PVR status also correlated significantly with RV ejection fraction (p < 0.05) and correlated marginally with LV end-systolic volume index (p < 0.07). Shape modes discriminated subsequent PVR better than standard imaging indices  and were significantly associated with RV and LV radial systolic strain. Biventricular shape modes discriminated differences between patients who did and did not require subsequent PVR better than standard imaging indices in current use. These regional features of cardiac morphology may provide insight into adaptive vs. maladaptive types of structural remodeling and point toward an improved quantitative, patient-specific assessment tool for clinical use.Current indications for pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (rTOF) rely on cardiovascular magnetic resonance (CMR) image-based indices but are inconsistently applied, lead to mixed outcomes, and remain debated. This study aimed to test the hypothesis that specific markers of biventricular shape may discriminate differences between rTOF patients who did and did not require subsequent PVR better than standard imaging indices. In this cross-sectional retrospective study, biventricular shape models were customized to CMR images from 84 rTOF patients. A statistical atlas of end-diastolic shape was constructed using principal component analysis. Multivariate regression was used to quantify shape mode and imaging index associations with subsequent intervention status , while accounting for confounders. Clustering analysis was used to test the ability of the most significant shape modes and imaging indices to discriminate PVR status as evaluated by a Matthews correlation coefficient (MCC). Geometric strain analysis was also conducted to assess shape mode associations with systolic function. PVR status correlated significantly with shape modes associated with right ventricular (RV) apical dilation and left ventricular (LV) dilation ( Current twenty-five-year mortality rates are ≤ 5%, but long-term sequelae in adult survivors with repaired tetralogy of Fallot (rTOF) lead to an acceleration in mortality thereafter2. Common late consequences of repair include residual pulmonary regurgitation (PR) and chronic right ventricular (RV) volume overload, which in turn are associated with exercise intolerance, arrhythmia, RV and/or left ventricular (LV) dysfunction, and a higher risk of sudden cardiac death4. The main strategy for preserving RV function relies on timely surgical or transcatheter pulmonary valve replacement (PVR), which has been shown to alleviate symptoms, normalize RV volumes, and improve RV function6. However, there continues to be disparity in the indications and timing for PVR9, which must strike a balance between being performed early enough to prevent irreversible adverse remodeling but late enough to reduce the number of re-interventions and potential surgical complications10.Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD) accounting for about 7–10% of all congenital cardiac malformations12. The American College of Cardiology/American Heart Association, the Canadian Cardiovascular Society, and the European Society of Cardiology provide recommendations on indications for performing PVR15; though, they are largely qualitative in nature, recommending intervention in cases of moderate to severe RV dysfunction and/or moderate to severe RV enlargement. Quantitative indications for intervention are based on global measures of cardiac mass and volume17, e.g. RV end-diastolic volume index (EDVi) > 160 mL/m2 and/or RV end-systolic volume index (ESVi) > 80 mL/m2, but these thresholds are subject to institutional bias and lead to mixed outcomes, leaving the subject up for debate18. While these indications have been guided by several CMR-based imaging studies, the wealth of morphological and functional information available in CMR images has been under-utilized, not taking into account three-dimensional, regional analysis of geometry and function.Current indications for PVR rely on cardiovascular magnetic resonance (CMR) imaging, which is the gold standard for evaluation of RV volumes, severity of PR, and RV function20. Other studies of RV remodeling in rTOF have shown that a decrease in RV free wall curvature is associated with a decrease in regional RV function as measured by a lower area strain21. However, these prognostic markers are not captured by global measures of ventricular function or used in current clinical decision-making to indicate intervention.Several studies have shown that bulging of the RV outflow tract, dilation of the RV apex, dilation of the pulmonary valve annulus, and a more circular tricuspid valve are associated with adverse remodeling in rTOF, specifically in the presence of chronic PRThe current study employed a statistical atlas-based approach to condense multi-dimensional, morphological data from CMR imaging into quantitative, interpretable markers of regional biventricular shape. These atlas-based biomarkers were assessed in their ability to discriminate differences in shape between patients who required subsequent PVR and those who did not, and the performance of these novel biomarkers was compared with standard imaging indices. The aim was to discover specific markers of cardiac morphology that could discriminate differences in adverse remodeling within the rTOF population, regarding referral for subsequent PVR, better than standard imaging indices.All methods were carried out in accordance with relevant guidelines and regulations.22. The CAP is a worldwide consortium that facilitates clinical data sharing and development of computational methods for analysis of cardiac structure and function across several CHD cohorts (https://www.cardiacatlas.org). Deidentified datasets employed in this study were contributed from two clinical centers  with approval from local institutional review boards via waiver of informed consent . Patients were divided into two groups, one in which patients were referred for PVR following imaging  and one in which patients were not referred for PVR following imaging , within a four-year period. Patients with previous PVR were excluded from the study. Patients with significant tricuspid regurgitation or only mild pulmonary insufficiency (PR fraction < 20%) by CMR were also excluded, such that the patients included in the study demonstrated an RV volume overload phenotype due strictly to moderate to severe PR. Out of the forty-eight patients included in the PVR cohort, twenty-six of them were symptomatic. The most common symptoms were tiredness, shortness of breath, and exercise intolerance, and in some cases, symptoms included chest pain or palpitations. While essentially all rTOF patients have a right bundle branch block (RBBB) pattern, none of the subjects in this study had significant degrees of atrial or ventricular ectopy or atrioventricular conduction disturbance. The decision to perform PVR at Rady Children’s Hospital was largely based on the criteria outlined by Tal Geva18, which includes thresholds for RV EDVi, RV ESVi, and RV and LV ejection fraction (EF), where the number of criteria that need to be met are reduced if the subject is symptomatic. The decision to perform PVR at The Center for Advanced Magnetic Resonance Imaging was based on the same threshold for RV EDVi as the Tal Geva criteria18, significantly reduced RV and LV EF, and considerations for the presence of symptoms. Summary characteristics of the study participants grouped by PVR status are shown in Table CMR images and associated clinical data from 84 rTOF patients were obtained retrospectively from the Cardiac Atlas Project (CAP) databaseEach patient underwent functional CMR examination within the scope of standard clinical practice. CMR images were acquired using 1.5T MRI scanners, including Siemens Avanto  and GE Discovery . Two-dimensional cine images were acquired using steady-state free procession imaging and were prospectively or retrospectively gated during breath-hold. Short-axis slices were obtained parallel to the tricuspid annulus plane, spanning both ventricles from apex to base. Long-axis slices were obtained through all valve annuli in standard 4-chamber, 2-chamber, LV outflow tract, and RV outflow tract views. Typical imaging parameters included: repetition time 24-32 ms; echo time 1.1–1.5 ms; flip angle 70–80°; field of view 200–300 mm × 200–300 mm; spatial resolution 0.59–1.75 mm × 0.59–1.75 mm × 4-6 mm; and number of time frames 20–35.Contours were drawn manually at end-diastole (ED) and end-systole (ES) on both short-axis and long-axis cine slices using Segment (Medviso). Papillary muscles were excluded from the endocardial contour segmentation. Mitral and tricuspid valve landmark points were defined from the intersection of the left and right atrial and ventricular contours delineated on the 4-chamber and 2-chamber long-axis images. Aortic valve landmark points were defined from the LV outflow tract images, and pulmonary valve landmark points were defined from the RV outflow tract images. When aortic and pulmonary leaflets were not visible, boundary points were defined by the change in appearance of the myocardial and vessel wall.Antegrade and retrograde pulmonary flow measurements were obtained from two-dimensional phase-contrast (PC) imaging using commercially available software, including Argus Flow  and cvi42 (Circle Cardiovascular Imaging). PC analysis of antegrade and retrograde flows in the main artery was performed on a plane just below the pulmonary artery bifurcation and perpendicular to the axis of the pulmonary artery. Typical imaging parameters included: repetition time 4.8–5.0 ms; echo time 2.3–3.0 ms; flip angle 15–30°; field of view 169–315 mm × 300–420 mm; spatial resolution 1.4–2.0 mm × 1.4–2.0 mm × 5–8 mm; temporal resolution 37–41 ms; and acceleration factor 3. Scouts were used to set the velocity encoding.CMR image analysis was performed by a senior researcher with more than ten years of cardiac image analysis experience. The expert analyst was blinded regarding the patient’s PVR status.23. The template mesh was automatically customized to each patient while correcting for breath-hold slice misregistration using an iterative registration algorithm. Valve locations were customized to the manual landmark points via landmark registration, and surfaces were customized to the manual contours via diffeomorphic non-rigid registration. Standard imaging indices, including LV and RV volumes and masses at ED and ES, were calculated by numerical integration of mesh volumes, which has previously shown good agreement with slice summation of manual contours24.A biventricular subdivision surface template mesh was constructed including the LV endocardium, RV endocardium, epicardium, and all four valves as described previouslyTo build a biventricular atlas of ED shape, patient-specific ED surface points were first aligned to population mean ED surface points by a rigid registration. Following the alignment, principal component analysis (PCA) was used to evaluate the distribution of shape variation across the rTOF cohort. PCA is an unsupervised dimensional reduction technique that, in this case, condenses cardiac shape features into statistical Z-scores represented as orthogonal components (modes), ranked by the amount of shape variance they explain in the population, that quantify degrees of patient-specific shape difference from the population mean.A subset of biventricular shape modes was chosen from the rTOF atlas to create a feature set with the same number of variables as standard imaging indices calculated (10 variables). Modes that cumulatively explained greater than 95% of the variation in shape in the rTOF cohort were ranked for predicting PVR status using chi-square tests, which is a commonly used technique for univariate feature ranking for classification. The 10 modes with the highest predictive importance score were retained for multivariate associations with PVR status.Multivariate regression models were constructed to quantify imaging index and biventricular shape associations with PVR status, while accounting for confounders. Sex, type of repair, time after repair, and body surface area (BSA) were included in the models to control for differences that exist in these characteristics between the PVR and No-PVR cohorts. When testing associations with imaging indices, the response variable was each imaging index. In these models, PVR status, sex, and type of repair were included as categorical predictors, and time after repair was included as a continuous predictor. When testing associations with biventricular shape, the response variable was the morphometric score for each shape mode. In these models, PVR status, sex, and type of repair were included as categorical predictors, and time after repair and BSA were included as continuous predictors. Imaging indices and shape modes that had the most significant associations with PVR status after accounting for confounders were retained for clustering to discriminate PVR status.1 score25.K-means clustering, an unsupervised clustering method, was employed to characterize the discriminatory power of imaging indices and biventricular shape (minimum two variables required in each feature set). Patients were divided into two clusters using the cosine distance metric to ignore the absolute sizes of measurements and only consider their relative sizes. The ability of imaging indices and shape modes to discriminate the PVR and No-PVR cohorts in these clusters was assessed through a matching matrix. The Matthews correlation coefficient (MCC) was used to measure the quality of clinical classification, which has been shown to be more reliable than accuracy and F27. LS and CS were calculated from the model mesh, and RS was calculated using a modified version of the centerline method28 using the intersection between short-axis slices and the model mesh. The interventricular septum was included in the calculation for LV systolic strain. Univariate regression models were applied to quantify the association between LV and RV systolic strains and imaging indices and shape modes associated with PVR status.Geometric strain analysis was conducted to assess if differences in imaging indices and biventricular shape that are associated with PVR status are also associated with differences in systolic function. Longitudinal strain (LS), circumferential strain (CS), and radial strain (RS), which represent longitudinal shortening, shortening along the circular perimeter, and thickening of the wall, respectively, were calculated from geometric arc length changes between ED and ES using the Cauchy strain formula and have shown good agreement with myocardial strains calculated from myocardial tagginghttps://www.scipy.org). Summary characteristics for the two groups are reported as mean ± standard deviation or as median (interquartile range), depending on the distribution, for continuous variables and as frequency for categorical variables. Normality was tested using Shapiro-Wilks. Differences between the two groups were tested using unpaired two-sample t-tests or Wilcoxon rank-sum tests, depending on the distribution, for continuous variables and Pearson’s chi-squared tests for categorical variables. All variables were normalized before regression and k-means clustering. Statistical associations in the regression analyses are denoted by p values with a significance level of 0.05.Statistical analysis was carried out using the SciPy Python library  with approval from local institutional review boards via waiver of informed consent .Models were successfully customized to manual contours and landmark points for all patients. Ventricular volumes and masses were calculated by numerical integration of mesh volumes, and PR volumes were calculated from PC imaging. Together these measurements constituted the feature set of standard imaging indices used in subsequent analyses. Measurements were indexed to BSA. Summary imaging indices for the PVR and No-PVR cohorts are shown in Table PCA on anatomically co-registered models of 84 rTOF patient hearts yielded a statistical shape atlas comprised of 83 orthogonal components (modes). The percent of shape variance explained by each mode and cumulatively for the first 35 modes is shown in Fig. Multivariate regression models were constructed to quantify imaging index and biventricular shape associations with PVR status while accounting for confounders including sex, type of repair, time after repair, and BSA. Summary results of imaging index and shape mode associations with PVR status are shown in Table In the feature set of standard imaging indices, RV EF was significantly associated with PVR status, in which patients in the PVR cohort had lower RV EF than patients in the No-PVR cohort Table . LV ESViIn the set of biventricular shape features, three shape modes were significantly associated with PVR status: ED4, ED6, and ED25. Shape changes along each of these modes are shown in Fig. K-means clustering was employed to assess the ability of imaging indices and biventricular shape to discriminate between patients in the PVR and No-PVR cohorts. The results of the clustering analysis for each subset of features are shown in Fig. p < 0.0001) and significantly associated with LV RS (p < 0.05), where increased RV EF was associated with increased systolic strains. For shape modes, univariate regression analysis revealed that ED4 was highly significantly associated with RV RS as shown in Fig. p < 0.05). A more positive ED6 and ED25 Z-score was associated with increased RV RS and decreased LV RS, respectively, and vice versa.Geometric strain analysis was used to assess if differences in imaging indices and biventricular shape that are associated with PVR status are also associated with differences in systolic function. Summary systolic strains for the PVR and No-PVR cohorts are shown in Fig. 31; differences in RV remodeling within the rTOF population and how they determine referral for subsequent PVR, however, are not well characterized. In this cross-sectional retrospective study, an atlas-based biventricular shape analysis framework was used to quantify specific, regional shape differences associated with PVR status and compared with standard imaging indices in their ability to discriminate patients who did and did not undergo PVR.Adverse RV remodeling in rTOF has been well juxtaposed with RV morphology in reference healthy populations18 recommend PVR in rTOF if progressive RV dilation results in RV EDVi > 160 mL/m2 and/or RV ESVi > 80 mL/m2; however, significant associations between these indices and subsequent PVR were not found. Interestingly, the degree of PR was also not significantly associated with PVR status, suggesting that the presence of volume overload alone was more important than current assessment of severity. This agrees with studies showing a compensatory increase in RV RS in response to PR and RV volume overload33. RV EF and LV ESVi had the highest associations with PVR status, although RV EF was the only imaging index with significant associations with PVR status. This was not unexpected as diminishing RV EF usually accompanies fairly rapid PVR (within a few weeks). These imaging indices were identified as preoperative risk factors for adverse outcomes post-PVR in the INDICATOR cohort study35, suggesting that these indices are not only associated with subsequent PVR but also are important determinants of long-term outcome.Current guidelines21, this study suggests that RV basal bulging may be a form of maladaptive remodeling that leads to RV dysfunction (as in the PVR cohort), while RV apical dilation may be a form of adaptive remodeling that preserves RV function (as in the No-PVR cohort). Several studies have proposed mechanisms by which RV basal bulging may lead to RV dysfunction. One study found that increased RV basal bulging correlated with increased RV vorticity and that these changes in flow could induce abnormal fibrosis in these regions36. Another study found that RV basal bulging correlated with increased diastolic force parameters that resulted in decreased RV function37. Patients in the PVR cohort also demonstrated increased LV dilation and conicity, which have independently been shown to lead to LV dysfunction in patients with acute myocardial infarction38. This is also an important long-term follow-up issue for rTOF patients40.Through biventricular shape analysis and geometric strain analysis, the present study shows that patients in the PVR cohort demonstrated increased RV basal bulging and pulmonary valve dilation, which was associated with reduced RV and LV RS, while patients in the No-PVR cohort demonstrated increased RV apical dilation, which was associated with increased RV RS. These specific, regional features of shape all contribute to RV dilation, but are not distinguished when relying solely on global ventricular measurements alone. While these shape changes agree with previously characterized features of adverse remodeling in the rTOF population as a whole18 was employed, while specifically only accounting for RV EDVi, RV ESVi, and RV and LV EF thresholds and the presence of symptoms. The overall performance of these criteria in discriminating patients in the PVR and No-PVR cohorts was lower than biventricular shape features (MCC = 0.23). Upon closer inspection, these criteria were highly sensitive in discriminating referral for PVR (sensitivity = 0.94) but not very specific (specificity = 0.22), while biventricular shape features were not as sensitive in discriminating referral for PVR (sensitivity = 0.69) but much more specific (specificity = 0.81).By clustering analysis, biventricular shape modes discriminated PVR status better than standard imaging indices, despite the fact that these indices are currently the cornerstone of clinical evaluation for PVR. The clustering analysis was also repeated with the same imaging index and biventricular shape features with only patients that were asymptomatic (Supplement Owing to the retrospective nature of this study, the clinical data available were heterogenous and limited in clinical indicators such as exercise capacity, rhythm disturbances, and functional scores. In the future, prospective studies should be conducted to assess biventricular shape mode relationships with differences in objective measures of outcome before and after PVR, rather than the decision to perform PVR itself, and supervised machine learning methods, such as decision trees or support vector machines, should be employed to fine-tune thresholds for atlas-based biomarkers that can serve as indications for PVR and give the desired specificity or sensitivity to maximize patient benefit. Another limitation of this study was the use of cross-sectional data. The temporal evolution of biventricular shape markers should be evaluated in longitudinal studies to get a better understanding of the time history of ventricular remodeling and how this relates to optimal timing of PVR. Finally, data employed in the study were contributed from multiple centers leading to selection bias that was unequally represented in each group. While confounders were accounted for, future analyses would benefit from an age and sex-matched comparison conducted at a single center.Specific biventricular shape modes in rTOF were able to discriminate differences between patients who did and did not require subsequent PVR better than standard imaging indices. These shape modes quantify regional features of cardiac morphology that may provide insight into adaptive vs. maladaptive types of structural remodeling that may be overlooked when relying solely on standard imaging indices alone. Routine clinical assessment of patients with rTOF using an atlas-based analysis of shape and function may reveal adverse effects of pathophysiologies over time, reduce qualitative observer and institutional measurement biases, and improve timing of interventions and patient prognosis.Supplementary Information.


Myocardial fibrosis (MF) is a non-reversible process that occurs following acute or chronic myocardial damage. MF worsens myocardial deformation, remodels the heart and raises myocardial stiffness, and is a crucial pathological manifestation in patients with end-stage cardiovascular diseases and closely related to cardiac adverse events. Therefore, early quantitative analysis of MF plays an important role in risk stratification, clinical decision, and improvement in prognosis. With the advent and development of strain imaging modalities in recent years, MF may be detected early in cardiovascular diseases. This review summarizes the clinical usefulness of strain imaging techniques in the non-invasive assessment of MF. Myocardial fibrosis (MF) represents the excessive deposition and disarrangement of fibrillary collagen in the myocardial extracellular matrix following acute or chronic myocardial damage, which is a common pathological manifestation in patients with end-stage cardiovascular diseases ,2. This Currently, the main examination modalities for detecting the presence of MF include endomyocardial biopsy, magnetic resonance imaging and echocardiography. Endomyocardial biopsy, an examination that directly visualizes myocardial tissues, is the gold-standard method to detect and quantify MF ,10. HoweMyocardial strain is the percent change in myocardial length relative to the baseline length, and it represents the degree of myocardial deformation and changes over time during the cardiac cycle ,24,25. ICMR is recommended for clinical research and practice to non-invasively quantify cardiac function and MF, as CMR can comprehensively assess cardiac morphological structure, function, myocardial perfusion, viability and MF, with high soft tissue resolution . At presEchocardiographic modalities such as STE and TDI are commonly used to the evaluation of myocardial strain, where STE can be used for quantifying global and regional myocardial function non-invasively and objectively by tracking myocardial speckles in a selected cardiac cycle, with the advantages of angle independency, feasibility, fast and high reproducibility ,38. STE STE is a pioneer in assessing two-dimensional strain. The main advantages of 2D-STE strain measurements in evaluating myocardial function in various diseases have been widely reported and 2D-STE allows for the evaluation of MF in a subclinical period of different cardiovascular diseases ,41,42,43MF is the underlying pathological manifestation of various cardiac diseases, causing HF and cardiac dysfunction. Historic studies have shown that left ventricular ejection fraction (LVEF), the commonly used clinical indicator of cardiac function, fails to identify subtle changes in left ventricular function caused by MF in the early stage. MF remains present in patients with subclinical HF despite normal LVEF ,13,46. Tp < 0.0001). RVFWLS was independently correlated with MF , and had the highest accuracy in diagnosing MF . RVFWLS was the major determinant of right ventricular MF and the independent predictor of poor prognosis [p < 0.0001) and New York Heart Association class . PALS was the strongest predictor of left atrial fibrosis in multivariate regression analysis  [p < 0.05; cut-off value = −9.46%, 83% sensitivity, 99% specificity). Three-dimensional speckle tracking echocardiography may be the most powerful imaging technique for accurately predicting the degree of right ventricular MF in end-stage HF patients [STE strain has a good accuracy in detecting early myocardial structural abnormalities and predicting prognosis in HF patients. Lisi et al. applied 2D-STE to measure left ventricular global longitudinal strain (GLS), right atrial longitudinal strain and right ventricular free wall longitudinal strain (RVFWLS) to investigate the accuracy of right ventricular strain in predicting MF. Their observations showed that the above strain indices were decreased in participants with advanced HF compared with healthy subjects  ,53. The p < 0.05) between participants with LGE (LGE+) and without LGE (LGE-). Only GLS was independently associated with left ventricular remodeling (over CMR-LGE) in multivariable logistic analysis  and could be used as an indicator for risk stratification to assess prognosis [p < 0.001). The three-dimensional GLS was the robust surrogate marker for assessing the extent of MF in DCM patients with HF  [p < 0.05). Three-dimensional speckle tracking echocardiography enabled accurate quantification of left ventricular twist dynamics to indirectly reflect the MF conditions in patients with DCM [Advanced strain imaging modalities (such as STE and CMR-FT) have the potential to analyze the presence and extent of MF before DCM develops . Chimurarognosis . In a prrognosis . Two-dim= −9.7%) . More rewith DCM .p < 0.01) were significantly lower and ECV  was significantly higher in the DCM group than in healthy controls. CMR-derived radial strain and circumferential strain were significantly correlated with ECV [p < 0.01) and provided additional information on risk stratification [A retrospective study by Azuma et al. explored MF in non-ischemic DCM patients by CMR-FT versus ECV and investigated the relationship between myocardial strain and ECV. Their data demonstrated that left ventricular longitudinal strain, radial strain, and circumferential strain  or unexplained left ventricular wall thickness ≥ 13 mm in first-degree relatives of HCM patients in the absence of load condition anomaly, with a prevalence of 0.2% in the US population and 0.08% in China ,62,63. Pp < 0.005) and the number of myocardial segments with MF . Both left ventricular wall thickness and MF were predictive factors of depressed segmental longitudinal strain (p < 0.005). Interestingly, they also observed the decreased longitudinal, radial, and circumferential strains in HCM patients without MF. In patients with HCM, MF was correlated with reduced longitudinal strain [p < 0.001). GLS appears to be an independent predictor of the extent of LGE in multivariate analysis . Two-dimensional speckle tracking echocardiography might provide valuable information on MF and MACE  in HCM patients with preserved ejection fraction [2 = 0.66, 0.50, respectively; p ≤ 0.001). Moreover, Two-dimensional segmental longitudinal strain  was the optimal deformation parameter for detecting subtle MF in HCM patients [p = 0.001), and 3D-STE could detect MF determined by CMR-LGE  [p < 0.05) [p < 0.005), where longitudinal strain independently correlated with MF and had incremental value over CMR-LGE for detecting MF [Many previous studies used strain imaging against pathological specimens or CMR-LGE to detect fibrosis, testing their hypothesis. Popović et al. sought to assess the relationship between MF and segmental strains using CMR-LGE and 2D-STE in HCM patients with preserved LVEF. The results showed that the mean longitudinal strain was associated with the extent of MF  . Song et < 0.05) . They prcting MF . Therefocting MF ,73,74,75p > 0.50). Two-dimensional speckle tracking echocardiography allows effective analysis of the presence and degree of myocardial scar in subjects with MI [p < 0.01). The 3D-STE was a sensitive tool for quantifying the transmural scars [Ischemic injury following MI elicits the reactive remodeling of the myocardium in which the damaged areas are replaced with permanent fibrotic scars produced by myofibroblasts and fibroblasts to prevent cardiac rupture. However, exaggerated and massive fibrosis causes the progressive reduction in cardiac function, alters the stiffness of the ventricular wall, and ultimately leading to HF ,77. Alti with MI . Huttin al scars . CMR wital scars ,81. In aal scars . Maret eal scars . CMR-FT p < 0.001). Stress–strain parameters before surgery were the independent predictors of circumferential and longitudinal stress–strain parameters after surgery ; predicting the degree of postoperative cardiac function recovery and recognizing patients with a large extent of MF [p = 0.0003) in severe AS patients. Compared to GLS and native T1, ECV was better to predict the extent of MF  [p = 0.007), and the cut-off value of peak longitudinal strain (<−11.6%) well- identified MF (LGE > 10%) had a specificity of 75% and a sensitivity of 65% (AUC = 0.69). There was a correlation between STE strain and the degree of MF measured by CMR-LGE [p < 0.001) and standardization  and independently related to replacement of MF. In addition, patients with GLS > −15.0%  had the increased MACE compared to those with LV-GLS < −15.0%. GLS was correlated with the replacement MF (LGE), whereas it is weakly associated with reactive interstitial MF (ECV and native T1). Two-dimensional speckle tracking echocardiography could be used as a good strain imaging technique to assess replacement MF in AS patients [p < 0.001). The degree of diffuse MF was associated with lower LVEF, increased pulmonary artery systolic pressure (PASP), increased NT-proBNP, left ventricular GLS and GCS . MF > 10%  and GLS > −15.5%  were independent predictors of PH in patients with severe AS. The combination of histological diffuse MF, GLS, and plasma NT-proBNP offers incremental value for risk stratification and prognosis in severe AS patients [Aortic stenosis (AS) is one of the most common types of valvular heart disease in Western countries with the prevalence of 12.4% in the elderly, 3.4% of whom are severe ,84. The nt of MF . Park etctively) . Interstctively) , and STE CMR-LGE . A prosppatients . Patientpatients . Combinepatients .p < 0.001), and the two-dimensional strain of left atrium might assist with predicting left atrial fibrosis in mitral valve patients [p < 0.0001) and was an independent predictor of left atrial fibrosis [p ≤ 0.01). Moreover, Global PLAS offered useful prognosis information  and risk stratification information (90 ± 5% (PALS ≥ 21%) vs. 52 ± 9% (PALS < 21%) for event-free survival in 5 years, p < 0.0004) for subjects with severe MR. It was an independent predictor of HF and mortality and was negatively correlated with histologically verified left atrial MF  vs. 76.6 ± 20.7% (PALS < 21%); p < 0.0001). Global PLAS was a crucial imaging marker of left atrial fibrosis [p < 0.001). Altered left atrial strain was significantly associated with raised left atrial remodeling, and PLAS was strongly related to the severity of left atrial fibrofatty replacement  [In patients with mitral regurgitation (MR), partial left ventricular blood flow ejected into the left atrium during systole and into the left ventricle again during diastole. Chronic volume overload offers a nidus for increased myocardial length and elevated diastolic stress, which contributing to progressive left cardiac dilatation, remodeling, aggravated MF and myocardial dysfunction ,95,96,97patients . A studyfibrosis . Subsequfibrosis . Ischemifibrosis . A recenfibrosis . Huber e= 0.017) . CMR-FT Several studies mentioned above have demonstrated the value of strain imaging in clinical practice. In early stages, strain imaging is of great help in identifying subclinical cardiac dysfunction and defining prognosis. Moreover, the functions of cardiac chambers are significantly reduced in patients with advanced cardiac disease due to significant MF, and the application of strain imaging is mainly focused on assessing severity and prognosis, when myocardial strains are the most accurate functional indexes ,33. NormThis study is limited by the inherent nature of literature review, such as publication bias and selection bias, as well as the articles indexed only in the PubMed and China National Knowledge Infrastructure databases . It is important to analyze thoroughly the weak aspects of strain imaging techniques to confirm their usability. The additional limitation of the study is that there are not many studies on the assessment of MF using strain imaging modalities; thus, more evidence based on larger sample sizes is needed to demonstrate its clinical utility and to incorporate the results into recommendation statements and clinical protocols.MF affects the progression of many cardiac diseases  and is an unmet public-health problem. Previously, MF could be identified only by invasive histological evaluation, while new advances in imaging methods have raised the likelihood of noninvasive myocardial tissue characterization in recent years. Conventional echocardiography and CMR indices show a low sensitivity since a decrease in cardiac function may be subtle, and the correlation between strain measures and MF is little-known . Strain MF is a critical pathological manifestation of chronic cardiac dysfunction and HF. Early identification and assessment of MF play a crucial role in risk stratification, therapeutic strategies, timing of intervention, and improvement in prognosis in patients with various cardiovascular diseases. Myocardial strain imaging has attracted attention because of its non-invasive, convenient, efficient, and accurate advantages. Many investigations have reported that strain indexes may act as the best surrogate marker of MF and were independent predictors of adverse cardiovascular events in patients with cardiovascular disease. With the continuous development and improvement in myocardial strain imaging technology, the combination of different imaging modalities with complementary advantages to accurately evaluate the degree of MF and changes in cardiac function offers a reference basis for clinical management and treatment in patients with cardiovascular disease.


We found a significant positive correlation between body mass index (BMI) and LV myocardial fat (p = 0.033). In the RV, this correlation was only at the borderline of significance (p = 0.052). The EAT volume was positively correlated with both RV and LV myocardial fat. We found no association with the waist–hip ratio (WHR) or the omental or kidney fat as measures of VAT. The myocardial fat was normal, most prominent in the RV, and correlated with the EAT and, partly, BMI. We found no association with VAT.The normal human heart contains epicardial adipose tissue (EAT) and myocardial fat. The associations between obesity, myocardial fat, visceral adipose tissue (VAT), and cardiovascular disease are not fully understood. The objective of this study was to estimate myocardial fat using stereological methods and investigate its relations with obesity, EAT, and VAT. To establish the EAT volume, 115 deceased individuals were included, and postmortem computed tomography was conducted on their eviscerated hearts. Six samples from the left and right ventricles (LV and RV) of the heart were stereologically examined to calculate the percentage of myocardial fat. Kidney and omental fat were weighed at autopsy, and the waist–hip ratio was calculated. Females had a slightly non-significantly ( Adipose tissue is present in and around the normal human heart. Epicardial adipose tissue (EAT) is fat tissue around the myocardium without a separation from the fascia. This includes the pericoronary adipose tissue, which surrounds the coronary arteries, extends into the myocardium, and is a type of visceral fat. Visceral adipose tissue (VAT) is fat that is around the organs, unlike subcutaneous and intramuscular fat. This also includes perirenal and omental fat. Myocardial fat comprises bundles of adipocytes that infiltrate the myocardium . There iMyocardial fat is typically located in the right ventricle (RV) , but it Classically, obesity is defined by a high body mass index (BMI) and is related to an increase in LV mass . The fatIn this study, we had the unique opportunity to combine whole-body CT scans, CT of eviscerated hearts, autopsy findings, and stereological techniques to assess the relations between BMI and different types of visceral adipose tissue.The aim of this study was to quantify myocardial fat using stereology and to investigate its correlations with BMI, EAT, and VAT. This study was a part of the SURVIVE study, a Danish national autopsy study from 2013 to 2015 [All cases were autopsied according to a standardized and accredited autopsy protocol that followed international guidelines, and the autopsies were extended for sampling regarding both tissue and data. Information regarding the included individuals was collected from police reports. The SURVIVE protocol thoroughly described the registration of physical parameters, organ-specific dissection, and sampling. The height, waist- and hip circumference was measured in the supine position  (REF). TThe occurrence of metabolic syndrome was defined with postmortem factors, as described in the article by Christensen et al. . ® software , as described by Hindsø et al. [PMCT scans were performed by using a standardized scan protocol on a 64-slice Definition Dual-Source CT scanner from Siemens. The total volume of EAT was obtained using the semi-automatic Mimicsø et al. .To determine the myocardial fat, gold-standard stereological principles were applied ,16. The As illustrated in p-value < 0.05 was deemed significant. The data were analyzed by using IBM SPSS Statistics for Windows, Version 27.0 Armonk, NY, USA: IBM Corp. To analyze correlations between continuous data, we used the Pearson correlation coefficient. The Mann–Whitney U test was used to analyze differences between groups. A The study was approved by the National Committee on Health Research Ethics, Denmark (registration number: 1305373). The final cohort consisted of 57% males and 43% females. The characteristics of the study group are summarized in n = 31), with the primary etiology being ischemic heart disease. Only one individual had myocarditis, and no cardiomyopathies were found. No significant differences in myocardial fat in the RV or LV were found between the group with a cardiovascular cause of death and the group with other causes of death .The most frequent manners of death were natural and accidental . Accidenp = 0.12), and for the LV (p = 0.54), the results were not significant. In addition, when analyzing the correlations of age with LV and RV myocardial fat and EAT, no significant differences were found. A significant positive correlation was found between RV and LV myocardial fat  , and that for the LV was 2.2% (±0.4). The highest percentage of myocardial fat was in the RV in women (13.2% ± 4.4). Men had a percentage of RV myocardial fat of 11.5% (±2.7). The difference between the sexes was only borderline significant for the RV ( < 0.01) C.r = 0.2, p = 0.03) was found; the variance explained was only 4.0%. The correlation of the RV with the BMI was borderline significant . A comparison of the total volume of the EAT and the myocardial fat in both ventricles yielded a moderate significant positive correlation; the variance explained was 10.5% and 14.5% for the LV and RV, respectively .The SURVIVE protocol, with its standardized information and thorough sampling of fat tissues, was an essential part of this study. However, the cohort is very selective, and in general, autopsy subjects are a very specific population not necessarily representing the background population. In this study, we chose not to distinguish among severe mental illness, other (aside from cardiac) comorbidities, and the use of medication, though all factors could be important for the development of visceral and/or myocardial fat. However, when comparing cardiovascular causes of death—which are suspected to involve myocardial fat—no significant differences were found in comparison with the other causes of death.Height, weight, and hip and waist circumferences were measured postmortem in the supine position. This does not always compare to the antemortem measurements. The waist size could be too large due to the development of gases during decomposition; however, one exclusion criterion was moderate to severe decomposition. This study has shown how myocardial fat is not correlated with sex, age, or visceral adipose tissue, and only LV myocardial fat showed a correlation with BMI. While LV myocardial fat seems to be associated with obesity, RV myocardial fat does not seem to be. The myocardial fat in both ventricles, however, was associated with EAT, and EAT was correlated with all types of VAT. Perhaps other factors—heart disease, mental illness, or medications—are more important for the accumulation of myocardial fat, which needs further exploration. In our setting, the possibility of combining imaging and autopsy studies could yield interesting results in the exploration of the interconnections among EAT, myocardial fat, and cardiac steatosis.


Heart failure (HF) is a complex syndrome of considerable burden with high mortality and hospitalization rates. Approximately two-thirds of patients with HF have ischemic etiology, which makes crucial the identification of relevant coronary artery disease (CAD). Moreover, patients with chronic coronary syndrome (CCS) can first show signs of dyspnea and left ventricular (LV) dysfunction. If establishing a diagnosis of HF and consequent management is clear enough, it will not be the same when it comes to recommendations for etiology assessment. Ischemic heart disease is the most studied disease by cardiac multimodality imaging with excellent diagnostic performance. Based on this aspect, the high prevalence of CAD, the worst outcome—HF patients should undergo a diagnostic work-up using these multimodality imaging techniques. The aim of this mini-review is to provide insights on multimodality imaging for diagnosing CCS in patients with new onset of HF and propose a diagnostic work-up based on current international studies and guidelines. Chronic Coronary Syndrome (CCS) is the leading cause of heart failure (HF) worldwide, especially in developed countries . CardiacThe incidence of newly diagnosed HF among patients with chronic CCS ranges between 7 and 28% in reports from major registries . The intThe 2019 Guidelines on diagnosis and management of CCSs introduce six different clinical scenarios most frequently encountered in patients with stable CAD, all of which involve various risks for future cardiovascular events . The secBased on current guidelines and recent evidence, a diagnostic work-up algorithm is needed based on cardiac imaging modalities to rule out ischemic cardiomyopathy as a potential cause for new onset of HF of unknown cause. These cardiac imaging modalities are not only safe and non-invasive but provide valuable data regarding coronary anatomy, myocardial ischemia, and tissue characterization.Stress echocardiography is a widely used technique recommended by the European Guidelines as an initial test in symptomatic patients for functional assessment of myocardial ischemia and for whom CAD cannot be excluded by clinical examination alone . In caseOverall, due to its wide availability, low cost, lack of ionizing radiation, supporting evidence, stress echocardiography remains an attractive first-choice imaging technique in patients with ischemic cardiomyopathy .The presence of CAD in patients with HF and reduced ejection fraction (EF) is predictive of long-term mortality . It is rp = 0.013; AUC 0.75 vs. 0.65, p = 0.0004) (p < 0.0001) and similar specificity with positive predictive value  in comparison to SPECT  , 18. In to SPECT . On top The diagnostic performance of stress CMR was tested by Pontone et al. in a meta-analysis of 77 studies on CCS where invasive fractional flow reserve (FFR) was considered the gold standard for diagnosing CAD. The study demonstrated higher sensitivity of stress CMR (81%) in detecting functionally significant coronary artery stenosis when compared to stress perfusion CT+CCTA (79%), stress echo (72%), SPECT (64%) but with lower sensitivity to FFR-CT (85%), CCTA alone (88%), and PET (87%) . In the All in all, stress CMR has gained a well-deserved place in the clinical guidelines and is now considered a trustworthy technique for myocardial ischemia assessment. However, there are some main limitations of stress CMR, and these are: limited spatial coverage, susceptibility artifacts in patients with cardiac devices, patients with claustrophobia, higher acquisition times and limited coronary anatomy analysis due to reduced spatial resolution , 27. BecCoronary computed tomography angiography is recommended as a first-choice option for diagnosing CAD where there is clinical suspicion with low-probability according to stable CAD guidelines and should be considered in HF patients with low-intermediate likelihood of CAD according to HF guidelines , 6. ThisCoronary computed tomography angiography can qualitatively and quantitatively assess coronary stenoses and provide valuable information on plaque features more accurately than other imaging techniques . These fFFR-CT is the non-invasive correspondent of FFR ICA and is defined by the ratio of flow distal and proximal to stenosis at rest or under stress conditions by computational fluid dynamics . The diaThe main advantage of CCTA is the possibility to evaluate in the same examination with high precision coronary stenosis while providing functional assessment for ischemia by adding stress perfusion or FFR-CT analysis. However, the main drawbacks are reduced temporal resolution and contrast-to-noise ratio, the use of ionizing radiation and iodinated contrast media with possible nephrotoxicity in patients with impaired renal function .Untill the appearance of stress CMR and stress CT, SPECT myocardial perfusion imaging (MPI) was the pillar in assessing functional ischemia in patients with suspicion of CAD. SPECT utilizes Tc99m radiotracer for the evaluation of blood flow distribution during stress and rest and also the cell membrane integrity. The radiotracer can identify transient regional myocardial perfusion deficit which is indicative of ischemia while on the other hand a fixed perfusion defect reflects myocardial scar or fibrosis. Underwood et al. showed in a meta-analysis that SPECT reached a sensitivity of 87% and specificity of 73% in diagnosing significant CAD . Even toIn PET scan, the radiotracers used  possess superior extraction characteristics and shorter half-lives which makes them more adequate for myocardial blood flow quantification while facilitating lower radiation doses . In the When it comes to properly assessing HF etiology the answer is “no.” One should keep in mind that a newly diagnosed patient with HF needs a comprehensive anatomical, functional, and viability assessment. It is ideal to have one imaging technique that comprises all the aforementioned features. Of course, there are imaging techniques that can assess all, but as shown in studies, cardiac imaging techniques have different sensitivities and specificities, which is why a multimodality imaging approach is needed. The question is: which is the better approach? Clearly, for anatomical coronary assessment, CCTA is the first and most accurate choice. For the functional assessment of ischemia, both stress CMR and stress CTP integrated to computed tomography angiography (CTA) have similar diagnostic accuracies . HoweverBaggiano et al. proposed a multimodality algorithm approach for clinical suspicion of CAD . As a fiCardiac multimodality imaging is a continuously growing discipline that seems to have a pivotal role in different cardiac pathologies. Time is not on the patient’s side from the first moment the diagnosis of HF is made, therefore a proper and precise workflow assessment of etiology should be done as soon as possible to improve the prognosis. It is crucial to immediately exclude CAD as it is the most frequent etiology encountered in HF patients. To do so, a multimodality approach is recommended firstly by evaluating coronary anatomy by CCTA followed by functional and myocardial viability assessment by CMR.All authors contributed to the writing and revision of the manuscript and approved the final manuscript.


Atrial fibrillation (AF) is one of the most commonly encountered arrythmia in clinical practice. AF itself can be driven by genetic predisposition, ectopic electrical activity, and abnormal atrial tissue substrates. Often there is no single etiological mechanism, but rather a combination of factors that feed back to remodel and worsen tissue substrate, “AF begets AF”. The clinical consequences of AF can often include emboli, heart failure, and early mortality. The classical AF cardioembolic (CE) concept requires thrombus formation in the left atrial appendage, with subsequent embolization. The temporal dissociation between AF occurrence and CE events has thrown doubt on AF as the driver of this mechanism. Instead, there has been a resurgence of the “atrial cardiomyopathy” (ACM) concept. An ACM is proposed as a potential mechanism of embolic disease through promotion of prothrombotic mechanisms, with AF instead reflecting atrial disease severity. Regardless, AF has been implicated in 25% to 30% of cryptogenic strokes. Natriuretic peptide(NP)s have been shown to be elevated in AF, with higher levels of both NT-proBNP and BNP being predictive of incidental AF. NPs potentially reflect the atrial environment and could be used to identify an underlying ACM. Therefore, this narrative review examines this evidence and mechanisms that may underpin the role of NPs in identifying atrial dysfunction, with focus on both, BNP and NTproBNP. We explore their potential role in the prediction and screening for both, ACM and AF. Moreover, we compare both NPs directly to ascertain a superior biomarker. Currently-two theories exist; focal triggers and a re-entrant mechanism32 or CHA2DS2-VASc is ≥ 2 in order to minimize embolic riskThe clinical consequences of AF are of paramount importance and include; emboli, heart failure, and early mortalityd-dimers, Von Willebrand Factors and Interleukin-6), left atrial enlargement and hypo contractility, as well as endothelial hypertrophy and fibrosisThe classical concept of stroke/TIA in AF revolves around the formation of a thrombus in the left atrial appendage, that then dislodges embolizing to the cerebral circulation causing an occlusionInitially AF was considered one of the most important underlying mechanisms in embolic stroke of unknown source (ESUS) patients, with 30 % of ESUS patients diagnosed with AF during long-term follow-up Finally, current stroke prophylaxis strategies in AF include; anticoagulation and left atrial appendage occlusion devices4N-Terminal Pro Brain Natriuretic Peptide (NT-proBNP) levels correlating to the degree of arteriosclerosisBaseline natriuretic peptide(NP)s have been shown to predict stroke, with NPs have been shown to be elevated in AFThe increase of NT-proBNP in AF patients can result from both atrial and ventricular production. During 2 and CHA2DS2-VASc models resulted in significant improvements in their discrimination performance for both TE events and cardiovascular mortality (c statistic Aristotle: stroke 0.62 to 0.65 and cardiovascular death 0.59 to 0.69). Interestingly, one prospective trial in non-anticoagulated AF who underwent transesophageal echocardiography has suggested that BNP levels > 251.2 pg/mL are independent predictors for left atrial thrombiIt is also thought that a raised NT-proBNP may signal atrial dysfunction. NPs possess antifibrotic effects, with plasma NPs being found to correlate with established serum markers of collagen I turn-over Cardiovascular risk factors such as age, hypertension and coronary disease etc. are associated with raised NPs, and can also promote ventricular dysfunction leading to atrial fibrillation/ACM Sub-clinical AF can often be difficult to detect. However, NPs could help predict the development of AF independent of heart failure, and other traditional risk factors5Currently the European Society of Cardiology guidelines on AF management do not recommend the use of NPs for AF screening. Instead, they recommend opportunistic screening in over 65s via a pulse check, or an ECG rhythm strip, and regular checks of a pacemaker or implantable cardiac defibrillator for atrial high rates. In post stroke patients they recommend at least 72 h of continuous cardiac monitoring in order to identify AF However, given the evidence outlined previously, particularly in the peri-stroke/cryptogenic stroke population, NPs could aid in identifying patients who may benefit from an implantable loop recorder, or other means of prolonged monitoring (outside the scope of the European Society of Cardiology recommendation). Recent studies have further stratified the predictive value of NPs in detecting AF. For example, to date, NT-proBNP levels of < 95 pg/ml and < 125 pg/ml have been associated with a negative predictive value of between 86 % and 98 %6Despite a multitude of studies demonstrating that both NPs can predict AFAlternatively, NT-proBNP through its longer half-life, higher measured values, and lower intra-assay variability7As previously alluded to, the temporal dissociation of AF, amongst others, has blurred the anticoagulation rules for patients in AF. This has led to a reassessment of the atrial cardiomyopathy (ACM) theory and its link potential link to embolic events. Currently, no universal clinical ACM exists, but clinical definitions to date have encompassed ≥ 1 biomarkers of left atrial dysfunction, including left atrial enlargement on echocardiography, P-wave terminal force in lead V1 on the ECG, atrial fibrosis demonstrated by cardiac Magnetic Resonance Imaging, or elevation in serum biomarkers such as NT-proBNP, and left atrial diameter index2). Already a reduction of cardiovascular events, particularly ischemic stroke, in sinus rhythm patients taking a combination of an anticoagulant and aspirin over aspirin alone has been demonstrated in the COMPASS trialIt will be interesting to see how important a role NPs can play in the diagnosis of an ACM and prevention of TE events, given their potential ability to reflect a dysfunctional atrial environment. Given the discrepancy of ANP levels with AF chronicity and structural changes, its likely NTpro-BNP or BNP may be more reliable in identifying ACM8In conclusion, NPs have shown promise in predicting AF. Further studies are required to confirm these results, and to potentially define the optimal NP subtypes, optimal cut off values in different clinical settings, and the frequency of checks required for AF screening. It is imperative that the ACM concept is further investigated, and its potential association with TE be clearly defined. If this association(s) can be confirmed and refined, these studies could and should strive to define the degree of benefit of these approaches on patient health outcomes, but also on health care economics. This could lead to more efficient AF screening, help risk stratify AF/ACM patients, and potentially reduce the burden of unnecessary screening and cost on healthcare systems, while reducing the clinical impact of these atrial pathologies.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


In the multivariable regression model containing echocardiographic variables, LAWMV was an independent predictor of SR maintenance at 12 months . Similarly, LAWMW was an independent predictor of SR maintenance at 12 months  in the multivariate regression model containing both echocardiographic and clinical variables. LAWMV predicts SR maintenance after DCCV for persistent AF. Echocardiographic markers of left atrial mechanical remodeling are better at predicting SR maintenance than markers of structural remodeling.Reduced left atrial wall motion velocity measured during AF (LAWMV) indicates left atrial remodeling. The aim of this study was to investigate whether LAWMV assessed with tissue Doppler imaging during atrial fibrillation (AF) predicts sinus rhythm (SR) maintenance after direct current cardioversion (DCCV) for persistent AF. The study included 126 patients who underwent DCCV and were followed for 12 months. At 12 months, maintained SR was reported in 55 patients (43.7%). We noted that LAWMV was higher in patients with maintained SR at 12 months than in those with recurrent AF (3.69 ± 0.84 vs. 2.86 ± 1.09;  Atrial fibrillation (AF) is a type of arrhythmia characterized by rapid and uncoordinated electrical and mechanical activation of the atria ,2. It isSo far, numerous studies have been published that assessed the clinical, biochemical, and echocardiographic risk factors for recurrent AF after direct current cardioversion (DCCV) ,5,6,7,8.Atrial remodeling may be caused by AF, but it can also be one of the factors that contribute to subsequent AF episodes . It is cTo date, numerous echocardiographic parameters that allow the prediction of sinus rhythm (SR) maintenance after DCCV have been described, including parameters of structural, mechanical, and electrical remodeling, as well as of left ventricular filling pressure. Some of them can be assessed using standard transthoracic echocardiography, whereas others require advanced techniques such as strain and strain rate measurements and transesophageal echocardiography. The more advanced techniques offer better possibilities for assessing SR maintenance than standard echocardiographic measures such as left atrial dimension or volume. However, the use of advanced measurements or transesophageal echocardiography is time consuming and requires additional software and echocardiographic probes. Moreover, some of the above parameters can be assessed during SR , whereas it would be optimal to predict DCCV efficacy before the procedure .In this study, we assessed the prognostic value of LAWMV measured using tissue Doppler imaging during AF in patients referred for DCCV due to persistent AF.Informed consent to participate in the study was obtained from each patient. The study protocol was approved by the Institutional Review Board of the Świętokrzyskie Medical Chamber. Patients presenting with persistent AF who underwent DCCV between February 2017 and August 2020 were included in the study. The inclusion criteria were as follows: symptomatic persistent AF lasting at least 7 days, ejection fraction during SR ≥ 40%, and adequate anticoagulation for at least 3 weeks before cardioversion . The exclusion criteria were age < 18 years, lack of consent to participate in the study or to undergo cardioversion, failed acquisition of left atrial wall velocity, poor-quality echocardiographic images, valvular prosthesis, moderate or severe valve regurgitation or stenosis, the presence of left atrial appendage thrombus, acute myocardial infarction, acute decompensation of heart failure, previous pulmonary vein isolation, dysthyroidism, anemia with hemoglobin levels < 6.9 mmol/L, immune disease, acute infection, and neoplastic disease.Clinical and echocardiographic data as well as blood samples were collected directly before cardioversion. Patients were followed clinically and with electrocardiography at 1, 6, and 12 months. In addition, all patients with SR underwent 24-h ambulatory Holter monitoring at 1 and 12 months. Patients were asked to report to our Cardiology Department when they experienced palpitations or when routine medical care revealed the recurrence of AF.2DS2-VASc score was assessed according to the European guidelines [The following clinical data were recorded at baseline: age, sex, body mass index, diabetes mellitus, hypertension, smoking status, history of stroke or transient ischemic attack, coronary artery disease, heart failure, and medical treatment. Patients were diagnosed with coronary artery disease if they had a history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting. The glomerular filtration rate was measured using the Modification of Diet in Renal Disease formula. The CHAidelines  on the mGeneral anesthesia was used for all DCCV procedures. If the effectiveness of anticoagulation was uncertain, transesophageal echocardiography was performed to assess for left atrial thrombi. All DCCVs were performed with paddles placed in the anterolateral position, and a biphasic defibrillator was used to deliver an electrical shock at 150 J to 300 J. If this proved ineffective, another shock was administered with an additional 100 J. Successful cardioversion was defined as SR maintenance for ≥24 h after the procedure. Patients with SR received anticoagulation, upstream therapy, or antiarrhythmic drugs according to clinical judgment. Based on the risk of AF recurrence, antiarrhythmic drugs (propafenone or amiodarone) were prescribed by a physician who was blinded to the echocardiographic data assessed in this study.Transthoracic echocardiography was performed based on current guidelines ,35 usingLAWMV was measured directly using transthoracic echocardiography with tissue Doppler imaging in the apical 4-chamber view with a 4-mm sample volume. The Doppler gate was placed approximately 10 mm below the lateral mitral annulus .Velocity measurements were taken for about 3 s. The view angle was obtained by positioning the lateral left atrial wall as much as possible along the direction of the ultrasound wave propagation.LAWMV was measured based on AF waves recorded just before the QRS complexes, after the wave corresponding to the e′ wave of the diastolic mitral annular motion. The measurements of the highest LAWMV towards the probe or from the probe were analyzed. The highest LAWMV value was selected for analysis. Considering that the s′ wave might coincide with the systolic mitral annular motion, no measurements were taken during the QRS complex. In addition, LAWMV was not measured in patients with AF with rapid ventricular activity in whom the cardiac pause was not recorded during echocardiography.t-test, and non-normally distributed variables were compared with the Mann—Whitney test or the chi-squared test.Results were described as means ± standard deviations. Categorical variables were presented as counts and percentages. Normally distributed variables were compared using the Student p values, as determined in the univariate logistic analysis, were included in a multivariable logistic analysis. Two multivariate models were created, one including selected clinical and echocardiographic variables with the lowest p value and the other including only echocardiographic variables with the lowest p value. The selected echocardiographic variables were parameters of structural and mechanical remodeling as well as of left ventricular filling pressure.Clinical and echocardiographic parameters with the lowest The receiver operating characteristic curves for predicting SR restoration and maintenance at 1, 6, and 12 months were calculated for LAWMV. The areas under the curve (AUC) and optimal cut-offs based on Youden’s J statistic were also calculated.p < 0.05. Statistical analyses were performed with STATISTICA 13.3 software .Statistical significance was set at Of the 126 patients included in the study, SR restoration after electrical cardioversion was noted in 107 (84.9%). At 12 months, 55 patients (43.7%) showed maintained SR. Patients who underwent successful DCCV and maintained SR at 12 months more often were male, had higher glomerular filtration rate, more often used beta-blockers before DCCV, and less often used diuretics before and after DCCV, as compared with patients without maintained SR at 12 months. Detailed clinical characteristics are presented in Patients who underwent successful DCCV and maintained SR at 12 months showed a greater size of the right ventricular outflow tract (RVOT), higher LVEF, lower LAV and LAVI, higher left atrial emptying fraction, higher systolic and early diastolic velocities on mitral annular tissue Doppler imaging, lower early filling wave, and higher LAWMV. Detailed echocardiographic data are presented in p = 0.009), glomerular filtration rate , diuretic use before  and after DCCV , greater size of the right ventricular outflow tract , LVEF , LAVI , left atrial emptying fraction , systolic mitral annular velocity , early diastolic mitral annular velocity , early filling wave , and LAWMV .In the univariate regression analysis, the significant predictors of SR maintenance at 12 months after DCCV were male sex  as well as SR maintenance at 30 days , 6 months , and 12 months  after DCCV , left ventricular filling pressure (E and e′ waves), structural remodeling , and mechanical remodeling have a prognostic value in terms of SR maintenance after DCCV in patients with persistent AF. However, in the multivariate regression models, only LAWMV  was an independent predictor of SR maintenance after DCCV.Previous studies assessed LAWMV in terms of its prognostic value for predicting SR maintenance after electrical cardioversion, but the measurements were done from color tissue Doppler images using the Q-Analysis software, and not directly as in our study . The assNumerous studies confirmed the prognostic value of echocardiographic parameters describing structural remodeling for predicting successful DCCV and the risk of recurrent AF ,13,14. ITransthoracic echocardiography allows the assessment of left atrial contractility by measuring the left atrial emptying fraction. It was shown that left atrial emptying fraction assessed after successful DCCV  as well as during AF before DCCV has a higher prognostic value for predicting SR maintenance as compared with markers of structural remodeling ,31. Kim Mechanical remodeling can be also assessed by measuring the contractility of the left atrial appendage. It was shown that the greater the contractility and left atrial appendage ejection fraction, the better the prediction of SR maintenance after DCCV ,18,19. IAmong the advantages, the LAWMV measurement is easy to perform and is not time consuming. It is done in the same way as the measurement of mitral annular motion velocity, but the Doppler gate should be placed approximately 10 mm below the annulus. In our study, LAWMV measurements were done using tissue Doppler imaging. The technique is dependent on the angle of the Doppler beam with respect to the moving object, which affects the outcome. The use of speckle-tracking echocardiography might eliminate a possible error resulting from the suboptimal placement of the ultrasound beam, but this technique requires additional software and may be time consuming. Measuring LAWMV requires a pause in the ventricular systolic function to visualize the left atrial wall contraction wave. When patients have a very fast ventricular rate, it is difficult to measure LAWMV .The limitations of our study include a single-center design and a small number of patients. When interpreting our results, it is important to bear in mind that echocardiography is operator-dependent and requires skill and expertise. Therefore, all echocardiographic measurements in our study were taken by a single experienced investigator. The use of constant heart rhythm monitoring was not feasible in our long-term study; thus, it is possible that we missed self-limiting episodes of AF recurrence. All DCCV procedures were performed in the anterolateral position, without changing the paddle position in case of cardioversion failure, which may have influenced the success rate.In this study, we did not assess AF duration because we were not able to determine it reliably. AF is often asymptomatic, or its symptoms can develop slowly. Many of our patients were unable to report the onset of AF.The levels of brain natriuretic peptide and N-terminal pro-B-type natriuretic peptide were not measured in all patients, although it may have been an important variable for statistical analysis, considering the confirmed effect of diuretics.The measurement of LAWMV during AF predicts the immediate success of DCCV and SR maintenance at 12 months after DCCV. The results of this study support the use of left atrial mechanical remodeling parameters over structural remodeling parameters to predict SR maintenance after DCCV. Considering the ongoing advances in ablation techniques, we encourage clinicians to study the echocardiographic markers of mechanical atrial remodeling for predicting SR maintenance after AF ablation as well as the risk of recurrent AF in patients after ablation for typical atrial flatter.


Heart failure patients demonstrate reduced functional capacity, hemodynamic function, and quality of life (QOL) which are associated with high mortality and morbidity rate. The aim of the present study was to assess the relationship between functional capacity, hemodynamic response to exercise and QOL in chronic heart failure.A single-centre prospective study recruited 42 chronic heart failure patients  with reduced left ventricular ejection fraction (LVEF = 23 ± 7%). All participants completed a maximal graded cardiopulmonary exercise test with non-invasive hemodynamic (bioreactance) monitoring. QOL was assessed using Minnesota Living with Heart Failure Questionnaire.2 consumption . No significant relationship between the QOL and selected exercise hemodynamic measures was found, including peak exercise cardiac power output , cardiac output , and mean arterial blood pressure .The average value of QOL score was 40 ± 23. There was a significant negative relationship between the QOL and peak O2 consumption, but not hemodynamic response to exercise, is a significant determinant of QOL in chronic heart failure patients.Peak O Exercise intolerance is a clinical hallmark of chronic heart failure. Reduced cardiac output and oxygen extraction are main underlying pathophysiological mechanisms explaining exercise intolerance in chronic heart failure –3. FunctPatients with chronic heart failure demonstrate significantly lower Quality of Life (QOL) in comparison with other chronic conditions . ImproveA prospective, single-centre, cross-sectional study was performed to assess functional capacity, hemodynamic response to exercise in chronic heart failure patients. Quality of life was also assessed as detailed below. A total of 42 patients with stable chronic heart failure due to reduced left ventricular ejection fraction were recruited into the study. Patients were additionally screened to ensure that they met study inclusion criteria, which included heart failure due to reduced left ventricular ejection fraction (LVEF < 40%), NYHA functional class II and III, age 50 years or more, clinically stable  for at least 6 weeks prior to the study, and an ability to perform maximal graded cardiopulmonary exercise stress testing.All participants were instructed not to eat two hours before the visit to the clinical research facility where assessment procedures were undertaken. Participants were also instructed not drink alcohol or caffeine on the day of assessment. Eligible participants signed an informed, written consent and all study procedures were in accordance with the Declaration of Helsinki and meets international ethical standards . The stuUpon arrival at the Clinical Research Facility, study participants’ anthropometric measurements (body weight and height) were obtained. Participants also answered a standardized health screening questionnaire according to the Standard Operating Procedure of the Clinical Exercise Laboratory. All patients completed a maximal graded cardiopulmonary exercise test using a semi-recumbent, electromagnetically controlled cycle ergometer  with non-invasive gas exchange  and bioreactance method for haemodynamic monitoring  . Exercis–3, is the conversion factor into watts [Hemodynamic variables measured during exercise stress test were heart rate, systolic and diastolic blood pressure, stroke volume, which are then used to calculate cardiac output, mean arterial blood pressure, and cardiac power output. Cardiac power output was calculated using the following formula:to watts .Non-invasive gas exchange measurement allowed determination of peak oxygen consumption and subsequent calculation of the arteriovenous oxygen difference using measured oxygen consumption and cardiac output. Minnesota Living with Heart Failure (MLHF) Questionnaire was used to assess heart failure related QOL.p value < 0.05 was considered statistically significant. Statistical analysis was carried out using SPSS version 24.0 .All results are expressed as mean ± SD unless stated otherwise. Before SPSS analysis, the data were screened for univariate and multivariate outliers using Z-distribution cut-offs and Mahalabonis distance test. Kolmogorov Smirnov test was used to assess normality. Baseline haemodynamic measures and response to exercise were compared between patients and healthy controls using independent sample t-test. Pearson’s coefficient of correlation (r) was used to assess the relationship between quality of life and measures of hemodynamic response to stress exercise in chronic heart failure. A Demographic, clinical, and physical characteristics of patients are indicated in Table p < 0.01, Fig. p = 0.02, Fig. p > 0.05).There was a higher proportion of males n = 31, 74%) and patients were categorised into NYHA functional class II (n = 19) or III n = 23). Metabolic and haemodynamic measures at rest and peak exercise are presented in Table 3. Metabo, 74% andThe major findings of the present study suggest that in chronic heart failure, QOL is significantly correlated with peak oxygen consumption mediated primarily via improved arterio-venous oxygen difference  but not exercise hemodynamic measures such as cardiac power output, cardiac output, or mean arterial blood pressure. These findings provide better understanding of determinants of QOL in chronic heart failure, further suggesting that impaired cardiac function may not consequently lead to reduced quality of life. On the other hand, patients with higher functional capacity (peak O2 consumption) will likely have better QOL as demonstrated with lower scores on Minnesota Living with Heart Failure quality of life questionnaire.Cardiac power output has been proposed to be the best indicator of overall function and pumping capability as it accounts for both flow and pressure generating capacities of the heart , 14. Whe2 consumption) reported in the present study is consistent with previous studies [Reduced exercise capacity  have become available to measure patients’ health-related quality of life. However, disease-specific questionnaires such as Minnesota Living with Heart Failure is more sensitive to detecting changes than generic questionnaires . In the Quality of life is increasingly becoming one of the primary outcomes in clinical and research practice in heart failure. Pharmacological, surgical, and physiological interventions known to improve functional capacity are likely to lead to improved QOL in chronic heart failure, while those focusing in improving haemodynamic function only may not necessarily lead to patient experience of better QOL.The following limitations of the current study should be taken into consideration. Firstly, the number of patients recruited into the study was only moderate. Secondly, majority of patients were males with less than one third of patients were females. Lastly, this was a cross-sectional study which evaluated exercise capacity using only one method. Therefore, generalisability of the present study findings and its conclusions should be considered with caution.In conclusion, patients with chronic heart failure demonstrate reduced functional capacity and overall cardiac function. Significant negative relationship between functional capacity and quality of life score suggests that peak exercise oxygen consumption mediated via increased skeletal muscle oxygen consumption is an important determinant of quality of life in chronic heart failure. In contrast, peak exercise central hemodynamic measures i.e., cardiac power output, cardiac output and mean arterial blood pressure were not significantly correlated with quality-of-life score, indicating their limited capacity to reflect quality of life in patients with chronic heart failure.


The usefulness of percutaneous approaches in structural heart disease could be limited if they have been defined in terms of often unrealistic scenarios. Thus, the long-term outcomes and consequences need to be painstakingly analyzed. Much attention needs to be paid to the global magnitude of this issue. One such example, is the transcatheter edge-to-edge mitral valve repair (TEER) and considerations of pivotal importance that arise from using this therapy to treat functional mitral regurgitation (FMR).,2. In fact, the lack of an annuloplasty ring is the most powerful predictor for failure after MV repair in the long term,4. This rule is universal and, therefore, applies to any MV repair in the adult. Alfieri’s edge-to-edge technique that underpins the principle of TEER is no exception to this rule-9. Nevertheless, it seems that all the implications of a ringless therapy such as TEER have not been completely addressed. Thus, we must define such limitations in the percutaneous approach for MV repair. Indeed, rules governing MV repair do not change just by shifting the approach. In fact, the percutaneous technique is constrained by the installation of a ringless TEER device. Due to TEER being a ringless therapy, dilatation of both commissures has been proposed as a possible explanation for the high occurrence of recurrent mitral regurgitation (MR) ≥ 2+ (23% at two years) observed in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial.Traditionally, surgical treatment has been the best option for mitral valve (MV) repair. When comparing TEER to surgical MV repair, several salient details need to be considered. One of the main drawbacks of the edge-to-edge technique is that it has never been the first option for any surgical MV repair. Furthermore, the most important difference between the percutaneous technique and surgery is the absence of an annuloplasty prosthetic ring in the first option. Consequentially, this factor renders the percutaneous procedure only partially effective. It must be emphasized in the strongest terms that it is insufficient to consider TEER without an annuloplasty ring. We must also acknowledge the important role of the annuloplasty, by means of a prosthetic ring in every MV repairThe occurrence of FMR directly linked to coronary artery disease may constitute an ever-increasing potential indication for TEER. However, evidence supporting TEER in FMR is only limited to two controversial randomized controlled trials.vs. 22.4%; hazard ratio [HR]: 1.11; 95% confidence interval [CI], 0.69 to 1.77) and rehospitalization for heart failure (HF)  at one year of follow-up. At two years of follow-up, there was no significant difference for the composite of death for any cause and HF rehospitalization . Rehospitalization for HF alone did not show important difference between groups .In the Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients with Severe Secondary Mitral Regurgitation (MITRA-FR) trial , TEER results were compared with medical treatment in patients with FMR. No statistically significant differences were observed between both groups for all-cause mortality (24.3% P<0.001). In light of the above, important questions arise in respect of the best treatment for this special group of patients.Contradictory results in favor of TEER were obtained in the COAPT trial, a study fully sponsored by the MitraClip™ device industry Abbott for TEER  at 2 - 3- years of follow-up. Rehospitalization rate for HF was 35.8% for TEER and 67.9% in the control group  volume ratio. The selected cut-off value is 0.14 . Thus, two main types of FMR can be identified, namely, those with preserved LV volume and significant MR (disproportionate), and those with dilated LV volume and large MR (proportionate). The former is typical of chronic ischemic MV regurgitation with posterobasal deformation of the left ventricle due to chronic coronary artery disease. The latter is generally observed in dilated cardiomyopathies, regardless of the underlying etiology. Hence, at a first glance, disproportionate FMR cases entail better prognosis. However, when moving from theory into practice, all these tools have failed to obtain a reasonable explanation about the differences between trials until now. By using this concept, Lindenfeld et al. found no consistent differences between groups when comparing MITRA-FR-like vs. COAPT-like patients. Adamo et al. demonstrated that the relative risk of HF hospitalization and death was independent from the presence of disproportionate FMR. In a study of 241 cases of TEER, Ooms et al. found no important difference for all-cause mortality and HF rehospitalization rates for disproportionate and proportionate FMR . Hagendorff et al. have clearly emphasized that the disproportionate FMR can only be explained by means of conflicting data on the reported echocardiographic values, such as those observed in the COAPT trial.Special efforts have been made in order to narrow the gap between the ideal and the real outcomes observed in COAPT and MITRA-FR trials, respectively. Theoretical explanation by means of the disproportionate/proportionate FMR concept has been proposed to provide a better understanding of the aforementioned data disparities. In the COAPT trial, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin/neprilysin receptor inhibitors were significantly underused in the medical therapy alone arm than in the TEER group throughout the whole trial period. Taken together, these data tend to create a major distortion towards the most optimum balance in both arms of the COAPT. Hence, it could explain the wide different outcomes in both trials. In the same COAPT trial, within the group of patients whose MR did not improve 30 days after the start of medical treatment, 33% and 40% — at one year and two years, respectively — had significant improvement in reducing the severity of MR. This strongly questions the efficacy of the medical treatment used within the COAPT trial. Finally, if the pool of medications and doses used in COAPT  is compared with current treatment protocols, we can state that such medical therapies in the COAPT are, at present, inadequate and obsolete. Moreover, in stark contrast to what current clinical guidelines for the management of HF recommend as an aggressive medical treatment from the outset, reaching maximum doses as necessary, the GDMT utilized in the COAPT trial leaves much to be desired.It is important to clarify the distinction in the guideline-directed medical therapy (GDMT) between the two trials, in order to dispel the popular misconception about the similar equivalence between them. While post-procedural GDMT has been largely questioned in COAPT, intensive medical treatment was carried out and maintained in nearly 80% of cases in MITRA-FR. Thus, medical management was quite different in both trials, especially after randomization,24. The obvious conclusion that the COAPT results can be applied to most of the patients with FMR is, therefore, biased and unfounded. The author of this article considers that before accepting this recommendation, all available information should be revisited again in an impartial manner. In fact, the author has repeatedly suggested that this TEER recommendation for FMR should be a Class IIb recommendation, and limited to a very selective pool of patients,26.Post-COAPT trial data considerations with respect to the absence of open, unbiased data transparency, alongside a lack of reproducibility in low-volume centers and the stringent patient selection criteria, make extrapolation to the majority of the population with FMR highly unlikely. Therefore, concern about the accuracy of all conclusions from the COAPT trial must be urged, and assiduous caution exercised when interpreting the results. Nonetheless, based on the COAPT results, the most recent European and American clinical guidelines for the management of valvular heart disease consider a Class IIa recommendation for TEER in FMR, in the absence of coronary artery disease. This recommendation is also applicable for cases of HF in stage D without an adequate response to GDMT. However, it is extremely important that this information be carefully considered. Firstly, specific echocardiographic parameters for MV repair in FMR were not included in this study. Significantly, systolic sphericity index > 0.7, LV end-systolic volume > 140 mL, LV diastolic diameter > 65 mm, LV systolic diameter > 51 mm, posterior papillary-fibrosa distance > 40 mm, interpapillary distance > 20 mm, coaptation depth > 1.1 mm, tenting area > 2.5 mm2, and posterior leaflet angle > 45° are considered as predictors of failure after restrictive annuloplasty in FMR. The second fact is that no etiology-specific designed annuloplasty rings were utilized in the trial. The GeoForm annuloplasty ring  and IMR ETlogix ring , instead of the classic Physio annuloplasty ring , have demonstrated a lower rate of MV regurgitation recurrence after operation in FMR,30.Much of the rationale for supporting TEER and downplaying MV repair surgery in FMR arises from research by Goldstein et al. and the Cardiothoracic Surgical Trials Network investigators, which demonstrated that the recurrent MR rate after MV restrictive annuloplasty was up to 58.8% at a two-year follow-up. Chikwe et al. reported 524 patients underwent MR surgery after failed TEER. Operative mortality was 10.2%, and 95% of these patients underwent MV replacement. The Transcatheter Mitral Valve Therapy STS/ACC/TVT Registry reed an occurrence of recurrent MR ≥ 3+ of 8.7% at just 30 days after TEER. An analysis from data of the Heart Failure Network Rhineland registry showed MR ≥ 3+ of 9.8% at one year after TEER, in stark contrast with the previously reported in the COAPT trial (5.3% at one year). Nevertheless, since many cases are not officially reported, there is vastly inadequate and insufficient information coming from the real world, regarding the need for reoperation after failed TEER.The consequences of applying a therapy without anticipating long-term results can be devastating. In the CUTTING-EDGE study, 332 cases that underwent MR surgery after failed TEER were analyzed. Operative mortality was 16.6%, and 92.5% of cases ended with MV replacementIn closing, durability of the TEER is currently unknown. A more complete technique for TEER should be a priority. Factors that govern the classic surgical principles for MV repair give genuine pause for thought. Why not begin to apply in TEER the same effective logic concerning surgical MV repair, in consideration of long-term durability and stringent patient selection by the most rigorous preoperative echocardiographic criteria?Finally, every clinical trial must be governed by the highest standards of ethical research principles. It is imperative to have scientific trials that are unbiased at all levels of design and funding. In this way, clinical trial outcomes can contribute to raising the quality of human life throughout the world.