Speckle tracking echocardiography may allow the evaluation of myocardial systolic and diastolic dynamics across different physiologic and pathologic conditions beyond traditional echocardiographic techniques. The use of STE longitudinal strain in identification and risk stratification of CAD has good reproducibility and accuracy. The study aims to detect the relationship between SYNTAX score and global longitudinal peak systolic strain (GLPSS) in patients undergoing coronary angiography, with no history of myocardial infarction.n = 10, control group), low SS , and high SS .The study included 70 symptomatic patients suspected to have chronic coronary syndrome aging 20–80 years . All patients underwent clinical evaluation, surface ECG, laboratory assessment, transthoracic echocardiographic (TTE), color TDI tracings, two-dimensional speckle tracking, and conventional coronary angiography with SYNTAX score calculation. Patients were divided into 3 groups based on the results of the coronary angiogram: normal CAD on angiogram (The mean age was 55 ± 9.6 years; 54% were males; two third of patients were hypertensive; 52% were diabetic; high percentage of high syntax score were noticed among males, diabetic patients, and smokers; and also low mean of GLS was noticed among diabetic patients and smokers. There was a statistically significant positive correlation between syntax score and each of LVEDD and LVESD and, on the other hand, statistically significant negative correlation between syntax score and each of E/A, GLS, AP2LS, AP3LS, and AP4LS was noticed. Peak GLS cutoff value of 17.8 and 16.5 showed 84% and 93% sensitivity and 70% and 91% specificity to detect high and low syntax score, respectively.2D longitudinal strain analysis has incremental diagnostic value over visual assessment during echocardiography in predicting significant coronary artery disease; GLS may offer a potential sensitive tool to detect significant CAD. The diagnosis and assessment of chronic coronary syndrome (CCS) involves clinical evaluation, identifying risk factors for atherosclerosis, and specific cardiac investigations such as different stress testing modalities and coronary imaging .Despite the widespread use of imaging and provocative testing, noninvasive identification of patients with CAD remains a clinical challenge; more than half of the patients had normal or non-obstructive CAD on coronary angiography .The diagnosis of CAD using echocardiography mostly depends on the detection of left ventricle (LV) abnormal wall motion and the assessment of LV ejection fraction (EF). However, there are no abnormal LV wall motions at rest in CAD patients without a history of myocardial infarction .The strain values are better than either wall motion or tissue Doppler in the assessment of regional contraction. Also, strain can be used in assessing myocardial viability either at rest or with stress .Significant coronary artery stenosis might cause persistently impaired longitudinal LV function at rest, so 2D-STE is more accurate than conventional 2D echocardiography in evaluating the regional and global myocardial function and assessing infarct size, viability of the infarcted myocardium, and mild changes of myocardial ischemia .Speckle tracking echocardiography is a semi-automated modality so it provides good intraobserver and interobserver reproducibility .The non-invasive quantification of regional myocardial function is an important goal in clinical cardiology. An ultrasonic method that quantifies regional deformation has been introduced based on the principles of “strain” and “strain rate” imaging; it requires a single cardiac cycle for further offline processing and interpretation .STE is a simple, rapid, and accurate method for evaluating the myocardial function, so it is best to assess regional contractile function by measuring peak systolic SR or rate of increase of SR .A good correlation between longitudinal strain and the left ventricular ejection fraction (LVEF) has been shown  also; loThe use of STE longitudinal strain can detect and risk-stratify CAD with good accuracy and reproducibility. Strain and SR are homogeneously distributed across the myocardium, so mild changes in either measure suggest myocardial dysfunction. Although strain imaging has a potential role in the diagnosis and management of virtually any myocardial disease, its greatest role is in the detection of ischemic heart disease .The Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score aims to describe coronary anatomy based on anatomic criteria, such as lesion site and complexity; it can predict clinical outcomes after PCI or CABG in multiple vessel disease (MVD) patients and/or left main coronary artery disease .www.syntaxscore.com [The SYNTAX score involves complex lesions including bifurcations, chronic total occlusions, thrombus, calcification, and small vessel diffuse disease. The score ranges from 0 to greater than 60 in very complex coronary lesions. Patients with SYNTAX scores of 0 to 22 showed comparable outcomes for CABG and PCI while patients with SYNTAX scores greater than 22 CABG patients showed better outcomes than PCI patients. The high SYNTAX scores indicate complex conditions and represent the greatest risks to patients undergoing PCI. The SYNTAX calculator is online at core.com .The SYNTAX score is the sum of the points of each individual lesion present in the coronary arteries with > 50% diameter stenosis in vessels > 1.5 mm diameter. The coronary tree is divided into 16 segments according to the AHA classification. The SYNTAX score algorithm then sums each of these features for a total SYNTAX score. A computer algorithm is then queried and the score value is produced . The SYNThis is a prospective cross-sectional study. It was conducted on 70 patients complaining of chest pain who presented to the cardiology outpatient clinic for evaluation of myocardial ischemia.Enrollment of patients commenced in June 2018 and was completed in April 2019.Symptomatic patients suspected to have stable coronary artery disease aging 20–80 were included in the study.Patients with acute myocardial infarction or high- risk unstable angina.Patients with a history of previous myocardial infarction or previous recent coronary revascularization.Patients with resting regional wall motion abnormalities in echocardiographyPatients with structural heart disease, e.g., significant left ventricular hypertrophy.Patients with more than mild valvular lesions.Patients with suboptimal echogenic window.Patients with persistent arrhythmia or frequent extra systoles.Careful history taking and thorough physical examination.12-lead surface ECG.Transthoracic echocardiography (TTE): Conventional 2D echocardiography was done for each patient then offline 2D-STE analysis was done for the digitally stored images to obtain the longitudinal deformation parameters at rest. Examination was done by using an ultrasound system (Philips EPIQ 7), with a frequency of 1.5–4.3 MHz transducer and high frame rate (60–90 frames/s); LV volumes were traced manually at end-diastole and end-systole in apical four- and two-chamber views using the modified biplane Simpson’s method. The mitral inflow velocity curves were measured using pulsed-wave Doppler in the apical position at the tips of the mitral valve leaflets, and the E/A-ratio was calculated. Peak velocity of early (E) and atrial (A) diastolic filling and deceleration time of the E-wave (DT) were measured. Color TDI tracings were used to measure the E/e′ after measuring the peak longitudinal early diastolic (e′) velocity from the average of the lateral and septal velocities.Two-dimensional speckle tracking echocardiography: Three standard apical views were obtained at rest according to the American Society of Echocardiography recommendation. Gain, depth, and sector width were adjusted properly in order to set the frame rate 60 to 80 frames/s. Well-defined cardiac cycle was acquired for each view and stored digitally for offline analysis using the Cardiac Motion Quantification (CMQ) feature on the Q lab 9 software (Philips ultrasound). The end-systole was defined first by defining the aortic valve closure (AVC) as seen in the apical long-axis view. Then, the region of interest (ROI) was set by identifying three points at the end-diastolic frame; 2 annular points low and inside the myocardium at the level of insertion of the mitral valve and 1 apical point at the endocardial border of the apex. The software automatically tracks the internal  border and external  border in the subsequent frames in 30 s. Each ROI is divided equally by the software into three segments , in addition to a shared apical cap. Tracking was accepted or rejected and manually corrected by the operator when needed. Numerical and graphical displays of the longitudinal strain were automatically generated for all segments from each view. The same procedure was followed with the apical 4- and apical 2-chamber views, using the same sequence. Finally, after completion of the analysis of the three apical views, the software generates a 17 segment bull’s eye display of the peak longitudinal systolic strain with automatic calculation of the mean global longitudinal strain (GLS).Coronary angiography: All patients underwent coronary angiography on a Siemens Axiom Artis coronary angiographic system  within 1 month of the echocardiography. Selective left and right coronary angiography in multiple views in order to avoid side branch overlaps and foreshortening of the relevant coronary stenosis.http://www.syntaxscore.com/calc/start.htm). Thereafter, the patients were divided into 3 groups based on the presence and/or the severity of coronary artery disease (CAD): no CAD on angiogram , low SS , and high SS .SYNTAX I score calculation: All images were evaluated by an experienced operator who was blinded to the results of STE. The SYNTAX score was derived from the summation of the individual scores for each separate lesion defined as ≥ 50% luminal obstruction in vessels ≥ 1.5 mm. The SYNTAX scores were calculated for all patients using dedicated software  was used as a test of significance. Pearson’s correlation was run to identify the relation of SYNTAX score and GLS with study parameters. The receive operating characteristic (ROC) curve was used to determine the discrimination value of GLS for low and high SYNTAX score and to define optimal cut-points for sensitivity and specificity. For the interpretation of the results of tests of significance, significance was adopted at p ≤ 0.05.The collected data were organized, tabulated, and statistically analyzed using SPSS software statistical computer package version 18 . For quantitative data, the mean and standard deviation .p > 0.05).There were no significant statistical differences between CAD and control groups as regard age, sex, DM, HTN, dyslipidemia, smoking, LVEDD, LVESD, and EF (p < 0.001), lower AP3 longitudinal strain compared to the control group , lower AP2 longitudinal strain compared to the control group , and lower global longitudinal strain compared to the control group  , E/A ratio (p < 0.04), AP2L strain, AP3L strain, AP4L strain, and GLS (p < 0.001) , LVEDD 9 (p = 0.02), LVESD (p = 0.004), E/A ratio (p = 0.008), AP2L strain, AP3L strain, AP4L strain, GLS, and SYNTAX score (p < 0.001)  is a semi-automated software that allows fast, quantitative, and angle-independent assessment of the three components of myocardial deformation, with great feasibility and reproducibility particularly of the longitudinal one. Several clinical studies confirmed the feasibility of STE-derived longitudinal strain analysis as an adjunctive method for CAD detection .In this prospective study, we studied 70 patients aged 20–80 and collected from an outpatient cardiology clinic; echocardiography  and coronary angiography were done for each patient, and then data was collected and analyzed.We could identify a cutoff value of GLS with high sensitivity and specificity to detect a high SYNTAX score.Biering-Sørensen et al. , GaibazzIn Billehaug et al. , GLS meap < 0.001).Our study showed that GLS decreased incrementally with increasing SYNTAX score which indicates increasing severity of CAD. Vrettos et al.  showed sp = 0.007); this was also noted in Srinivasan et al. [p = 0.019) when compared to those with less diabetes duration.There was a positive correlation between high SYNTAX score and being diabetic ; this was found in several studies, among them El Kersh et al. [p < 0.05).Another positive correlation was present between SYNTAX score and smoking  while our study did not reach these results as the E/A ratio was lower in the high SYNTAX group (p = 0.04).El-Sayed et al.  found thp = 0.001), and this was similar to the results of Elgohary et al. [p = 0.0001.In our study, mean GLS was lower in diabetic patients 13.7 ± 2.4 than non-diabetics 15.8 ± 2.7 , Farsalinos et al. [On the other hand, while we found that smokers had significantly lower mean GLS , and Benyounes et al. [r = − 0.53; p < 0.001). Also, Lima et al. [r = 0.95; r2 = 0.89; p < 0.001), especially in patients with LV systolic dysfunction than those with normal LVEF.Our study results showed a good correlation between left ventricle EF and GLS  can predict significant CAD with high sensitivity of 84 and 93% for the detection of low and high SYNTAX score, respectively.The present study recommends that adding STE to the standard echocardiography protocol for evaluation of myocardial ischemia in patients with chronic coronary artery disease and using the found cutoff values of GLS can predict patients likely to have more severe and complex CAD and might benefit from invasive coronary angiography and revascularization, but these values should be tested in larger population studies.Relatively low number of studied patients and single-center study.Excluding patients with wall motion abnormalities at baseline echocardiogram.Strain and strain rate are influenced by left ventricular mass, various hemodynamic variables, and software platform type, in addition to myocardial ischemia. All these factors could be potential confounders.


These improvements persisted at the 2-year follow-up. In the multivariable analysis, the improvement in the RV-PA coupling was independent of the left ventricular remodelling. Conclusions: in patients with HFrEF, sacubitril/valsartan improved the RV-PA coupling; however, further trials are necessary to evaluate the role of sacubitril/valsartan in the treatment of right ventricle (RV) dysfunction either associated or not associated with left ventricular dysfunction.Background: right ventricle-pulmonary artery (RV-PA) coupling assessed by measuring the tricuspid anular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio has been recently proposed as an early marker of right ventricular dysfunction in patients with heart failure with a reduced ejection fraction (HFrEF). Methods: As the effects of sacubitril/valsartan therapy on RV-PA coupling remain unknown, this study aimed to analyse the effect of this drug on TAPSE/PASP in patients with HFrEF. We retrospectively analysed all outpatients with HFrEF referred to our unit between October 2016 and July 2018. Results: At the 1-year follow-up, sacubitril/valsartan therapy was associated with a significant improvement in TAPSE (18.26 ± 3.7 vs. 19.6 ± 4.2 mm,  Sacubitril/valsartan is the latest “disease-modifying drug” approved for the management of patients with heart failure with reduced ejection fraction (HFrEF) .In addition to a reduction in the rate of mortality and hospitalisation ,3, both Despite the considerable amount of data on the benefits of sacubitril/valsartan for LV function, data on the effect of this drug on the RV are limited. RV-pulmonary artery (RV-PA) coupling, an index of the in vivo RV length vs. developed force, and a non-invasive assay of the RV contractile state  have beeWe retrospectively analysed all outpatients with HFrEF, defined as those with an EF ≤40%, referred to the Heart Failure Unit of Ospedale Monaldi , between October 2016 and July 2018. This study was conducted in accordance with the Declaration of Helsinki, all the patients provided written informed consent and the study was approved by local ethical committee (455 of June 2020).2), moderate-severe liver disease , severe chronic obstructive pulmonary disease , prior heart surgery with pericardial incision, prior pulmonary embolism, and HF-related hospitalisation ≤3 months before the administration of angiotensin receptor neprilysin inhibitor.We excluded patients with severe renal disease  equation ≤30 mL/min/1.73 mDuring the study period, 215 patients with HFrEF received sacubitril/valsartan therapy; among these patients, 8 (3.7%) with severe renal disease, 7 (3.2%) with moderate-severe liver disease, 9 (4.1%) with moderate-severe chronic obstructive pulmonary disease, 7 (3.2%) who previously underwent heart surgery with pericardial incision, and 21 (9.7%) who were recently hospitalised due to HF were excluded.In the 163 patients enrolled in the study, sacubitril/valsartan was administered at a dose of 24/26 mg twice daily in 102 patients (62.5%) and at a dose of 49/51 mg twice daily in the remaining 61 patients (37.5%). A complete echocardiographic examination was performed in the echocardiography laboratory by an experienced and skilled cardiologist.The mean pulmonary artery pressure (mPAP) was calculated as 0.61 × PASP + 2.RV-PA coupling, estimated as the TAPSE/PASP ratio values, was detected at the beginning of the sacubitril/valsartan therapy, and those measured at 1 year and at 2 years after the initiation of therapy were evaluated.p-values were two-sided, and a p-value of <0.05 was considered significant.All the statistical analyses were performed using Prism 8 . Variables with a normal and non-normal distribution were expressed as mean  ±  standard deviation and median/interquartile range, respectively. The differences between the baseline and treatment were compared using the Wilcoxon signed-rank test for variables with a non-normal distribution and the t-test for dependent samples for variables with a normal distribution. All the The demographic, clinical, and echocardiographic characteristics of the overall population are shown in The patients’ mean age was 57.9 ± 12.3 years, and 78.1% of the population were men. Approximately 31.3% of the patients had New York Heart Association (NYHA) class III.Of the total population, 83 (50.9%) had ischemic dilated cardiomyopathy according to Felker’s definition .Hypertension was noted in 62.5% of the patients, ischaemic heart disease in 50.9%, diabetes in 48.4%, and chronic obstructive pulmonary disease in 37.4%. The mean left ventricular ejection fraction (LVEF) was 28.9% ± 6.4%.All the patients were treated with β-blockers, 18.4% with ivabradine, 64.4% with mineralocorticoid receptor inhibitors, and 23.3% with digoxin. Of the diabetic patients, 34  had SGLT2 inhibitors.During follow-up sacubitril/valsartan was up-titrated according to standard practice and at two years 115 patients (70.5%) took 97/103 mg twice daily, 40 (24.5%) patients the dose of 49/51 mg twice daily and 8 patients (5%) the dose of 24/26 mg twice daily.p < 0.01), no significant changes were observed in the other “disease-modifying” drugs during follow-up.With the exception of a statistically significant reduction in the dose of furosemide , LV end diastolic volume , LV end-systolic volume , left atrial volume index , and estimated mean pulmonary capillary wedge pressure .At the 2-year follow-up, sacubitril/valsartan therapy was associated with a significant improvement in a series of left-side echo parameters: the LVEF , peak systolic S wave , PASP , mPAP , and RV-PA coupling (0.57 ± 0.25 vs. 0.68 ± 0.30 p < 0.01) at the 1-year follow-up.With regard to the RV function , there wThe improvements in RV-PA coupling persisted at the 2-year follow-up .p = 0.98), in diabetic and non-diabetic patients .In the subgroup analysis, the effects of sacubitril/valsartan on the RV-PA coupling were the same in men and women .The effects on RV-PA arterial coupling was higher in patients that assumed the dose of 97/103 twice daily respect patients that assumed the dose of 49/51 mg twice daily  sacubitril/valsartan improves RV-PA coupling, (2) this improvement is related to both an increase in the TAPSE and a reduction in the pulmonary arterial pressure, and (3) the improvement in the TAPSE/PASP ratio is independent of the LV reverse remodelling.In HFrEF, a low TAPSE value i.e., <16 mm) indicates an advanced disease stage and leads to an increased risk of death by HF, sudden death, and hospitalisation ,16. mm indicIn patients with HFrEF, an increase in the left atrial (LA) pressure and a reduction in LA compliance ,18 leadsPASP was associated with a prognosis in HF with type II pulmonary hypertension ,22.RV-PA coupling quantifies the adaptation of the RV to its afterload and is considered to be one of the main determinants of functional capacity  and survThe gold standard in quantifying RV-PA coupling is the RV end-systolic elastance to the pulmonary arterial elastance ratio, measured invasively with multi-beat RV pressure-volume loop acquisitions by conducting a dedicated right heart catheterisation ,27. HoweCompared with right cardiac catheterisation, which is the reference method, two-dimensional echocardiography allows the calculation of combined indices such as the TAPSE/PASP ratio, which is a reliable index of RV-PA coupling ,29. The To date, data on the effects of β-blockers and renin-angiotensin-aldosterone inhibitors on the RV function are limited ,32,33,34p < 0.001) and decreased the PASP  [In a recent study enrolling 60 consecutive patients with HFrEF, Correale et al. showed that sacubitril/valsartan increased the TAPSE  .In our study, we evaluated the effects of sacubitril/valsartan on RV-PA coupling by measuring the TAPSE/PASP ratio; the results clearly indicate that sacubitril/valsartan improved the RV performance by acting on the RV contractility (indirectly estimated by TAPSE and S wave) and reducing the RV afterload (indirectly estimated by PASP), with an improvement in the RV-PA coupling.The same improvements were observed in men and women, in diabetic patients compared with non-diabetic patients, and in ischemic patients compared with non-ischemic patients.These findings are in agreement with those of previous studies, which showed that sacubitril/valsartan therapy resulted in an equal inverse remodelling of the LV in women, diabetic individuals, and ischemic heart disease patients ,38,39.Therefore, both the remodeling of the LV and the favourable effects on the function of the RV are independent of these parameters but are related to the dose of sacubitril/valsartan, confirming that higher the dose is related to better outcome. Consequently, any action must be taken to reach the target dose of sacubitril/valsartan or the maximum dosage tolerated by the patient.Finally, the finding that the improvement in the RV function is not related to the reverse remodelling of LV but only to the reduction in LAVI is also of great interest; in fact, LAVI reflects the magnitude and chronicity of elevated cardiac filling pressures. Hence, the improvement in LAVI is indicative of a reduction in the LV filling pressure, which results in a reduction in pressure transmission to the pulmonary vascular shaft with a reduction in both the PASP and mPAP.Future studies are required to confirm these data, which would then allow us to hypothesise the use of sacubitril/valsartan even in patients with heart failure (HF) and isolated/predominant RV dysfunction.The small sample size, single-centre study design, and observational nature of the study may affect the generalizability of our results. These preliminary results need to be confirmed in a properly powered multicentric study and randomised trials.In patients with HFrEF, sacubitril/valsartan therapy increased the TAPSE and decreased the PASP with an improvement in the RV-PA coupling; this effect is not related to LV reverse remodelling. Further studies are necessary to confirm these data in order to evaluate the role of sacubitril/valsartan in the treatment of RV dysfunction in HFrEF patients.


The identification of predictors of major cardiovascular events (MACES) represents a big challenge, especially in early and stable cardiovascular diseases. This prospective study comparatively evaluated the prognostic importance of left ventricular (LV) and right ventricular (RV) systolic and diastolic function, pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) in a stable patient’s cohort with cardiovascular risk factors. The LV ejection fraction, mitral annular plane systolic excursion (MAPSE), tricuspid annular plane systolic excursion (TAPSE), functional mitral regurgitation (FMR), doppler tissue imaging of mitral and tricuspid annulus with systolic and diastolic peaks estimation, tricuspid regurgitation velocity (TRV), pulmonary velocity outflow time integral (PVTI), mean pulmonary artery pressure (MPAP) and PVR were estimated at enrollment. During the follow-up, MACES and all-cause mortality were recorded. 369 subjects with or without previous MACES were enrolled. Bivariate analysis revealed LVEF, TAPSE, MPAP, TRV, PVR, LV diastolic function, and FMR were associated with the endpoints. When computing the influence of covariates to the primary endpoint  through Cox analysis, only LV diastolic function and TAPSE entered the final model; for the secondary endpoint (MACES) only TAPSE entered. TAPSE was able to predict MACES and all-cause mortality in early and stable cardiovascular diseases. The use of TAPSE should be implemented. Many clinical variables and ultrasound parameters play a prognostic role in advanced or unstable cardiovascular diseases . The ideUntil now, to our knowledge, in stable patients with cardiovascular risk factors a comparative study has not been conducted yet. This prospective, observational cohort study was designed to ascertain the prognostic value of old and new ultrasound parameters of LV and RV systolic and diastolic function , FMR, pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) in stable patients with cardiovascular risk factors with or without previous MACES.This study was performed in accordance with the Ethical Standards of the 1975 Helsinki Declaration revised in 2013. The study was approved by the Ethics Committee of Modena  and written informed consent was obtained from participants before the enrollment.Patients referred to our Echolab, from October 2011 through August 2014, were eligible. The data of patients about medical history and cardiovascular risk factors were collected. Subjects with at least one of the major cardiovascular risk factors or with previous MACES  that were stable during the last 12 months, were eligible. Patients with MACES during the last 12 months were excluded. Patients suffering from severe valvular diseases, chronic obstructive pulmonary disease, severe pulmonary hypertension, congenital heart disease, atrial fibrillation, with cardiac stimulators and with bad acoustic windows were also excluded.According to the recommendation of the American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI), at enrollment a complete echocardiographic study was performed including M-mode, two-dimensional, pulsed and continuous Doppler spectral recording, as well as Doppler tissue imaging (DTI) evaluation of the mitral and tricuspid lateral annulus ,9. Two-dTwo echocardiographic systems  were used. For each patient the following parameters were estimated: LV ejection fraction (EF), mitral and tricuspid annular plane systolic excursion , FMR, pulmonary valve outflow time-velocity integral (PVTI), tricuspid regurgitation velocity (TRV), mean pulmonary artery pressure (MPAP) and PVR [LV EF was measured through the biplane method of discs; the modified Simpson’s rule was obtained from the apical 4- and 2-chamber view by determining the end-diastolic and the end-systolic volume. Reduced LV EF was defined as <55% .MAPSE represents the systolic movement of the base of the LV free wall; it was measured in the apical 4-chambers view, determining with the M-mode guide the maximal excursion of the LV free wall at the junction with the mitral valve plane from the lowest position to the systolic peak. Reduced MAPSE was defined as <1.5 cm .TAPSE represents the longitudinal function of the RV by determining, with the M-mode guide, the maximal systolic excursion of the RV free wall at the junction with the tricuspid valve plane in the apical 4-chambers view. As with other regional methods, it assumes that the displacement of the basal segment is representative of the entire RV function. Reduced TAPSE was defined as <1.7 cm .FMR is a dynamic condition whose severity varies depending on loading conditions. FMR was assessed at rest through vena contracta width in the parasternal long-axis view, effective regurgitant orifice area, left atrial size and regurgitant volume. According to all these parameters, FMR was then classified into four classes: absent, mild, moderate and severe .PVTI was measured placing a pulsed wave sample volume in the right ventricular outflow tract at the level of the pulmonic valve in the parasternal short-axis view.MPAP was obtained, in the absence of pulmonary outflow tract obstruction and/or pulmonary valve stenosis, when pulmonary regurgitation was performed by applying the simplified Bernoulli equation from the early diastolic peak of pulmonary valve regurgitation  or was dPVR was calculated from the peak of the tricuspid regurgitation velocity and PVTI placing a pulsed wave sample volume in the right ventricular outflow tract at the level of the pulmonic valve in the parasternal short-axis view . Increas−1 [LVSyP velocity was measured by determining the DTI systolic peak with the sample volume placed at the junction of the LV free wall with the mitral valve plane. Reduced LVSyP was defined as <9 cm s−1 .−1 [RVSyP and RVPrP velocities were measured by determining DTI presystolic and systolic peaks with the sample volume placed at the junction of the RV free wall with the tricuspid valve plane. Reduced RVSyP was defined as <10 cm s−1 ; RVPrP i−1 .e’ and a’ peaks, their ratio and the E/e’ ratio were calculated. LV diastolic filling patterns were classified by the combined quantitative analysis of these parameters into four classes: normal, impaired relaxation, pseudonormal and restrictive [e’ velocity, high A and a’ velocity, decreased E/A ratio and increased E deceleration time. The pseudonormal filling pattern cannot be recognized only with the evaluation of the mitral inflow pattern but needed an additional assessment, such as the Valsalva manoeuvre, e’ evaluation and E/e’ ratio estimation. The restrictive pattern showed a higher E wave, greater E/A ratio and E/e’ ratio [The evaluation of LV diastolic function was assessed studying the mitral inflow and DTI of the mitral lateral annulus. E and A peaks, their ratio, the E deceleration time, trictive . Impairee’ ratio .e’ and a’ peaks, their ratio and the E/e’ ratio were estimated. RV diastolic function was then classified according to these parameters into three classes: normal, impaired relaxation and restrictive [RV diastolic function was assessed studying the tricuspid inflow and DTI of the tricuspid lateral annulus. From the apical 4-chamber view, the Doppler beam should be aligned parallel to the RV inflow; alignment could be facilitated by displacing the transducer medially toward the lower parasternal region. The parameters used to assess RV diastolic function were the same as those used to assess the LV diastolic function. E and A peaks, their ratio, trictive .All the echocardiographic parameters were measured at end-expiration during quiet breathing, and three measurements on consecutive heart cycles were averaged. Special care was given to obtain an ultrasound beam parallel to the direction of the annular motion and the transvalvular flows, and also to optimize the focus, gain, and compression setting . If necessary, echocardiographic parameters were calculated from multiple views. Intra- and inter-observer variability was calculated.The enrolled patients were followed-up with every 6 months through clinical-electrocardiographic evaluation or through hospital databases consultation. During the follow-up period MACES  and all-cause mortality were recorded.p value ≤ 0.05 was considered statistically significant, with 95% confidence interval.Continuous variables are displayed as means ± standard deviation, while categorical data are displayed as frequencies. A two-tailed Bivariate analysis was used to find which ultrasound parameters were associated with all-cause mortality and MACES (primary composite endpoint) and with MACES (secondary endpoint). An independent-sample t-test was used for continuous variables and a Chi-squared test for categorical variables. Cox regression analysis was used to find a model predictive for the endpoints; only the meaningful parameters found at bivariate analysis were entered into the Cox model, stratifying according to the presence of previous MACES. The sample size was calculated. SPSS/PC release 2013  was used.A total of 1667 consecutive patients referred to our Echolab were assessed for study eligibility; of these 369 were enrolled (mean follow-up 1178 ± 391 days). During the follow-up period 55 MACES were recorded  and 29 patients died . Bivariate analysis revealed the following parameters were related to all-cause mortality and MACES: LVEF, TAPSE, MPAP, TRV, PVR, LV diastolic function, and FMR . When coCardiovascular risk factors have an early influence on the heart, vessels and lungs . PreviouConcerning the LV, RV has peculiar characteristics such as a larger volume, a greater longitudinal contraction and a smaller mass. RV has a greater dependence on preload  and on afterload (determined by the forces that oppose RV output and a reflection of PAP and PVR) . PAP is This study simultaneously analyzed old and new echocardiographic indexes of LV and RV function derived from annular motion, PAP and PVR and revealed the lack of importance of most of the considered parameters. In early and stable cardiovascular diseases echocardiography did not provide a powerful prognostic role except for LV diastolic function, for the primary endpoint, and TAPSE, for both the primary and the secondary endpoints. Most of the studied parameters and TAPSE were within the normal range but TAPSE turned out to be a more powerful predictor of outcome than LV function, FMR and PAP, known predictors of MACES and mortality in advanced cardiovascular diseases ,5.The clinical importance of RV function in the early stages has not been completely identified. We previously reported in a small cohort of stable outpatients with a poorer echocardiographic evaluation that TAPSE—within the normal range—was able to predict MACES . MoreoveIn the overall population of the Copenhagen City Heart Study with cardiovascular risk factors, Modin and colleagues have recently shown that TAPSE was an independent predictor of cardiovascular death as an expression of LV diastolic dysfunction . This stTAPSE is easy to measure, reproducible and has unique characteristics which derive from forces that contribute to RV preload and afterload . SimilarTAPSE represents the great longitudinal contraction of the RV and seems to early perceive vascular stiffness and increased preload and afterload. RV function indexes derived from DTI are not useful in the early stages since they are less load-dependent, while the left heart is a powerful structure whose function is usually preserved, especially if measured with standard techniques .The cohort was heterogeneous: patients in primary prevention with cardiovascular risk factors and stable patients in secondary prevention were enrolled. Moreover, cardiovascular risk factors decline with different mechanisms of cardiac, vascular and lung function. The echocardiographic evaluation was made only with standard techniques, especially derived from annular motion.This study confirms that TAPSE has a pivotal role between the LV and RV function. Larger studies are required but pieces of evidence are growing: the simple use of TAPSE in early and stable cardiovascular diseases should be implemented and, for this purpose, TAPSE limits probably should be reconsidered.


We hypothesized that the use of a novel non-peptide AT2-R agonist Compound 21 (C21) would significantly reduce adverse post-MI remodeling in mice as measured by cardiac magnetic resonance imaging (CMR). Such a compound could offer significant translational potential.Cardiac overexpression of the angiotensin II type 2 receptor  image analysis program was used to define LV end-diastolic (LVEDV) and systolic volumes (LVESV), stroke volume (SV), ejection fraction (LVEF) and LV mass at baseline and day 28 post-MI as well as infarct size on day 1 post-MI as % of total LV mass.Forty nine C57/BL6 mice underwent 60-minute occlusion of the left anterior descending artery, followed by reperfusion. Nine died early post-MI, leaving 40 for further study. Twenty three received 0.3 mg/Kg/day C21 SQ by Alzet minipump and 17 were untreated. CMR images were obtained at baseline and post-infarct (days 1 and 28) using a Clinscan 7 T MRI system (Siemens/Bruker). Using cine gradient echo black blood imaging, six to 8 continuous short-axis slices were acquired, each 1 mm thick, from the apex to the base. Images were both electrocardiographic and respiratory gated, with echo time of 1.9 ms, 15 degree flip angle and field of view 25.6 mm, giving a spatial resolution of 200 × 200 × 1000 μmAt baseline, LV end-systolic volume, mass and EF were similar between groups. Baseline LV end-diastolic volume in the treated group was larger . Infarct size was similar between groups . By CMR at day 28 post-MI, end-diastolic volume, end-systolic volume, stroke volume, and LV mass were higher in the treated group, although ejection fraction was similar. (See Table 2 receptor agonist Compound 21 in the post-infarction period appears to cause LV hypertrophy and an increase in LV volumes without a decrement in ejection fraction. This finding counters the previously demonstrated protective benefit of transgenic overexpression of the receptor. Potential mechanisms for the lack of protective benefit of the receptor agonist include angiotensin II AT2 receptor down-regulation or an inadequate dose used in this preliminary study.Treatment of WT C57BL/6 mice with 0.3 mg/Kg/day of the novel non-peptide angiotensin II AT


It is uncertain whether right ventricular (RV) lead position in cardiac resynchronization therapy impacts response. There has been little detailed analysis of the activation patterns in RV septal pacing (RVSP), especially in the CRT population. We compare left bundle branch block (LBBB) activation patterns with RV pacing (RVP) within the same patients with further comparison between RV apical pacing (RVAP) and RVSP.In silico computer modelling was applied to assess the effect of RVAP and RVSP in order to validate the clinical results.Body surface mapping was undertaken in 14 LBBB patients after CRT implantation. Nine patients had RVAP, 5 patients had RVSP. Activation parameters included left ventricular total activation time (LVtat), biventricular total activation time (VVtat), interventricular electrical synchronicity (VVsync), and dispersion of left ventricular activation times (LVdisp). The direction of activation wave front was also compared in each patient (wave front angle (WFA)). p = 0.046). VVsync was significantly greater in LBBB  but LVdisp was greater in RVP . WFA did rotate clockwise with RVP vs. LBBB (82.5 ± 25.2 vs. 62.1 ± 31.7 op = 0.026). None of the measurements were different to LBBB with RVSP; however, the differences were preserved with RVAP for VVsync, LVdisp, and WFA. In silico modelling corroborated these results.Patients were aged 64.6 ± 12.2 years, 12 were male, 8 were ischemic. Baseline QRS durations were 157 ± 18 ms. There was no difference in VVtat between RVP and LBBB but a longer LVtat in RVP The online version of this article (10.1007/s10840-019-00567-2) contains supplementary material, which is available to authorized users. Patients with left bundle branch block (LBBB) are more likely to benefit from cardiac resynchronization therapy (CRT) than other intrinsic conduction delays establishing this activation pattern as the primary target for response to resynchronization –3. StandRV apical pacing has been used as a surrogate for LBBB ; howeverin silico modelling to validate the activation patterns observed with septal and apical RV pacing.We hypothesised that RVSP would produce a different activation pattern to RV apical pacing (RVAP) that would be more likely to mimic LBBB and therefore alter the latest activated LV segment, changing the target segment for LV lead placement. To study this, we evaluated ventricular activation patterns with non-invasive electroanatomical body surface mapping in patients with LBBB receiving CRT during intrinsic activation and RV pacing . We also performed The local ethics authority approved the study and all patients provided written informed consent; the study complies with the Declaration of Helsinki. Consecutive patients with an indication for CRT  and LBBB were included in the study.Biventricular pacing was undertaken using standard techniques. Positions of the RV leads were not predetermined but at the operators’ discretion and dependent upon optimal electrical parameters. LV lead position was targeted at posterolateral placement within the constraints of the patients’ coronary sinus anatomy in all patients. RV pacing position was confirmed on biplane chest radiograph post-procedure. Biventricular pacing was not programmed directly after implant as body surface mapping was undertaken the following day or at the earliest opportunity, and the device was turned on following the body surface mapping protocol.Non-invasive ventricular epicardial activation maps were acquired using 252 electrode high-resolution ECG mapping system . Body surface potentials were collected from the 252 electrodes positioned around the thorax supported in a single-use vest; following this, a thoracic computer tomography (CT) scan was performed in order to orientate each electrode to the epicardial shell. Subsequent to segmentation of the cardiac silhouette and the electrode positions from the thoracic CT images, 1500 unipolar electrograms were reconstructed as previously described .The raw data was analysed with ecSYNC software  in order to derive 4 key activation metrics: VVtat ; VVsync ; LVtat ; LVdisp  see . The angin silico computer modelling [We performed odelling  to assesodelling . Intrinsodelling , with a odelling . Simulatodelling .t test for normally distributed data, and the Mann-Whitney U test if deemed non-parametric. Values of p < 0.05 were considered statistically significant.Statistical analysis was performed on PASW Statistics 21 . The Kolmogorov-Smirnov one-sample test was used to ensure variables were normally distributed. Continuous variables were expressed as mean ± SD. Group comparisons were performed using an independent-samples Fourteen patients were studied. Mean age was 64.4 ± 12.1 years, 12 were male, 8 had an ischemic aetiology. The mean QRS duration was 159.9 ± 20.8 ms and all had LBBB. Nine patients (64%) were implanted with a RV apical lead and 5 (36%) were implanted with a mid septal RV lead. The devices implanted were St. Jude Medical Quadra Assura (8 patients), St. Jude Medical Quadra Allure (2 patients), Boston Visionist, Medtronic Viva Quad, Medtronic Brava Quad, and Sorin Paradym (each in 1 patient). There was no difference in baseline demographics between the two groups ; there was no significant change in VVtat but a significant reduction in VVsync . The reduction in VVsync and increase in LVdisp were also present in the apical group analysis , with no statistical change in VVtat or LVtat. However, analysing the data for the septal pacing group demonstrated no difference between LBBB and pacing for any activation parameters. The activation wave front angle rotated anticlockwise from LBBB with RVP  and RVAP  with no significant change with RVSP  (Table When comparing activation time parameters between intrinsic (LBBB) and RVP, there was a significant increase in LVtat and LVdisp with RVP .The last segment or segments activated in LBBB, all RV pacing patients, RVAP, and RVSP are represented in Fig. o. RV pacing led to a significant change in LVdisp ; there were no other significant changes in these 8 patients when analysed as a whole or separated into the RVAP and RVSP groups.The analysis was repeated in the 8 ischemic patients in whom 5 had apical pacing and 3 had septal pacing. Baseline QRS duration was 160.5 ± 18.5 ms and ejection fraction was 25.5 ± 5.37% with intrinsic activation times of 43.1 ± 18.5 ms for VVsync, 105.1 ± 24.4 ms for VVtat, 93.3 ± 21.5 ms for LVtat, and 29.9 ± 6.6 ms for LVdisp. The baseline wave front angle was 78.8 ± 28.9The activation times were normalized with respect to the VVtat . The Pearson correlation of the activation times across the mesh was then calculated for the intrinsic LBBB model in comparison with the three RVAP and RVSP simulations. Consistent with the observations seen in the patient studies with electroanatomical mapping in the clinic, it was found that the RVSP simulation had a higher correlation to the LBBB simulation in comparison with the RVAP simulations at the anterior, middle, and posterior sites at the RV apex (81% vs 26–73%) Fig. . The latBiventricular total activation time was the same with RVP and LBBB, however LV total activation time (LVtat) was longer with RV pacing than LBBB. This difference was driven by those patients with RV apical pacing with no difference in LVtat between RV septal pacing and LBBB.Left/right electrical synchrony was more prolonged in LBBB than in RVP; again this difference was significant with RV apical but not RV septal patients studied.The dispersion of activation within the LV was greater with RV apical but not RV septal pacing compared to LBBB.The direction of travel of the activation wave front was significantly different in with RV apical pacing compared to LBBB with the wave front angle rotated anticlockwise during RVP RV septal pacing led to a similar spread of terminally activated segments to LBBB, with the majority of sequences terminating in the basal and mid inferolateral segments. RV apical pacing tends to lead to the basal segments predominating as the terminal activated segments.in silico modelling with a higher correlation between the intrinsic LBBB model when pacing at the mid septal wall in the RV than when pacing at the mid, anterior, or posterior RVA . The latest activation region in the LV free wall did not shift significantly with RVS pacing (1 mm); however, RVA pacing caused a change in the latest activation region by 10–41 mm.These changes were consistent with the In this study, we have observed significant differences between activation patterns and timings between LBBB and RVP in patients studies with non-invasive imaging and with in-silico computer modelling. The main findings are as follows:p = 0.06); however, the mechanism by which this difference exists can be explained simply by the greater basal to apical length than the left ventricular width; therefore, conduction takes longer from base to apex as opposed to from septal to lateral wall  is used. They suggest that operators should consider measuring Q-LV following RV lead implant rather than at baseline and perhaps target more basal LV pacing with an apical RV lead.These results of the This is a small study of activation patterns in RVP and LBBB. One particular shortcoming is that there are fewer RV septal pacing patients than RV apical pacing patients. However, despite the small numbers, there is a strong signal that RV apical pacing produces a very different activation pattern to LBBB, whereas septal pacing activation leads to a similar activation to LBBB. Also, the fact that RV pacing activation pattern is directly compared with LBBB within the same patient helps to strengthen the statistical outcomes. LBBB leads to heterogeneous activation patterns  and ischRV apical pacing has previously been used as a surrogate for LBBB. This study suggests that RV septal pacing may be closer to intrinsic LBBB activation than RV apical pacing. Although there is yet to be clinical data to suggest that RV lead position effects outcomes in CRT, this study suggests that the RV lead position will impact the activation pattern and therefore, attention may need to be paid to LV lead positioning on the basis of the RV pacing site. In conclusion, RV apical pacing activation differs from LBBB where RV septal pacing appears similar.ESM 1(DOCX 19 kb)


Though the current staged surgical strategy for palliation of single ventricle heart disease, culminating in a Fontan circulation, has increased short-term survival, mounting evidence has shown that the single ventricle, especially a morphologic right ventricle (RV), is inadequate for long-term circulatory support. In addition to high rates of ventricular failure, high central venous pressures (CVP) lead to liver fibrosis or cirrhosis, lymphatic dysfunction, kidney failure, and other comorbidities. In this review, we discuss the complications seen with Fontan physiology, including causes of ventricular and multi-organ failure. We then evaluate the clinical use, results, and limitations of long-term mechanical assist devices intended to reduce RV work and high CVP, as well as biological therapies for failed Fontan circulations. Finally, we discuss experimental tissue engineering solutions designed to prevent Fontan circulation failure and evaluate knowledge gaps and needed technology development to realize a more robust single ventricle therapy. Single ventricle heart disease (SVD) is a complex and severe congenital heart defect (CHD) that is characterized by a single pumping chamber and an inability to septate the heart surgically into dedicated pulmonary and systemic circulations. SVD represents roughly 3% of all CHD cases and may affect several structural components of the heart including the valves, ventricles, aorta, and septa . TreatmeFor the purposes of this review, the focus will be on hypoplastic left heart syndrome (HLHS), the most common type of SVD where the left heart structures are underdeveloped ; howeverWhile the series of palliative procedures culminating in the Fontan-Kreutzer operation addresses the issues of obstructed systemic blood flow and cyanosis, it introduces a host of other complications. Heart failure and circulatory dysfunction remain difficult to characterize in this heterogenous population and deviate from the classical biventricular heart failure phenotype. Fontan failure has several different presentations, ranging from a phenotype similar to that of traditional “right heart failure” to inexorable lymphatic leak . As a reThe thoracic duct, which drains mesenteric and thoracic lymphatics, inserts into the innominate vein, which has a pressure of 12–15 mmHg after the Fontan-Kreutzer operation . As a result, there is a decrease in the pressure gradient driving lymphatic flow, which impairs lymphatic drainage with increases the risk of lymphatic dysfunction and failure. Experts believe PLE is due to retrograde drainage of lymphatic fluid into the intestinal tract after a direct connection between the lymphatics and the gut lumen has been established, for example, following an acute gastroenteritis . PLE leaAnother common issue in this patient population is acquired Fontan-associated liver disease (FALD). Hepatic arterial flow is altered in the Fontan circulation and studies have indicated that a combination of abnormal perfusion of the liver combined with hepatic congestion can lead to hepatic fibrosis, which can lead to hepatic cirrhosis or even hepatocellular carcinoma with prolonged fibrotic scarring , 17. WhiStudies have indicated that the number of Fontan-associated comorbidities are directly related to age and result in increased risk of death, length of hospital stay, and cost of healthcare , 19, 20.Once circulatory failure is apparent, heart transplantation is the only defined option for patients after clinical decompensation. Outcomes of heart transplant in this population vary widely between centers and single ventricle anatomy –23. GrafAdvancements in research have combined scaffold and stem cell technologies for prevention and reversal of Fontan failure. These technologies will be reviewed here, in addition to analyses of other bioengineered solutions. Further, this review will compile and detail design considerations for a preventative, tissue engineered solution for the SVD population. This is the first review, to our knowledge, that summarizes both preemptive and reactionary bioengineered solutions for the Fontan patient.As circulatory mechanical support device (MSD) technology develops, these devices are increasingly used in the single ventricle population. As previously mentioned, in the short-term, these devices are used for “bridge-to-transplantation” or emergency situations. Extracorporeal membrane oxygenation (ECMO) is used to support pediatric patients with cardiopulmonary failure and represents the first MSD, albeit with an oxygen delivery component, used in patients with SVD. However, reports suggest patients with single ventricle physiology on ECMO are less likely to survive compared to children with biventricular CHDs  . SimilarThe first MSD developed for long-term support of pediatric heart failure patients has appeared within the last several decades—The Berlin Heart (BH). This device is a pneumatically driven extracorporeal ventricular assist device (VAD) that was approved by the Food and Drug Administration (FDA) under a Humanitarian Device Exemption in 2011 (HDE #H100004). This device has the ability to support patients with Fontan circulation until cardiac transplantation , 40–50. In addition to the BH, many mechanical assist devices approved by the FDA for use in adults with heart failure have been used off-label in the pediatric population. Data regarding the HeartMate (HM) II in a Fontan circulation is limited to case studies, lowering one patient's CVP levels by 19 mmHg  56, 59), 5956, 5Off-label use of several other mechanical assist devices intended for adult heart failure (HF) are noted in in vitro system, with tunable capacitance and resistance, representative of Fontan physiology (in vitro change in pressure (7.6 mmHg) was found by Rodefeld et al. using a derivative of the Von Karman viscous rotary pump , 67in viary pump  68). Th. Thin viary pump , 67, 68.ary pump  (67). Thin vitro and in situ experimentation of a venous assist device placed at the four way junction of the PA, IVC, and SVC  without lowering CVP or curbing symptoms of circulatory dysfunction, which begs the question of whether or not using MSDs indefinitely is a plausible solution for the SVD population. Further, venous assist devices under development have experienced similar issues of thrombosis and this complication must be addressed prior to human trials. Based on the results discussed in this section, we believe an MSD is not the ideal candidate for long-term support of patients with a Fontan circulation due to the characteristic nature of heavy alloys and the inevitable hematological complications.Tissue engineering was coined by Langer and Vacanti nearly 30 years ago as an interdisciplinary approach that utilizes cells, scaffolds, and bioactive molecules to develop biological substitutes for damaged tissues . Since i2), maintained superior RV ejection fraction (mean 41.8 vs. 32.3%), and exhibited a larger absolute change in RV ejection fraction (mean +5.7% and −2.2%)  . Followid −2.2%) . The 34 d −2.2%) . A year d −2.2%) . ResearcIn addition to cardiac progenitor cells, several groups have investigated the benefit of mesenchymal stem cells (MSCs) on systemic ventricular function in patients with SVD . MSCs arLastly, a phase I/IIb clinical trial named Allogenic hMSC Injection in Patients With HLHS (ELPIS) began in March 2015 at the University of Maryland. The study was designed to enroll 30 patients with HLHS, beginning with 10 patient injections during stage II palliation to ensure safety, followed by 20 patient injections to determine efficacy of improved RV function . HoweverTissue engineered conduits for use in the Fontan-Kreutzer procedure are being studied to replace commercial, non-living grafts. A pediatric surgeon, Toshiharu Shin'oka, implanted the first autologous engineered grafts in SVD patients during a 2001 Japanese clinical trial . Midtermin vitro  using neonatal rat cardiomyocytes, in combination with biomaterials, and tested them in the vena cava of male rats . Two EHTin vitro performance of a modular tissue engineered pulsatile conduit (TEPC)  . Brieflyt (TEPC) . This det (TEPC) . The TEPt (TEPC) . This stpreventing Fontan circulation failure is discerning the impact of early intervention on late outcomes. While it is evident that both MSCs and CDCs improve single ventricle function short-term, it would be extremely difficult to ascertain the effect that each cell type has on late Fontan failure years after intervention, especially in patients where HF symptoms stray from the classic phenotype. A main takeaway from the MSC and CDC based clinical trials, though, is the safety and efficacy of autologous stem cell use within the SVD population, and the ability to modulate tissue engineered structures by delivering cells to a scaffold in doses. This information has undoubtedly informed the tissue engineering community working toward Fontan failure therapies, which is evident in the design of each solution discussed here. We strongly support a push toward human induced pluripotent stem cells as the most scalable and efficient path forward for such therapies, and we recommend the use of scaffolds for cell retention purposes. In order to properly evaluate and compare said therapies, a standardized in vitro protocol would be invaluable and accelerate the development of a tissue engineered solution for preventing Fontan failure.The caveat in determining the clinical relevance of the discussed tissue engineered solutions in Very few groups have utilized tissue engineering for reversal of Fontan failure, as the risk of imminent death is high once symptoms present, and alternative rescue methods are well-understood and fairly reliable . The following section discusses the few case studies and research groups that have used tissue engineering strategies for repairing circulatory failure in children with Fontan physiology.One clinical trial to date has examined the benefit of MSCs on declining ventricle function after Fontan palliation (NCT02549625). The cells utilized in this trial were bone marrow derived mononuclear cells (BM-MNCs), which contain a heterogenous population of cells, including MSCs, and regenerative paracrine factors, delivered via an intracoronary catheter . This phThe aforementioned clinical trial has published a report detailing infusion of BM-MNCs in the right and left coronary arteries of a 25 years old man with Fontan circulation, an ejection fraction of 34%, severe ascites, aortic valve regurgitation, and a dilated RV . The patAn early case report from Giessen, Germany details a patient with declining ventricle function after stage II palliation for correction of HLHS . ChronicFew research groups have targeted the SVD population as a recipient of a tissue engineered cardiac patch for improvement of the systemic ventricle. This may be due to the fragile nature and rapid decline of these patients, or the barriers presented when seeking approval from regulatory bodies. However, many groups have investigated the effect of tissue engineered structures for improvement of ventricle function in adults with heart failure –107. A cThe studies detailed in this section highlight the usefulness of small molecules in signaling the damaged myocardium to regenerate. As was previously stated, BM-MNCs contain an array of paracrine molecules and progenitor cells, both of which have the ability to cause regeneration provided the appropriate scaffold. However, the topology, rigidity, and chemical makeup of the scaffold that progenitor cells are seeded onto or in can alter cell function and phenotype , indicatFamilies and patients face an arduous journey when diagnosed with SVD, involving years of palliative surgeries and impending patient decline. This population experiences Fontan failure in a variety of presentations, ranging from lymphatic to ventricular dysfunction, and are nearly always accompanied by high CVP. In addition, Fontan failure is multifactorial and arrythmia, cardiac failure, valvular incompetence, systemic outflow obstruction, desaturation due to arteriovenous malformations, and lymphatic congestion can all lead to raised CVP. These elevated pressures are likely responsible for multi-organ decline, but the pathogenesis is not entirely understood, making it difficult to develop targeted therapies.Upon developing circulatory dysfunction, patients with SVD are destined for a heart transplant or death. In the event that neither is an option, MSDs are used until a suitable donor heart is available. While it seems that MSDs are able to support patients until transplantation, many still experience Fontan failure symptoms or problems associated with the MSD implantation. In the long-term, complications arise with MSDs and are most often related to blood irregularities, eliminating this as a viable solution for indefinite use.in vitro testing method should include pulsatile flow and alike Fontan parameters in order to compare tissue engineered therapies. Ultimately, cell-based therapies have displayed improvements in cardiovascular function in patients with SVD and represents a promising area for further investigation.Development of a tissue engineered structure for Fontan failure, both for the single ventricle and venous return, have developed significantly in the past several decades. However, researchers have taken various approaches, and this has slowed progress. Stem cells delivered to the ventricle show promising results but likely don't have a lasting effect years after they are administered, leading us to recommend the use of a scaffold for cell and structural retention. It is also unclear whether or not a tissue engineered patch on the single ventricle has the ability to lower CVP and the associated complications, as the absence of a pulmonary ventricle is likely responsible. A uniform animal model and JJ and MF: manuscript conception and design. MF: interpretation of relevant literature and drafting of manuscript. MD: medical expertise in single ventricle physiology. JJ and MD: critical manuscript revisions. MF and MD figure preparation. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pediatric patients are becoming increasingly referred for cardiovascular magnetic resonance (CMR). Measurement of ventricular wall thickness is typically part of the assessment and can be of diagnostic importance, e.g. in arterial hypertension. However, normal values for left ventricular (LV) and right ventricular (RV) wall thickness in pediatric patients are lacking. The aim of this study was to establish pediatric centile charts for segmental LV and RV myocardial thickness in a retrospective multicenter CMR study.CMR was performed in 161 healthy children and adolescents with an age range between 6 and 18 years from two centers in the UK and Germany as well as from a previously published CMR project of the German Competence Network for Congenital Heart Defects. LV myocardial thickness of 16 segments was measured on the short axis stack using the American Heart Association segmentation model. In addition, the thickness of the RV inferior and anterior free wall as well as biventricular mass was measured.The mean age (standard deviation) of the subjects was 13.6 (2.9) years, 64 (39.7%) were female. Myocardial thickness of the basal septum  was 5.2 (1.1) mm, and the basal lateral wall  measured 5.1 (1.2) mm. Mid-ventricular septum  measured 5.5 (1.2) mm, and mid-ventricular lateral wall  was 4.7 (1.2) mm. Separate centile charts for boys and girls for all myocardial segments and myocardial mass were created because gender was significantly correlated with LV myocardial thickness  and biventricular mass .We established CMR normal values of segmental myocardial thickness and biventricular mass in children and adolescents. Our data are of use for the detection of abnormal myocardial properties and can serve as a reference in future studies and clinical practice. Cardiovascular magnetic resonance (CMR) is a well-established imaging modality for assessment of cardiac disease in the adult and pediatric population . It is cCMR is considered the reference standard for non-invasive biventricular volumetric measurements . The proA recent review about normal CMR values in pediatric patients revealed that there are limited data available for children and adolescents with regard to measured parameters, sample sizes and age range . MoreoveChildren with cardiomyopathy or a family history of cardiomyopathy are increasingly being referred for CMR assessment . HypertrUnlike in the adult population, where the normal cut-off values for myocardial thickness are well defined , this doThe aim of this multicentre retrospective study was: (1) to establish centile charts for myocardial thickness of 16 segments of the LV and 6 segments of the RV analyzing previously acquired scans of healthy children, and (2) to assess the impact of demographic parameters including gender on wall thickness measurements.Scans of healthy children for this multicenter retrospective study were recruited from Royal Brompton Hospital in London, UK (n = 117), the University Hospital Schleswig–Holstein, Campus in Kiel, Germany (n = 16) and from a previously published CMR project of the German Competence Network for Congenital Heart Defects (n = 28).The indications for the scans were as follows: (1) non-diagnostic echocardiographic scan, (2) uncertainty about the anatomical structures on echocardiography, (3) syncope or (4) chest pain with low pre-scan probability of being cardiac in origin, (5) participation in a previous study. Exclusion criteria comprised: (1) congenital or acquired heart disease, (2) arterial hypertension (3) medication for arterial hypertension,(3) other types of disease that involve structural and functional abnormalities of the heart and (4) pregnancy.The study was approved by the Local Research Ethics Committee and by Health Research Authority . Parents or guardians signed a written consent.All CMR scans were performed at 1.5 T. Contiguous standard short axis cines with full myocardial coverage were acquired using ECG-gated balanced steady-state free-precession (bSSFP) sequences. All images were analyzed with validated software . Volumes and mass were calculated excluding the papillary muscles and all measurements were indexed to body surface area . The following parameters were calculated: BSA indexed LV and RV end-diastolic volume , indexed LV and RV end-systolic volume , LV and RV ejection fraction , indexed LV and RV stroke volume , indexed LV and RV mass  and cardiac index.LV myocardial wall thickness of 16 segments was measured in the short axis stack at the end of diastole using the American Heart Association segmentation model  was used for the statistical analysis . All tesThe statistical analysis was performed stratified for girls and boys and separately for the LV and the RV. The mean of three wall thickness measurements for each segment Fig.  was usedCentile graphs and tables were generated according to the LMS-method of Cole and Green . An exteThe impact of demographic factors on wall thickness and myocardial mass was analyzed for each variable separately and in a multiple fashion using linear regression models with and without interactions. Outcome variables were basal, mid-ventricular and apical wall thickness as well as diastolic myocardial mass for the LV and RV, while demographic variables were gender, BSA, age, body height, body weight and average heart rate. Because gender showed an interaction with several of these variables, multiple analyses were stratified for gender. Model selection was performed by backward selection and a p value threshold of 0.05.Two experienced operators with 14 years (IV) and 3 years (SBG) of experience evaluated the measurements separately for all segments of the LV in 30 children. The inter-observer agreement was evaluated by the intraclass correlation coefficient (ICC). For this, the R package irr with the command icc  was applied .CMR scans of 161 healthy subjects of 6–18 years of age fulfilled the criteria and were included into the study Fig. . The demMyocardial thickness of the basal septum  of the whole study group was 5.2 ± 1.1 mm (mean ± SD), and the basal lateral wall  measured 5.1 ± 1.2 mm. Mid-ventricular septum  measured 5.5 ± 1.2 mm, and mid-ventricular lateral wall  was 4.7 ± 1.2 mm. LV mass at end-diastole ranged between 23.9 to 156.0 g in the entire study group.Strong correlations were observed between BSA and body weight  and between BSA and body height .Linear regression Table  showed tAs a consequence of the regression analysis above, the centile charts and tables in the main manuscript are shown by BSA. Figure Linear regression Table  showed tIn multiple regression analysis Table , BSA shoFigures The inter-observer ICC for basal myocardial thickness measurements was 0.815 , for mid-ventricular 0.883  and for apical measurements 0.860 .Assessment of myocardial thickness is important for many cardiovascular diseases already in childhood. CMR is increasingly used in pediatric patients for detailed global and regional myocardial characterization but normative biventricular data for myocardial thickness in children and adolescents are lacking.In the current study, we present normal segmental myocardial thickness values of 16 LV and 6 RV segments as well as normal values for myocardial mass in children and adolescents between 6 and 18 years. BSA was found to be the major determinant factor of the segmental myocardial thickness in childhood. Therefore, centile charts and tables for all segments of both ventricles and for myocardial mass were established primarily with respect to BSA and gender and only for completeness with respect to age and gender.Linear regression showed associations of the segmental myocardial thickness with all studied variables (except average heart frequency), i.e. with age, weight, height and gender for LV segments and the same, except for gender, for RV segments. This difference might be caused by the overall much thinner RV thickness (0.9–2.7 mm) and the inability to distinguish between very small differences given the spatial resolution of the bSSFP cine images (voxel size 1.6 × 0.6 × 8.0 mm). In multiple regression analysis, body surface area was the strongest determinant for the majority of the segments and BSA correlated strongly with weight or height. We, therefore, include centile charts and tables that show wall thickness as a function of BSA.LV myocardial thickness has been measured in a large study of healthy middle-aged adults. Similar to our study, the mean LV myocardial thickness was found to be positively associated with BSA and also weight. No relationship was detected between mean LV myocardial thickness and age or height . In anotTables and charts were created by the Lambda-Mu-Sigma (LMS) model introduced by Cole and Green . This moInterobserver variability demonstrated good agreement for basal, midventricular and apical and this was comparable with a previous published study .All measurements in the current study were performed on short axis images. Comparison has been made between measurements of myocardial thickness in different planes in the adult population and the myocardial thickness was found to be 6% higher at basal level, 10% higher at mid-ventricular level and 20% lower at apical level on long axis images compared to short axis images . TherefoThis is a retrospective study with associated limitations. The study includes only children from the age of 6 and 18 years as there were not enough younger healthy children who underwent CMR. This is typically because children younger than 6 years usually require general anesthesia or sedation and therefore, the indication for the scan is much stricter than for awake scans performed in older children. In addition, the numbers of included children and adolescents with an age of 6–8 years and an age of 18 years are small. However, the applied statistical methods model a general trend over the whole age range. Therefore, good results can even be achieved for age groups with low sample size. Nevertheless, the estimation accuracy is smaller in those groups.The provided normal values are those for European population and cannot necessarily be used for children from other populations.With development of real time imaging, which is more often used in uncooperative children, another problem arises with regard to interpretation of the myocardial thickness measurements. Further studies would be needed to investigate if segmental myocardial thickness can be measured reliably from these sequences.We provide normal values for segmental myocardial thickness and mass of both ventricles, which can serve as a reference standard for the diagnosis of acquired and congenital heart disease in children and adolescents. BSA was the major determinant of the myocardial thickness and mass for both ventricles.Additional file 1. Additional tables.Additional file 2. Additional figures.


Psoriasis is a chronic inflammatory disease. The effect of psoriasis on the cardiovascular system has not been studied in children before. We studied ventricular strain and vascular functions to assess early cardiovascular effects of psoriasis during childhood.  The study population consisted of 20 psoriatic and 20 age- and sex-matched control subjects. Two-dimensional echocardiography images, longitudinal and global strain, and carotid and brachial ultrasound studies were performed.  The mean age of psoriatic children was 14 ± 0.89 years and that of the controls was 14.05 ± 0.88. There were significant increases in terms of interventricular septum diastolic and left ventricular posterior wall diastolic diameter and decreases in mitral E, mitral A, and E/A values between groups. Tissue Doppler imaging revealed significant differences between groups in terms of lateral annulus E’, A’, E’/A, isovolumetric contraction time, and ejection time. Aortic stiffness was significantly higher and global circumferential strain and longitudinal strain were significantly lower in the psoriasis group. Carotid intima media thickness and flow-mediated dilatation did not differ significantly between the groups.  Cardiac left ventricular and arterial functions are affected in psoriatic children and may be an alarming sign of atherosclerotic heart disease in the long term. Early detection of these changes may be helpful for eliminating other risk factors.  Psoriasis is one of the most common immune-mediated chronic inflammatory diseases among adults, affecting nearly 1%–4% of the population (1). There are increasing data about the effects of psoriasis on the cardiovascular system and development of atherosclerotic vascular changes. The role of inflammation in atherosclerosis pathogenesis has been studied extensively. With the chronic inflammatory status leading to the release of inflammatory and proatherogenic mediators, arterial functions are altered and atherosclerotic changes are promoted (2).Previous studies conducted in adult psoriatic patients have shown impaired ventricular functions, decreased ventricular strain, increased carotid intima media thickness (CIMT), and decreased flow-mediated dilatation (FMD) of the brachial artery. Echocardiographic methods such as tissue Doppler imaging (TDI) and strain echocardiography are beneficial methods in detection of subtle changes in myocardial performance that cannot be identified by routine echocardiographic examination. Magnetic resonance imaging and scintigraphy were also used to detect left ventricular systolic function in adult psoriatic patients. These advanced techniques may be used in detection of early cardiac effects of psoriasis during childhood (3). On the other hand, ongoing inflammation in psoriatic patients may accelerate the atherosclerotic process, leading to impaired vascular functions such as aortic strain, distensibility, and stiffness, which results in compromised left ventricular function (4).The aim of this study is to assess cardiac involvement in pediatric cases by evaluating subclinical myocardial changes and arterial functions using TDI, strain echocardiography, arterial distensibility, stiffness, CIMT, and FMD. The study group was recruited from the patients under follow-up with a diagnosis of pediatric psoriasis in outpatient clinics of the Marmara University Dermatology Department. The control group consisted of healthy children. Informed consent was received from all patients and controls. The study was approved by the local ethics committee of the Marmara University School of Medicine (Date: 02.02.2018/09.2018.114).Twenty consecutive children with a diagnosis of psoriasis vulgaris  and 20 sex- and age-matched controls  were enrolled in the study. The mean duration of the disease between diagnosis and cardiac assessment was 8.7 ± 1.2 months (5–14 months).Children with other risk factors such as obesity, diabetes, and renal or liver disease and those who were taking oral medications that may affect the cardiovascular system were excluded from the study. Patients for whom the echocardiographic image quality was poor were also excluded. The severity of psoriasis was assessed using Psoriasis Area and Severity Index (PASI) scores, which have a range between 0 and 72, scores over 10 indicating moderate-severe disease (5).All patients underwent an echocardiographic examination using the Philips IE33-model echocardiography machine , equipped with a 5 MHz sector and 7–11 linear transducers. Two-dimensional echocardiographic images were obtained using apical four-chamber (4C) and 2C views and a parasternal long axis (LAX) view. Left ventricular dimensions, interventricular septum diastolic (IVSD) and left ventricular posterior wall diastolic (LVPWD) thicknesses, and left ventricle end-diastolic (LVED) and left ventricular end-systolic (LVEDS) dimensions were measured and left ventricular ejection and shortening fractions (LVEF-SF) were calculated by using the Teichholtz formula (6). Left ventricular diastolic functions were studied using pulse wave echocardiography using mitral inflow Doppler velocities; early (E wave) and late (A wave) velocities, deceleration time, and isovolumetric relaxation time (IVRT) were measured. The E/A ratio was calculated.TDI was used for assessment of left ventricular myocardial functions. The velocities were obtained from the lateral mitral annulus throughout the cardiac cycle; early and late diastolic myocardial velocities (E’ and A’), systolic velocity S’, IVRT, and isovolumic contraction time (IVCT) were measured. The myocardial performance index  was calculated by using the formula IVRT + IVCT/LVET.Left ventricular global and longitudinal strain was studied by semiautomated speckle-tracking echocardiography. Images of the apical 4C, 2C, and long axis views were optimized at a frame rate of 60 frames/s. The systole was defined in the apical long axis view by opening and closure of the aortic valve, simultaneous with the peak of the T wave on electrocardiography (7). Aortic (Ao) diameters were measured from the LAX view on M-mode tracing at a level of 3 cm above the aortic valve. The systolic diameter (AoSD) was measured at the maximum anterior motion of the aorta and the diastolic diameter (AoDD) was measured at the peak of the QRS complex on the simultaneously recorded ECG. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by sphygmomanometry just before echocardiographic examination (4). The following indexes of aortic function were calculated:· Aortic stiffness (AS)% = 100 × (AoSD – AoDD)/AoDD· Aortic distensibility (AD) = 2 × (AoSD – AoDD)/(AoDD × PP)Carotid intima media thickness (CIMT) was measured with the L-11 MHz linear transducer. CIMT measurements were obtained when the patient was lying in supine position and the neck was rotated to the opposite side of the examiner. The average of three measurements was used for statistical analysis. The CIMT was accepted as the distance between the interface of the lumen and intima and the interface between the media and adventitia (8).FMD of the brachial artery was calculated by using the L-11 MHz linear array transducer after 10 min of resting in the supine position from the brachial artery. A nonbranching, straight segment of the brachial artery above the antecubital fossa was identified and images were recorded. Baseline brachial artery diameter was measured offline at the tip of the R-wave of simultaneous ECG tracings. A pneumatic cuff on the upper arm was then inflated up to 50 mmHg above systolic blood pressure for 5 min and then released. After cuff deflation, brachial artery diameter was measured at every 30 s for 3 min in the end-diastolic phase. FMD was calculated as the percentage change in diameter from baseline value to the biggest value after cuff deflation (9). Statistical analysis was performed using SPSS 20 for Windows . The independent-samples t-test or Mann–Whitney U test was used to compare study variables. For categorical variables the chi-square test was used. Correlations were evaluated by univariate and multivariate linear regression analysis. P < 0.05 was accepted as an indication of statistical significance.Patients and control subjects were similar in terms of age and sex. PASI scores were 7.0 ± 1.84, indicating moderate disease. The clinical and demographic characteristics of the groups are shown in Table 1. In comparison of M mode echocardiographic measurements, IVSD and LVPWD were found to be thicker and LVEDD was larger in patients with psoriasis compared to controls (P < 0.05). LVESD, ejection fraction, and shortening fraction did not differ between the groups. In assessment of left ventricular diastolic functions, the velocity of the E wave was decreased and the A wave was increased significantly (P < 0.05). The E/A ratio was decreased in patients, indicating more restrictive left ventricles. Comparison of echocardiographic values is shown in Table 2.In the comparison of TDI parameters, the velocity of the E’ wave was decreased while the A’ wave was increased in the psoriasis group. Decreased E’/A’ values in the patient group also indicate an early result of restrictive left ventricle physiology (Table 2). The MPI was also increased in patients as an indication of impaired global ventricular function.While there was a significant increase in terms of aortic stiffness (P < 0.05), no significant change was observed in terms of aortic distensibility. CIMT and FMD% values did not differ significantly between the groups (Table 3).In assessment of left ventricular strain parameters of the groups, there was a significant difference between the groups in terms of both circumferential and longitudinal strain parameters (Table 2).When we correlated clinical PASI scores with arterial functions, a positive correlation was found between CIMT and PASI scores (r: 0.03). Disease duration was correlated positively with vascular parameters of aortic stiffness, aortic distensibility, FMD 1’, and FMD 3’  .Psoriasis is one of the most prevalent immune-mediated skin disorders. It is increasingly recognized to be related to cardiovascular events in adults (1). In the last decade several studies of adult patients with psoriasis have been carried out using echocardiography; however, no studies have been conducted in children previously (10). This study is the first study to describe the early effects of the disease in children.The present study has shown that children with psoriasis had significantly hypertrophic and enlarged left ventricles compared to the healthy children. Saricaoglu et al. (11) reported increased left ventricular end-diastolic and end-systolic diameters in adult patients with psoriasis. Shang et al. evaluated patients by using conventional echocardiography and TDI and demonstrated subclinical LV dysfunction even in those without other cardiovascular risk factors (12). Our findings are in line with these studies and suggest that these ventricular changes start at an early age. Diastolic dysfunction may precede systolic dysfunction in the course of heart failure. We found impaired diastolic function by using pulse-wave Doppler and TDI. These findings may be early markers of diastolic dysfunction and restrictive physiology.In this report we also evaluated aortic elastic properties. Factors known to affect aortic elasticity include age, sex, hypertension, diabetes mellitus, and coronary artery disease (13). None of our patients had any systemic disease other than psoriasis; therefore, the changes that we found in aortic elasticity and increased stiffness may be related to psoriasis and ongoing inflammatory processes. There was a significant positive correlation between aortic stiffness, distensibility, and disease duration. In adult studies, the degree of decrease in aortic distensibility, or increase in aortic stiffness, correlated with clinical severity and duration of the disease . We demonstrated these results even in childhood, indicating that immunologic processes are in charge even in the early stages.The CIMT is another ultrasonographic parameter used for early detection of atherosclerosis risk. Shaharyar et al. (15) demonstrated increased CIMT in adult psoriatic patients. However, in our study the difference between study and control groups in terms of CIMT was not statistically significant. This may be related to relatively shorter duration of the disease that may cause detectable atherosclerotic changes in children. We also found a positive correlation between PASI scores and CIMT in our study group. This finding also supports our speculation about the shorter duration of the disease preventing the difference from reaching significant levels.The vascular endothelium is an immunologically active organ. It regulates vascular tonus, secretes adhesion molecules, and plays a role in inflammation and angiogenesis. In the presence of hypertension, diabetes mellitus, obesity, oxidative stress, or dyslipidemia, endothelial dysfunction develops (16). FMD may be an early sign of endothelial dysfunction. We know that psoriasis sufferers with severe disease, as well as those with joint involvement, are more likely to have a greater systemic inflammatory burden with increased effects on the vascular system. In our study, albeit not reaching significance, decreased levels of FMD were observed even in the absence of these additional clinical involvements. We found a positive correlation between FMD 1’, FMD 3’, and disease duration. Balci et al. reported impaired endothelial function in adult psoriatic patients (17). Gonzalez et al. demonstrated that patients with arthritis without cardiovascular risk factors also exhibited endothelial dysfunction (18). In this study we demonstrated similar results that could be seen in childhood. Compared to conventional echocardiography, strain echocardiography provides a better measure of cardiac physiology and subclinical changes by evaluating global and longitudinal strain parameters . Wang et al. found that in early stages of heart failure, longitudinal strain is reduced while circumferential strain is preserved, because the subendocardial longitudinal fibers are primarily affected in psoriatic patients. With disease progression interstitial fibrosis develops, and circumferential strain impairment occurs later than longitudinal strain (21). We found that even with normal ejection fraction both longitudinal and circumferential strain were affected, indicating early subclinical dysfunction in psoriatic children. There are several limitations of this study. First, our sample size is small; we could not correlate these echocardiographic parameters with hematologic parameters, such as high-sensitivity CRP and lipid profile. Second, the disease duration is short, making it impossible to understand the long-term cardiac consequences of the disease. This is the first report of a study attempting to evaluate the early cardiac and vascular effects of psoriasis in children. Early identification of patients at risk and elimination of other contributing risk factors for prevention of long-term cardiac disease will prolong the life expectancy and improve quality of life in this population. Further studies are required to monitor cardiac and vascular health in childhood psoriasis.