proBNP, nor with the traditional marker for inflammation C-reactive protein, and by the fact that neither by traditional clinical-laboratory means nor by metabolomic (Fischer ratio) criteria did we find any evidence for important (Fontan-associated) liver disease in our patients. Given that many adult Fontan patients will develop ventricular dysfunction, to hypothesise subtle heart failure in our patient group might well be appropriate1. Still, with respect to the definition of heart failure, which is the “inability of the heart to meet resting and exercise demands at low filling pressures”2, we cannot exclude with certainty that the metabolic alterations delineated solely reflect Fontan-specific pathophysiology with its circulatory abnormalities, with paramount abnormal systemic or pulmonary endothelial function, and with a tendency towards the formation of veno-venous or aortopulmonary collaterals48.ADMA also has been used to track heart failure in patients with CHD, and with regard to heart failure is even more sensitive than NT-proBNP. However, only 13% of the patients studied had univentricular heart disease; in addition, patient exercise capacity was lower than that in our patient group50.To examine the amino acid profile of Fontan patients with frank ventricular, circulatory, or hepatic impairment and to correlate increases in serum ADMA and Met-SO content with direct measurement of endothelin or with collateral vessel flow via magnetic resonance imaging studies thus would be of interestBecause Fontan patients are few, the studied group size is small, possibly limiting the extent to which our findings can be generalized. Also limiting may be our choice of a targeted metabolomic approach and a commercial kit, as metabolites not assessed may be important. That we analyzed serum samples precludes direct comparison between our results and those of studies that used tissue samples, and we acknowledge that having assayed serum rather than vascular or myocardial tissue, we cannot rule out certain system-driven aspects of disease pathogenesis: That is, unknown confounders that affect metabolic profiles might be the true basis for the observed differences. Moreover, differences in body composition or lifestyle parameters might have influenced our results to an unknown degree. We strove to lessen the likelihood of such errors by following a strict inclusion and exclusion protocol, especially with regard to (known) comorbidities or medication.The striking alterations in amino acid profile that we found may link Fontan pathophysiology with altered cell energy metabolism, oxidative stress, and endothelial dysfunction as found in biventricular patients with congestive heart failure. Markers identified through mass spectrometry-based extended amino acid metabolism might thus complement traditional diagnostic tools such as imaging, exercise capacity testing, and traditional laboratory biomarker determinations, yielding a better understanding of Fontan pathophysiology, and they are promising candidates for the early detection of ventricular or circulatory dysfunction in Fontan patients.9.Like our recently published results on phospholipid and acylcarnitine metabolomic examinations, this work is a subwork of the main study protocol 9. All patients had undergone two-stage palliation with partial and total cavopulmonary anastomosis. None had had aortic reconstruction or aortopulmonary shunting. Table https://strobe-statement.org/index.php?id=strobe-home]) , at the anaerobic threshold , and maximum uptake of oxygen  were measured.Clinical and laboratory examinations were performed as described in detail elsewhere9.Blood studies required samples 0.5 ml greater than those for routine assessments to permit determinations of concentrations of amino acid-metabolism analytes. The blood sample was directly drawn into a tube containing a clotting activator and centrifuged within 20 min  for separation of serum. Serum aliquots were immediately frozen and stored at -80 °C for further analyses. Frozen samples were transported on dry ice to the analysing laboratory. Analyses were performed in batches of 10 samples9. The AbsoluteIDQ p180 kit assay  permitted targeted, fully automated quantification of 188 analytes (42 amino acids or biogenic amines and their derivatives) based on phenylisothiocyanate derivatization in the presence of internal standards followed by liquid chromatography mass spectrometry using a TSQ-Vantage  instrument with electrospray ionization.Before analysis, all serum samples were processed as described, with samples thawed on ice, then centrifuged; the supernatant was subjected to further analyses9.To exclude metabolites below the limit of detection (LOD), the raw data (µmol/L) were cleaned applying a modified 80% rule; for statistical analysis at least 80% valid values above LOD needed to be available per analyte in the samples for each group. This reduced the dataset to 143 analytes (29 amino acids or biogenic amines and their derivatives). Remaining values below LOD were imputed applying a logspline method with values between LOD and LOD/2. After log2 transformation of metabolomics data as well as of routine analytes and clinical data the dataset underwent multivariate  and univariate statistical analyses. Student’s t-testing with a Benjamini-Hochberg correction identified significant metabolite  differences between patients and controls. P-values were calculated to identify significant changes between controls and Fontan patients, and were adjusted for multiple testing, or false discovery rate (FDR), according to Benjamini and Hochberg. To interpret the correlation, the significance of the correlation was calculated from r and from the degrees of freedom (a variable dependent on the sample number) , and of the Heart and Diabetes Center North-Rhine Westphalia, Ruhr University of Bochum, Germany (AZ 52/2016), the methods were carried out in accordance with the relevant guidelines and regulations, and the subjects gave written informed consent.https://www.metaboanalyst.ca/ and on the Kyoto Encyclopedia of Genes and Genomes (KEGG).Information about analytes and the pathways in which they are involved was based on Supplemental Figure 1.Supplemental  Table 1.Supplemental Table  2.


GLS impairment was also moderately correlated with the percentage edema at CMR . At follow-up, GLS improved in all patients (p < 0.001), and normal values were found in 13/19 patients with baseline reduction. Accordingly persistent global and regional impairment was still observed in 6 patients. Patients with persistent LS reduction demonstrated residual focal cardiac fibrosis at follow-up CMR. Both global and regional LS is able to identify abnormalities in systolic longitudinal mechanics in children and adolescents with focal myocarditis and normal ejection fraction. The reduction in LS is consistent with edema amount and localization at CMR. Furthermore, LS identifies regional recovery or persistent cardiac function impairment, possibly related to residual focal fibrosis.The aim here was to describe the role of speckle tracking echocardiography (STE), in identifying impairment in systolic function in children and adolescents with focal myocarditis and without reduction in ejection fraction. We describe data from 33 pediatric patients (age 4–17 years) admitted for focal myocarditis, confirmed by cardiac magnetic resonance (CMR), and without impaired ejection fraction and/or wall motion abnormalities. All children underwent Doppler echocardiography examination with analysis of global (G) and segmental longitudinal strain (LS) and CMR for the quantification of edema and myocardial fibrosis. Reduction in LS was defined according to age-specific partition values. At baseline, impaired GLS was present in 58% of patients (n = 19), albeit normal ejection fraction. LS was also regionally impaired, according to the area of higher edema at CMR (i.e. most impaired at the level of the infero-lateral segments as compared to other segments ( In contrast, incidence of pediatric focal myocarditis with normal ejection fraction (EF) might be significantly underestimated, as in children and adolescents, clinical presentation is limited to non-specific chest pain2. Accordingly, when symptoms are mild and non-specific, children not always undergo ECG tracing and testing for laboratory troponin levels in the Emergency Room4. In addition, when cardiac evaluation is performed, abnormalities might not be evident on ECG and no significant abnormalities in regional and/or global systolic abnormalities might be found on echocardiography4. In fact, since in focal myocarditis edema is located in the epicardial layer of the ventricular wall, only cardiac magnetic resonance (CMR) permits its direct detection5.The incidence of overt myocarditis with impaired contractile function in children is estimated around 1 per 100,000 children per year6. However, when left ventricular (LV) EF is normal and symptoms are transient , EMBs are usually not performed, especially in children due to the inherent procedural risk of this invasive procedure7. CMR has been used as a non-invasive diagnostic tool, offering a 79% accuracy rate, when applying strict diagnostic criteria8. However, accessibility of CMR is often limited and thus it might not always be performed in children with suspected myocarditis. Furthermore, in younger children limited patient compliance might require sedation to perform the study. Eventually, evaluation of focal myocarditis using CMR requires substantial experience, which might not be available in all clinical settings9. Consequently, diagnosis and risk stratification of acute focal myocarditis by an objective measure remains a clinical challenge in pediatric setting. Standard 2D echocardiography is often the preferred imaging test, but its diagnostic accuracy is significantly limited. In contrast, quantitative measurement of regional myocardial deformation by Speckle Tracking Echocardiography (STE), may offer better sensitivity than conventional echocardiography for the detection of subclinical LV dysfunction and it may therefore improve the diagnostic and prognostic accuracy in acute focal myocarditis patients12. This might be particularly relevant in children with normal conventional echocardiographic parameters of the left ventricle.In severe forms of myocarditis, endomyocardial biopsy (EMB) with Dallas diagnostic criteria, is suggestedOur aim was to evaluate the ability of STE in identifying acute abnormalities in systolic function occurring during focal myocarditis (confirmed by at least one revised CMR Lake Louise criteria) in children with normal EF and no evident wall motion abnormalities. In addition, our secondary aim was to evaluate whether STE might have a role in identifying patients with persistent subclinical systolic dysfunction at follow-up, possibly due to residual myocardial fibrosis.As shown in Fig. Exclusion criteria for the present analysis were: (1) Abnormal admission 2D echocardiography defined as: presence of regional wall motion abnormalities and/or reduced EF (< 55%) and/or more than mild pericardial effusion; (2) No cardiac edema and/or fibrosis found at baseline CMR. Among 52 patients admitted for chest pain associated with elevated troponin levels, 12 were excluded for reduced EF with wall motion abnormalities at baseline echocardiogram and 7 were excluded due to baseline CMR negative for myocarditis. All of the 7 patients excluded due to negative CMR, had reported intense physical activity performed before the occurrence of chest pain, possibly justifying the presence of mildly increased troponin levels in the absence of myocarditis. Of note, all patients excluded due to negative CMR had normal both EF (68.4 ± 5.5%) and GLS (–24.9 ± 3.0%). Accordingly, the study included 33 patients, comprising 25 boys and 8 girls (age 2–17 years: median 13 years [IQR 10–16]).According to our clinical protocol, patients were admitted to the hospital for clinical observation, laboratory testing with troponin level curve and viral PCR analysis, serial ECG evaluation, complete echocardiography examination and CMR.Echocardiographic evaluation was performed at admission and discharge. CMR for the analysis of myocardial edema and fibrosis, was performed at admission. Patients with confirmed focal myocarditis and impaired global (G) longitudinal strain (LS), where asked to volunteer for a follow-up CMR performed 4 ± 1 weeks after discharge. Among patients with evident impaired GLS, 53% agreed to perform a follow-up CMR.The study was approved by the “Ospedale Pediatrico Bambino Gesù Ethics Committee” and the investigation conformed to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from a parent and/or legal guardian.13.All patients underwent complete transthoracic echocardiographic examination with commercially available machines . Examinations were analyzed off-line on dedicated workstations  by two expert independent readers blinded of the clinical data . Two-dimensional images were obtained for the analysis of LV volumes on three consecutive beats from apical 4- and 2-chamber views. Wall thickness and chamber dimensions were obtained from the two-dimensional parasternal long axis or M-mode short axis at the midventricular level, when perfect alignment of the left ventricle was possible, on three consecutive beats13. LV mass was analyzed both as unindexed and as indexed by age-specific allometric powers. To define LV hypertrophy, a partition value of 45 g/(m2.16 + 0.09) was used14. For evaluation of LV geometry, myocardial thickness  was divided by LV minor axis (diameter) to generate a relative wall thickness (RWT) normalized to a mean age of 10 years old. A value of 0.38 was used as the cutoff to define concentric LV geometry15.Parameters measured in our study included LV diameters and wall thicknesses to obtain LVM. LV mass was calculated according to Devereux’s formula16. Standard Doppler analysis was performed to obtain LV inflow velocities at the mitral valve tips, including peak early diastolic filling (E) and late diastolic peak velocities (A).Tissue Doppler analysis was performed to obtain longitudinal early diastolic (E′) velocities at both the septal and the lateral was in order to derive the mitral E/e′ ratio17.LV systolic function was determined by LV EF calculated using the biplane Simpson formula. Normal EF was defined according to current adult guidelines with a cut-off of 55%18, comprising a total of 9 beats for each GLS analysis. In details, when adequate echocardiographic examinations were available , feature tracking of the myocardium was achieved through the combination of echocardiographic tracking of speckle signals, mitral annulus motion, tissue-blood border detection, and periodicity of the cardiac cycle using R–R intervals. Accuracy of border tracking was visually confirmed by viewing the cardiac cycle with only border information displayed. If necessary, individual regions of the border were adjusted until the border was correctly tracked for each frame. Cardiac strain was used to calculate myocardial deformation and displayed it in a 17-segment model according to AHA guidelines17. Averaged segmental peak strain were calculated to obtain regional and global longitudinal strain. The software provides peak orthogonal deformation of the cardiac muscle during contraction, accordingly as in systole the myocardium reduces its wall length in the longitudinal planes, more negative values of longitudinal strains represent a better cardiac contraction. Intra- and Inter-observer variability for STE analysis was also tested.Strain analysis was used to obtain regional and global longitudinal strain (GLS) of the left ventricle on three consecutive beats from each apical window 19.Prevalence of subclinical cardiac systolic dysfunction was defined by previously reported age-specific strain partition values obtained from a meta-analysis of over 1,100 children, with impaired GLS defined as GLS > −20.5% in age range 2–9; GLS > −19.1% in age range 9–13; and GLS > −19.2 in age range 14–218.CMR studies were performed with a Siemens Aera 1.5-T scanner with 32-element coil . CMR at baseline was performed for analysis of cardiac ejection fraction, and for the identification of acute edema, inflammatory damage and/or myocardial necrosis and at follow-up to rule out cardiac fibrosis. CMR was considered positive for focal myocarditis if at least one modified Lake-Louis criteria was satisfied2, slice thickness 7 mm, no interslice gap, acquisition matrix 256 × 173, voxel size 1.5 mm × 1.5 mm × 7 mm, echo/repetition time (TE/TR) 1.1/40 ms, readout bandwidth 930 Hz/pixel, flip angle 69°, 25 phases.CMR images were acquired at end-expiration, applying a vector-ECG triggering. Imaging protocol in all patients included cine steady-state free precession (SSFP) sequences acquired on the short axis (SAX) from base to apex and long axis cardiac planes: FOV 400 × 310 mm2, slice thickness 7 mm, acquisition matrix 256 × 156, voxel size 1.3 × 1.3 × 7, inversion time (TI) 180 ms, TSE factor 25, bandwidth 504 Hz, half scan factor 0.65, TE 100 ms, TR 2 RR intervals for heart rates ≤ 80/min or 3 RR for heart rates > 80/min and 2 signal averages.Myocardial edema was assessed using a T2-weighted triple inversion recovery black blood sequence, on the same planes of cine SSFP sequences, with the following parameters: FOV 400 × 290 mm2, acquisition matrix 256 × 156, slice thickness 7 mm, voxel size 1.3 × 1.3 × 7, repetition time 747 ms, echo time 3 ms, flip angle 25°, inversion time (TI) ranging from 280 to 400 ms. The correct TI for nulling the signal of healthy myocardium was identified with a look-locker sequence acquired in SAX plane].Late gadolinium enhancement (LGE) imaging was performed using a phase sensitive inversion recovery (PSIR) T1-weighted gradient echo pulse sequence, acquired along the same planes previously described, 10 min after intravenous administration of contrast agent  at 0.2 mmol/kg  and InterCC: (ICC of 0.88 [IC95% 0.72–0.91]).As shown in Table p < 0.001). Reduction in longitudinal strain was not uniformly distributed in all left ventricular segments, but was most frequently found at the infero-septal, inferior and infero-lateral segments.LV geometry was normal in all patients with no evidence of LV hypertrophy and/or dilation. Pattern of diastolic filling was also in the normal range for age, with no evidence of increased LV filling pressure (defined as E/e′ > 12). Seven patients (or 21%) presented pericardial effusion, which was mild in all cases (max 0.4 cm). In contrast, prevalence of clear-cut reduced global longitudinal strain was present in 58% of patients (n = 19) who showed mildly reduced global longitudinal strain .p < 0.05)  and as compared to the mean of the other segments .In regression analysis, a borderline association was found between reduction in global longitudinal strain and peak troponin I levels , with no evident regional hypokinesia. Analysis of myocardial edema at presentation showed a mean edema of 22 ± 13 g of edema, representing a 20.9 ± 9.5% of edematous myocardial mass (range 4.9–39.3%). In regression analysis, a moderate association was found between percentage of edema at CMR and GLS at admission . In contrast, a significant reduction in longitudinal strain could be observed in all children, with a mean improvement of 2.21% [range from 1.22 to 3.65 (p < 0.001)]. When analyzing regional variation in longitudinal strain, the highest improvement was observed at the infero-lateral segments (mean + 4.85%). As a result, the prevalence of clear-cut impaired GLS, decreased from 58 to 19% (p < 0.05), demonstrating full recovery in systolic function in 13 kids and persistent subclinical dysfunction in 6 patients . At follow-up, 10 patients among the 19 with impaired GLS at baseline underwent a second voluntary CMR. Of these, 4/10 had persistent dysfunction at discharge echocardiography while GLS had recovered in 6. Patients with persistent dysfunction demonstrated higher cardiac fibrosis at LGE analysis , demonstrating higher presence of post-myocarditis myocardial fibrosis in patients without GLS recovery at follow-up . This is in partial agreement with previously reported findings from adults12, and it has been speculated that one of the possible explanation for the partial lack of correlation between TnI and GLS in focal myocarditis is that the inflammation caused by acute myocarditis does not necessarily induce proportionate myocytolysis11. Thus, the amount of myocardial lysis does not necessarily reflect the amount of cardiac edema22, which in turn is the main determinant of LS impairment, as also demonstrated by our current findings. Also, given the focal nature of myocarditis in our population, GLS might not accurately reflect the regional impairment found in cardiac muscle. Of note, the Dallas pathological criteria for the diagnosis of myocarditis although requiring presence of inflammatory cellular infiltrate, do not consider myocyte necrosis a compulsory finding to confirm the diagnosis of acute myocarditis8.Accordingly, in the acute phase of myocarditis, cardiac necrosis markers (as troponin I) are consistently increased, and thus have been found to have high specificity (89%) in the diagnosis of otherwise clinically silent focal myocarditisOur findings might be of considerable clinical interest as the regional edema induced by myocarditis, does not usually lead to overt abnormalities in regional and/or global cardiac function and thus are usually not detected by conventional echocardiography, unless the percentage of cardiac edema is of considerable amount. However, especially in the setting of acute focal myocarditis, the amount of myocardial edema involvement is usually minor. Thus, in this setting the value of strain imaging might be of paramount importance as it allows identification of regional edema and resulting regional subclinical systolic dysfunction.12. Also, the amount of edema was associated to the severity of GLS dysfunction, independently of echocardiographic EF11. This finding suggests that myocardial deformation analysis is more likely to detect subtle changes or mild myocardial damage as compared to traditional echocardiographic parameters of both systolic and/or diastolic function. In addition, we found that the reduction in LS was due to a regional reduction in systolic function, rather than in a global systolic impairment. The reduction in LS was mostly consistent with CMR findings in which presence of edema was mainly localized in the infero-postero-lateral segments.In agreement to previous studies performed in adults, global and regional myocardial deformation was reduced in a significant amount of our patientsOur findings suggest that analysis of regional and global LV myocardial deformation by LS in young population gives additional information on both the location and the degree of cardiac involvement in focal myocarditis as compared with conventional echocardiography. In particular, analysis of LS performed at admission provides reliable information on the location and severity of the myocardial edema occurring in children with acute myocarditis, without evident reduction in traditional indices of cardiac performance. In addition, analysis of LS at discharge suggested that the reduction in cardiac performance is reversible in most cases, as demonstrated by the normalization of GLS and regional values. However in a percentage of patient, GLS remains impaired also at follow-up, suggesting some degree of myocardial damage occurring in these patients beyond acute edema. This was confirmed, albeit only in a small subgroup of patients, when comparing data from follow-up CMR. In fact, late evidence of LGE (i.e. fibrosis) was significantly higher in children with persistent reduced GLS as compared to those in which GLS returned to normal values at follow-up echocardiogram. It is interesting to highlight that focal myocarditis is generally considered a benign, self-limiting event. However, our analysis suggests that despite no clinically evident cardiac impairment, focal myocarditis may lead to subclinical mid-term cardiac dysfunction in a relevant number of children (18% in our study sample).The main limitation of our study relies on the small study sample included in the analysis. This limitation is even more relevant regarding the follow-up CMR, which was in fact available only in 10 out of 33 patients. It should be noted however, that in children CMR often requires general anesthesia and thus, giving the limited evidence of clinical relevance of repeated CMR in focal myocarditis in children with normal EF, the follow-up CMR could be included in our study protocol, only if performed on a voluntary basis. Another intrinsic limitation of the study relies on in its retrospective design from a single-center.Nonetheless, despite these limitations, our data supports that LS might be of use especially when repeated CMR is not performed, as it provides accurate data on residual fibrosis, thus providing additional information for risk stratification in this clinical setting.In conclusion, our data suggest that analysis of cardiac function by two-dimensional STE, provides useful diagnostic information in pediatric acute myocarditis with normal EF. CMR, remains the gold standard and should be always considered in the diagnostic test of pediatric patients with suspected acute myocarditis. However, when CMR is not available or requires total anesthesia, analysis of advanced parameters of cardiac mechanics by STE, might provide important surrogate information.


Cardiovascular aging is a complex process of adaptive structural and functional changes over time. With advancing age, the arterial tree thickens and decreases in compliance, resulting in increased pulse wave velocity, systolic blood pressure, and left ventricular afterload. In response to these arterial changes, the myocardium remodels to maintain systolic function and diastolic filling. These adaptive mechanisms are not necessarily pathologic but increase the susceptibility for myocardial ischemia and heart failure in the presence of common age‐associated comorbidities. This article reviews the pathophysiology of cardiovascular aging and discusses therapeutic interventions that may ameliorate these processes. This section will describe the effects of aging on each of these processes.C = ΔV/ΔP, where C equals compliance, V equals volume, and P equals the pressure. Compliance is directly proportional to volume and inversely related to changes in pressure. Vascular elastance, which is the “recoil tendency” of a vessel, is the reciprocal of compliance; therefore, a decrease in compliance results in an increase in elastance. With aging, arterial walls thicken due to reductions in elastin and increases in nondistensible collagen deposition.Vascular compliance is the ability of a blood vessel to change in cross‐sectional area  in response to dynamic intramural pressures. Vascular compliance can be calculated by the equation ΔT = P × r/h, where T equals wall tension (impedance), P equals LV systolic pressure, r equals LV radius, and h equals LV thickness. Arterial impedance, the pulsatility component of arterial afterload, is the ratio of pressure to flow at a given harmonic frequency.Ventricular afterload is another component of arterial mechanics that increases with age. Although a complex parameter, ventricular afterload can be described as the summed stress the myocardial fibers must overcome to complete ejection. In vitro models describe load as the weight  that papillary muscles can lift. Therefore, afterload can be approximated by the pressure  applied by the left ventricle (LV) muscle fibers to eject blood into the arterial tree. Ventricular afterload can be estimated by a simplified form of the Young‐Laplace equation, 3Presumably in response primarily to the arterial aging changes described above, the myocardium remodels over time. The overall number of cardiac myocytes decreases with age due to apoptosis, possibly driven by an underlying chronic inflammatory state. However, the myocyte size increases, likely in compensation for the reduced myocyte number, leading to LV hypertrophy.Left ventricular ejection fraction (LVEF), the most commonly used measure of systolic function, is preserved across the adult age span in persons without clinical heart disease.In contrast to the overall preservation of systolic LV function with aging, diastolic LV function undergoes pronounced alterations. With advancing age, there is a decrease in peak early diastolic filling (echocardiographic E‐wave) and increased reliance on left atrial contraction (A‐wave) to maintain LV filling.Alterations in cardiac electrophysiology with age are largely attributed to calcification of the cardiac skeleton resulting in electrical conduction delay.4The aging myocardium responds to external stressors by using a variety of compensatory mechanisms. Hemodynamic parameters such as blood pressure and heart rate are blunted or accentuated, depending on the specific stress employed. The hemodynamic adjustments made with stress are often useful in the assessment of CV health and diagnosis of subclinical disease.4.1In healthy older adults, there is a blunted heart rate response to assumption of upright posture. The reduced heart rate response is likely due to an age‐related reduction in baroreceptor sensitivity and decline in cardiac beta‐receptor density, given the documented increase in circulating levels of catecholamines, coupled with a reduction in neurotransmitter reuptake, during orthostatic stress or exercise.4.2With advanced age, the contractile reserve of the LV decreases with acute increases in systemic blood pressures elicited during sustained handgrip maneuvers as well as low‐dose phenylephrine infusion under concurrent beta‐blockade.4.3The LV of a healthy older adult maintains a normal resting LVEF but has blunted augmentation of LVEF with aerobic exercise.Variations in load‐bearing capabilities of the LV and the systemic arterial vasculature contribute to exercise‐induced CV dysfunction in older adults.The sympathetic nervous system also plays an integral role in effective CV modulation during exercise. It regulates increases in heart rate, changes in myocardial inotropy and relaxation, systemic vasodilation, and redistribution of arterial blood flow to necessary organs. When considering multiple scientific perspectives , a decreased response of beta‐adrenergic modulation has proven to be the most consistently observed CV physiologic response that occurs with advancing age.55.1It is well established that oxidative stress is increased with advancing age through the release of reactive oxygenation species produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to mitochondrial dysfunction and a maladaptive endothelial function.5.2In addition to myocyte hypertrophy, the cardiac ECM also thickens with age due to increased deposition of collagen mediated by profibrotic agents.5.3In addition to the myocardial structural changes mentioned above, there is also an increased incidence of misfolded protein deposition in the aged heart. Mutated wild‐type transthyretin protein has been detected in up to 25% of heart autopsies in older adults.6Over the past half‐century, significant advances have been made in understanding the physiology of aging. Although advances in therapeutics to reduce the rate of aging in humans have been limited, interventions such as caloric restriction, exercise training, and pharmacological agents show promise in blunting aging changes in the CV system and elsewhere.It has long been established in animal models that caloric restriction extends longevity and may attenuate CV aging changes.It is known that oxidative stress promotes pathologic aging by decreasing NO production in endothelial cells, leading to impaired vasodilation, atherogenesis, and increases in apoptosis. The resultant endothelial dysfunction contributes to hypertension and increased atherosclerosis among other pathologic changes.Exercise is another potent attenuator of age‐related CV changes. Regular moderate‐intensity aerobic exercise has been shown to reduce body fat, weight, and blood pressure, improve insulin sensitivity, increase endothelial function, and improve maximal oxygen uptake.7The CV system undergoes structural and functional changes over the adult lifespan. With advancing age, the arterial tree becomes stiffer, leading to higher systolic blood pressure and pulse pressure, and a higher risk of systolic hypertension, which predisposes to LV hypertrophy to maintain a normal LVEF. As a compensatory mechanism for reduced early diastolic filling rate, the older heart becomes more reliant on late diastolic filling from the left atrium. These maladaptive processes may predispose an older individual to myocardial ischemia and heart failure. Deposition of mutated proteins over time increases the prevalence of ATTRwt in the elderly. Blunted CV responses to postural, exercise, and afterload stress are also characteristic of advancing age. Recent studies of caloric restriction, exercise training, and antioxidants have shown promise to decrease the rate of CV aging. Further research in this field will have important implications for reducing the incidence of clinical CV disease that so commonly occurs in older adults.The views expressed in this review are those of the authors and do not necessarily represent those of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the United States Department of Health and Human Services.The authors declare no potential conflict of interests.