Right ventricular (RV) and left ventricular (LV) dysfunction is an important determinant of poor clinical status in repaired patients with tetralogy of Fallot (TOF). The purpose of our study is to assess the impact of surgical repair on short-term RV and LV function by 2-dimensional speckle tracking echocardiography (STE).P < 0.05 for all). The surgical approach of the pulmonary valve ring was predictive of RV and LV systolic function postoperatively .Sixty-seven patients (median age 12 months) with TOF before and 6 months after repair and 35 healthy subjects were studied. The patients were divided into the younger (age at surgery ≤12 months) and older (age at surgery >12 months) subgroups. RV and LV global longitudinal systolic strain and strain rate (SR), and LV global circumferential and radial systolic strain and SR were measured by STE. After repair, RV longitudinal strain and SR increased in the younger patients, whereas RV longitudinal SR was decreased in the older patients. LV deformation parameters were unchanged in all patients. In the multivariate analysis, patients with better RV and LV deformation parameters preoperatively were identified to have better RV and LV strain and SR postoperatively (After TOF repair, short-term RV function improvement is identified in the younger but not in the older patients, whereas LV function is unchanged in all patients. The preoperative RV and LV deformational indices are the determinant of postoperative biventricular function improvement. STE appears to be a valuable tool for assessment of biventricular function after congenital heart disease surgery. Geva et al demonstrated that right ventricular (RV) and left ventricular (LV) systolic dysfunction was an important determinant of poor clinical status of survivors of TOF repair. Therefore, the investigation of the short-term effects of TOF repair on RV and LV function is of vital importance because the early identification of individuals at greatest risk and timely intervention will most likely improve clinical outcomes. Previous studies focus predominantly on the long-term RV and LV function after TOF repair.,3 Furthermore, very limited data are available on the short-term impact of TOF repair on RV function evaluated by tissue Doppler imaging (TDI). It is well known that TDI has an intrinsic limitation of angle-dependence, which could less accurately assess myocardial performance.Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. Survival of patients with TOF has steadily increased since the introduction of intracardiac surgery, with early mortality <2%. Moreover, STE could be widely used in the evaluation of RV and LV function in patients with a variety of cardiovascular diseases,–8 including congenital heart diseases. To the best of our knowledge, no studies have been performed to determine the impact of surgical correction of TOF on short-term RV and LV function as assessed by STE.Recently, 2-dimensional speckle tracking echocardiography (STE) is an emerging method to evaluate myocardial performance. The STE-derived strain and strain rate (SR) have been demonstrated as more sensitive markers for detecting early changes in myocardial performance than conventional echocardiographic parameters.Therefore, the objective of the present study was to investigate the short-term effects of TOF repair on RV and LV function using STE and to explore the possible factor that might predict postoperative RV and LV myocardial function improvement.22.1From June 2008 to November 2014, 67consecutive patients with TOF were scheduled for intracardiac repair in our hospital  and were enrolled in our study. Four patients were in New York Heart Association (NYHA) functional class I, 53 patients in NYHA functional class II, and 10 patients in NYHA functional class III. Inclusion criteria were included: concomitant small atrial septal defects or patent foramen ovale. The patients with ≥1 following criteria were excluded: pulmonary atresia, atrioventricular septal defect, residual intracardiac shunt, RV—pulmonary arterial connection by conduit. The patients were divided into younger  and older  subgroups.The control group consisted of 35 age- and sex-matched normal subjects  who had no evidence of cardiopulmonary diseases through physical check-up, electrocardiogram, chest X-ray, and echocardiography. All subjects were determined to be in sinus rhythm. The study was approved by the local research ethics committee at Union hospital, Tongji medical college, Huazhong University of Science and Technology, China. The subjects or their parents in our study gave informed consent.2.2 RV end-diastolic area (EDA) and end-systolic area (ESA) were also measured from the apical 4-chamber view to calculate RV fractional area change (RVFAC). The degree of pulmonary regurgitation (PR) was graded as mild (no retrograde diastolic flow in pulmonary trunk with detectable regurgitant jet in the RVOT), moderate (retrograde diastolic flow in main pulmonary artery), or severe . Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were measured by biplane Simpson method.All echocardiographic parameters were obtained before and 6 months after repair. Echocardiography was performed using a commercially available ultrasound transducer and equipment . Right ventricular end-diastolic diameter (RVEDD) was determined from the apical 4-chamber view. The peak gradient across the right ventricular outflow tract (RVOT) was measured using continuous-wave Doppler from the RVOT view. For conventional RV function assessment, the tricuspid annular peak systolic velocity (Sm), early-diastolic velocity (Em) and late-diastolic velocity (Am) assessed by TDI, and the tricuspid annular peak systolic excursion (TAPSE) obtained from M-mode echocardiography were measured from the apical 4-chamber view at the RV free wall level.Two-dimensional grayscale images of subjects at a frame rate of 60 to 90 frames/s were obtained from the apical 4-chamber view and parasternal LV short-axis view at mid-ventricular level. RV and LV longitudinal strain and SR were measured from the apical 4-chamber view; LV radial strain and SR, and circumferential strain and SR were measured from the LV mid-ventricular short-axis images. All images were stored for off-line analysis . For speckle tracking analysis, the RV and LV endocardial borders were manually traced in the end-systolic frame at the point in the cardiac cycle in which the endocardial border was the clearest. The region of interest in each image was automatically generated. The position of the region of interest and its width was adjusted manually when the speckle tracking appeared to be poor. The software automatically tracked and accepted segments of good tracking quality and rejected poorly tracked segments. When all segments of the RV or LV were accepted, the RV and LV longitudinal strain and SR curves and the LV radial and circumferential strain and SR curves were automatically generated. RV and LV global longitudinal systolic strain (GLS) and strain rate (GLSRs), and LV global circumferential systolic strain (GCS) and strain rate (GCSRs) were automatically obtained from the strain and strain rate curves. LV global radial systolic strain (GRS) and strain rate (GRSRs) referred to the average of the LV 6 segments at the mid-ventricular short-axis images. Representative examples of RV and LV strain and SR curves in patients with TOF are shown in Figure 2.3t test. Correlations between biventricular global systolic function improvement postoperatively and the preoperative parameters , the surgical approach of the pulmonary valve ring level, clinical variables , and the degree of PR were calculated as Pearson or Spearman correlation coefficient depending on data distribution. Multivariate stepwise linear regression analysis was used to test the possible role of the above preoperative parameters, the surgical approach of the pulmonary valve ring level, clinical variables, and the degree of PR in the prediction of biventricular function improvement after surgery. Intraobserver and interobserver variability were assessed in randomly selected 15 subjects. Intraobserver variability was determined by having 1 observer remeasurement after 2 months. Interobserver variability was determined by a second observer who was blinded to the clinical and the STE findings. Interobserver and intraobserver reproducibility were evaluated by means of intraclass correlation coefficient (ICC). For all analyses, a value of P < 0.05 was considered as statistically significant.Statistical analysis was performed with a SPSS software package . Continuous data were expressed as mean value ± standard deviation or median. Comparison among the preoperative and postoperative values was made with Student paired 33.1Clinical and conventional echocardiographic parameters before and 6 months after repair are listed in Table 3.2The changes in RV and LV global strain and SR before and after repair in the younger and older patients are presented in Table 3.3r = 0.435, P = 0.038). We also identified the correlation between LV deformation parameters and RVEDA and RVESA in our study .Before repair, RV GLS was associated with LVEDV . Similarly, RV GLSRs was related to LV GLSRs, GCSRs, and GRSRs . LV GLSRs was correlated with RVEDA and RVESA . Likewise, LV GRSRs was associated with RVEDA and RVESA . The degree of PR was related to LV GRSRs .After repair, a correlation between RV GLS and LV GLSRs and LV GCS was found in our study . Similarly, a significant correlation between postoperative RV GLSRs and the age at repair was found in our study . The relationship between the preoperative RV and LV deformation parameters and change in RV and LV function after surgery is depicted in Figure r1 = 0.823, P1 < 0.001; r2 = 0.806, P2 < 0.001). Likewise, better LV GLS and GCS preoperatively were related to better LV GLS and GCS after repair, respectively . Better LV radial strain and SR preoperatively were associated with better LV radial strain and SR after repair, respectively . However, the patients who had the most improvement were those with worse function preoperatively, as shown in Figure The age at repair was related to LV GLSRs and GCSRs after repair in our study . The surgical approach of the pulmonary valve ring level (transannular or nontransannular patches) was the predictor of RV and LV longitudinal SR, and LV circumferential strain postoperatively .In the multivariate analysis, the better LV circumferential and radial strain, and RV longitudinal strain and SR preoperatively could predict better LV and RV strain and SR postoperatively, respectively . Other studies also observed that older age at the time of surgical repair was associated with the postoperative deterioration of RV myocardial function.,13 Our findings show the earlier surgical repair (patients younger than 12 months) favors postoperative RV function recovery, which was advocated by cardiac surgeons in most centers.In the present study, we found that RV deformation parameters increased only in the younger patients after repair, whereas RV deformation indices decreased in the older patients after surgery. We speculate that postoperative RV function recovery in the older patients may be later than that in the younger patients. In our previous study, found decreased RV strain 1 month after RVR, which, although increased at 6 months, still remained lower than the preoperative values and the values from the controls. In contrast, Kutty et al observed that RV deformation indices using velocity vector imaging shows mild improvement after PVR, but is not normalized. Sabate Rotes et al showed that RV systolic and diastolic deformational parameters were unchanged after PVR. Therefore, we conclude that the responses of pressure versus volume load relief on RV function are different.Our study shows that RV function improvement after TOF repair differs depending on preoperative disease course, which is discordant with the previous reports showing the effect of pulmonary valve replacement (PVR) on RV function. Knirsch et al4.2 who did not observe a change in LV strain and SR after transcatheter percutaneous pulmonary valve implantation, we did not find short-term effects of TOF repair on LV function. Our results are also consistent with those of Sabate Rotes et al, who did not find a change in LV strain and SR after PVR. Therefore, we could conclude the similar responses of RV pressure versus volume load relief on LV function. The absence of significant improvement in LV deformation parameters after repair may be because of the fact that strain and SR are remodeling-dependent parameters where one would not expect significant short-term changes after repair.Our study also provided the opportunity to study the short-term effects of TOF repair on LV function. Similar to the findings of Moiduddin et al,4.3 Unfavorable ventricular–ventricular interactions were identified in our study. An association between RV and LV systolic deformation parameters after repair was found, similar to previous studies. We also identified a close correlation between chamber size and contralateral ventricular function before and after repair, different from previous studies. A correlation between the degree of PR and LV radial strain rate was also found in our study. This finding is consistent with the study of Fernandes et al, which demonstrated that higher PR volume was associated with decreased LV radial strain.That the RV influences LV function should not be surprising given the anatomic context of shared myofibres encircling both ventricles, a common ventricular septum and a single pericardial cavity. Evidence for hemodynamic impact of the RV on the LV, and vice versa, has been demonstrated in previous study.4.4,13,22 Our results indicate that early repair of TOF is advised to minimize the effect of long-standing hypoxia and pressure overload. Geva et al demonstrated that an older age at TOF repair was the strongest independent factors associated with poor clinical status. Therefore, cardiac surgeon suggests early repair of TOF, which has an advantage on postoperative biventricular recovery and improving long-term prognosis.In the present study, we observed that postoperative RV and LV systolic performance was correlated with age at repair. These findings are similar to those of previous studies. who found that preoperative LV and RV deformation was associated with LV and RV function after PVR. In addition, we also showed that the surgical approach of the pulmonary valve ring level was predictive of postoperative RV and LV function improvement. RV and LV deformation indices were lower in patients with transannular patches than in those with nontransannular patches, similar to previous studies.,23 Our results indicate that trying to avoid transannular patch during the operation is very important to improve RV and LV function postoperatively.In the multivariate analysis, patients with better RV and LV deformation parameters preoperatively were identified to have better RV and LV systolic function after repair, suggesting that STE based on myocardial deformation may help refine the decision-making process in these patients. Our results are consistent with the findings of Sabate Rotes et al,4.5Our study has some limitations. First, cardiac magnetic resonance imaging is the criterion standard of RV volume and function; the absence of cardiac magnetic resonance assessment is one shortcoming of our study. Second, speckle tracking analysis software that is originally designed for left ventricle was applied to the RV analysis in the present study. Therefore, deformational changes of the RVOT, wherein more or less surgery was performed, could not be assessed using 2-dimensional STE.A third limitation of this study is that it is a single-center study. Surgical techniques may differ from center to center. Different surgical techniques may impact postoperative RV or LV function. A fourth limitation is the lack of 3-dimensional echocardiography, which provides more appropriate information about RV and LV volume and function postoperatively compared with 2-dimensional echocardiography.Finally, our study included a relatively small number of patients, and future studies with larger samples are warranted to determine the effect of surgical correction on long-term biventricular function in patients with TOF.5Assessment of myocardial function using STE demonstrates that the postoperative remodeling process of myocardial function is different for the LV and the RV. The short-term RV function improvement postoperatively is only identified in the younger but not in the older patients, whereas LV systolic function is unchanged after surgery. Patients with better preoperative LV and RV deformation parameters have better LV and RV systolic function after repair. The surgical approach of the pulmonary valve ring level has been demonstrated to predict RV and LV function improvement postoperatively. Therefore, STE appears to be a valuable quantitative tool for follow-up evaluation of biventricular performance after congenital heart disease surgery.


Significant correlations were found between CTR and LVEDVI, and LVESVI and LVEF in the depressed LVEF group . However, there was no significant association detected between CTR and LV systolic function parameters in the other subgroups. The LVEDVI and LVESVI showed an inverse correlation with the LVEF in each group. Although the CTR was not a reliable indicator of LV size and systolic function in patients with preserved LVEF, it was correlated with LV size and LVEF in patients with depressed LVEF.The present study aimed to investigate the association between cardiothoracic ratio (CTR) and left ventricular (LV) systolic function parameters in patients with or without preserved LV ejection fraction (LVEF). A total of 203 subjects suspected with coronary artery disease underwent chest radiography and dual source computed tomography coronary angiography (DSCT-CA). The LV systolic function parameters: LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), and LVEF were measured from the DSCT-CA. The association between CTR and LV systolic function parameters was analyzed according to LVEF value  and CTR value . The LVEDVI and LVESVI were higher in the depressed LVEF group compared with the preserved LVEF group (108.56±57.15 vs. 67.52±14.56 ml/m Left ventricular (LV) contractile function indicators, including ejection fraction (EF) and LV size, contribute to diagnosis ,2, prognThe cardiothoracic ratio (CTR) derived from CR is traditionally used to estimate LV size ,12 and iThe aim of this study was to assess the association of LV systolic function parameters evaluated by dual source CT coronary angiography (DSCT-CA) and the CTR derived from CR in patients with suspected coronary artery disease (CAD) with or without preserved LVEF. The CTR was hypothesized to have different correlations with the LV systolic function parameters according to the value of the CTR and LVEF.The institutional review board approved this retrospective study and waived the requirement for informed consent. A total of 203 consecutive patients were involved between June and October 2010, who were suspected of exhibiting CAD and underwent CR and DSCT-CA within three weeks. Exclusion criteria were congenital heart, pericardial, valvular heart and pulmonary hypertension diseases. The patients were divided into four subgroups according to the LVEF value  and CTR value .®); Schering AG, Berlin, Germany] was administered with a mechanical power injector  via a 20-gauge cannula inserted into an antecubital vein. Subsequent to contrast material delivery, 40 ml of saline solution was chased at the same rate as the contrast material. The images were reconstructed retrospectively using overlapping transversal images and a medium sharp convolution kernel (B26f) with an image matrix of 512×512 pixels, and slice thickness of 0.75 mm. A total of 10 datasets of axial images from the entire heart were reconstructed at increments of 5% of the R-R interval, starting at 5% throughout the cardiac cycle using a retrospective ECG-gated half-scan algorithm.All the CT examinations were performed with a DSCT . Four electrocardiograph (ECG) leads were attached to the chest of the patient in standard position and the ECG was continuously recorded throughout the scan. Bolus tracking was used for timing and scanning automatically started 6 sec after contrast enhancement reached 100 HU in a region of interest placed in the descending aorta. The scanner setting was as follows: Tube voltage of 120 kV and effective tube current of 380 mAs for the two tubes, and ECG pulsing window of 28–80% of the R-R interval for all the patients. The pitch was adapted for the lowest expected heart rate during scanning. Expected scan time was determined prior to scanning by scan length and pitch. Scan direction was craniocaudal starting above the coronary ostia and ending at the diaphragm below all the cardiac structures. High concentration contrast material [370 mg I/ml iopromide , LV end-systolic volume index (LVESVI), LV stroke volume index (LVSVI), LVEF and cardiac output (CO), using a semi-automatic software tool  and calculated by the standard cube formula and indexed to body surface area. The end of the systolic and diastolic phases was determined by previewing images at the level of the mitral valve in 5% steps throughout the entire cardiac cycle . The endocardial and epicardial border contours were detected automatically and adjusted by manual tracing when necessary  in the tThe CTR from the postero-anterior upright position CR was performed using standard radiological techniques. The CTR was calculated as the ratio of the maximal transverse diameter of the cardiac silhouette to the distance between the internal margins of the ribs at the level of the right hemidiaphragm .Two experienced observers blinded to the clinical data of the patient and heart rate during the scan independently measured the CTR and LV systolic function parameters of the patients. All the results were estimated by the average of two observers.Continuous data were described as the mean ± standard deviation, and categorical data were described as the percentage. The analysis was stratified according to the LVEF (<55% vs. ≥55%) and CTR (<0.5 vs. ≥0.5) values. The CTR and LV systolic function parameters were compared with the Student’s t-test between subgroups. Pearson correlation and linear regression were used to describe the correlation and linear association between the CTR and LV systolic function parameters. Hypothesis test values of P<0.05 were considered statistically significant. Data management and statistical analyses were performed using SAS V9.1.3 software . The investigators had full access and responsibility for the integrity of the data.All the examinations were performed without technical problems, and the image quality was good for the data analysis in all cases. The study cohort consisted of 203 subjects that underwent DSCT-CA and CR, including 122 male and 81 female subjects with an age range of 29–85 .2, P<0.001 and 64.07±37.81 vs. 20.23±7.23 ml/m2, P<0.001, respectively). These two mean values in the normal range CTR group were lower compared with the larger CTR group . In addition, no significant difference of CTR and LVEF was identified between the groups according to the values of LVEF and CTR.The CTR and LV systolic function parameters, such as LVEDVI, LVESVI, LVSVI, LVEF and CO, were compared according to the LVEF (<55% vs. ≥55%) and CTR (<0.5 vs. ≥0.5) values as shown in The correlation between the CTR and LV systolic function parameters, including LVEDVI, LVESVI and LVEF, according to the value of LVEF and CTR are provided in With regard to the association between LVEDVI and LVESVI and LVEF, significant negative correlations were observed in the overall group and nearly all the subgroups with the exception of the normal range CTR group in which LVEDVI was not correlated with LVEF  and V. NCR is commonly used as an initial test for the diagnosis of heart size and systolic dysfunction, particularly in general practice. The present study indicates that CTR derived from CR directly was associated with LV volume index and LVEF in patients suspected of having CAD with depressed LVEF as opposed to with preserved LVEF. To the best of our knowledge, this is the first demonstration regarding the correlation between CTR and LV systolic function parameters measured in patients according to the value of LVEF without congenital heart, pericardial, valvular heart and pulmonary hypertension diseases.et al (et al (The correlation between CTR and the LV volume or diameter is known to be controversial in previous studies. Hemingway et al  and Clarl (et al  reportedl (et al . The prel (et al ,22. Thuset al (Clinicians have extrapolated that the CTR can be used to predict LV systolic function or predict the independent mortality risk in patients with CHF or congenital heart disease ,17. The et al  demonstret al  reportedCertain clinical variables may interfere with the association between CTR and LV systolic function. Patients with HF and enlarged heart shadow, which includes cavity dimension and wall thickness, may still have preserved LVEF ,25. For However, for patients in the later stages of CAD, dilated cardiomyopathy or HCM often present with LV myocardial infarction and remodeling, which usually cause LV dilatation and LVEF decrease. Any degree of cardiomegaly observed on the CTR is a risk factor in these patients. Although CTR is not helpful in all patients, it could play an important role in the assessment of LV systolic dysfunction and the sequential follow-up of patients with depressed LVEF.By contrast, a strong association between LV volume index and LVEF was observed in the patients in the present study. In the majority of patients with chronic left-sided CHF, LV systolic function decreases, filling pressure increases and the chamber dilates . DilatioThe present study had several limitations. Firstly, this was a retrospective study and it was not possible to be certain of the standardization for CR position. A poor inspiration and the shape of the heart could make a falsely raised CTR. However, the wide scatter of the points indicated that this was not a systematic error. Secondly, in the present study, LVEDVI and LVESVI were regarded as indexes to predict LV size without considering LV wall thickness. Although there is a high correlation between LVEDVI and LV size ,22, LV wIn conclusion, the present data shows an improved correlation between CTR and LV systolic function and volume index in patients with depressed LVEF compared with preserved LVEF. LV volume index is inversely correlated with LVEF in all the patients. Thus, the CTR as measured on the CR is not able to distinguish between patients with depressed or preserved LV function, but may have a role in predicting the degree of LV dysfunction and ventricular enlargement only once LV function has been reduced.


Echocardiography is used in cardiac resynchronisation therapy (CRT) to assess cardiac function, and in particular left ventricular (LV) volumetric status, and prediction of response. Despite its widespread applicability, LV volumes determined by echocardiography have inherent measurement errors, interobserver and intraobserver variability, and discrepancies with the gold standard magnetic resonance imaging. Echocardiographic predictors of CRT response are based on mechanical dyssynchrony. However, parameters are mainly tested in single-centre studies or lack feasibility. Speckle tracking echocardiography can guide LV lead placement, improving volumetric response and clinical outcome by guiding lead positioning towards the latest contracting segment. Results on optimisation of CRT device settings using echocardiographic indices have so far been rather disappointing, as results suffer from noise. Defining response by echocardiography seems valid, although re-assessment after 6 months is advisable, as patients can show both continuous improvement as well as deterioration after the initial response. Three-dimensional echocardiography is interesting for future implications, as it can determine volume, dyssynchrony and viability in a single recording, although image quality needs to be adequate. Deformation patterns from the septum and the derived parameters are promising, although validation in a multicentre trial is required. We conclude that echocardiography has a pivotal role in CRT, although clinicians should know its shortcomings. Thus far, echocardiography has a pivotal role in cardiac resynchronisation therapy (CRT), underlined by the wide field of application, determining cardiac function and specifically left ventricular (LV) function and response due to desired reverse electro-mechanical remodelling. The range of tools, from brightness mode or Doppler imaging to deformation imaging, offers the possibility of patient selection and response prediction, lead placement optimisation strategies and optimisation of device configurations . International guidelines on CRT define a cut-off for LVEF at ≤ 35 %, independent of the imaging tool used , 10. A m2: 0.69). A mean difference of 0.2 % was found, although a wide confidence interval was observed (95 % CI: − 17.4–17.8 %). Moreover, 20 % of all patients would have been reclassified by another centre, using a cut-off for LVEF of 30 % [Although the biplane Simpson’s method is the most robust method to determine LV volume and function for echocardiography, intraobserver and interobserver variability can be high, with reported differences in LVEF of up to 18 % (Bland-Altman limits of agreement or two standard deviations) [ of 30 % . These rVolumes derived with echo are underestimated compared with ‘gold standard’ magnetic resonance imaging (MRI) , 15. NevAveraging of several measured beats improves accuracy in general, and is applicable to all patients and specifically in atrial fibrillation. Contrast-enhanced echocardiography for volume assessment can further reduce intraobserver and interobserver variability , 17. An Based on these findings, the cut-off for selection of patients eligible for CRT should depend on the imaging tool. Moreover, subgroups for LVEF 30–40 % could be incorporated in future guidelines . PatientSelection criteria for patients eligible for CRT based on electrical or mechanical dyssynchrony show a preference for an electrical substrate . CorrectMechanical dyssynchrony parameters Table  should bVisual assessment or ‘eye-balling’ of mechanical dyssynchrony is perhaps the most feasible method for routine clinical applications. Two parameters are known: apical rocking and septal flash Fig.  Both areIVMD is the delay in onset of outflow between the left and right ventricle. Delayed activation and subsequent contraction of the LV free wall due to LBBB leads to a delayed rise in LV pressure and outflow. LV dyssynchrony therefore lengthens the LV pre-ejection period, increasing IVMD, while ‘normal’ right ventricular (RV) activation leads to a fast rise in pressure and outflow through the RV outflow tract. IVMD can, however, be confounded by reduced RV function and a lengthened RV pre-ejection period. It can be easily measured using pulsed-wave Doppler signals obtained in any standard echocardiogram. IVMD reflects dyssynchrony of interventricular dynamics, by subtracting the difference in onset between QRSonset and flow through both the left and right ventricular outflow tract . Although a cut-off of 40 ms is used to determine dyssynchrony, IVMD has a linear relationship with response, and a specific cut-off for response is unsuitable . It is tDeformation imaging or strain analysis with echocardiography uses either tissue Doppler imaging or speckle tracking echocardiography. The latter is less angle dependent and covers the whole ventricular wall, in contrast to tissue Doppler imaging, and is therefore more reliable for detection of delayed activated segments.Septal to lateral wall delay (SL delay) is obtained by either tissue Doppler velocity imaging or speckle tracking echocardiography, calculated by the time difference between peak velocity (Doppler) or contraction (Doppler and/or speckle tracking) of the basal septal and lateral wall . SL delaMost deformation parameters use time delays in peak contraction, either absolute, relative or as a standard deviation, to determine evidence of dyssynchrony . These pDyssynchrony can also be assessed by three-dimensional echocardiography 3DE). The predominant 3DE parameter is the systolic dyssynchrony index, using the standard deviation of difference from a reference time point in the QRS complex to minimal systolic volume of 16 segments. Systolic dyssynchrony index (mean cut-off 9.8 %) was able to predict treatment response with a sensitivity and specificity of 93 and 75 % respectively . The intDE. The pRadial strain obtained with speckle tracking echocardiography from parasternal short axis images prior to implantation can indicate segments with delayed peak contraction. During implantation, LV lead placement can be guided to these segments, resulting in a remote, adjacent (i.e. neighbouring), or concordant placement, based on the 17-segment model of the American Heart Association. Observational studies have shown that a concordant or adjacent position to the latest contracting segment is superior to a remote position, in terms of reverse remodelling, death and hospitalisation during 2 years of follow-up , 41. TarAnother advantage of strain analysis is information on myocardial viability by peak strain values. Scarred regions are known to have lower strain amplitudes, and pacing in a region of scar tissue correlates to non-response . Both abHigh image quality is important for reliable strain analysis, which is relatively difficult to obtain in typical CRT patients with dilated left ventricles. Segments distal from the echo probe  are prone to noise, and therefore result in more random strain curves. Even if quality is sufficient, time-to-peak strain values can be quite comparable between segments, as can be appreciated in Fig. Echocardiography can be used to optimise atrioventricular and/or interventricular delays (AV/VV delay). AV-delay optimisation influences ventricular filling and may cause fusion with intrinsic conduction, thereby also influencing intraventricular and interventricular interaction. VV-delay optimisation also influences intraventricular and interventricular dynamics, leading to more homogenous LV contraction. Optimisation methods used in previous trials are: iterative or Ritter method of mitral valve inflow characteristics, velocity time integral of Doppler echocardiography of LVOT, and dyssynchrony indices using visual assessment, speckle tracking echocardiography or tissue Doppler imaging. Optimisation influences acute haemodynamic and mechanical interaction . Van DeuOptimisation has comparable results on long-term outcome to standard or fixed delays . The SMAFor response prediction, an echocardiogram is performed at least 6 months after CRT implantation, to compare volumetric status pre- and post-implantation (after a period of preferred reverse remodelling). Reverse remodelling is characterised by a decrease in LV volume. A ≥ 15 % decrease in LV end-systolic volume is commonly used to define response to CRT, or if lower, non-response. Although clinical response to CRT is multifactorial and is observed in patients without remodelling, volumetric change (i.e. decrease in end-systolic volume) predicts clinical response and prognosis of CRT patients. A larger decrease in end-systolic volume means fewer hospitalisations for heart failure and a lower mortality rate. When divided into subgroups , there is an upscaling effect. Super-responders had almost no events during 5 years of follow-up, while non and negative responders have progressive heart failure and subsequent events . MoreoveEchocardiography could play a larger role in CRT, especially if 3D acquisition were to become more feasible for clinical practice. Increased spatial and temporal resolution could make 3DE applicable for fast acquisition of volumetric status and myocardial strain , 39. A sAlthough validation in a large multicentre trial is required, dyssynchrony parameters based on patterns (i.e. SRSsept and strain patterns) instead of timing are promising for response prediction. These indices define a treatable substrate of dyssynchrony and have shown their predictive value in several studies , 35.Patients with LVEF > 35 %  are an interesting group for further research. These individuals might benefit from CRT. Whether their LV volumes should be determined by echocardiography or MRI and whether guidelines should distinguish between the technique used, also requires further study. Lastly, measurement variability should be addressed for reliable assessment. Measuring and averaging multiple beats should be common practice, although not all software tools incorporate average values for volume and ejection fraction .Echocardiography is a practical clinical tool and used for assessment of volumetric status, function and outcome in CRT patients . Clinicians should know its shortcomings when implementing results in clinical decision making. Specific cut-off values determined by a less accurate technique require a lenient approach. So far, response prediction and patient selection by mechanical dyssynchrony parameters have been disappointing. However a new set of parameters (i.e. deformation imaging) has shown promising results in single-centre studies and requires a multicentre approach to prove its benefit. While implementation of AV or VV delay optimisation is difficult with current techniques, deformation parameters may guide LV lead placement, increasing response rates and improving prognosis. We therefore conclude that echocardiography is a friend of CRT, with known limitations. Their relationship could become even stronger, with promising applications of 3DE and deformation imaging to patient selection and optimisation of lead placement.None.None declared.


Abnormal myocardial rotation and torsion have been investigated earlier as markers of ventricular failure1-2. However, there are no previous studies on global or regional torsion in functional single ventricle (SV) or the contribution of torsion to biomechanical differences between single RV (SRV) and single LV (SLV) hearts. Additionally, regional variations in rotation between the ventricular free wall and the septal wall which borders the hypoplastic chamber in SV have not been studied. Purpose: In normal subjects and in asymptomatic patients with SLV and SRV after total cavopulmonary connection (TCPC), to compare: 1) Global rotation (ROTglo). 2) Regional rotation in systole at free wall (ROTfree) and septal wall (ROT sept) for each slice location. 3) Torsion across the ventricle from apex to base.We performed a prospective analysis of 18 subjects. Seven subjects had normal cardiac anatomy (age 11.8 +/- 3), six subjects had a SV of right ventricular morphology (age: 11.4 +/- 2.3), and 5 had a SV of left ventricular morphology (age 12.7 +/- 4.2). Acquisition Protocol: On a 1.5T Philips Acheiva MRI scanner, one long-axis (4-chamber), two short axis (SAX) slices at basal and apical locations were obtained in all subjects using Complementary Spatial Modulation of Magnetization (CSPAMM)3 technique with a temporal resolution of 35 to 50 ms, spatial resolution 2*2*6 mm. Data Analysis: Rotation (in degrees) across all cardiac phases within 400 ms of the R wave (to account for tag fading) was calculated for both the slices using DiagnosoftTM. ROTglo, ROTsept, and ROTfree were then calculated for each patient by performing a polynomial fit. Global Torsion (τ) was calculated as difference in global rotation between apical and basal slices. Normalized global torsion (τNorm) was calculated as τ/L, where L is the distance between the apical and basal slice Figure . CounterThe following observations were made (See Figure SLV and SRV patient demonstrated a significantly impaired rotation compared to normal subjects, with SRV patients more severely affected. In single ventricular patients, basal rotation is more impaired compared to apical rotation, suggesting a deleterious effect of the hypoplastic chamber connected to the base.None.


It is characterized by pulmonary arterial vasoconstriction and vessels wall thickening, mainly intimal and medial layers. Several molecular pathways have been studied, but their respective roles remain unknown. Cardiac repercussions of PH are hypertrophy, dilation, and progressive right ventricular dysfunction. Multiple echocardiographic parameters are being used, in order to assess anatomy and cardiac function, but there are no guidelines edited about their usefulness. Thus, it is now recommended to associate the best-known parameters, such as atrial and ventricular diameters or tricuspid annular plane systolic excursion. Cardiac catheterization remains necessary to establish the diagnosis of PH and to assess pulmonary hemodynamic state. Concerning energetic metabolism, free fatty acids, normally used to provide energy for myocardial contraction, are replaced by glucose uptake. These abnormalities are illustrated by increased  Pulmonary hypertension (PH) is a serious disease, which evolves progressively to cardiac insufficiency and death , 2. It iWithout treatment, survival does not exceed 2–3 years with chronic PAH. Moreover, the diagnosis is usually made when cardiac repercussions and clinical symptoms are already severe [75% of patients in New York Heart Association (NYHA) class III or IV] , 5. ThusThe aim of this article is to review current knowledge about pathophysiology and cardiac repercussions of PAH, as well as the different clinical, biological, and imagery parameters used to assess PAH and right heart function.Etiologies and forms of PH are classified in five groups, according Dana Point classification (2008). Different forms of PAH are joined in Group 1, to know idiopathic PAH, heritable PAH, PAH related to drugs and toxins, connective tissue disease, HIV, schistosomiasis, portal hypertension, and congenital heart disease. As previously mentioned, PWP is <15 mmHg, and PVR is >3 WU. Treatments for PAH are described below. Second group is PH related to left heart disease. Echocardiography and cardiac catheterization show left ventricular dysfunction. PWP is >15 mmHg, and PVR is >3 WU. These forms are mainly treated with usual treatments of left ventricular dysfunction or repair valvular diseases. If these are not sufficient, specific treatments for PH, such as vasodilators, can be added. Third group contains PH forms related to lung disease, such as chronic obstructive pulmonary disease, interstitial diseases, or sleep apneas. They are characterized by a PWP <15 mmHg and pathological pulmonary functional tests. First line treatment is an optimal therapy of the underlying disease and long-term oxygen therapy. Fourth group is chronic thromboembolic PH. As in PAH, PAPm is >25 mmHg, and PWP is <15 mmHg. Multiple thrombi can be found by pulmonary computed tomography or magnetic resonance angiography or by pulmonary ventilation/perfusion scan. Chronic thromboembolic PH can be reversed by endarterectomy, and long-term anticoagulation is recommended. In inoperable patients, or if PH persists after surgery, treatments of PAH can be useful. Last group contains PH forms from multifactorial and unclear mechanisms, such as hematologic diseases, sarcoidosis, or metabolic disease. PWP is a variable . The aimMultiple abnormalities are found in histological analysis of lungs from PAH patients, mostly in small arteries. They all induce thickening of vessels wall. The first step in this process is thickening of intima, by increased proliferation and migration of local stem cells. Medial and adventitial layers are also altered, by medial smooth muscle cells hypertrophy, which invade the wall of small arteries, usually not muscularized, and by accumulation of fibroblasts from the adventitia. Extracellular matrix is produced and degraded in excess by metalloproteinases, which releases mitogenic factors for smooth muscle cells. Eventually, adventitial mesenchymatous cells called myofibroblasts migrate to the media and induce proliferation of smooth muscle cells. Later in the obstructive vascular process, hypertrophy and hyperplasia of endothelial cells, also known as neointima formation, continue and form plexiform lesions. Plexiform lesions are a monoclonal proliferation of endothelial cells forming multiple channels into one obliterated arteriole, surrounded by smooth muscle cells, extracellular matrix, and myofibroblastes Figure . Beyond via cyclic guanosine monophosphate (cGMP). It also inhibits proliferation of smooth muscle cells, platelets aggregation and activation, leukocytes migration, and endothelin (ET) secretion (Many studies identified the nitric oxide (NO) pathway to be linked to the emergence of PAH. NO is produced by NO synthase (eNOS) in endothelial cells. It is the predominant factor inducing vasodilation in normal conditions, ecretion , 12. In ecretion . In humaecretion .Pathogenesis of PAH can be partly explained by increased ET secretion. ET is a neuropeptide released by vascular endothelium. It can bind, on vascular wall, to type A receptors, leading to vasoconstriction, or type B receptors, leading to vasodilation. In pathological conditions, vasoconstrictor effect is predominant and takes part to PAH development. ET seems to be acting partly by inhibition of Kv1.5 potassium channels synthesis. Increased potassium rate in cells induces depolarization and calcium influx through voltage-dependant calcium channels. Increased intracellular calcium and potassium rates promote vasoconstriction, proliferation, and apoptosis resistance. ET is thus responsible of both hyperplasia and endothelial dysfunction Figure , 10, 15.Prostaglandins (PGI) pathway could also play a role in PAH development. PGI are derived from arachidonic acid and inhibit cellular proliferation, inflammation, coagulation, platelets aggregation, and vasoconstriction. A reduced rate is found in PAH patients Figure  7, 9, 1, 16.This endothelial dysfunction is the target of current PAH treatments, such as ET receptors antagonists, PGI derivates, phosphodiesterases inhibitors, calcium-channel blockers, or cGMP kinase activators. However, it seems that remodeling and occlusion of small arteries contributes primarily to the increase of PAP and right atrial pressure (RAP). Thus, the therapeutic response is highly variable, frequently insufficient, and these treatments cannot reverse the underlying histological abnormalities , 9, 15.Several studies identified an inflammatory component in pathogenesis of PAH. Indeed, different types of inflammatory cells are found on the surface and into the vessels wall. Furthermore, several cytokines and chemokines are excessively produced, by inflammatory and endothelial cells, and also take part to smooth muscle cells proliferation. Soon et al. demonstrated that blood levels of some cytokines, such as interleukin (IL)-2, IL-6, IL-8, or IL-10, could be correlated with survival, which support their implication in pathogenesis of PH. For many years, the presence of autoantibodies has been discovered in PH related to connective tissue disease and systemic sclerosis. Recent studies have also brought them out in idiopathic PAH cases. Indeed, immunoglobulin G (IgG) not only against endothelial cells components but also against fibroblasts and smooth muscle cells is found in about 60% of patients. Although little is known about the role of those antibodies, they could cause endothelial injuries and then trigger the excessive proliferation process –19.1, which induce proliferation and remodeling of vascular wall, seem to be present. Thus, there could be an imbalance between BMPR2 and TGF-β1, in favor of an excessive proliferation (Mutations of bone morphogenetic protein receptor type II (BMPR2), a kinase receptor from transforming growth factor-beta (TGF-β) family, are not only found in 70% of patients with heritable PH but also in about 25% of patients with idiopathic PAH. BMPR2 is usually expressed in pulmonary endothelial cells and regulates cell growth, differentiation, and apoptosis, through a factor named Smad. Some studies showed that inactivation of BMPR2 promotes endothelial cell survival, proliferation, angiogenesis, and migration. A loss of BMPR2 could be one of the bases of PAH pathogenesis, leading to endothelial injuries, apoptosis resistance, and plexiform lesions. It could also be involved in remodeling and dysfunction of the right ventricle (RV). However, prevalence of PAH in patients with BMPR2 mutation is low, which suggests that those mutations remain predisposing factors and that other vascular injuries are necessary to develop the disease , 9, 20. feration , 20.Those different pathways have a common consequence: excessive proliferation and apoptosis resistance. As mentioned previously, survivin is involved in some proliferative diseases. McMurtry et al. showed that its expression is increased not only in pulmonary vascular wall, mainly in smooth muscle cells, but also in endothelium and fibroblasts. Survivin inhibits apoptosis and opening of Kv1.5 potassium channels. In rats, survivin inactivating treatments are useful to reduce wall remodeling, PAP, and RV hypertrophy. It seems that survivin expression can occur after endothelial injuries, which is consistent with results obtained about the signaling pathways presented above. This factor could be one of the links between those pathways and vascular wall remodeling .Recent studies in rats showed that another link between these pathways could be related to micro-ribonucleid acids (miRNAs). miRNAs are a family of non-coding RNAs, which regulate expression of coding RNAs through binging and cleavage in the cytoplasm. Different mechanisms, such as hypoxia, hypoxia-inducible factor-1alpha (HIF-1α), inflammation, and growth factors, regulate miRNAs. It seems that the expression of miRNAs could be dysregulated in PAH, as some are increased and others decreased. We can mention the example of miR-204, which regulates cellular proliferation and apoptosis through B-cell lymphoma-2 (Bcl-2) and nuclear factor of activated T-cells (NFAT). This one seems to be decreased in smooth muscle cells. ET and PDGF could be involved in inhibition of miR-204 . Other m2O2), normally responsible of HIF-1α inhibition, is inhibited. These signaling alterations by reactive oxygen species could be the basis of normoxic activation of HIF-1α  and diminishes wall stress , 35. HowIt is well known that, following exposition to elevated PAP, the RV becomes hypertrophic. Histological examination of PAH hearts has demonstrated that the myocytes diameter is increased, in comparison with normal hearts. It seems that increased right ventricular mass is also secondary to cytoplasmic proteins and sarcomeres production , 42. MorIn the myocardium, alterations of energetic metabolism, similar to pulmonary vessels, participate to right ventricular hypertrophy and dysfunction. They lead to decreased oxygen consumption, increased lactate production, and reduced energetic reserves. Increased GLUT-1 channels and HIF-1α activation are found in PAH myocardium and seem to be associated with greater right ventricular dysfunction , 26, 30.Interventricular septum acts like a passive membrane during diastole and systole, whose position depends on blood volume and pressure in the left ventricle (LV) and the RV. In PAH, when the right ventricular pressure becomes greater than the left ventricular pressure, septum is moved leftward, according to pressure gradient. We talk about abnormal eccentricity when the septum is moved leftward during systole , 45. TheRight heart dysfunction, by several mechanisms, can also lead to a left cardiac dysfunction, related to interdependence of both ventricles. Septal abnormal eccentricity, as previously described, induces an abnormal left ventricular morphology. Furthermore, as the pericardium is not much extensible, the hypertrophied RV can compress the LV and diminish its volume. This results in left cardiac dysfunction, characterized by a reduced left ventricular filling, responsible for a diminished ejection volume , 45.Finally, in PAH, we can find a dyssynchrony between both ventricles: right ventricular free wall is still contracting when the diastole has begun in the LV, which accentuates septal deviation and shortens diastole in the RV. Thus, filling is also reduced in the RV , 34, 46.Cardiac perfusion has been mostly studied in left cardiac hypertrophy. In the left coronary artery, in normal conditions, blood flow depends on arterial pressure, or aortic pressure, myocardial capillary pressure, determined by several neurohumoral and metabolic factors, and left ventricular pressure . In normO2), ventilatory equivalent for carbon dioxide (VE/VCO2), which reflects respiratory adaptation to exercise and carbon dioxide (CO2) production, heart rate, arterial oxygen saturation (SaO2), and systemic arterial tension. It has been showed that VO2 is decreased in PH and, as it reflects maximal cardiac output (CO), is a marker of impaired cardiac function. Indeed, several studies showed that decreased VO2 and increased VE/VCO2 are correlated with cardiac function. CPET seems to be a good test to evaluate functional capacity, as it is correlated with NYHA class, disease severity, clinical worsening, and survival in PAH. It is thus suitable for risk stratification. Studies also showed that it is a good test to evaluate treatment response. However, CPET is not suitable for most severe forms of PH and its realization needs technical expertise (Cardiopulmonary exercise test (CPET) has been widely used to assess exercise capacity in PAH patients. The patient undergoes ergometry with defined initial load, which is progressively increased until maximal symptom-limited intensity is reached. Several variables are measured: oxygen pulse which is oxygen consumption per heartbeat, maximal oxygen consumption  is a peptide released by myocardium when ventricular wall stress is increased by volume overload. It may be increased by any left or right cardiac pathology leading to reduced cardiac function, and its rate reflects changes of ventricular wall stress. In PAH, it has been demonstrated that a higher rate is associated with reduced survival , 56–58. Diffusion capacity for carbon monoxide (DLCO) is used in a large number of pulmonary diseases, because it allows non-invasive detection of pathological processes inducing perturbations in gas exchanges in pulmonary vessels. It is frequently used in systemic sclerosis to reveal the presence of PH, as its diffusion is altered by arterial wall remodeling. In this pathology, DLCO is also strongly correlated with prognosis . In othe2, and venous oxygen saturation (SvO2). As previously mentioned, it is used in clinical practice to differentiate pre- and post-capillary PH: PWP < 15 mmHg and diastolic pressure gradient (PAPd-PWP) >7 mmHg suggest pre-capillary PH , PAPm, diastolic PAP (PAPd), PWP, cardiac index (CI), defined as the ratio between CO and body surface area, or SaOllary PH . A lot oion unit , 66–70. ion unit , 71. Evoion unit . Nickel p values . During p values .However, cardiac catheterization is not suitable for patients’ long-term follow-up, as it is quite invasive. Furthermore, values are most of the time, obtained at rest and cannot allow evaluation of cardiovascular adaptation to stress.V). Pressure differential (ΔP) between the RV and the right atrium (RA) is obtained by Bernoulli equation: ΔP = 4V2. Without pulmonary stenosis, PAPs can then be estimated by adding RAP, obtained from the diameter of the vena cava and its respiratory variation: a diameter of vena cava >21 mm with a collapse <50% with deep inspiration suggests a pathological RAP value (>15 mmHg). According to the guidelines, this value cannot, itself, make the diagnosis of PAH. Indeed, in about 50% of patients, PAPs values estimated with ultrasound do not correspond with values obtained at cardiac catheterization. Furthermore, in certain situations, Bernoulli equation cannot be applied, because pressure gradient is underestimated . Several studies demonstrated that a reduced TAPSE is correlated with a greater right ventricular dysfunction and a worse survival , 75, 76.Septal position can also be assessed by the eccentricity index (EI), described first by Ryan et al., which seems to be a marker of both volume and pressure overload in the RV. It is calculated as the ratio between anteroposterior and septo-lateral diameters of the LV, on a short axis view in two-dimensional echocardiography. Figure  79). Se. Se79). Several studies agree about pericardial effusion to be an excellent predictive factor of mortality , 66, 70.Tei myocardial index is defined as the sum of isovolumetric contraction and relaxation, divided by ejection time. It is a good indicator of global right ventricular function and patient’s prognosis which is, furthermore, little influenced by ventricle geometry, tricuspid regurgitation, and right ventricular filling state. It is reproducible and easily calculated, by pulsed or tissular Doppler, from pulmonary and tricuspid valves. Increased Tei index is associated with a major right ventricular dysfunction , 70, 74.Cardiac magnetic resonance imaging is frequently used in PH to assess morphology and function of the RV. It is not the first tool used to diagnose PH, even if PH should be considered in presence of vascular late gadolinium enhancement and reduced pulmonary arterial distensibility . Quite tIn conclusion, in PAH, a lot of markers of right ventricular function have been developed Table . However18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), both in myocardium and in pulmonary vessels , an index measured as: SUV = tracer concentration in a given place/(injected activity × body mass). In experimental studies, it has been shown that 18F-FDG uptake in PAH is secondary to increased GLUT-1 channels expression and anaerobic glycolysis activation , associated with a stress test and a cold pressor test, is a sensitive and non-invasive exam that can be used to evidence the presence of endothelial dysfunction and perfusion abnormalities in coronary arteries (82Rb-PET/CT could be used to study perfusion abnormalities of the RV and to better understand right ventricular dysfunction.Studies about left ventricular hypertrophy showed that the PET/CT with rubidium-82 (arteries –90. Howearteries –93. In tDespite major discoveries have been made these past years concerning the mechanisms underlying the development of PAH, mortality rates remain high and available treatments cannot reverse vessels wall injuries. Other treatments targeted on the pathogenesis are being studied. It will be necessary, in the coming years, to develop their clinical utilization in order to improve prognosis of patients with PAH.Right ventricular dysfunction, mostly due to right ventricular dilation, is the main cause of death. More and more markers of right ventricular function have been studied, but clinical practices disagree concerning parameters that should be used. Currently, hemodynamic values, obtained by cardiac catheterization, remain decisive to establish, not only the diagnosis but also the prognosis, and to follow the evolution of the disease. It is recommended to associate biological, hemodynamic, and imagery parameters. However, it will be necessary to standardize patients’ care and to determine prognostic values of those parameters, in order to optimize follow-up and allow a better monitoring of right heart function.18F-FDG-PET/CT. Their participation in right heart dysfunction has also been highlighted. Even though these first results showed a good sensitivity to assess ventricular metabolism and function, further studies are necessary to confirm its usefulness and its adequacy for clinical patients’ follow-up.Finally, nuclear cardiac imaging has been recently used to assess cardiac repercussions of PAH. Number of evidences demonstrated that metabolic abnormalities are present in the right myocardium and that they can be observed by This article has been written mainly by CS, under supervision of Prof. LN, JP, and J-DA. Dr. PY and Dr. PM helped with information collection.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


NT–pro BNP, MIG, IP10, I–TAC all increased (p ≤ 0.014) across the categories of worsening left ventricular dysfunction. In patients with symptomatic disease, MIG, IP10, and I–TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT-pro BNP. The optimal discrimination limits, obtained by maximizing Youden’s index were 246 pmol/L, 65 pg/mL, 93 pg/mL, and 24 pg/mL, respectively. The odds ratios associated with the four biomarkers were significant (p ≤ 0.010), ranging from 4.00 for IP10 to 9.69 for MIG. With adjustment for NT–pro BNP, the CXCR3 ligands retained significance (p ≤ 0.028). Adding optimized thresholds for the CXCR3 ligands to NT–pro BNP enhanced (p ≤ 0.014) the integrated discrimination improvement and the net reclassification improvement. In conclusion, congruent with the concept that inflammation plays a key role in the pathogenesis of LV dysfunction, MIG, IP10 and I–TAC add diagnostic accuracy over and beyond NT–pro BNP.Detecting left ventricular (LV) dysfunction at an early stage is key in addressing the heart failure epidemic. In proteome profiling experiments in mice subjected either to aortic banding or sham, the circulating CXCR3 ligands monokine induced by interferon-γ (MIG) and interferon-γ inducible protein 10 (IP10) were 5 to 40 fold up-regulated at eight weeks. We assessed the diagnostic value of circulating NT-pro BNP and CXCR3 ligands  in patients with hypertension (≥140/90 mm Hg) associated with subclinical ( Heart failure is a major public health problem affecting more than more than 23 million patients worldwide . IncreasScreening tools that can identify heart failure patients early during the long asymptomatic course of the disease are of crucial importance in addressing the heart failure epidemic. Such tools not only allow timely intervention, but also help in characterizing the underlying molecular mechanisms and better targeting interventions. Circulating  or urinan = 30) were sacrificed by exsanguination through blood sampling from the abdominal aorta. It was then allowed to clot for 4 hours at 4°C before centrifugation at 2000 g for 10 minutes. Next, serum was removed, immediately aliquoted, and stored at –80°C. The profile of 40 inflammatory mediators was determined, using the Proteome Profiler Mouse Cytokine Array Kit, Panel A  with improved fluorescence detection, as described previously. Membranes were incubated with 1 mL of pooled serum obtained from 4 to 6 animals per group. A total volume of 1000 μL (maximum possible volume) was applied to the membrane. To determine 40 extracellular cytokines in a semi-quantitative manner, we followed the manufacturer’s instructions available online at http://www.rndsystems.com/product_detail_objectname_ProteomeProfilerArray.aspx. We modified this protocol after step 9 to acquire semi-quantitative measurements by use of a fluorescence read-out [The Animal Care and Use Committee of Maastricht University approved the experimental studies in male C57BL/6J mice . As described in detail elsewhere , we induread-out .n = 19) or symptomatic (n = 16) diastolic left ventricular dysfunction and controls were normotensive healthy controls [705IT device . Hypertension was a blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic or use of antihypertensive drugs. Body mass index was weight in kilogram divided by height in meter squared.FLEMENGHO is a large-scale family-based study on the genetic epidemiology of cardiovascular phenotypes, for which recruitment started in 1985 and continued through 2008 ,14. The controls  and intacontrols  OMRON 70With participants fasting for at least 6 hours, venous blood samples were drawn for measurement of serum cholesterol, plasma glucose, and biomarkers. Diabetes was identified by the use of antidiabetic drugs, a plasma glucose of at least 7.0 mmol/L, a self-reported diagnosis, or diabetes documented in practice or hospital records . Blindedt-test or ANOVA and proportions by Fisher’s exact test, using SAS software, version 9.3 . Significance was a two-tailedWe compared means by a α–level of 0.05 or less. We normalized the distributions of the circulating biomarkers by logarithmic transformation. We modeled the odds of being a case in relation to the circulating biomarkers by logistic regression. We used mixed models to test the null hypothesis that increases in new biomarkers in patients with left ventricular dysfunction were identical to that observed for NT–pro BNP. We determined optimal discrimination limits for biomarkers by maximizing the Youden’s index (sensitivity plus specificity minus 1) . We assevs. 155 ± 3 mmHg/s at 4 weeks, and 149 ± 20 vs. 156 ± 13 mmHg/s at 8 weeks. However, upon maximal stimulation with dobutamine (6–7 ng/g/min), the increase in +dP/dt was attenuated (p < 0.05) in banded compared with control mice, averaging 239 ± 19 vs. 298 ± 17 mmHg/s at 4 weeks and 215 ± 19 vs. 296 ± 8 vs. mmHg/s at 8 weeks.We assessed cardiac hemodynamics in mice subjected to transverse aortic banding and in sham operated controls before and after dobutamine infusion. Baseline +dP/dt before infusion of dobutamine was similar in banded and control animals, averaging (SE) 129 ± 7 In the proteome profiling experiments, 5 of 40 cytokines stood out as being at least 2–fold up-regulated . They inCompared to healthy controls , patientCirculating levels of MIG, IP10, I–TAC and NT–pro BNP all increased (p ≤ 0.014) across the categories of worsening left ventricular dysfunction . CompareI–TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT–pro BNP . By maxiThe main finding of our study was that by performing an unbiased screen for inflammatory biomarkers in a mouse model of heart failure, we identified a cluster of three related chemokines that were present in elevated concentrations in the plasma of patients with symptomatic diastolic left ventricular dysfunction. These three CXCR3 ligands enhanced diagnostic accuracy over and beyond NT–pro BNP, as exemplified by the integrated discrimination improvement and the net reclassification improvement.Heart failure is a major and growing public health problem with a complex etiology . The diaIn the past decade, the research community made large efforts to identify novel biomarkers that would allow a better characterization of the disease process underlying left ventricular dysfunction and an improved stratification of prognosis and success of pharmacotherapy. C-reactive protein is an independent predictor of adverse outcomes in patients with acute or chronic heart failure . Other bInflammatory biomarkers probably contain valuable information with respect to the molecular mechanisms initiating left ventricular dysfunction and its progression to symptomatic heart failure. In the present study, we focused on the circulating CXCR3 ligands, MIG, IP10 and I–TAC. These CXCR3-agonistic cytokines are involved in autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus . They plAn important prerequisite for a biomarker is its involvement in the disease. Is it just an innocent bystander or a causal component of the pathological process ? InflammOne of the limitations of the present study is that due to the experimental setup we could not identify the source of the CXCR3 ligands that were elevated in the circulation of patients with left ventricular dysfunction. Inducible expression of IP10 has been demonstrated in monocytes, endothelial cells and fibroblasts ,43 and rIn conclusion, left ventricular dysfunction is associated with elevated circulating levels of the CXCR3 ligands MIG, IP10 and I–TAC. Adding the levels of these chemokines to the risk prediction model provided a significant net reclassification and integrated discrimination improvement. However, further experimental, clinical and epidemiological studies are required to substantiate the findings from our pilot study.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


After surgical correction of Tetralogy of Fallot (TOF), residual pulmonary regurgitation (PR), right ventricular (RV) dilatation and RV failure have been associated with adverse clinical events and are considered criteria for pulmonary valve replacement. Cardiovascular magnetic resonance imaging (CMR) is the gold-standard for evaluation of these parameters. However it is an expensive technique which is not readily available in all hospitals and outpatient clinics. NT-proBNP is a biomarker which may overcome these CMR limitations and might be used as a cost-effective biomarker for monitoring patients with TF.The aim of this study is to evaluate whether NT-proBNP plasma levels may help as a biomarker for monitoring ventricular dilatation, pulmonary valve regurgitation and heart failure in patients with repaired TFSingle-centre observational prospective study including 40 patients  with corrected TOF referred to our MRI unit. Data collection included: Clinical Parameters , Biochemistry (NT-proBNP levels) and CMR  and aortic and pulmonary flow assessment by 2D-phase contrast flow .i) of 55±19ml/m2, moderate to severe PR-fraction of 36±17% and good biventricular ejection fraction .Mean time since last surgery was 13.1±6.3 years. Most patients were asymptomatic , with QRS duration of 125±19 ms and a cardiothoracic ratio of 0.57±0.1. The mean NT-proBNP was 175±109 ug/ml. CMR analysis revealed a dilated indexed RV-end-diastolic-volume (RV-EDVi) of 125±32 ml/m2 and RV-end-systolic-volume  and RV-ESVi  and also with the PR fraction . There was no statistically significance found between NT-proBNP and RV-EF (Pearson=0.26), LV-EF (Pearson 0.24) or any clinical parameters.The statistical analysis showed a statistically significant correlation between the NT-proBNP and RV dilatation for both the RV-EDVi dilatation over over percentile 95 [i dilatation over percentile 951  and severe PR>40% .The receiver operating curve analysis evidenced that a NT-proBNP cut-off value above 145 pg/ml predicts the presence RV-EDVIn patients with surgically corrected TOF, NT-proBNP levels correlate with RV dilatation and the degree of pulmonary regurgitation. Ambulatory determination of NT-proBNP might be an easy, readily available and cost-effective alternative for follow-up evaluation of these patients and may help decide when to request an MRI study for follow-up evaluationN/A.


The prevalence of pregnant women with cardiovascular heart disease is increasing. Transthoracic echocardiography is safe during pregnancy, and it is an important diagnostic tool in pregnant women with established heart disease in order to monitor ventricular and valvular anatomy and function. In addition, it can be used to delineate cardiac anatomy in complex congenital heart disease and help stratify maternal risk during pregnancy. This review will focus on the use of echocardiography in the diagnosis and management of pregnant women with common congenital lesions and with prosthetic valves. Cardiovascular disease is a common cause of maternal mortality. Maternal risk during pregnancy can be assessed according to the modified World Health Organization (WHO) risk classification. In women who are WHO class I and II, risk is considered to be low to moderate and WHO Class III is considered high risk. In women who are WHO Class IV, pregnancy is considered a contraindication . TransthDue to advances in surgical repair, the number of women with congenital heart disease (CHD) who survive to childbearing age is increasing . The maiMany women with atrial septal defects (ASD) may remain asymptomatic and are diagnosed initially during pregnancy. ASDs are generally associated with a left-to-right shunt across the septum. Shunt size can be estimated by 2D echo and pulse wave (PW) Doppler velocity measurements to estimate flow volume across the pulmonary and systemic circulations (expressed by the Qp/Qs ratio). Flow volume is the product of time velocity integral of blood flow and the cross-sectional area of the outflow tract. The degree of shunting depends on the defect size and right ventricular compliance. Usually, a typical ostium secundum ASD is well tolerated if there is no significant shunting . ClosureIn contrast to ASDs, ventricular septal defects (VSD) are typically diagnosed and treated in childhood. Most detected VSDs in adulthood are small, perimembranous, and restrictive, with normal pulmonary artery pressure. On Doppler, a high velocity jet is seen from LV to RV with normal chamber dimensions and function . These dSimilar to VSDs, left ventricular overload and pulmonary hypertension can be detected in pregnant women with a large patent ductus arteriosus (PDA). In a small PDA, chamber sizes are usually normal, although mild left atrial and left ventricular enlargement may be present. Careful color and spectral Doppler evaluation should be performed . In significant PDA, main and branch pulmonary arteries are dilated, color aliasing is seen in systole and diastole in the main and branch pulmonary arteries depending on the location of PDA communication, and CW Doppler shows continuously increased systolic and diastolic velocities across the pulmonary arteries. Further evaluation should be performed in the suprasternal view to visualize the main pulmonary artery and right pulmonary artery, as well as the proximal descending aorta to visualize the PDA. If during pregnancy, left atrial and ventricular enlargements are more than expected and diastolic flow reversal is seen in the descending aorta in the absence of severe aortic regurgitation, a PDA should be suspected .Pulmonary hypertension encompasses multiple conditions, including pulmonary arterial hypertension (idiopathic or heritable), pulmonary hypertension related to left heart disease, pulmonary hypertension related to lung disease and/or hypoxia, chronic thromboembolic disease, and pulmonary hypertension associated with congenital heart disease, with or without previous corrective surgery. A PASP of 50 mm Hg or greater than two-thirds the systemic pressure is considered high-risk during pregnancy. A high maternal mortality risk is reported (20–50 % in older series and 17–33 % in more recent papers) in patients with severe pulmonary arterial hypertension and Eisenmenger’s syndrome . In Eisel-arginine  and exercise intolerance before pregnancy [Tetralogy of Fallot (ToF) is one of the most commonly repaired congenital lesions seen in adulthood –31. Unopregnancy . MRI is In 90 % of patients with complete D-transposition of the great arteries (D-CTGA), the aorta is anterior and to the right of the posterior and leftward pulmonary trunk, which can be identified on 2D echocardiography. The aorta is identified by the coronary arteries and the brachiocephalic arteries, while the pulmonary artery is identified by its major branches . D-CTGA Congenitally corrected L-transposition of the great arteries (L-CTGA) is a rare form of CHD, in which there is atrioventricular and ventriculoarterial discordance. In this case, the RV serves as the systemic ventricle. The morphologic right ventricle is in the subaortic position and can be identified by the septal insertion of the left atrioventricular valve  that is more apically displaced compared to the right atrioventricular valve . The morphologic RV can also be identified by a moderator band. Associated defects include VSD, pulmonary stenosis, and Ebstein’s-like anomaly of the tricuspid valve. Outcomes of pregnancy depend on associated defects and systemic ventricular function. For both D- and L-TGA, women with NHYA Class III–IV and ventricular function <40 % and those with severe systemic atrioventricular valve regurgitation should be counseled against pregnancy. During pregnancy, evaluation for systemic atrioventricular valve regurgitation and systemic ventricular dysfunction is critical. Echocardiographic surveillance should be performed every 4 to 8 weeks ••.The Fontan operation is a palliative procedure to relieve cyanosis by directing systemic venous blood directly to the pulmonary arteries, in a patient in whom a single ventricle supplies both the systemic and pulmonary circulation. 2D echo and spectral Doppler assessment are essential in the evaluation of atriopulmonary or venopulmonary anastomosis and atrioventricular valve regurgitation. Complications which can be identified include cavoatrial shunting, atrial septal shunting, and obstruction to the surgically created anastomotic sites. Due to the increased venous flow in pregnancy and the fixed cardiac output of a Fontan circulation, women are at high risk of atrial arrhythmias and right-sided heart failure . TEE hasPregnancy outcomes are significantly affected by the presence of prosthetic heart valves (PHV). Prior to surgery, a detailed discussion regarding the type of valve needs to be considered. Specifics include durability of valve, thromboembolic risk, and the use of anticoagulation. Previously, it was reported that the rate of bioprosthetic valve degeneration in young patients ages 16–39) was high, 50 % at 10 years and 90 % at 15 years  was high. There aEvaluation of prosthetic valves may be confounded by the normal hemodynamic changes that occur during pregnancy. Both the increased heart rate and stroke volume can alter Doppler evaluation of velocities and pressure gradients across the prosthetic valves. New murmurs can be secondary to a physiologic increase in flow; however, at least one echocardiogram should be performed during pregnancy and should be done with any development of symptoms. Similar to imaging native valves, prosthetic valve assessment includes color flow, PW and CW Doppler from multiple windows. Particular attention should be paid to occluded leaflet motion, presence or absence of echo densities attached to the sewing ring, cage, or struts, and the integrity of the sewing ring/annular interface . These e2/m2 for aortic prostheses and <1.2 cm2/m2 for mitral prostheses. Severe mismatch occurs when the indexed effective orifice area is <0.65 cm2/m2 for aortic prostheses and <0.9 cm2/m2 for mitral protheses [Elevated transvalvular gradients can be seen secondary to intrinsic valve dysfunction but can also be seen in high flow states such as pregnancy, due to increased heart rate and blood volume. Therefore, careful evaluation of valve structure and comparison to prior echocardiograms are helpful to compare to postoperative (baseline) values. Prosthesis-patient mismatch (PPM) occurs when a valve is placed that is too small for a patient’s body size, resulting in a smaller area compared to the native valve . In generotheses . It is iProsthetic valve stenosis can be secondary to thrombosis, endocarditis, pannus formation, or calcific degeneration of the valve leaflets. On serial echocardiograms, significant increases in gradients will be seen over time. Acceleration time (AT) can be used to help differentiate between aortic PPM vs acquired prosthetic stenosis. AT is measured from the onset of aortic flow to the peak velocity flow. PPM is associated with an AT <100 ms, compared to pathologic obstruction, in which AT is >100 ms . The calIt is essential to establish if prosthetic valve dysfunction is secondary to pannus formation versus thrombus to determine appropriate treatment. In general, pannus is annular in location, gradually progressive, more common in the aortic position, and occurs in patients who have been on subtherapeutic anticoagulation . CompariBioprosthetic valve regurgitation is secondary to leaflet degeneration. Mechanical valve prostheses are commonly designed with a bileaflet occluding mechanism. These valves have two small “washing jets” traveling between the inner edge of the sewing ring and the outer edge of the leaflets. In theory, these jets help to prevent thrombus formation. Pathologic transvalvular regurgitation is generally caused by thrombus or pannus formation causing incomplete closure of the discs—as opposed to paravaluvlar regurgitation, which is secondary to dehiscence of the valve ring. Quantification of regurgitation is similar to the assessment in native valves, except mechanical mitral prostheses that have significant shadowing, making color Doppler interpretation more difficult. If regurgitant jets are reliably visualized, then the standard methods for native valve assessment can be used to estimate the degree of severity. If transthoracic imaging is unsuccessful, TEE imaging may be indicated. Several parameters, such as mitral E velocity and Doppler velocity index, have been used to predict mitral regurgitation but have not been validated .The prevalence of pregnant women with cardiovascular heart disease is increasing. Echocardiographic assessment of biventricular function, valve function, quantification of shunts, and pulmonary pressure is essential. For mechanical and bioprosthetic valves, quantification of the degree of stenosis and regurgitation is similar to native valve assessment; however, gradients and the type of normal regurgitant jets vary depending on the type of valve. Echocardiography can be used for preconception counseling, to help advise termination of pregnancy in high-risk conditions and to decide mode of delivery. Lastly, both transthoracic echo and TEE have been used to monitor diagnostic and therapeutic procedures, such as treatment in valve thrombosis, percutaneous ASD closures, and balloon mitral valvotomy , 56, 58.


In congestive heart failure the balance between cell death and cell survival in cardiomyocytes is compromised. Sirtuin 1 (Sirt1) activates cell survival machinery and has been shown to be protective against ischemia/reperfusion injury in murine heart. The role of Sirt1 in heart failure, especially in human hearts is not clear.The expression of Sirt1 and other (associated) downstream molecules in human cardiomyocytes from patients with advanced heart failure was examined. Sirt1 was down-regulated . The modulation of molecules involved in cardiomyocyte survival and death in advanced heart failure were also examined. The expression of Mn-superoxide dismutase and thioredoxin1, as well as an antiapoptotic molecule, Bcl-xL, were all significantly reduced in advanced heart failure cardiomyoctes ; whereas the expression of proapoptotic molecule Bax was significantly increased (1.62 ± 0.18-fold vs. control). Increased TUNEL-positive number of cardiomyocytes and oxidative stress, confirmed by 8-hydorxydeoxyguanosine staining, were associated with advanced heart failure. The AMPK-Nampt-Sirt1 axis also showed inhibition in advanced heart failure in addition to severely impaired AMPK activation. Increased p53 (acetyl form) and decreased FoxO1 translocation in the nucleus may be the mechanism of down-regulation of antioxidants and up-regulation of proapoptotic molecules due to low expression of Sirt1.In advanced heart failure, low Sirt1 expression, like aging change may be a significant contributing factor in the downregulation of antioxidants and upregulation of proapoptotic molecules through the p53, FoxO1, and oxidative stress pathways. Despite recent progress, congestive heart failure remains a major cause of death in Western countries. The prevalence of congestive heart failure (CHF) increases with age . Due to There has been great progress towards understanding CHF pathogenesis and the implications of aging. Increasing evidence suggests that the progression of heart failure is determined by the imbalance between cell death promotion and cell survival/protective mechanisms . In CHF Sirtuin 1 is a member of the Sirtuin family of class III histone deacetylases. Sirt1 is involved in gene silencing, longevity, cellular senescence, cell differentiation, and cell survival ,5. It haIn vitro, endogenous Sirt1 has been found to play an essential role in mediating cardiomyocyte survival: overexpression of Sirt1 has provided protective effects for cardiomyocytes from apoptosis, whereas downregulation of Sirt1 may be associated with apoptotic cell death [Sirt1 has been shown to inhibit apoptosis and to delay changes associated with aging in cardiomyocytes using a transgenic mouse as the model . We havell death . Howeverll death : howeverll death .In CHF, the ventricle or atrium wall tension is increased which subjects the cardiomyocytes to higher pressure and relative ischemia compared with normal healthy control hearts. It is implied that the molecular change following ischemia or ischemic/reperfusion in the mouse heart could be applied to the condition of CHF in human beings. Therefore, the goal of this study was to determine the expression of Sirt1 and the associated molecules involved in cell death or survival in a human model.This study was performed according to the guidelines of the Declaration of Helsinki. All procedures involved human tissue were approved by the institutional review boards of the Taipei Veterans General Hospital. Consent was obtained from patients or their families before tissue procurement. Myocardial samples over the posterior wall of the left atrium were collected from donors while being prepared for transplantation. Myocardial samples near the mitral annulus were obtained from patients at the time of therapeutic transplantation. Samples for biochemical analyses were stored at -80°C immediately after procurement. Selected samples for immunostaining were fixed in 4% paraformaldehyde in phosphate-buffered saline (pH 7.4), paraffin-embedded, and sectioned. C57BL/6JNarl mice were obtained from National Laboratory Animal Center of Taiwan, and the investigation conformed with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.2 at 37°C. Compound C (Merck) was added to the medium for the times and at the doses indicated. The antibodies used included Sirt1, 8-OHdG goat polyclonal (Millipore), MnSOD (Upstate Biotechnology), Sirt1 rabbit polyclonal, Trx1, Troponin C mouse monoclonal (Santa Cruz), p53, Acetyl-p53 (Lys379), AMPKα and phospho-AMPKα(Thr172) , Nampt (Bethyl), Bcl-xL (Pharmingen), Bax (Abcam), FoxO1 rabbit monoclonal (Epitomics), and tubulin (Sigma).H9c2 cells (rat cardiomyoblasts), obtained from ATCC , and were cultured in DMEM supplemented with 10% fetal bovine serum under an atmosphere of 95% air/5% COHeart samples were placed in lysis buffer . Densitometric analysis was performed using Scion Image software (Scion).The paraffin-embedded heart specimens, sectioned at 4-μm thickness, were deparaffinized and rehydrated in PBS. Pretreatments included microwave antigen retrieval in a 10 mM citrate buffer for 20 min. Immunohistochemical staining was performed using an immunocruz staining system (streptavidin-biotin peroxidase method), and sections were counterstained with hematoxylin. Immunofluorescence analysis was achieved using primary antibodies of Sirt1 (Santa Cruz), FoxO1 (Epitomics), acetyl-p53 , and/or Troponin C (Santa Cruz) after a blocking step with 3% BSA for 30 minutes. DyLight ™488-conjugated and/or ™594-conjugated affinipure IgG (Thermo Fisher Scientific) were used for secondary antibodies.in situ using TUNEL Briefly, deparaffinized tissue sections were incubated with proteinase K, and DNA fragments were labeled with fluorescein-conjugated dUTP using TdT . Myocyte was identified by Troponin C antibody. Cell nuclei were counterstained with DAPI (blue).Deoxyribonucleic acid (DNA) fragmentation was detected All values were expressed as mean ± SEM. Statistical analyses between groups were done using a one-way ANOVA, and when F values were significant at a 95% confidence limit, differences among group means were evaluated using Fisher’s project least significant difference post-test procedure for group data. A P value less than 0.05 was considered significant.P = 0.637). The cardiothoracic ratio of recipients was 67.65 ± 1.06%, measured by posteroanterior film of chest x ray.Totally, the cardiac tissue samples were harvested from 10 donors  and 10 recipients of dilated cardiomyopathy  which is modulated by Sirt1 , Trx1, aTUNEL staining for both recipient and donor hearts was performed to further investigate changes associated with aging. The number of TUNEL positive cardiomyocytes in the heart failure group was increased significantly compared with normal donor control cardiomyocytes Figure A. Due toSince both AMPK and Nampt are the upstream molecules of the functional signaling pathway of the AMPK-Nampt-Sirt1 axis , we examDue to lower expression of Sirt1 and MnSOD in heart failure, translocation of transcriptional factor FoxO1, which could modulate the expression of MnSOD , was exaThis is a cross-sectional study designed to investigate the expression of Sirt1 and its associated molecules in the left atrium from the end-stage heart failure patients, and compared those from even younger donors. Simultaneously, these changes in heart failure are found to be similar to those observed in aging mice. Both of our study and Sakamoto et al’s,  showed tin vivo heart models [ex vivo Langendorff model [It is widely agreed that Sirt1 plays a cardioprotective role in many aspects. There have been various studies conducted on t models ,20, ex vff model ,20,21, off model ,12,22, wff model ,8,10.We currently demonstrate that Sirt1 is down-regulated in the myocardium in patients with advanced heart failure, The result, as was supposed, is very similar to our previous report , and conin vitro, the deacetylation of p53 by Sirt1 inhibits cardiac myocytes apoptosis [We have previously reported that Sirt1 can stimulate the expression of MnSOD in cultured cardiomyocytes, for which FoxO1 has been shown to play an essential role , and in poptosis . We currRegardless of the stressor, downregulation of Sirt1 in the heart was associated with loss of cardioprotection in the literatures, such as our result that low expression of Sirt1 in advanced heart failure may lead to additional irreversible heart injury via downstream effectors. However, further studies are necessary to fully elucidate the mechanism of how Sirt1 down-regulated, especially the relationship between Sirt1 and mechanical or neurohormonal stimulus of the failing heart before we target it.+ biosynthetic pathways, in which Nampt plays a critical role as a regulator for NAD+ synthesis in cardiomyocytes [Sirtuin activity is regulated by NADmyocytes . Fulco emyocytes . We alsoOur result suggests that the AMPK-Nampt-Sirt1 pathway may be disordered in heart failure and the mechanism of aging and heart failure is similar but not exactly the same. It also implicates that multiple molecular pathways involved in determining aging process. Recently, Ma et al.  also shoDownregulation of Sirt1 may have important meaning in the advanced heart failure, though cause and effect relationship is not yet established in our observation. Sirt1 agonists, such as Resveratrol, has been shown to protect the heart from ischemia/reperfusion . RecentlThere are several limitations in the study. One is because of impossibility to obtain the ventricular sample from the donor heart, we only used left atrium samples instead of left ventricle. Even though, we can not get the similar region from left atrium between donor and recipient heart while heart transplantation. Another is that the cause of heart failure is dilated cardiomyopathy in our study, younger than congestive heart failure due to ischemic heart disease, hypertension, or valvular heart disease. The observations may not be applied completely to other causes of congestive heart failure. Further investigations may be necessary to explore the difference.In conclusion, in advanced heart failure, the changes associated with aging may be accelerated and the cardioprotective effect of Sirt1 is reduced due to the lower expression level and changes to downstream effector molecules. In addition, the reduced overall expression of AMPK-Nampt-Sirt1 may partly explain the molecular basis of this mechanism.The authors declare that they have no competing interests.T-ML and J-YT carried out the molecular studies. J-YT drafted the manuscript. Y-CC carried out the immunostainings. C-YH performed the statistical analysis, H-LH and C-FW perfromed the sample harvesting and preparation. T-ML participated in its design. C-CS and C-PH conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.The regression analysis of relative expression of Sirt1 and age of patient in our sample. The coefficient of determination (R-Square) of both donor and recipient sample is 0.Click here for file


Myocardial fibrosis and abnormalities of the microcirculation are features of non-ischemic dilated cardiomyopathy (DCM) and may contribute to adverse remodeling. However, relationship between perfusion abnormalities and diffuse fibrosis has not been fully characterised. CMR allows quantification of the extracellular volume fraction (ECV), a marker of fibrosis, and absolute myocardial blood flow, in a single study. We hypothesised that increased ECV was associated with impaired myocardial perfusion reserve (MPR) in DCM patients.Consecutive DCM patients referred for a clinical CMR study and age/gender-matched controls were prospectively enrolled. All subjects underwent CMR (1.5T Siemens Avanto) according to a standardized protocol which included T1-mapping and first-pass perfusion imaging. Mid-ventricular short-axis T1-parameter maps were acquired using a Modified Look-Locker Inversion recovery sequence prior to contrast and 20 minutes after gadolinium administration (Gadobutrol 0.1 mmol/kg). The pre- and post-contrast T1-maps were co-registered and using the haematocrit, an ECV map generated  and 28 controls  were studied. Baseline clinical and CMR data are summarized in Table ECV is raised and MPR is impaired in DCM. There is a significant but weak association between these two parameters. Further work is required to assess if a temporal relationship exists between MPR and ECV, as well whether they individually correlate with markers of disease severity.This project was supported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust, the British Heart Foundation, and CORDA (research charity). Dr Andrew Arai, Dr Peter Kellman and Dr Li-Yueh Hsu are funded by the National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.