However, multivariable analysis showed that only the association between nLAP and LV reverse remodelling after CRT is independent (p < 0.01). Adding LA strain analysis to the guideline algorithm improved the feasibility of LAP estimation without affecting the association between estimated LAP and CRT outcome. Conclusion: Normal LAP before CRT, estimated using the 2016 ASE/EACVI guideline algorithm, is associated with LV reverse remodelling and long-term survival after CRT. Albeit non-independent, it can serve as a non-invasive imaging-based predictor of effective therapy. Furthermore, the inclusion of LA reservoir strain in the guideline algorithm can enhance the feasibility of LAP estimation without affecting the association between LAP and CRT outcome. Background: We investigated the impact of baseline left atrial (LA) strain data and estimated left atrial pressure (LAP) by applying the 2016 American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) guidelines on cardiac resynchronization therapy (CRT) outcomes. Methods: Datasets of 219 CRT patients were retrospectively analysed. All patients had full echocardiographic diastolic function assessment before CRT and were classified based on the guideline algorithm into normal LAP (nLAP = 40%), elevated LAP (eLAP = 49%) and indeterminate LAP (iLAP = 11%). All relevant baseline characteristics were analysed. CRT-induced left ventricular (LV) reverse remodeling was measured as the relative change of LV end-systolic volume (LVESV) at 12 ± 6 months after CRT compared to baseline. Patients were followed up for all-cause mortality for a mean of 4.8 years [interquartile range (IQR): 2.7–6.0 years]. Results: At follow-up, CRT resulted in more pronounced reduction of LVESV in patients with nLAP than in patients with eLAP. In univariate analysis, nLAP was associated with LV reverse remodelling ( Evaluating left ventricular (LV) filling pressures is essential for establishing the diagnosis, guiding therapy, and determining prognosis of heart failure patients . Although invasive measurements of LV filling pressures are the current gold standard, they are not routinely performed in patients. In 2016, the American Society of Echocardiography (ASE), together with the European Association of Cardiovascular Imaging (EACVI), introduced an echocardiography-based guideline algorithm for estimating left atrial pressure (LAP) .p-value of <0.05 was considered significant.Continuous data are expressed as mean ± standard deviation. Normally distributed data were compared between the three groups  using the one-way analysis of variance (ANOVA) test for continuous variables and the Chi-square test for categorical variables. The significance of pairwise comparisons among groups was adjusted according to Bonferroni’s method. Survival rates were expressed using Kaplan–Meier’s curves, and the significance of differences in survival rates between groups was compared using a Log-rank test. The Cox proportional hazard model was used to determine predictors of survival, and the linear regression model was used to determine predictors of relative changes in LVESV at follow up. In both models, all relevant baseline variables were first tested separately in a univariate analysis and then tested all together in a multivariable model to determine variable/s with an independent association with the outcome. Additionally, to test whether the association between LAP and survival after CRT is affected by potential interaction with baseline variables, the statistical interaction between baseline nLAP and each of the variables was separately analysed in a univariate analysis. Receiver operating characteristic (ROC) with Area Under the Curve (AUC) values and Youden’s index analysis were used to identify the optimal cut-off value of the LA reservoir strain to determine the LAP category . Data analysis was performed using SPSS . A two-sided Applying the guideline algorithm for estimating LAP to our database, 40% of the patients had nLAP, 49% had eLAP and 11% had iLAP because of missing echocardiographic data. The baseline characteristics of the study population and the diastolic echocardiography parameters stratified by the LAP category are summarized in p < 0.01), and larger absolute increase in LVEF at follow up .At follow-up, CRT resulted in significantly more pronounced LV reverse remodelling in patients with nLAP than in eLAP patients, as shown by a larger relative decrease in LVESV . In multivariable analysis, the association remained significant after adjustment of baseline variables (p < 0.01). LBBB was the other independent predictor of relative change of LVESV at follow up , 33% had eLAP (n = 68), and 33% had iLAP (n = 65). Patients with nLAP both at baseline and follow up showed the most pronounced relative reduction of LVESV and absolute increase of LVEF at follow up. In contrast, patients with eLAP at both baseline and follow up showed the least pronounced relative reduction of LVESV and absolute increase of LVEF at follow up . Independent predictors of long-term survival were age at implantation , AF  and LBBB [HR: 0.42, CI: : 0.39, confidence interval (CI): 0.22–0.72, Furthermore, our data showed that there was significant statistical interaction between baseline LAP and most of the baseline variables in predicting survival after CRT, namely: age at CRT implantation, New York Heart Association (NYHA) class, serum creatinine, LBBB, QRS duration, baseline LVEF and the use of ACEi and BB .n = 142). Using ROC analysis, an LA reservoir strain value of 13% had a sensitivity of 0.83 and a specificity of 0.70 with an AUC of 0.81 (CI: 0.73–0.89) and Youden’s index of 0.53 for the discrimination between patients with nLAP (≥13%) and eLAP , LA reservoir strain was accordingly used to further identify patients with nLAP and eLAP. Applying the combined guideline + LA strain algorithm decreased the size of iLAP subgroup from 11% to 3%; thus, the feasibility of estimating LAP was improved from 89% to 97% compared to the guideline algorithm  baseline nLAP is independently associated with LV reverse remodelling at CRT follow up; (2) baseline nLAP is associated with better survival after CRT, although it was not significant in multivariable analysis; (3) supplementing the guideline algorithm with LA reservoir strain improves the feasibility of LAP estimation in a CRT population without affecting the observed association between LAP and CRT outcome.We did not use a specific cut-off value of LV reverse remodelling for defining CRT response. Earlier data showed that any amount of LV reverse remodelling after CRT is associated with better survival . AccordiOur data showed that baseline nLAP is independently associated with LV reverse remodelling after CRT. This finding is in line with earlier data, where baseline LAP assessed both non-invasively by echocardiography and invasively by measuring pulmonary capillary wedge pressure (PCWP) was an independent predictor of LV reverse remodelling at CRT follow up . Recent Data investigating the association between baseline LAP and hard endpoints including mortality after CRT are few. Recent data showed that grade I DD (nLAP) was independently associated with a better CRT outcome . HoweverAccording to our data, the better survival of patients with nLAP compared to patients with eLAP could be explained by: (1) most favourable baseline characteristics for better CRT outcome were relatively more prevalent in nLAP than in eLAP patients including less DM, lower serum creatinine, less AF and higher prevalence of female sex and LBBB; (2) nLAP was associated with LV reverse remodelling at CRT follow up. Previous data showed that LV reverse remodeling and survival after CRT are significantly positively correlated ,15. NeveIn the work by Inoue et al., in patients with LVEF < 50%, an LA reservoir strain of <18% was able to identify patients with elevated LAP, defined as PCWP > 12 mmHg, with an accuracy of 81% . AlthougThe main limitations of the current work are the relatively small sample size, the retrospective design of the study, and the lack of invasive measurements of LAP. In the current work, LAP was non-invasively estimated using echocardiography not only by applying the 2016 ASE/EACVI guideline algorithm, but also using LA strain data. The combined guideline + LA strain algorithm has been previously validated; however, this was carried out with a non-CRT population . AlternaNormal LAP before CRT, estimated using the 2016 ASE/EACVI guideline algorithm, is associated with LV reverse remodelling and long-term survival after CRT. Albeit non-independent, it can serve as a non-invasive imaging-based predictor of effective therapy. Furthermore, the inclusion of the LA reservoir strain in the guideline algorithm can enhance the feasibility of LAP estimation without affecting the association between LAP and CRT outcome.


The Simpson’s method is the standard technique to determine left ventricular (LV) ejection fraction (EF) on echocardiography. The large inter-observer variability of measuring LVEF is well documented but not fully understood. A graphical analysis was used to elaborate what contributes to the inter-observer difference. Forty-two cardiologists  evaluated the LVEF using the Simpson’s method on 15 different echocardiograms (2 and 4 chamber view (2CH/4CH)); the program did not show the result of EF to prevent a bias. End-diastolic (ED) and end-systolic (ES) frames were predefined ensuring measurement at the same time point of the cardiac cycles. After standardization of the LV contour, the differences of the individual contours compared to a reference contour were measured. Also, the spreading of lateral/medial mitral annulus contours and the apex were depicted. A significant spreading of LV-contours was seen with larger contours leading to higher EFs (p < 0.001). Experience did not influence the determination of LVEF. ED-volumes showed more spreading than ES-volumes ((3.6 mm (IQR: 2.6–4.0) vs. 3.4 mm (IQR: 2.8–3.8), p < 0.001). Also, the differences were larger for the 2CH compared to the 4CH (p < 0.001). Variability was significantly larger for lateral than septal wall (p < 0.001) as well as the anterior compared to the inferior wall (p < 0.001). There was a relevant scattering of the apex and medial/ lateral mitral annulus ring. There was a large variability of LV-volumes and LVEF as well as position of mitral valve ring and apex. There were global differences , regional aspects  and temporal factors (ED vs. ES). Thus, multiple factors contributed to the large variability.Trial registration: The study was registered at “Netherlands Trial Register” . The determination of left ventricular (LV) ejection fraction (EF) is one of the most important parameters in cardiology. Many therapeutic strategies e.g. in patients with heart failure (HF) are based on a certain LVEF threshold .LVEF can be analyzed using different imaging techniques but echocardiography remains the most applied one , 3. HoweThe purpose of this study was to evaluate sources of LVEF measurement variability using a graphical analysis.Convenience sampling was used to identify cardiologists known to two of the organizers . 46 physicians responded and 42 (Netherland: 31 and Germany: 11 physicians) were included (32 (76%) male, mean age: 39 ± 7 years). Results from four cardiologists were excluded due to technical problems during data acquisition that could not be solved. Importantly, all participants had passed their clinical rotation in the echocardiography lab to ensure adequate experience. In addition, all participants, except cardiologists, had to be found capable using a standardized “entrustable professional activities” approach and reaching level 3 .The following characteristics of the participating cardiologists were collected using a questionnaire: age, gender, position at institution, years practicing as cardiologist, cardiology subspecialty, years performing echocardiograms, experience in other imaging modalities .The majority of participants worked as residents (in training to become cardiologist) , others as attending cardiologists , one as fellow  or some as director of departments/ sub-departments ; three individuals did not provide their status . The median work experience as cardiologist  was 5 years (IQR: 0–8). The median time span performing echocardiograms was 6.5 years (IQR: 3–12). There was a broad distribution of different sub-specialties: interventionalists , electrophysiologists , intensive care specialists , imaging specialists , heart failure specialists . Almost half of the physicians  had experience in other imaging techniques.www.trialregister.nl; study number: NL5131).A list containing the name and contact information of the physicians was given to GS from TOMTEC Imaging Systems having several functions: (1) providing a specific study code to each individual cardiologist which was used for labeling study material sent to the physicians, (2) technical support if needed, (3) receiving the return envelops and gathering data in a database and (4) sending back the pseudonymized results to the organizers of the study . Importantly, the list containing names and individual study keys was not accessible to anybody except GS (neither the participating cardiologist nor the investigators). This approach was approved by the local ethics committee of Maastricht UMC + (study ID METC 15-4-151) to guarantee anonymity and discretion. The study was registered at “Netherlands Trial Register”  informed consent form, (b) short inventory regarding the personal status, (c) USB-drive with the program LV2D for LVEF evaluation, (d) document containing a detailed stepwise instruction how to perform the analysis and (e) return envelope (to be sent back to TOMTEC Imaging Systems GmbH).The LV2D prototype  was used for contouring of the LV needed for the Simpson analysis. The program included a database consisting echocardiograms of 15 patients with a two-chamber view (2CH) and a four-chamber view (4CH). Those were selected from the echocardiogram database of the MUMC + Maastricht by CK and HPB. They were obtained by different sonographers and were not done with contrast. Details can be found in Table Cardiologists were asked to start the LV2D program, select a patient and start the measurement tool. Due to study reasons, the analysis was performed on personal computers. This was the only way to perform the study but this manner could have potentially influenced the results.A pre-defined end-diastolic (ED) and end-systolic (ES) frame was displayed for analysis. Also, a loop of the whole heart cycle was shown as a moving image. All segments that were not traced in the correct frame were excluded from later segmental analysis. Of note, the program did not display the actual result of the Simpson measurement; only the drawn contours were visible. The idea was to prevent adjustment of the contours based on the visual assessment.The following steps were applied for analysis:For all individual contours (2CH/4CH and ES/ED), equidistant resampling was performed using 99 points to achieve comparability between echocardiograms as the length of the LV differs in individual patients.a single echocardiogram were superimposed. This was done separately for 4CH  for all 99 measuring points of the 15 echocardiograms/ all participants was calculated .The distance between each individual measurement and the reference contour on each standardized measuring point was calculated.For analysis, 2CH and 4CH were divided into 6 segments defining the adjusted length step 1) of the LV into six comparable segments  as well as the inferior/anterior walls (2CH).per segment as well as per wall region. Finally, the values obtained from the steps above were combined to a median value for all echocardiograms for a standard 2CH and 4CH  distance between septal annulus and apex and b) distance between lateral annulus and apex) are equidistantly resampled. The resulting standardized contour ensures that the indices 1 and 99 refer for both annuli and index 50 for the apex, see step 1 above). This was done for all 15 echocardiograms separately Figs. .Fig. 3a A graphical depiction was performed combining all 15 echocardiograms (2CH and 4CH separately) Fig. .For the complete depiction, 2CH and 4CH were aligned in 3D. The center point of all apical contours was defined in 3D for all information obtained from 2 and 4CH.For 2CH and 4CH separately, the contour of the lateral and the septal mitral valve annulus was noted . This was done for all 15 echocardiograms Figs. .More specifically, some colleagues did not draw a u-shaped contour for the LV but a whole circle. In those cases, the contours had to be adjusted to as both mitral annulus were connected. This was done in consensus by CK and GS.Then, a graphical depiction was performed for septal and lateral annulus. Again, this was done for all 15 echocardiograms and both views (3).All contouring including calculation of volumes and LVEF was done with MATLAB9.9. This holds also true for all visualization of measurements. More specifically, for LV volumes the discrepancy between volumes contoured by individual cardiologists was calculated Fig. . Under- Characterization of the population was done using descriptive statistics: quantitative data is expressed as mean ± 2SD or median ± interquartile ranges as appropriate. Physicians were categorized by years of echocardiography experience: < 5 years (n = 17), 5–10 years (n = 13) or > 10 years (n = 12).Groups  were compared regarding the median LVEF using an Independant- Samples Kraskul Wallis Test Fig. b. ComparThe ED-LV volume (biplane) was 125 ± 41 ml and ES-LV volume (biplane) was 68 ± 34 ml. The mean biplane LVEF was 49 ± 15%  compared to the ED-LV volume (r = − 0.5113).There was no difference between categories according to experience regarding absolute EF (p = 0.998) or relative EF differences (p = 0.990). The median EF was 49% (IQR: 46–51.5) for colleagues with < 5 year (n = 17), 48% (IQR: 46–51) with 5–10 years (n = 11) and 48% (IQR: 46–51) > 10 years of experience (n = 14). The same held true for the relative EF difference from reference EF: − 1% (IQR: − 3.7–3.2), − 1.1% (IQR: − 2.4–0.8) and − 1.2% (IQR: − 2.97–2.7).Overall, there was a median difference between contours and the reference contour of 3.6 mm (IQR: 2.8–3.9).Combining systolic and diastolic contours, there was a larger difference  for the 2CH (3.6 mm (IQR: 2.8–4.0) compared to the 4CH (3.4 mm (IQR: 2.7–3.8) (p < 0.001). Looking at systolic contours only, the range of 2CH contours was 3.5 mm (IQR: 2.9–3.8) and for the 4CH 3.4 mm (IQR: 2.7–3.8) (p < 0.001). Regarding the diastolic contours, 2CH showed a spreading of 3.9 mm (IQR: 2.7–4.1) whereas for the 4CH, this distance was 3.6 mm (IQR: 2.6–3.9) (p < 0.001).When comparing different regions/LV walls, there was a significant difference regarding the mean measuring band width (p < 0.001). More specifically, difference was significantly larger for lateral as compared to septal wall (p < 0.001) as well as larger for anterior than inferior wall (p < 0.001). This held true for both ED and ES contours (p < 0.001). Figure Overall, there was a larger median difference between individual contours and the reference contour for the ED of 3.6 mm (IQR: 2.6–4.0) compared to the ES of 3.4 mm (IQR: 2.8–3.8) (p < 0.001). Also, this difference was seen for the 2CH (ED: 3.9 mm (IQR: 2.7–4.1) vs. ES (3.5 mm (IQR: 2.9–3.8), p = 0.003) as well as the 4CH (ED: 3.6 mm (IQR: 2.6–3.8) vs. ES (3.4 mm (IQR: 2.8–3.8), p = 0.028).Differentiating between apical, mid and basal segments, there was a significant difference between individual contours and the reference contour (p < 0.001). This was seen for ED but also ES contours for, both 2CH and 4CH  a graphical depiction of contours of (b) a large group of cardiologists. Several global, local and temporal aspects could be depicted implying that there is probably no single, simple solution to improve variability: a larger variability for 2CH compared to 4CH, diastolic contours larger than systolic contours, septal less variability than lateral/ inferior less than apical. In addition, apical and mitral valve ring position added to the spreading.Overall, our findings of large inter-observer variability of echocardiographic measurement of LVEF and LV volumes using different methods e.g. visual assessment or Simpson’s method are not new , 8, 11. Probably, every echocardiographer shares the impression that the cardiac septum is better visualized compared to the lateral wall . This ho2D echocardiography remains the standard approach in clinical practice as shown in a recent survey, whereas 3D and deformation imaging are only performed in the minority of patients . ConsequWe do not intend to say that echocardiography is the wrong method to determine LVEF as it will remain the main measurement until more experience is gathered using a more individual, precision based approach , 21. HowThe central question is, what do we find acceptable as variability? The evidence regarding the inter-/ intra-observer variability of large core labs dealing with multicenter studies is sparse . Even thThe main challenge is rather how we can improve the method and overcome shortcomings in clinical practice. Unfortunately, education does not seem to be the key as seen in this study but also found by other groups , 28, 29.Obviously, one of the drawbacks of the two-dimensional Simpson’s method is the need of geometric assumptions. Therefore, three-dimensional imaging seems to be the better approach –25. ThisLast but not least, there is much interest in the use of automated or semi-automated algorithms , 8, 30. In a large group of physicians, we saw a large variability between LV contours in apical 2CH and 4CH views with larger LV volumes leading to higher LVEFs. Apparently, there were global (2CH vs. 4CH) and regional aspects  as well as temporal factors (diastolic vs. systolic contours) that contributed to those differences. Also, mitral valve ring localization and apical positioning varied extensively. Overall, there were several aspects contributing to the large spreading.


P = 0.0001, P = 0.001, P = 0.01, respectively). The mitral E/E′ ratio was higher in the patient group than in the control group (P = 0.007), indicating LV diastolic dysfunction in patients. At the same time, LV systolic function evaluated by 2D-STE was comparable to that in the control group. The abdominal aorta circumferential strain and ascending aorta M-mode-derived strain were significantly lower in patients compared to those in the control , indicating increased aortic stiffness in the patients’ group; moreover, 85.7% of patients had mild aortic insufficiency.Familial hypercholesterolemia (FH) is a rare autosomal dominant genetic disorder caused by defective low-density lipoprotein (LDL) receptors or abnormal apolipoprotein B. FH raises the risk of premature atherosclerotic disease and cardiovascular death in young adults. However, cardiovascular affection in children needs to be more adequately studied. Our study aimed to evaluate the effect of hypercholesterolemia on the cardiovascular system of pediatric patients with homozygous FH using conventional and advanced echocardiographic parameters such as tissue Doppler imaging (TDI) and 2-dimensional speckle-tracking echocardiography (2D-STE). This case-control study matched 25 healthy children with 21 patients with homozygous FH. Both groups had conventional echocardiography, TDI, and 2D-STE. Myocardial velocities of the left and right ventricles, left ventricular strain, and aortic stiffness parameters were measured. The FH group had greater systolic blood pressure, dilated coronary arteries, and hypertrophied left ventricle (LV) compared to the control  diastolic dysfunction, and increased aortic stiffness are among early cardiovascular markers in pediatric patients with homozygous FH before impaired LV systolic function. Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder associated with elevated levels of low-density lipoprotein cholesterol (LDL), which can cause atherosclerotic disease, cardiovascular consequences, and premature death. FH is classified into two categories, the homozygous and heterozygous variants. According to previous studies, the prevalence of homozygous and heterozygous variants in the general population is around 1 in 1,000,000 and 1 in 500,000, respectively. FH is caused by mutations in LDL receptors, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 . Hyperchhomozygous familial hypercholesterolemia, including systolic and diastolic cardiac functions and aortic stiffness, using conventional and advanced echocardiographic techniques like TDI and 2D-STE.Some publications have discovered familial hypercholesterolemia (FH) is related to a remarkable decrease in arterial compliance compared to normocholesterolemic healthy individuals . CardiovCare providers’ informed consent was obtained, and the local ethical committee approved the study. This case-control study included 21 children with familial hypercholesterolemia and 25 healthy controls. Patients’ clinical and laboratory data were collected  to the target wall. Three cardiac cycles were recorded, and the average velocity and time were estimated to limit the effect of respiration on tissue velocities since breath-holding is not possible in small children. The measured parameters included systolic (S′) and diastolic  myocardial velocities, the isovolumic contraction time (IVCT), and isovolumic relaxation time (IVRT) and ejection time (ET) at the base of the LV lateral wall, septal wall, and the basal part of the right ventricle (RV) free wall : M-mode derived strain measured using M-mode at the ascending aorta at the parasternal long axis, and aortic diameters during systole (As) and diastole (Ad) were measured , where ΔP is the difference between systolic and diastolic blood pressure. Aortic elastance was calculated using the following formula: aortic elastance = (ΔP/ΔV) where ΔV equals aortic systolic, diastolic dimension differences. (B):2D or B-mode for abdominal aorta short-axis view for the measurement of systolic area (S), diastolic area (D), and area change %. Aortic area change was calculated using the following formula: aortic area change, % = (S − D)/D [Aortic (AO) stiffness parameters measured by echocardiography included the following: red Fig. C. The aoS − D)/D .U test for non-normally distributed numeric data, the Student T test for normally distributed numeric data, and the chi-square test for the categorical variables. The correlation between variables was determined using Pearson and Spearman correlation coefficients. P values less than 0.05 were considered statistically significant.The Statistical Package for Social Science  was used for statistical analysis. The data were checked for normality and then expressed as the median and interquartile range (25th–75th percentile). Numbers and percentages were used to summarize categorical data. Comparison between groups was made using the non-parametric Mann-Whitney Patients and control groups were matched regarding age, weight, height, gender, and body surface area. The patient group had higher systolic blood pressure than the control group. All patients had xanthomas and positive family history. One had chest pain with activity, and patients also showed high total cholesterol and LDL levels. Table Few patients had aortic stenosis (14.3%), while most FH patients had mild aortic insufficiency (85.7%). Based on 2D images and M-mode in the echocardiography, the left ventricle was significantly hypertrophied, and the right and left main coronary arteries were more dilated in patients than in the control. Fractional shortening (FS) and ejection fraction (EF) values were notably lower, while the left atrium (LA) dimension was higher in the patient group. TAPSE was comparable between patients and control. Table The LV showed some diastolic dysfunction in patients compared to that in control, as the Septal and LV lateral E′ velocities were significantly lower in patients. Moreover, the mitral E/E′ was higher in the patient group than in the control group Table .Table 3T2D-STE measured the global and segmental longitudinal, circumferential, and radial left ventricular strains. There was no statistically significant difference between the patients and the control group regarding global or segmental LV strain parameters, indicating that global and segmental LV systolic function was preserved in both groups Table .P = 0.024), ascending aorta M-mode strain (P = 0.0001), abdominal aorta area change (P = 0.0001), and aortic distensibility index (P = 0.0001). In contrast, aortic elastance was more significant in the patients compared to that in the control group (P = 0.003), indicating increased aortic stiffness in patients with FH as illustrated in Table Measuring the aortic stiffness of study participants revealed substantial differences between the sick and control groups. The FH group showed lower abdominal aorta circumferential strain , segmental or global strain values recorded by 2D-STE in this cohort. Unlike TDI and 2D-STE, the M-mode LV systolic parameters, FS and EF were significantly lower in patients compared to those in the control, with median values in the patient group of 34%  and 64% , respectively, which are still within normal limits for the pediatric age group. Mertens et al. reported that normal FS measurement varies between 28 and 38%, with values below 28% suggesting reduced systolic function and above 38% indicating hyperdynamic function .Although considerable affection of longitudinal and circumferential deformation of the left ventricle in patients with FH was reported previously, this was not the case in our study. This discrepancy may be attributable to our cohort’s small sample size and younger mean age .Patients in this group displayed LV hypertrophy compared to controls, probably because of higher afterload caused by arterial stiffness. Our patients’ greater systolic blood pressure could explain the reported LV hypertrophy.Like previous studies, this cohort showed an early LV diastolic dysfunction in FH patients, as the mitral E/ E′ was higher in the patient group. Also, E/E′ was correlated to elevated levels of LDL , 15. AccCoronary artery ectasia in our patients with FH was evident. Several reports found frequent coronary artery ectasia in patients with hypercholesterolemia , 21.Thompson et al. showed improvement in coronary ectasia following plasma exchange in a patient with familial hypercholesterolemia, supporting a relationship between plasma lipoproteins and ectasia .It has been established that the interaction of LDL with collagen and elastin promotes endocytosis by macrophages with the development of foam cells. After absorbing modified LDL, macrophages release elastase and collagenase, damaging coronary artery collagen and elastin fibers and causing ectasia. Immunohistochemical detection of apolipoprotein (apo) B, the major protein of LDL, close to collagen and elastin fibers in the intima, supports that hypothesis –25.In our study, there was a statistically significant difference between cases and controls in aortic distensibility and aortic change area, which were lower in the FH group than in the control group. This can be explained by the loss of elasticity of arterial wall due to the binding of LDL cholesterol particles to elastic fibers, the release of elastase enzyme by macrophages in atheromatous plaque areas, and the formation of free radicals due to oxidative stress , 24Aortic root and ascending aorta atheromatous plaques have been reported in FH. Furthermore, it has been revealed that the internal diameter of the supra valvular aortic ridge is smaller in FH patients than in healthy controls, resulting in decreased distensibility .We examined the elasticity of the ascending aorta and the strain of the abdominal aorta in our study. Both were considerably impaired in patients and negatively linked with the mitral E/E′ ratio, indicating the possible effect of aortic stiffness on LV diastolic performance.Some researchers have adopted STE to measure arterial strain as an index of arterial stiffness . Cho et One of the study’s significant limitations was the small number of patients recruited. Stress ECG, stress echocardiography, multidetector computed tomography, and coronary angiography were not performed on the patients, even though these modalities are critical for evaluating coronary arterial pathology. The assumed diastolic dysfunction was based on echocardiography and was not confirmed by interventional cardiac catheterization, the gold standard for assessing diastolic cardiac dysfunction. In contrast, cardiac catheterization for coronary angiography and hemodynamic evaluation is invasive.Aortic valve insufficiency, aortic valve stenosis, coronary artery dilatation, left ventricular (LV) diastolic dysfunction, LV hypertrophy, and increased aortic stiffness are among the early cardiovascular markers in pediatric patients with homozygous FH. These markers may appear before the deterioration of LV systolic function.


Non-ischemic etiology, shorter duration of HF, and absence of a history of AF were independently associated with LVRR (p < 0.05). TAPSE and TAPSE/PASP, a non-invasive index of right ventricular (RV) coupling to the pulmonary circulation, significantly improved at follow-up . 41% of patients with baseline RV dysfunction obtained favorable RV remodeling despite only a moderate correlation between RV and LV function was observed . Our data point to a potential long-term reverse global remodeling effect by S/V, especially in patients who start S/V at an early stage of the disease, and focus our attention on a possible direct effect of the drug in synergistic hemodynamics between RV and pulmonary circulation.Sacubitril/Valsartan (S/V) carries potential anti-remodeling properties, however long-term effects and biventricular adaptive response are poorly described. 76 HFrEF patients who underwent progressive uptitration of S/V, completed the annual scheduled follow-up. After a median follow-up of 11 (8–13) months, left ventricular (LV) reverse remodeling (RR) is defined as (1) absolute increase in LV ejection fraction (EF) ≥ 10% or LVEF ≥ 50% at follow-up and (2) decrease in indexed LV end-diastolic diameter (LVEDDi) of at least 10% or indexed LVEDDi ≤ 33 mm/m Sacubitril/Valsartan (S/V) is a Class I level of evidence B or A pharmacological approach to chronic heart failure with reduced ejection fraction (HFrEF) according to the European Society of Cardiology (ESC)  and the It is now established that Right ventricular (RV) remodeling and failure are the main determinants of the prognosis in patients with HFrEF ,9 and thThe purpose of our study was to focus on the long-term effects of S/V on left and right remodeling by evaluating changes over time of conventional and emerging echocardiographic parameters, supporting the hypothesis that a parallel modulating activity on chamber geometry and function may explain the remarkable impact on hard end-points.2 (MDRD formula); serum potassium > 5.4 mmol/L at randomization; known history of hereditary or idiopathic angioedema or angioedema related to previous ACEI or ARB therapy; severe hepatic impairment. Per good clinical practice, after verifying the criteria for S/V initiation and the absence of contraindications, patients were prescribed S/V at a low or intermediate dose depending on systolic blood pressure and previous treatment with ACEi/ARB or naïve to drugs. Patients receiving ACEi therapy went through a 36 h washout period before starting administration. Doses of S/V were optimized to individual tolerance. Changes in doses of other medications were allowed when appropriate. Clinical data included age, sex, height, weight, body surface area (BSA), body mass index (BMI), and NYHA functional class, which were obtained by reviewing each patient’s medical charts. Comorbidities were documented by review of medical records and included hypertension (patients receiving antihypertensive medications or having blood pressure >140/90 mmHg), diabetes , chronic obstructive pulmonary disease (COPD), chronic kidney disease  Clinic of our institute (January 2017–January 2021) who underwent a progressive uptitration to maximal doses of S/V. A Comprehensive Transthoracic Echocardiographic Examination, Clinical and laboratory data  were collected prior to starting the treatment with S/V and at one year of follow-up. All data were collected on an electronic database . S/V was started by the treating physician based on clinical indications and in keeping with recommendations that were available at the time of the study enrollment. According to the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic HF, patients had to meet the following criteria to be included in the study: New York Heart Association (NYHA) class II–III; therapy with an individual optimal dose of beta blocker, angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB); an echocardiographic examination documenting LVEF < 35% . The excequation ) and a k2 [Transthoracic echocardiographic examinations were performed within a routine practice by trained sonographers and reviewed by experienced cardiologists with commercially available ultrasound equipment. Recordings were saved on a digital medium and post-processed on a workstation . Considering the observational design of our study, the timing of the follow-up echocardiograms ranged from 5 to 22 months. The echocardiographic data were retrieved unaltered from the original reports and inserted into the electronic database. The 2D echocardiographic linear measurement of LV internal diameter at end-diastole was obtained from the parasternal long axis view (LVEDD). LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) were measured from the apical two- and four-chamber views using the biplane modified Simpson’s rule; LVEDDi, LVEDVi, and LVESVi were obtained after adjusting for BSA using the Du Bois and Du Bois formula . LVEF wa2 . In our p < 0.05.Continuous variables are presented as mean and standard deviation (SD) for normally distributed variables or as median and 25–75th percentile for asymmetrically distributed data, as appropriate. Categorical variables are summarized as frequencies and percentages. Pearson chi-squared test was used for comparison among categorical variables and Mann-Whitney U-test was used for continuous variables to test differences among independent samples. To examine changes in clinical and echocardiographic parameters before and after therapy with S/V the Wilcoxon Signed Rank test was used for continuous non-normally distributed data or ordinal variables and the McNemar test was used for categorical variables. The following formula was utilized to calculate the percentage change of echocardiographic parameters  from baseline to follow-up: (follow-up parameter—baseline parameter)/baseline parameter ×100. Spearman correlation coefficient (r) was used to measure the strength of association between the left and RV functions. To examine the predictive value of baseline variables on LVRR, first, we performed a univariate analysis of all clinical-laboratory and echocardiographic parameters collected at enrollment; then, multivariable analysis was applied to the parameters that resulted significantly in the univariate analysis. SPSS for Windows version 21  was used for all the statistical analysis. Statistical significance was defined as two-tailed During the study period, 104 patients met the inclusion criteria. Among them, 18 patients were excluded due to a follow-up shorter than 5 months or because they were lost at follow-up. The final study population consisted of 86 patients. The baseline characteristics of the study population are shown in The mean age was 69 ± 12 years, 78% were males, and 49% had non-ischemic etiology. At the time of the start of S/V, the median duration of HFrEF since the first diagnosis was 28 (7–58) months. 35 (41%) patients had received cardiac resynchronization therapy (CRT) at a median of 20 months before starting S/V. Only 10 (12%) subjects were implanted with a CRT at the same time or slightly after S/V introduction. 64 (74%) patients had an implantable cardioverter defibrillator (ICD). Patients were on optimized medical therapy at the highest tolerated dose with 92% receiving ACEi/ARB, 93% beta-blockers, and 58% MRA.The median duration of follow-up was 11  months since S/V was started. During follow-up 3 patients died before the scheduled follow-up echocardiogram, 7 discontinued the drug earlier than 12 months due to side effects . Therefore, 76 patients had data available to compare follow-up versus baseline and specifically to evaluate heart remodeling . S/V wasp < 0.001) and LV diastolic and systolic volumes decreased significantly (p < 0.001). LAVi was enlarged at baseline and decreased significantly at follow-up along with the degree of mitral regurgitation and PASP. The median TAPSE significantly increased compared to baseline, and consequently, the median TAPSE/PASP ratio significantly improved at follow-up (p = 0.02). RAESVi also significantly decreased (p = 0.009). Among clinical and laboratory variables, NYHA class improved compared with baseline (p = 0.001) and NT-proBNP levels decreased significantly (p = 0.022), while renal function remained substantially unchanged.As shown in LVRR occurred in 21 out of 76 patients (27.6%) .p < 0.001). As expected at follow-up LVRR patients showed significant improvement in LVEDDi (p = 0.0004), LVEDVi (p = 0.002), LVESVi . About functional RV parameters, TAPSE, PASP, and TAPSE/PASP ratio were at lower limits of the normal range in the two groups, at baseline. At follow-up, PASP improved in both groups (p = 0.068), TAPSE improved in both groups but more noticeably in LVRR patients (p < 0.005) along with TAPSE/PASP ratio (p = 0.004). At logistic regression analysis , had a TAPSE lower than 17 mm at baseline.Favorable RV remodeling was obtained in 41% of patients with baseline RV dysfunction at one year of follow-up.p for PASP at baseline = 0.549) and NT-proBNP values (p for NT-proBNP at baseline = 0.104).At baseline, patients with and without RV remodeling had similar RV function and comparable loading conditions as shown by similar PASP (p = 0.019); moreover, patients with RV function improvement, showed a better left ventricular function at follow-up .TAPSE/PASP ratio was pathologically reduced at baseline in both groups and significantly improved at follow-up in the favorable remodeling group  and a trend for lower mortality rates .Regarding interactions between heart structural changes and clinical disease status, patients with RV remodeling showed lower values of cardiac biomarkers at follow-up  with normal TAPSE value at baseline maintained a normal RV function during SV treatment, and only 4 (10%) deteriorated.p = 0.002), ∆ Fractional Area Change (FAC) , and ∆TAPSE/PASP . No correlations were found between ∆LVEF and ∆RVEDD .In bivariate correlational analysis, ΔLVEF moderately correlated with ΔTAPSE . This change is equivalent to the one observed in the PROVE-HF trial in which LVEF raised from 28.2% at baseline to 37.8% after 12 months [In our study, LVEF was severely depressed at baseline and improved from 30% to 36%  patients received a CRT at the same time or slightly after S/V introduction, but this proportion is unlikely to have affected the results.p < 0.001). Furthermore, a significant decrease in left ventricular and atrial volumes was observed in the LVRR group. LAVI reflects the magnitude of elevated cardiac filling pressures. In patients with HFrEF, an increase in LA pressure and a reduction in LA compliance leads to LA remodeling resulting in an increase in LA stiffness, which may contribute to the development of pulmonary hypertension [In our study, although LVEF significantly improved in both patients with and without LVRR at follow-up, the change was more remarkable in patients with positive LVRR  and PASP (p = 0.034) at follow-up. TAPSE/PASP ratio, a non-invasive index of RV coupling to the pulmonary arterial circulation (RV-PA coupling) also improved at follow-up (p = 0.020).Broadening the spectrum of cardiac remodeling to the right side, we observed that switching from ACEi/ARB to S/V impacted echocardiographic parameters of right heart function including TAPSE (Already in the aforementioned Daunia registry  and in tp = 0.019). This effect appears to be independent of the severity of RV dysfunction at baseline and hemodynamic loading, conditions in this subgroup of patients. In HFrEF, a low TAPSE value , a measure of RV systolic dysfunction, indicates an advanced disease stage and leads to an increased risk of death (both due to worsening HF and sudden death), and hospitalizations [p = 0.03) and a trend for lower mortality rates .The most novel finding of the present investigation is that the extent of S/V benefits were more evident on RV function. 41% of patients with RV dysfunction at baseline showed a positive remodeling after one year of treatment with S/V, with a more favorable ventricular to arterial coupling (izations ,32. Convizations . Moreoveizations ,34 as weizations . The TAPizations . In agreLV function improvement obtained after S/V has a role in RV remodeling. The beneficial effects of S/V on biventricular structure and function may be partly explained by hemodynamic effects on peripheral resistance and natriuresis with a reduction of LV filling pressures and better LV-RV interactions ,37. HoweMoreover and not least, in our study S/V prevented the evolution of RV dysfunction also in patients with preserved TAPSE at enrolment.As in all observational studies our HFrEF patients were treated with other disease-modifying drugs which may have positively affected cardiac remodeling. However, considering the time the study was conducted, most patients had chronic HF before the start of the drug and in the majority, the HF therapies remained substantially unchanged during the study.We acknowledge the small number of patients enrolled as the main limitation. Thus our results need to be confirmed in larger trials.We also acknowledge that echocardiographic data and data on RV remodeling were not available in some patients.Our data point to a potential long-term left and right reverse global remodeling effect by S/V, especially in patients who begin S/V at earlier stages. Findings recall attention on a possible direct effect of the drug in the coupling physiology between RV and pulmonary circulation. Overall, our data may support the hypothesis that the main benefits of S/V on hard end-points could be, at least in part, the result of these biventricular cardiac-related effects.


Granulomatosis with polyangiitis (GPA) is an ANCA-associated small-vessel vasculitis. Vessel wall inflammation induces multiple vascular damages, leading to accelerated atherosclerosis. Metabolic profile and cardiovascular risk are somewhat understood in GPA patients. Cardiovascular atherosclerotic disease (ASCVD) may represent a risk for outcomes. Our purpose is to evaluate ASCVD risk in GPA patients. Thirty-six patients received GPA diagnosis (T0) and were evaluated after 1 (T1) and 2 (T2) years follow-up. All patients were treated with high-dose glucocorticoid, one-year tapered, along with immunosuppressants. Total cholesterol significantly increased in T1 vs. T0 and T2. LDL exhibited the same trend, while triglycerides increased in both T1 and T2 vs. T0. No difference was found in HDL. A significant hsCRP decrease was detected at T1 and T2 vs. T0, but not between T2 and T1. Moreover, we found a significant reduction in ESR at T2 compared with T1 and T0 and at T1 compared to T0. Hypertensive patients presented a pronounced increase in lipids, while inflammation reduced slowly compared to normotensives. Our data suggest that the increase in cholesterol and LDL in T1 is a consequence of glucocorticoids. These data can be useful in the evaluation of both CV diseases and lipid metabolism, which are closely related to vessel inflammation. Granulomatosis with polyangiitis (GPA) is a small–medium vessel-necrotizing vasculitis  classifiWe retrospectively evaluated 63 patients relating to the Immunology clinic of the Unit of Internal Medicine, ‘Guido Baccelli’ of the Policlinico of Bari, Italy, who received a diagnosis of GPA between 1 January 2006 and 31 December 2021. Diagnoses was re-evaluated according to the recent international guidelines  where appropriate. Friedman test was used to evaluate the trend over time and Tukey’s multiple comparisons test was a second-step evaluation. The distribution of dichotomous values was analyzed using Chi-squared test. About half (55%) of patients were hypertensive; thus, 5% of them were treated with ACE2 inhibitors (ACE2is), 27% with angiotensin receptor blockers (ARBs), 23% with calcium antagonist (CA), and 14% with beta blockers (BBs), in particular, propranolol and bisoprolol . Ten patp = 0.026 and p = 0.037, respectively), along with a reduction in L at T2 vs. T0 (p = 0.031) and a growth of N at T2 vs. T0 (p = 0.001). This resulted in a significant spread of NLR at T1 and T2 (p = 0.015) vs. T0 (p = 0.005) (p = 0.029) and in ESR at T2 (p = 0.015) and at T1 (p = 0.034) vs. T0 (p = 0.003) vs. T0 (p = 0.001), and T2 vs. T1 (p = 0.006) was observed. No differences were found in lymphocytes between the different time points. This resulted in a great reduction in NLR at T1 vs. T0 (p = 0.021), of hsCRP at T1 vs. T0 (p = 0.034) and vs. T2 (p = 0.038), and in ESR at T1 and at T2 vs. T0  (We selected patients with hypertension (n. 20) and evaluated the same parameters described in = 0.005) . Further) vs. T0 . A diffectively) .p = 0.024) and T0, (p = 0.024) (p = 0.017) and a significant increase in eGFR at T1 vs. T0 and T2  with a decrease at T2 vs. T0 (p = 0.049)  . On the = 0.049) .p = 0.003) and T2 (p = 0.036)  (p = 0.0001) and T2 (p = 0.047), while T2 and T1 overlapped  . LDL pre= 0.004) . Triglycerlapped .p = 0.03 and p = 0.0005, respectively) (p = 0.0001) and at T1 (p = 0.003) compared with T0  . Similar with T0 . Finallyp = 0.008 and p = 0.044, respectively) in all patients, and considering only hypertensives or normotensives as well , with a great increase in LDL at T1 vs. T0 (p = 0.001) and in T1 vs. T2 (p = 0.021)  .p = 0.042) was seen (p = 0.0001) and at T1 vs. T2 (p = 0.010) (A reduction in HDL at T2 vs. T0 (was seen . Moreove= 0.010) .p = 0.005), with an increase in HDL at T1 (p = 0.002) and T2 (p = 0.017) vs. T0, and a reduction in LDL at T2 vs. T1 (p = 0.008) and T0 (p = 0.009). A increase in triglycerides was found at T1 (p = 0.038) and T2 (p = 0.0001) vs. T0  found in the survival analysis . Pro-inflammatory cytokines led to the development of an inflammatory granulomatous vascular lesion .The correlation between atherosclerosis and vasa inflammation burden has been analyzed, revealing its significant role in the increase in atherosclerosis itself, cardiovascular risk, and cardiovascular events .Evidence in the general population demonstrates that LDL-C is the most important causal risk factor for ASCVD , leadingOral glucocorticoids are the most used for GPA patients for remission induction and maintenance . AlthougSome studies suggest that low doses of glucocorticoids might mitigate the toxicity of the treatment, while maintaining the anti-inflammatory effects, but their data are not always accepted by physicians due to the risk of a poor prognosis of an uncontrolled disease . GlucocoThe variations in lipid profile  in the first year of follow-up should be related to glucocorticoid treatment needed for remission induction and maintenance of the disease. Evidence referring to changes in lipid profiles during patients’ follow-up in AAV is minimal. Wallace et al.  observedA study performed on 535 patients with AAV found that, after the first year following the diagnosis, the major cause of death was CV disease . MoreoveOur data underline how lipid profile increases in the first year, especially in hypertensives, increasing the risk of CV events, but during the second year, the same data decrease without lipid-lowering drugs, according to decreases in inflammation. However, differences are evident, also considering hypertensives in inflammation. In fact, in these patients, we found a slower decrease in inflammatory markers along with a faster change in lipid profile. Therefore, these changes may interfere with CV risk evaluation.The SCORE2 currently used is validated on the general population therefore it is non-specific for GPA. This score was higher in hypertensives, but there has been no increased risk of death found compared to normotensives when analyzing survival percentages. However, data are still controversial on CV risk change in GPA. The correlation between inflammation and change in metabolic/lipid profile is also testified by our findings despite a controversial presentation. In particular, BVAS is inversely related to CV risk in all patients. Moreover, it decreases during follow-up, resulting in a higher decrease in hypertensives. The increase in Hb values observed during the different time points could be related to the control of the inflammation. Furthermore, kidney function increases in the first year in non-hypertensives, despite it not changing in hypertensives. A possible explanation of this finding may be related to a double damage occurring in hypertensives. In these patients, better control of disease may not change the kidney damage. On the contrary, in normotensives, kidney failure is only associated with vasculitis. Thus, when GPA is treated and under control, there is an increase in filtration rate. All these data could be related to the high-dose glucocorticoid therapy that these patients take for vessel inflammation.This study has potential limitations, such as the small sample size; on the contrary, GPA is considered a rare disease. This is also a retrospective study, including a long-time evaluation. Moreover, few patients were diagnosed via biopsy, and no histological evaluation was performed in follow-up. Finally immunosuppressive therapy may modify the lipid profile (mostly VLDL and triglycerides), making inferences about the effects of glucocorticoid therapy alone on lipid profile more difficult; however, after the first year of treatment, patients were only administered only immunosuppressants . FurtherOur data suggest that a change in lipid profile may not relate to inflammation. On the contrary, although the population analyzed was small and this was a significant limitation for this study, we found that the increase in total cholesterol and LDL cholesterol in the first year of follow-up should be a consequence of glucocorticoid treatment that is needed to control the spread of disease. The CV risk results increased at the time of diagnosis. Looking at metabolic risk factors, it would appear that the CV risk may worsen, especially in the first year or in hypertensive patients. However, it must be considered as a theoretical evaluation of the risk. On the contrary, real data did not show an increased incidence of CV disease, and hypertensives did not show increased mortality when GPA was detected.These data may be helpful in evaluating CV disease and lipid metabolism due to the connection between the two parameters and vessel inflammation. However, specific patterns may be identified in order to better characterize the risk and evolution of CV in this specific group of patients.


Tricuspid regurgitation (TR) is a highly prevalent valvular heart disease that has been long overlooked, but lately its independent association with adverse cardiovascular outcomes was recognized. The time point to intervene and repair the tricuspid valve is defined by the right ventricular (RV) dilation and dysfunction that comes up at a later stage. While guidelines favor tricuspid valve repair before severe RV dysfunction ensues, the definition of RV dysfunction in a universal manner remains vague. As a result, the candidates for transcatheter or surgical TR procedures are often referred late, when advanced RV dysfunction is established, and any derived procedural survival benefit is attenuated. Thus, it is of paramount importance to establish a universal means of RV function assessment in patients with TR. Conventional echocardiographic indices of RV function routinely applied have fundamental flaws that limit the precise characterization of RV performance. More recently, novel echocardiographic indices such as strain via speckle-tracking have emerged, demonstrating promising results in the identification of early RV damage. Additionally, evidence of the role of alternative imaging modalities such as cardiac computed tomography and cardiac magnetic resonance, for RV functional assessment in TR, has recently arisen. This review provides a systematic appraisal of traditional and novel multimodality indices of RV function in severe TR and aims to refine RV function assessment, designate future directions, and ultimately, to improve the outcome of patients suffering from severe TR. Clinically significant tricuspid regurgitation (TR) is a common valvular heart disease affecting 0.55% of the general population, with functional TR accounting for the most severe TR cases ,2. DespiSignificant TR has a deleterious impact on right ventricular (RV) size and function; TR will progressively induce tricuspid annular dilation and tricuspid leaflet tethering due to RV remodeling, while retaining normal RV function at the compensating phase. When the point of RV adaptation to volume overload is surpassed, patients suffer RV functional compromise and enter a vicious cycle of recurrent heart failure admissions, further aggravating their prognosis  7]. In . In 7]. The current review aims to enlighten the assessment of RV dysfunction in the presence of severe TR by addressing the merits of novel imaging modalities in echocardiography, cardiac computed tomography (CCT), and cardiac magnetic resonance (CMR). It ultimately endeavors to provide a guide for multiparametric assessment of RV function that will enable well-timed therapeutic decision making in TR.Challenges in the evaluation of RV performance stem mostly from its complex anatomy. The RV is a crescent-shaped structure including an outlet, apex, and inlet portion. Hence, incorporating the contractile force of all three components with the measurement of one single index is practically impossible . ConventTricuspid annular plane systolic excursion (TAPSE) evaluates the distance of systolic excursion of the RV annular segment along its longitudinal plane, while S’ measures the peak systolic annular velocity via Doppler tissue imaging at the tricuspid annulus level. Both are widely established indices, recommended for RV function assessment with a suggested cutoff value of 17 mm and 9.5 cm/s, respectively . In contDespite their widespread use, evidence of the prognostic value of those indices is contradictory in severe TR. In the study by Karam et al., which included 249 high-risk patients with severe TR undergoing transcatheter repair, neither TAPSE nor FAC assessed pre-intervention could elicit long-term prognostic information . ConversKwon et al. associated reduced preoperative S’ with unfavorable outcomes in patients with severe functional TR, with previous mitral valve surgery having isolated tricuspid valve surgery, but their study was small and underpowered . For surTAPSE and S’ are simplified estimates of RV function and subjects to significant limitations in the setting of severe TR. Both indices are angle and load dependent and they assume that the displacement of a single point of the tricuspid annulus represents the overall function of the complex, three-dimensional structure of the RV . TherefoLeft ventricular EF by two-dimensional Simpson’s biplane method is the main echocardiographic parameter implemented to evaluate ventricular function for left-sided valvular heart disease in clinical practice. Simpson’s biplane method cannot be applied for the RV, which can only be assessed from a single plane in an apical RV-focused view via two-dimensional echocardiography. However, echocardiography allows the estimation of RV EF with the use of two-dimensional imaging that allows real RV full-volume capture and it is not dependent on the image plane orientation of the two-dimensional imaging.Three-dimensional echocardiography has shown less volume underestimation than two-dimensional echocardiography and acceptable performance for volume quantification, comparable to CMR . A head-Despite the benefits of three-dimensional echocardiography, the use of RV EF can markedly overestimate RV function for patients with severe TR, as it does not account for the relationship between contractility and afterload, but only describes the percentage of volume change per cardiac cycle . Three-dIn patients with severe TR presenting with RV volume overload, the contraction of subendocardial longitudinal fibers might be the first to be insulted indicating an early phase of ventricular damage, while contractility of the mid-circumferential RV layers can still be preserved or even augmented to compensate for the loss of longitudinal force  24]. Wh. Wh24]. For over two decades, two-dimensional speckle-tracking echocardiography has emerged as a novel imaging technique assessing intrinsic myocardial function. Despite being initially utilized for the left ventricle, its applicability has recently been extended to the RV. RV global longitudinal strain (RVGLS) and RV free-wall longitudinal strain (RVFWLS) are the two main indices of speckle-tracking echocardiography for the assessment of RV performance, with a strong correlation to CMR-derived RV EF . These iRV longitudinal strain has provided evidence of refined risk stratification for TR patients. Prihadi et al. studied a large cohort of 896 patients with moderate or severe functional TR and disclosed that RV FWLS identified a higher number of patients with abnormal RV function compared to the traditional TAPSE and FAC . This obApart from the ability to detect RV dysfunction in advance of the conventional parameters, RV longitudinal strain provides prognostic information for patients with severe TR treated conservatively. Prihadi et al. demonstrated that RV FWLS is associated, over and above TAPSE and FAC, with long-term outcomes . In the RV strain could serve as a tool to select appropriate surgical candidates for TR repair at an early stage of the disease, before irreversible RV damage ensues, to optimize outcomes. Kim et al. indicated in a cohort of 115 patients with severe functional TR undergoing isolated tricuspid valve surgery that a pre-operative RV FWLS > −24% could independently predict dismal post-operative outcomes . FurtherRV longitudinal strain provides information on the myocardial contraction beyond a mere description of volumetric RV changes. As such, it appears to be superior to other RV indices and could potentially refine risk stratification and optimal thresholds for intervention in TR. Although RV function assessment is paramount in severe TR, it fails to account for the subtending RV afterload, which may vary substantially between patients. Besides RV dysfunction, the prognostic role of pulmonary hypertension, which is a common hemodynamic complication of long-standing heart failure and TR, has been recognized . RV-pulmTAPSE/PASP ratio has demonstrated good correlation with the invasive pressure-volume loop-derived end-systolic/arterial elastance, which is the gold-standard measure of RV-PA coupling . This inWhile TAPSE/PASP could play a role to select appropriate candidates for percunatenous tricuspid valve interventions with severe TR, its utility is questionable for cases with greater than severe  TR. In such cases, TAPSE/PASP may overestimate the true coupling of the RV-PA circuit, as echocardiographic PASP is underestimated and correlates poorly with the respective invasive PASPs. In a cohort of 126 patients with greater than severe TR undergoing transcatheter repair, only the TAPSE/PASP using the invasive PASP could provide prognostic information, whereas the echocardiographic TAPSE/PASP could not .CCT use in patients with significant TR is advocated for use in pre-procedural planning of the transcatheter repair. CCT has a high spatial resolution and provides three-dimensional cardiac data. This enables the precise assessment of the tricuspid annular morphology and the sub valvular anatomy, the characterization of surrounding structures, the determination of pacing lead location, the definition of optimal fluoroscopic angulations, and vascular access root planning .Beyond the value of CCT for anatomical assessment, its role in RV function evaluation has recently been explored. Due to its optimal spatial resolution, CCT enables excellent endocardial–blood pool interface definition  and concCurrently, CCT is not implemented in everyday clinical practice for the RV EF evaluation, due to a lack of availability, radiation exposure, and the need for an iodinated contrast, making the available data scarce. However, RV EF assessment should be encouraged in all the patients with TR undergoing a CCT for any reason, such as coronary artery disease evaluation or pre-procedural planning of valvular repair or replacement.CMR is considered the gold-standard modality for volumetric quantification of the RV. CMR derived RV EF bypasses any potential geometrical assumptions of the RV shape and is based on the real RV volumes in end-diastole and end-systole . This inPark et al. identified RV EF as an independent predictor of cardiac death and major postoperative cardiac events in 75 consecutive patients undergoing corrective surgery for severe functional TR . In a coDespite its excellent accuracy in volume quantification, CMR-derived RV EF still relies on a mere description of RV volumetric changes in a cardiac cycle, potentially overestimating RV function for patients with a severe TR background. Even the effective RV EF that accounts for the regurgitant volume does not providing any information about the myocardial RV function per se, and is considered to be impaired in an advanced stage of RV dysfunction. However, earlier signs of RV decompensation might be of stronger clinical relevance to drive the interventional decisions on TR.Most available evidence of longitudinal strain in TR stems from speckle-tracking echocardiography which, however, is limited by the two-dimensional nature of this modality for a complex three-dimensional structure. Recently, CMR has allowed the estimation of strain using standard cine images, without the need for separate pulse sequences . A multiA unique advantage of CMR is the myocardial tissue characterization which has been studied for the left ventricle in cases of left-sided valve disease ,64, but In an attempt to monitor the trajectory of severe TR and apply timely intervention, the approach to RV function assessment should be holistic. The assessment of imaging indices should be complemented by biochemical biomarkers in clinical practice. Elevated B-type natriuretic peptide levels before intervention may connote advanced disease and have been associated with poor post-operative course in severe TR . OverallIn patients with severe TR and right heart failure, physical signs of overt tissue oedema resulting from long-standing intravascular and interstitial fluid volume expansion is the prevailing symptom. Carbohydrate antigen 125 is a reliable surrogate of congestion in heart failure and is independent of renal function, age, and weight. Particularly in the setting of severe TR, carbohydrate antigen 125 has demonstrated stronger association with mortality compared to natriuretic peptides, which may not reflect the contribution of functional TR towards the disease pathophysiology . MoreoveEarly intervention for left-sided valve diseases to prevent irreversible left ventricular damage is an established practice applied in everyday clinical practice. However, a long way has to be made to achieve an early intervention on the tricuspid valve in case of TR to avoid RV dysfunction. The high operative morbidity and mortality documented for the surgical treatment of TR is largely attributable to the lack of universally established indices of RV dysfunction and accepted cutoff values, leading to inconsistent practices regarding the right time for intervention . This miAccording to the ESC and ACC/AHA guidelines, severe TR should be treated interventionally/surgically when RV failure symptoms arise, and for the asymptomatic patients intervention is recommended in the presence of progressive RV dilatation or systolic dysfunction. No recommendations are available for patients with severe asymptomatic functional TR ,9. HowevPromising evidence has emerged on the role of strain imaging via speckle-tracking echocardiography, which is an index of early RV damage associated with outcome in asymptomatic patients with severe TR ,35,37,38In the current era of the new TR classification and the accompanied phenotypes of RV remodeling, the implementation of different cutoff values for RV dysfunction might be necessary . For insSince RV function should dictate the timing of tricuspid valve repair in severe TR, it has to be assessed in a universal, easily accessible, and widely available manner that can detect even subtle RV dysfunction. RV strain imaging seems to be the key in revealing in advance the anticipated RV decompensation. RV longitudinal strain via speckle-tracking echocardiography has considerable strengths compared to traditional simplified parameters of RV function in describing early RV damage. Moreover, CMR-derived feature-tracking strain has arisen, showing additive value over the gold-standard measure of RV EF. Although evidence is promising, further prospective research is crucial before strain-driven patient management in TR can be advocated.


This review discusses the evolving topic of atrial cardiomyopathy concerning valvular heart disease. The pathogenesis of atrial cardiomyopathy involves multiple factors, such as valvular disease leading to atrial structural and functional remodeling due to pressure and volume overload. Atrial enlargement and dysfunction can trigger atrial tachyarrhythmia. The complex interaction between valvular disease and atrial cardiomyopathy creates a vicious cycle of aggravating atrial enlargement, dysfunction, and valvular disease severity. Furthermore, atrial remodeling and arrhythmia can predispose to atrial thrombus formation and stroke. The underlying pathomechanism of atrial myopathy involves molecular, cellular, and subcellular alterations resulting in chronic inflammation, atrial fibrosis, and electrophysiological changes. Atrial dysfunction has emerged as an essential determinant of outcomes in valvular disease and heart failure. Despite its predictive value, the detection of atrial fibrosis and dysfunction is challenging and is not included in the clinical routine. Transthoracic echocardiography and cardiac magnetic resonance imaging are the main diagnostic tools for atrial cardiomyopathy. Recently published data have revealed that both left atrial volumes and functional parameters are independent predictors of cardiovascular events in valvular disease. The integration of atrial function assessment in clinical practice might help in early cardiovascular risk estimation, promoting early therapeutic intervention in valvular disease. The concept of atrial cardiomyopathy was defined in 2016; however, it is still not profoundly characterized in terms of pathophysiology, risk factors, stages, progression, and prognostic value . Atrial The atrial myocardium consists of two thin layers of muscle. The atrial cardiomyocytes are arranged in well-organized muscle bundles. Between the muscle bundles extends the thin atrial interstitium, which is composed mainly of an extracellular matrix of collagen type I fibers, which account for 5% of the atrial wall volume. The main cellular components in the interstitium are fibroblasts, adipocytes, mesenchymal cells, and inflammatory cells  Figure . The car2+ overload and fibroblast proliferation [2+ overload and fibrosis via the mitogen-activated protein kinase (MAPK) pathway [2+ overload, the release of endothelin-1 (ET-1), and reduced nitric oxide production are the main pathways leading to atrial cardiomyopathy [The increased atrial pressure in valvular heart diseases triggers mechanical stimuli in the atrial wall and initiates complex molecular, cellular, and neurohormonal interlinked pathways ,17 Figu. The mecferation ,6  is a cell surface protein that contributes to leukocyte infiltration, inflammation, and atrial remodeling; however, it is not used in clinical practice . ADAMs ) [2DS2-VASc Score ≥ 2) and paroxysmal (self-terminating) or persistent (lasting more than seven days or requiring cardioversion) atrial fibrillation have a similar risk of stroke compared to patients with permanent atrial fibrillation, as prothrombogenic molecular atrial alterations persist even during periods of sinus rhythm in these populations [2DS2-VASc Score ≥ 2 [It is recognized that atrial fibrillation and atrial cardiomyopathy are associated with a risk of atrial thrombogenesis and cardiogenic embolization ,57. Inefle sex)) . Notablyulations ,70. Conscore ≥ 2 . Previoucore ≥ 2 ,72,73. Tcore ≥ 2 ,77. Thiscore ≥ 2 ,79,80. Tcore ≥ 2 ,81,82,83core ≥ 2 .2 for both genders; meanwhile, the normal upper limit of right atrial volume is 25 ± 7 mL/m2 in men and 21 ± 6 mL/m2 in women [Current recommendations suggest conventional two-dimensional (2D) transthoracic echocardiography to measure atrial dimensions and volumes which have prognostic value ,86. The in women . Howeverin women . Overallin women . Left atin women ,89,90. Tin women ,91,92. Fin women ,94,95. Tin women ,96. Thesin women . Local tin women . Howeverin women . Notablyin women ,97,98.Advanced echocardiography methods, such as speckle tracking echocardiography, represent a sensitive tool to assess atrial function. This technique analyses the unique fingerprint-like natural acoustic marker pattern (or speckle pattern) of grayscale B-mode images of the myocardium, which are tracked consecutively frame-by-frame during the cardiac cycle . Atrial Cardiac computed tomography (CCT) is an accurate tool to assess atrial volumes and dimensions . HoweverCardiac magnetic resonance is frequently used for ventricular fibrosis imaging; however, the detection of atrial fibrosis is still challenging due to the suboptimal image resolution of the thin-walled atrium (2–4 mm). Beyond the cost and availability of CMR, the time and expertise required for image processing are not negligible . Late-gaAortic valve stenosis is the most common valvular heart disease, especially in the elderly population . Left veCurrent guidelines recommend aortic valve replacement to treat severe aortic valve stenosis, as no medical treatment is available ,119. BesMitral regurgitation is the second most common valvular heart disease with a complex pathophysiology . DiseaseSeveral studies have investigated the cellular and molecular pathophysiology of atrial cardiomyopathy in mitral regurgitation. Atrial volume and pressure overload result in atrial myocardial overstretching and increased myocyte oxidative stress ,158. ChaSurgery and transcatheter interventions are invasive treatment options for severe mitral regurgitation . The cesAortic valve regurgitation occurs when the aortic valve does not close tightly due to a disease of the valve cusp and/or a dilatation of the aortic root. This leads to the diastolic backflow of blood from the aorta into the left ventricle, leading to left ventricular volume and pressure overload, mainly in severe conditions. The systolic function of the left ventricle is preserved and filling pressure is normal in a compensated state due to adaptive left ventricular eccentric hypertrophy caused by lengthened myofibrils . In advaMitral valve stenosis is rare; however, it remains common in developing countries due to rheumatic etiology. Mitral stenosis significantly increases left atrial pressure through upstream hemodynamic effects, with less impact on the left ventricle. This can lead to pulmonary hypertension and right ventricular dysfunction. Furthermore, rheumatic etiology promotes atrial dysfunction through atrial myocytolysis and inflammation, supplementary to upstream pressure increase . ProgresMitral valve commissurotomy is used to repair mitral valve stenosis. Shenthar J. et al. observed a significant improvement in left atrial reservoir strain from 11.23 ± 6.83% pre-commissurotomy to 16.80 ± 8.82% at 6 months post-procedure time . In addi2 vs. 62 mL/m2, and the right atrial/right ventricular end-systolic volume ratio is 2.2 vs. 0.9 in atrial and ventricular phenotypes, respectively [Tricuspid valve regurgitation is common in the general population . The ageectively . The mosectively ,205. Atrectively . It is rectively ,208,209.ectively . Furtherectively   inhibitors induce glucosuria, natriuresis, and osmotic diuresis leading to a reduction in cardiac preload, afterload, and myocardial oxygen consumption; subsequently, these drugs can potentially reduce atrial pressure and dilatation . Recent,Atrial fibrosis and atrial fibrillation might be initiated by aldosterone binding to the mineralocorticoid receptor and promoting inflammation, oxidative stress, and connective tissue growth factor upregulation ,229. PreIn conclusion, atrial cardiomyopathy has been defined as structural, functional, or electrophysiological atrial changes with potential clinical manifestations . Clinica


The right ventricle (RV) has a critical role in hemodynamics and right ventricular failure (RVF) often leads to poor clinical outcome. Despite the clinical importance of RVF, its definition and recognition currently rely on patients’ symptoms and signs, rather than on objective parameters from quantifying RV dimensions and function. A key challenge is the geometrical complexity of the RV, which often makes it difficult to assess RV function accurately. There are several assessment modalities currently utilized in the clinical settings. Each diagnostic investigation has both advantages and limitations according to its characteristics. The purpose of this review is to reflect on the current diagnostic tools, consider the potential technological advancements and propose how to improve the assessment of right ventricular failure. Advanced technique such as automatic evaluation with artificial intelligence and 3-dimensional assessment for the complex RV structure has a potential to improve RV assessment by increasing accuracy and reproducibility of the measurements. Further, noninvasive assessments for RV-pulmonary artery coupling and right and left ventricular interaction are also warranted to overcome the load-related limitations for the accurate evaluation of RV contractile function. Future studies to cross-validate the advanced technologies in various populations are required. Howe2.2.1.Heart failure is defined by the European Society of Cardiology as “a clinical syndrome consisting of cardinal symptoms  that may be accompanied by signs ” . It is d2.2.Normal RV function is an interaction between preload, afterload, and contractility. Most cases of RVF occur as a result of an existing or new-onset cardiac or pulmonary disease, or a composite illness affecting both organs. RVF can result from pressure or volume overload, or decreased RV contractility, due to abnormalities of the coronary arteries, valves, pericardium, myocardium, heart rhythm, and pulmonary hypertension resulting in primary or secondary etiology . To unde2.3.2.3.1.Pressure overload is the predominant pathophysiologic mechanism in RVF for both cardiac and pulmonary etiologies. The concomitant occurrence of LV systolic or diastolic dysfunction and pulmonary hypertension in patients with RVF is particularly high. This corroborates the concept that the majority of RVF is secondary to left-sided cardiac disease  as post-capillary pulmonary disease or Group 2 pulmonary hypertension . PressurRVF caused by pulmonary disease is well described. In 25%–60% of cases, these changes can occur suddenly, as seen, for example, in the majority of cases of massive pulmonary embolism (PE) , 10. An Cor Pulmonale , resulting in its dilatation, which leads to augmented wall tension, and subsequently an inevitable simultaneous increase in afterload. RV interacts with the LV through the intraventricular septum. This interaction, called ventricular interdependence is defined as a direct transmission of forces affecting one ventricle to the other . RV dila2.3.3.Acute reductions in RV contractility can be caused by direct myocardial injury from numerous mechanisms including myocardial ischemia and inflammation  . CardiacAs highlighted by the heterogenous etiological and mechanistic development of RVF, a systematic approach to exclude different pathophysiological mechanisms is paramount for targeted therapy. Therefore, this review will comprehensively describe the clinical assessment of RVF.3.3.1.3.1.1.Classical signs and symptoms of RVF are non-specific, as they derive from systemic venous congestion and hypoxemia , 22. At 3.1.2.P pulmonale, dominant R wave in V1 and a dominant S wave in V5 or V6 (Electrocardiography is likely the first step in workup of patients with suspected right heart issues. Patients with RV hypertrophy due to PAH have right axis deviation (axis greater than 90 degrees), features of V5 or V6 . In addiV5 or V6   dilatation with distal collapse might be noted . Further3.1.4.RV biomarkers can be used to assist in identifying RVF as well as monitoring disease progression. RV biomarkers can be divided to those which reflect inflammation and those which increase when myocytes are injured or experiencing stress . Of the Of inflammatory biomarkers, suppressor of tumorgenicity 2 (ST2) and soluble ST2 (sST2) are elevated in myocyte stress, hypertrophy and fibrosis reflecting RV remodeling . Recent 3.2.Among various imaging modalities for cardiac assessment, echocardiography remains the mainstay because of its availability, non-invasive nature, and cost-effectiveness . In part3.2.1.3.2.2.In intensive care settings, patients who are critically ill requiring urgent assessment cannot be easily mobilized. Additionally, it may also be difficult to obtain appropriate echo windows. To deal with these challenges, point of care cardiac ultrasound (POCUS) and transesophageal echocardiography (TEE) are useful tools.3.2.2.1.The purpose of POCUS is to obtain adequate information within the shortest time possible by applying a problem-oriented protocol for assessing specific clinical problems  , and immRight heart evaluation by POCUS includes RV size, global function, inferior vena cava (IVC) collapsibility , gross tricuspid regurgitation, and the detection of pericardial effusion , 51. AltThe major limitation of POCUS includes potential difficulties in getting appropriate echocardiographic windows due to the interruptions such as sternal wires, dressings, and chest drainage tubes. In addition, POCUS provides insufficient information for a comprehensive cardiac assessment  , and thu3.2.2.2.The purpose of TEE is to obtain additional and more accurate information than transthoracic echocardiography (TTE) by taking advantage of the proximity of the esophagus to the heart , especiaOne of the advantages of TEE is higher resolution images due to the proximity of the probe to the heart. In contrast, the higher frequency of the transducer reduces tissue penetration and increases attenuation, which may limit far field imaging. The effects of anesthesia on the hemodynamics can further limit assessment via TEE .3.2.3.3.2.3.1.(1)S′ of >4 mm with exercise has reasonable sensitivity of proximal right coronary artery obstruction (The change of systolic parameters (tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RVFAC), S’) following stress induced can be estimated as the contractile reserve, which is the compensatory improvement of heart function during cardiac stress. Despite a lack of clear criteria of RV contractile reserve in guidelines, some revealed the prognostic significance of this value. For instance, a decline in truction  Moreovertruction .(2)Stress-induced pulmonary hypertension is defined as a pulmonary hypertension that happens only when stress is induced but not at rest . This caThe disadvantages of SE include a risk of deterioration in heart failure and arrhythmias (Stress echocardiography (SE) can further assess RV function that cannot be appreciated under the rest condition by inducing stress against heart via exercise or drugs . SE has hythmias , thus it3.2.3.2.Contrast echocardiography (CE) is indicated to improve structural or functional assessment of cardiac chambers and masses under sub-optimal image quality . BesidesCE can clearly visualize the RV endocardial border and allow more accurate assessment of RV dimensions and regional wall motion. By combining CE with 3-dimensional (3D) echocardiography, more accurate and reproducible measurements can be obtained . In caseLimitations include workflow issues (such as the need for intravenous cannulation), potential artifacts, and lack of standardized normal values of chamber volumes .3.2.3.3.Speckle-tracking echocardiography (STE) is one of the advanced analyses to assess cardiac function with higher precision than previous echocardiographic parameters , 67. CarRV longitudinal strain has been mostly used for the assessment in the RV contractility among several STE parameters. In addition, there are two methods to assess RV longitudinal strain (RVLS); one is RV free wall longitudinal strain (RV-fwLS) and the other is RV global longitudinal strain (RV-GLS). RV-fwLS is based on the evaluation of only free wall of RV, while RV-GLS additionally includes intraventricular septum area. The normal values differ between the two parameters (RV-fwLS < −20% and RV-GLS < −14%). The American Society of Echocardiography/European Association of Cardiovascular Imaging/Industry Task Force recommends reporting RV-fwLS, while RV-GLS is optional .(1)RVLS can reveal an early-stage RV dysfunction and can be useful as a better prognostic predictor , 69–72. (2)With the advantage of being angle independent unlike the Doppler technique, STE analysis provides not only global but also regional assessment that could be helpful for differentiating the etiology of diseases such as atrial septal defect, arrhythmogenic RV cardiomyopathy and cardiac amyloidosis –79.RVLS has two notable characteristics; (1) the improved accuracy enough to identify an early RV dysfunction, and (2) a regional assessment of RV Function.3.2.3.4.Three-dimensional (3D) echocardiography is helpful to accurately measure RVEF, which is one of the most reliable RV contractile parameters . It is d3.2.4.Although RV function and size are significantly affected by PAP as well as LV function, vast majority of echocardiographic parameters of RV contractility recommended by the American Society of Echocardiography guidelines  and EuroOne of the parameters considering the inter-relationship between ventricular function and arterial pressure is stroke work (SW). Conventionally, SW was described as the area surrounded by the catheter-based pressure-volume (PV) curve. However, Russell et al. reported that myocardial work (MW), a non-invasively measured STE parameter, is well corelated with invasively measured LV SW . The cliThe gold standard of RV-PA coupling is described as the ratio of end-systolic/arterial elastance (Ees/Ea).This value plays a key role for the detection of RV dysfunction in the early stage of PAH  because Ees/Ea is derived from an invasive assessment using the PV loop (as described below) and thus has not been commonly used in both clinical practice and research since its introduction a decade ago. Therefore, a less-invasive surrogate maker of Ees/Ea is earnestly desired. Tello et al. reported on the utility of TAPSE/systolic PAP as a surrogate of Ees/Ea with simplified methodology by using 2D echocardiography and found that this value can be a predictor of poor outcomes in PAH . Also, R3.3.CMR is the gold standard non-invasive diagnostic tool for assessment of cardiac structure and function. It can provide static images using the spin-echo sequence as well as multiple images by using the gradient-echo sequence during the cardiac cycle . It acquCurrent guidelines for heart failure still recommend TTE as an initial imaging modality; however, they also recommend CMR to assess myocardial structure and function in patients with poor echocardiogram acoustic window and to characterize the myocardial tissue in suspected infiltrative and inflammatory diseases including myocarditis, sarcoidosis, Fabry disease, Chagas disease, noncompaction, iron overload, amyloidosis, and cardiomyopathies  3, 4). , 4. 3, 43.3.1.CMR can provide accurate and reproducible measurements of the LV parameters –99. Acco3.3.2.CMR is expensive and its access can be limited in some countries and centers, although some authors reported that CMR could reduce the cost of surveillance in patients with RVF . They co3.3.3.Recently, artificial intelligence (AI)-based fully automated analyses were introduced to overcome the observer-variability resulting from manual preparation and reselection of CMR images . AccordiAssessment of RV contractile reserve in PAH patients under stress conditions allows early detection of subclinical disease. Recently introduced CMR, using ultra-fast compressed sense sequence, exercise CMR allows accurate assessment of cardiac function under stress conditions in PAH patients. Lin et al. examined effects of exercise on the RV and demonstrated significantly higher RV contractile reserve in controls compared to PAH patients and the RV-PA coupling ratio failed to increase in PAH patients during exercise .3.4.Approximately 50 years ago, Strauss and his colleagues reported recognizable nuclear cardiac images which could measure LVEF in patients without cardiac catheterization by using a method they referred to as “gating” . Ever si18F] fluorodeoxyglucose positron emission tomography can demonstrate changes in myocardial glucose metabolism in these conditions  are also crossing the valve. Furthermore, the calibration technique is challenging, and, very importantly, a standardization of interpretation of the loops is still needed as the technique becomes more widely adopted and incorporated into various research and clinical practices .3.5.2.(1)PAH: PV analysis can identify occult RV dysfunction (RV-PA coupling assessed by Ees/Ea ratio) with greater sensitivity than traditional measurements , 139 and(2)Heart failure with preserved EF: using the end-diastolic PV relationship, PV analysis can reveal impairments in diastolic function (such as increased load-independent RV stiffness and impaired active relaxation) . Conside(3)End-stage heart failure supported by LVAD: PV analysis in LVAD recipients can demonstrate that even patients with echocardiographically normal appearing RV have only modest inotropic reserve during exercise and experience dramatic increase in LV filling pressures . The ong(4)Valvular Heart Diseases: the broad variability in outcomes seen in real-world practice following technically successful transcatheter and surgical aortic valve replacement may be partially explained by pre-procedural and procedural RV dysfunction . In addiWith improved catheter technology and easier signal processing, RV PV loop analysis is being performed with increased regularity in several clinical scenarios . As disc3.5.3.18F] fluorodeoxyglucose positron emission tomography (PV loops are an accurate means of recognizing the uncoupling of the ratio of PA to RV end-systolic elastance characteristic of RVF . Howevermography . This nemography . CurrentThere are still many limitations in these non-invasive methods, but their potential is significant: by easing the barriers to data acquisition, non-invasive PV loops may become a fast, convenient way to monitor changes in ventricular function over time or in response to certain interventions . In orde4.There have been challenges of standardizing assessment of RV function and quantifying RVF in general, and more so in critically ill patients. et al. investigated prediction of RV failure in patients following implantation of a LVAD (et al. demonstrated reliable identification of cardiovascular structures, including accurate reporting of RV volumes, using deep learning to analyze coronary computed tomography angiography images (Echocardiography, when coupled with AI analytic technology, is a promising non-invasive alternative to RV PV loop measurement. Some recent studies in recent years have begun to investigate the accuracy of AI in evaluating RVF. Zhu et al. published results recently demonstrating AI-based analysis of 3D echocardiography provided comparable estimates to CMR . Howeverf a LVAD . The deey images .5.Appropriate assessment of RV function is important in predicting patients' outcome and deciding the optimal timing of treatment in various cardiac diseases. Nevertheless, standardized method for the assessment of RV function and following RVF diagnosis have not yet been established. Although imaging modalities have developed and been essential for the evaluation of RV function, more reproducible and accurate methods are required. Advanced technique such as automatic evaluation with AI and 3D assessment for the complex RV structure can play key roles for this purpose. Further noninvasive assessments for RV-PA coupling and RV-LV are also warranted to overcome the load-related limitations for the accurate evaluation of RV contractile function. Robust evidence cross-validating technologies in various etiologies is required.