The above data indicate that the presence of monoclonal λ chains in patients with AL amyloidosis may be associated with more severe damage to cardiomyocytes and dysfunction of the myocardium.There are reports indicating that myocardial dysfunction in systemic immunoglobulin light chain amyloidosis (AL amyloidosis) stems not only from the amyloid deposit in the organ but also the cardiotoxicity of the amyloid precursor free light chains (FLCs) circulating in the blood. The aim of the study is to analyze the role of sFLC κ and λ in the assessment of heart involvement and the degree of myocardial damage in AL amyloidosis. The study involved 71 patients diagnosed with primary AL amyloidosis. The relationship between sFLC concentrations and cardiac biochemical and echocardiographic parameters was assessed. The median concentrations of N-terminal pro b-type natriuretic peptide(NT-proBNP) and troponin I (TnI) were significantly higher in patients with amyloids formed from monoclonal λ chains compared to patients with monoclonal κ proliferation. In patients with heart involvement by amyloids formed from monoclonal FLC, the study demonstrated a statistically significant positive correlation between the concentration of monoclonal antibody λ chain and TnI (R = 0.688;  Light chain amyloidosis (immunoglobulin light chain amyloidosis (AL)) is caused by clonal neoplastic plasma cells or B-cell clones that produce misfolded light chains (κ or λ). Misfolded proteins deposited in tissues result in progressive organ damage ,2. AL amThe main unfavorable risk factor for AL is cardiac involvement since 75% of deaths in this group of patients are caused by heart failure or arrhythmias resulting from amyloid fiber deposition ,7. In adThis study aims to analyze the relationship between the free ĸ and free λ chain serum concentration and myocardial involvement markers. We also aim to evaluate which of the monoclonal chains, ĸ or λ, is associated with greater myocardium damage and could be an unfavorable prognostic factor in AL amyloidosis.Presence of secondary organ abnormalities resulting from amyloid deposition based on the applicable criteria for organ involvement in AL amyloidosis  13,14];,14;13,14Amyloid presence confirmed by Congo Red staining of tissue biopsies ;Confirmation that amyloid is made of monoclonal immunoglobulin light chains (immunohistochemistry);Confirmation of the presence of plasmocyte dyscrasia .The study included patients of the Department of Hematology, Oncology and Internal Diseases of the Medical University of Warsaw with primary AL light chain amyloidosis. In this group of patients, a retrospective analysis of the results obtained in the period between January 2009 and May 2016 was performed both as part of initial diagnostics and during treatment monitoring. The criteria for the diagnosis of primary systemic AL amyloidosis included the following:All four of the above criteria had to be met for the diagnosis of primary systemic AL amyloidosis. In localized amyloidosis, the only diagnostic criterion was the presence of amyloids localized in one organ and composed of light chains of immunoglobulins, without the presence of monoclonal proteins in serum and/or urine ,3. ExcluComparative studies included type of monoclonal light chain forming amyloid ; percentage of plasmocytes with trepanobioptosis at the time of diagnosis; echocardiography parameters, including LV (left ventricular and diastolic dimension), IVS (diastolic ventricular size), PW , RV (right ventricular and diastolic dimension), and EF (left ventricle ejection fraction); laboratory findings, including NT-proBNP, TnI concentrations as parameters assessing cardiac dysfunction and damage, the concentration of free ĸ and λ chains in serum, difference between the concentration of involved and uninvolved free light chain (dFLC), and the free ĸ and λ light chain ratio (ĸ/λ). The number of the analyzed data was not equivalent to the patients’ number. The results were evaluated, including both diagnosis and treatment monitoring. In addition, the commissioned test panels did not cover the compared parameters each time. The study population was a very diverse group in terms of frequency, number, and type of commissioned tests. There were patients monitored every two months for four years, including those who had a one-day stay at the hospital. Laboratory findings and echocardiography were performed in groups based on type of monoclonal amyloid-forming chain ; FLC ratio (ĸ/λ): <0.26, 0.26–1.65, >1.65; dFLC: <180 and >180 mg/L; clinical stage based on Kumar et al.’s [® Human Kappa/Lambda . Then, the ratios of ĸ/λ FLC in serum (reference range 0.26–1.65) and dFLC were calculated. NT pro-BNT and TnI concentrations were measured using a Dimension EXL analyzer  using a one-step sandwich chemiluminescent method based on the Luminescent Oxygen Channeling Immunoassay (LOCI®) method. Reference intervals were less than 125 pg/mL for patients aged less than 75 years old and less than 450 pg/mL for patients aged 75 and more years old for NT pro-BNP and 0.000–0.056 ng/mL for TnI. Echocardiography was performed ±2 weeks from the laboratory test . The following data from echocardiography were evaluated: left ventricular end-diastolic dimension ; diastolic dimension of the interventricular septum ; thickness of the posterior wall of the left ventricle in diastole ; right-ventricular end-diastolic dimension ; ejection fraction of the left ventricle .FLC ĸ and λ concentration was measured by the immunoturbidimetric method on Cobas c501  using FreeliteResults are presented as median and interquartile range (IQR) or absolute numbers and percentages where appropriate. The Kolmogorov–Smirnov test was used to assess the normality of the distributions. In the comparative analysis of the tested material, depending on the type of amyloid-forming monoclonal chain  and dFLC values, the Wilcoxon test was performed.p < 0.05 was considered significant.In the comparative analysis of the tested material, depending on the ratio of FLC κ/λ, clinical stage, and type of organ affected by amyloids, ANOVA by rank was used. Correlation analysis was performed using the Spearman test. In multivariable linear regression, ANOVA was applied with TnI and NT-proBNP as dependable variables. Statistica 12.0  was used for statistical analysis. A retrospective study was accordant with the rules of the Bioethical Committee of the Medical University of Warsaw.The laboratory results and clinical analysis of subjects with κ and λ amyloids are presented in To assess the difference in the laboratory and clinical results of patients whose FLC ratios (κ/λ) were <0.26, 0.26–1.65, and >1.65, a one-way ANOVA test was performed. There were no differences in age, LV, PW, EF, and RV parameters. However, statistically significant differences were found for plasmocytes percentage, TnI, NTpro-BNP, κ and λ concentrations, dFLC, κ/λ, and IVS parameters .Comparative analysis of study groups with involved and uninvolved free light chains—dFLC <180 and ≥180 mg/L—is presented in The study group was divided into four subgroups depending on Kumar et al.’s classification (Stages I–IV). Comparative analysis of the obtained results is presented in Median free light λ “i” concentration in serum was significantly higher in Stage IV vs. Stages I, II, and III. All patients from the Stage IV group have shown the presence of monoclonal λ chains. It was shown that the median IVS values in Stages III and IV were significantly higher than in Stages I and II, and the median of PW and RV values were significantly higher in Stage IV. The median EF value was significantly lower in Stage IV compared to Stages I, II, and III. A comparative analysis, depending on the diagnosis, is presented in The concentrations of TnI and NT-proBNP and the value of PW show significantly lower values in the group of patients with localized AL amyloidosis.Multivariable linear regression analysis of the group with involvement of the myocardium by amyloids formed from monoclonal λ chains, with TnI and NT-proBNP as dependent variables, was performed.p = 0.003), the independent predictor retained in the final regression model was λ. The remaining factors were eliminated . A λ rise of 1 mg/L caused a rise of TnI concentration of 0.0005 ng/mL (For TnI (05 ng/mL .p < 0.001), the independent predictors retained in the final regression model were λ, eGFR, and κ. The remaining factors were eliminated . A λ rise of 1 mg/L caused a rise of NT-proBNP concentration of 41 pg/mL, while an eGFR decrease of 1 mL/min 1.73 m2 caused an increased NT-proBNP concentration of 63 pg/mL. A κ increase of 1 mg/l caused an increase in NT-proBNP of 114 pg/mL (For NT-proBNP (14 pg/mL .p > 0.05).Multivariable linear regression analysis of the group with involvement of the myocardium by amyloids formed from monoclonal κ chains, with TnI and NT-proBNP as dependent variables, was performed. In the group with cardiac involvement where the amyloid is formed by monoclonal κ chains, no significant independent influence of the concentration of free light chains κ and λ, κ/λ, dFLC, and eGFR values on TnI concentrations was observed (p <0.001), the independent predictor retained in the final regression model was λ. The remaining factors were eliminated . A λ rise of 1 mg/L caused an increase in the NT-proBNP concentration of 204 pg/mL.  was found for TnI and The heart is, next to the kidneys, an organ in which amyloids during amyloidosis accumulate most frequently. One of the goals of this study is to assess the relationship between the concentration of free κ and λ light chains and markers of myocardial injury and dysfunction—TnI, NTpro-BNP—and echocardiography parameters in patients with AL amyloidosis. An attempt was made to choose the type of monoclonal chain that is associated with greater damage and dysfunction of the heart, which may turn out to be a potential adverse prognostic factor in AL amyloidosis. In the present study, in a group of 71 patients with AL amyloidosis, in 43 (61%), amyloid was formed from monoclonal λ chains, and, in 28 (31%), amyloid was formed from monoclonal κ chains. This confirms the thesis that in patients with AL amyloidosis, clonal plasmocytes are more likely to produce the monoclonal chain λ, in contrast, for plasmocyte myeloma and non-amyloid deposit diseases of monoclonal immunoglobulins, where the presence of a monoclonal κ chain (3:1) is more frequent ,16. In 5In the group with dFLC values ≥180 mg/L, considered an unfavorable prognostic factor in patients with AL amyloidosis , the medThe average concentration of the involved κ chains was significantly higher in Stage II patients compared to Stages I and III. None of the Stage IV patients showed the presence of monoclonal κ chains. The median concentrations of the involved λ chains increased with the severity of the disease (Stages I–IV). The highest median concentration of involved λ chains was found at Stage IV, in which the median total survival was 5.8 months, and the lowest at Stage I, with median survival assessed at 94.1 months. The highest median concentrations of the involved κ chains were at Stage II, with a total median survival of 40.3 months. It can be concluded that the presence of amyloid formed from λ monoclonal chains and the increase in the concentration of its precursors are potentially associated with the shorter survival of patients with AL amyloidosis. The increase in the concentration of monoclonal λ chains was also associated with changes in echocardiographic parameters characteristic for cardiac amyloidosis. The smallest median value of EF% was related to Stage IV, compared to Stages I, II, and III. Moreover, a comparative analysis, depending on the diagnosis, showed that the concentrations of TnI and NT-proBNP and the value of PW showed significantly lower values in patients with localized AL amyloidosis. In this group, circulating amyloid precursors  are undetected.Similar relationships between echocardiography parameters and the stage of severity of AL amyloidosis were presented by Kumar et al. in the paper that proposed the current prognostic criteria. . In thisAnalysis of the correlation between the concentration of κ- and λ-involved chains, echocardiography parameters, and TnI and NT-proBNP concentrations confirmed that there is a significant relationship between the concentration of λ-involved chains and the degree of cardiomyocyte injury and myocardial dysfunction. In the group with cardiac involvement and amyloid formed of monoclonal κ chains, similar relationships did not occur. There was no correlation between the concentration of κ chains involved in the process of amyloid formation accumulated in the myocardium and the parameters of echocardiography and TnI concentration. A statistically significant correlation occurred in this group only between the concentration of κ chains involved and the NT-proBNP concentration. Contrary to other results, the clinical studies of Rappezzi et al. showed no correlation between the number of amyloid fibrils present in the myocardium and the degree of its damage and, thus, the average length of survival of patients . On the The above data indicate that the presence of monoclonal λ chains in patients with AL amyloidosis may be associated with more severe damage to cardiomyocytes and dysfunction of the myocardium. To state with finality that monoclonal chain λ is a disadvantageous factor in patients with primary amyloidosis would require further research, preferably multicenter, to assess the dependence of the type of chain involved on the overall survival of patients.


In patients with mitral annular disjunction (MAD), it can be difficult to assess the severity of mitral regurgitation (MR), as they present with a prolapsing volume  rather than a regurgitant jet. The influence of the mitral prolapsing volume (MPV) on cardiac dimensions is unknown. We hypothesised that the severity of MR is underestimated in these patients. Our aim was to measure MPV and to investigate its influence on cardiac dimensions in patients with MAD.We retrospectively included 131 consecutive patients with MAD from our institution’s echocardiographic database. Transthoracic echocardiography was used to assess MPV. Additionally, we established a control group of 617 consecutive patients with degenerative mitral valve disease and performed propensity score matching.p < 0.001). In patients with large prolapsing volumes (> 15 ml), LVEDD , LVESD  and left atrial volume  were significantly increased compared to matched patients with degenerative mitral valve disease and similarly assessed severity of MR.Median MPV in the MAD group was 12 ml. MPV was an independent predictor for left ventricular end-diastolic (LVEDD) and end-systolic diameter (LVESD) and left atrial volume  contains supplementary material, which is available to authorized users. Severity assessment of mitral regurgitation (MR) can be difficult in patients with mitral annular disjunction (MAD).Patients with MAD present with a prolapsing volume rather than a regurgitant jet.Increased prolapsing volume was associated with an increase in cardiac dimensions.The prolapsing volume could be included in severity assessment of MR in MAD patients.During systole, the mitral valve annulus copes with strong forces, such as annular translation, contraction and folding . In addiAs it remains unknown what the effect of MAD might be on mitral valve prolapse and subsequent MR, it is important to explore the haemodynamic consequences of MAD. It is widely accepted that increasing effective regurgitant orifice area is a predictor of an unfavourable outcome in MR patients . HoweverIn addition to ventricular and atrial dilatation due to regurgitation, we hypothesise that mitral prolapsing volumes (MPVs) in mitral valves with MAD can also have an impact on left atrial and ventricular dimensions. As this volume shift is not part of the stroke volume, this could subsequently lead to volume overload, even if MR is not quantified as severe. As recently described, bulging of the floppy mitral valve into the LA could be measured by delineating the MPV by cardiac magnetic resonance imaging (CMR) , but in Furthermore, in most mitral pathologies, left atrial volume increases with increasing MR severity , 9. To oThe aim of the current study is to examine the effect of the MPV on the left atrial and ventricular dimensions in patients with MAD.In this observational single-centre retrospective analysis we identified in the Maastricht University Medical Centre echocardiography database all patients with MAD who underwent transthoracic echocardiography (TTE) between January 2009 and December 2015. Patients with MAD on TTE were identified by a senior imaging cardiologist with > 30 years’ experience (E.C.). MAD was defined as a clear separation between atrial wall-mitral valve junction and the left ventricular muscle attachment.To acquire a control group consisting of patients with degenerative mitral valve regurgitation without MAD, we also evaluated the echocardiography database for all patients labelled as ‘degenerative mitral valve disease’ between 2009 and 2015.Medical records were studied to retrieve biometric data, severity of dyspnoea based on the New York Heart Association (NYHA) scale, atrial fibrillation (AF) and coronary artery disease. If there was no history of AF, all electrocardiograms (ECGs) were reviewed to verify sinus rhythm. The presence of coronary artery disease was examined by means of the patient’s history, ECG review or analysis of any available coronary imaging. The need for informed consent was waived by our institutional review board, due to the observational character of the study.Data were obtained using a Philips IE33 workstation . Left ventricular end-diastolic diameter (LVEDD) was measured in the parasternal long axis view after closure of the mitral valve. Left ventricular end-systolic diameter (LVESD) was measured in the same view after closure of the aortic valve. Echocardiographic measurements were examined by two independent cardiologists  and categorised according to the most recent guidelines , 11. In Left atrial volume was calculated by the modified Simpson’s method . To defiCategorical data are presented as numbers and percentages (%). Variables are presented as median (range) or mean ± standard deviation (SD) according to normality of distribution.Univariable and multivariable regression was performed to identify predictors of either left atrial volume, LVESD and LVEDD.Propensity score matching was performed to match the ‘disjunction group’ with the ‘degenerative group’, to assess differences in cardiac dimensions between these groups. Covariates included in the model were determined using the multivariable regression model. A caliper of 0.15 was used with nearest neighbour matching in a 1:1 ratio.Statistical analyses were carried out using commercially available software ; matching was performed in R through the SPSS R‑plugin package (PSMATCHING3 R Extension v3.03).For the study group, 131 consecutive patients meeting the inclusion criteria for MAD were identified in our centre. Baseline characteristics of the 131 patients are summarised in Tab. p < 0.001] with an R2 of 0.328. In this model, BSA, MPV and MR severity were independently associated with LVEDD , MPV and MR severity were associated with LVEDD. These factors were assessed in a multivariable model, in which a significant regression equation was found  with an R2 of 0.203. In this model, BSA and MPV were associated with LVESD  = 7.598, p < 0.001] with an R2 of 0.484. In this model, BSA, MPV, MR severity and AF proved to be independent predictors of left atrial volume  = 13.171, For the degenerative mitral valve disease control group, 617 consecutive patients were identified and included for analysis. Pre-matching baseline characteristics are presented in the Electronic Supplementary Material (Table S1). As found in the multivariable models, covariates such as age, gender, BSA and MR severity were included in the matching model. Eventually, 105 pairs were matched. Characteristics of these pairs are presented in the Electronic Supplementary Material (Table S2). After matching, there were no persisting differences in baseline characteristics.p = 0.041). No further differences in demographics were observed. The LPV group exhibited significantly larger left atrial volumes , larger LVEDD  and larger LVESD .While the whole range of prolapsing volumes was included in these analyses , we assessed the influence of a large prolapsing volume . Tab. In our MAD patient cohort, we observed a blood volume shift towards the LA due to bulging of the valve into the LA, subsequent to disjunction. However, this finding has not yet been described or quantified, and its haemodynamic consequences and effect on MR severity have not been studied.Severity assessment of MR is based on qualitative, semi-quantitative and quantitative measurements , 13. NotWe observed a volume shift towards the LA due to MAD, which could hypothetically lead to an underestimation of MR severity. Therefore, the aim of the current study was to examine the effect of MPV on the left atrial and ventricular dimensions in MAD patients.The main finding of the current study is that the MPV due to MAD is associated with increased left ventricular and atrial dimensions. Furthermore, MPV is not related to the conventionally assessed MR severity, meaning that the current MR severity assessment is insufficient to determine the influence of MPV on atrial and ventricular dimensions (which is due to retrograde volume displacement rather than to a regurgitation jet in MAD patients).Based on our findings, we propose novel terminology to assess MR severity in MAD patients. MR itself is a regurgitant jet, flowing through the mitral valve back into the LA. In contrast, the MPV in MAD patients is volume displacement, not part of the stroke volume, while still contained within the mitral valve.If we regard MR as a volume, then the MPV would also be part of this regurgitant volume. However, MR is mostly calculated by the proximal isovelocity surface area (PISA) method. In MAD patients, this would not be valid because the volume is contained within the valve .This also explains the difference in severity assessment of MR between echocardiography and CMR. CMR measures differences in stroke volume by planimetry of left and right ventricular volumes and flow measurements of the ascending aorta , 16. ThiAlthough we did not find significant differences regarding cardiac dimensions in the overall matched groups, we sought to evaluate the potential influence of LPV (> 15 ml) on cardiac dimensions. We found significantly larger LVEDD, LVESD and left atrial volume in the LPV group. There was a significant difference in gender distribution between these groups. However, this was not considered important as multivariable regression analyses for these dimensions revealed gender not to be an independent predictor of any of the cardiac dimensions. This is probably due to the independent predictive value of BSA (which is gender-dependent) for these dimensions , which iAlthough we did not find a difference in the incidence of AF between the groups, it is generally accepted that patients with larger left atrial volumes are more prone to develop AF , 19 whilFinally, we did not find a relationship between MR severity and MPV, although we did find larger cardiac dimensions in patients with LPV. However, MPV is not in any way used as a parameter in current severity assessment, while MPV does independently negatively influence cardiac dimensions, and potentially also symptomatology. Subsequently, these findings imply that the MR severity of these patients could be underestimated using the current severity assessment standards.Our study has several limitations. First, this study is retrospective in nature. We have limited potential bias by using propensity score matching to correct for known covariates and baseline differences. However, AF was not taken into consideration for propensity score matching analysis. Still, this important predictor for left atrial volume did not differ between the two groups.Second, by formation of a new group (LPV) these potential biases were reintroduced, although there were no important differences in baseline characteristics between the studied groups. Finally, the regurgitant volume (including MPV) could potentially be measured more accurately with CMR, although echocardiography is the most widely used technique.Therefore, the above-mentioned limitations could encourage future studies to use at least a combination of these modalities to assess MR severity in this specific patient group.Mitral annular disjunction represents a special entity in mitral valve disease. Patients with MAD may present with various degrees of MR, which is difficult to assess accurately with current echocardiographic parameters.In the present study, we describe a new parameter in patients with MAD that has an effect on cardiac dimensions and function: mitral prolapsing volume. Patients with prolapsing volumes > 15 ml present with larger ventricular and atrial dimensions. This finding implies that the severity of MR in these patients could be underestimated using the current standard of severity assessment. Future prospective studies are warranted to determine the exact influence of various prolapsing volumes on ventricular dimensions and clinical outcomes.Supplementary Data S1. Pre-matching demographic characteristics. Supplementary Data S2. Post-matching demographic and echocardiographic characteristics.


Despite limitations attributed to LA deformation imaging , LASr constitutes a promising marker for cardiovascular events prediction and risk evaluation in patients with CKD.Left atrial strain (LASr) represents a relatively new but promising technique for left atrial and left ventricle function evaluation. LASr was strongly linked to myocardial fibrosis and endocardial thickness, suggesting the utility of LASr in subclinical cardiac dysfunction detection. As CKD negatively impacts cardiovascular risk and mortality, underlying structural and functional abnormalities of cardiac remodeling are widely investigated. LASr could be used in LV diastolic dysfunction grading with an excellent discriminatory power. Our objectives were to assess the impact and existing correlations between LASr and cardiovascular outcomes, as reported in clinical trials, including patients with CKD. We searched PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials for full-text papers. As reported in clinical studies, LASr was associated with adverse cardiovascular outcomes, including cardiovascular death and major adverse cardiovascular events (HR 0.89, 95% CI, 0.84–0.93,  Chronic kidney disease (CKD) represents a significant health care problem with a global prevalence of 697.5 million cases and 1.2 million deaths in 2017 ,4,5,6,7.2. Among CVD, ischemic heart disease and heart failure are the main factors associated with an increased CKD patients mortality [Moreover, studies suggest that mortality is primarily driven by CVD in patients with CKD, especially when the estimated glomerular filtration rate (eGFR) is under 60 mL/min/1.73 mortality . Additioortality .As CKD negatively impacts cardiovascular risk and mortality, underlying structural and functional abnormalities of cardiac remodeling are widely investigated in the literature. Many physiopathological mechanisms are incriminated in CVD development: uremic toxins, left ventricular hypertrophy, myocardial fibrosis, inflammation, oxidative stress, growth factors, Klotho proteins, fibroblast growth factor 23, and the soluble receptor for advanced glycation end-products .In the last years, great importance was given to the prevention of CVD in patients with CKD. A better stratification of cardiovascular and mortality risks represented one of the most important research directions, using dedicated clinical tools or novel biomarkers and imagistic techniques ,15,16,17Left atrial (LA) volume and dimensions evaluated by two-dimensional transthoracic echocardiography represent established imagistic markers associated with an increased risk of CVD, mortality, and AF in patients with CKD, including ESKD ,21,22. OAs new evidence has emerged in favor of deformation imaging, the European Association of Cardiovascular Imaging/American Society of Echocardiography/Industry Task Force published a consensus regarding standardization of left atrial, right ventricle, and right atrial deformation imaging in order to improve the quality and replicability of further research . Brieflyp < 0.001) than in the case of standard echocardiographic measures [p < 0.0001) and endocardial thickness (p = 0.0001), suggesting the utility of LASr in subclinical cardiac dysfunction detection [LASr represents a relatively new but promising technique for LA and left ventricle (LV) function evaluation . A recenmeasures . Moreoveetection . LASr coetection .Our objectives were to assess the impact and existing correlations between LASr and cardiovascular outcomes, as reported in clinical trials, including patients with CKD.We used Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist in conducting the systematic review .The search was performed in one step, from 12 January 2021, to 25 January 2021, in PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials. The time of publication was restricted to the interval between January 2000 and January 2021. The following terms were used in searching process: “left atrium”, “strain”, “deformation imaging”, “chronic kidney disease”, “cardiovascular”, “outcomes”, “risk” and “mortality”. Additionally, the search was restricted to trials involving humans. The reference sections of relevant articles were also searched manually for additional publications. Two independent reviewers  selected studies after screening the title and abstract.2 were included; (3) original data were reported regarding LASr relationship with adverse cardiovascular events; (4) LASr was compared with traditional echocardiographic measures (when available); (5) at least one of the following outcomes was included in the analysis: major adverse cardiovascular events (MACE), death due to cardiovascular causes, all-cause death, AF, hospitalization for heart failure, exercise capacity, mean pulmonary arterial wedge pressure; (6) duration of follow-up was at least six months if outcomes investigated were all-cause death, CV death, and MACE.Studies were considered for inclusion in the systematic review if they met several criteria, according to the PICOTS framework : (1) at least ten patients aged > 18 years were included; (2) patients with eGFR < 60 mL/min/1.73 mSeveral critical exclusion criteria were set: studies published in languages other than English; letters, editorials, case reports, meta-analyses, or the inability to extract data.p-value, predictive power, and AUC—when available. Whenever possible, data are presented as percentages, mean or median values, ranges of variation. Disagreements were resolved by discussion and consensus.The following data were extracted from included studies: year of publication, study design, number of patients, patients’ age, clinical setting, CKD definition, outcomes investigated, duration of follow-up, odds ratio (OR), risk ratio (RR), hazard ratio (HR), confidence intervals (CIs), We assessed the quality of non-randomized studies in the systematic review using the Newcastle-Ottawa scale, a star-based tool that evaluates studies at three different levels: selecting groups, comparability of groups, and outcome of interest . It compWe searched the prespecified databases and identified 893 references. After screening for duplicates, 118 citations were excluded. Additional 743 citations were excluded based on title and abstract, leaving 32 articles for eligibility assessment. Six studies were included in our systematic review after excluding 26 references because the inclusion criteria were not met .The characteristics of studies and population included and the outcomes measured were summarized in Of the included studies, three were performed in Australia ,35,36, on = 8; MACE, n = 46). Of all echocardiographic parameters investigated, only LASr was associated with the primary outcome . Regarding the prediction of the primary outcome, LASr had a better discriminatory power, with AUC 0.84 , in comparison with LV global longitudinal strain (LVGLS)—AUC 0.696 , LA volume index (LAVI)—AUC 0.671  and LV mass index (LVMI)—AUC 0.658 . Moreover, patients with LASr ≤ 20.46 were at particular high risk, as 42% of them had an adverse event over three years (MACE or CV death).Gan et al.  evaluatep < 0.01). The predictive performance of LASr was better  than in case of E/e’ ratio during exercise  or rest , suggesting a clear advantage of LASr.Gan et al.  exploredp = 0.006). Notably, this study included stage 3 CKD patients, highlighting the usefulness of LASr even in the early stages of renal disease. Other parameters associated with MACE during follow-up were LAVI (p = 0.04) and LV late diastolic strain rate (LVSRA) (p = 0.03).Kadappu et al.  evaluatep = 0.003), LASr rate (p = 0.001), E/e’ (0.005), LAVI (p = 0.05) and LVMI (p = 0.005). In the multivariate analysis, the LASr rate remained strongly associated with an increased AF risk (p = 0.010). Nevertheless, limited by a small number of patients (n = 79), LASr proves to be a better marker than traditional echocardiographic measures in the CV risk stratification of ESKD patients.The relationship between LASr and the risk of paroxysmal AF in patients with ESKD and hemodialysis was explored by Papadopoulos et al. . The autp < 0.05). Additionally, PALS was significantly reduced in patients with diastolic dysfunction grade I  and grade II . Moreover, eGFR was independently correlated with PALS .A case-control study dealing with ESKD patients and preserved ejection fraction without CV disease symptoms investigated the relationship between peak LA longitudinal strain (PALS) and diastolic dysfunction . InteresS-S, left atrial systolic strain; LAS-A, left atrial late diastolic strain; LAS-E, left atrial early diastolic strain). All three components of LASr were strongly associated with PCWP, suggesting that LASr could be used as a marker to predict LV dysfunction in ESKD patients. However, this study limitation is represented by estimating PCWP using a formula, which could differ from the values measured invasively.Altekin et al.  evaluateThe quality assessment using the Newcastle–Ottawa scale and NIH tool for observational studies was presented in To the best of our knowledge, this systematic review is the first one that included studies exploring the relationship between LASr and cardiovascular outcomes in patients with CKD.LA structure and function evaluation gained interest in the last years, as it could be an early marker of a complex underlying cardiac disease with prognostic implications. LA modulates the LV preload by acting as a reservoir, conduit, and booster pump directly related to LV compliance and function. In the last years, LA function was extensively studied for its potential in risk stratification of patients with/without CVD with severe clinical implications .p = 0.025).The Dallas Heart Study  showed tp = 0.021, for each 5% PALS decrease). Moreover, LASr was linked to an increase in thrombotic events and unsuccessful electrical cardioversion in patients with AF or atrial flutter, suggesting the utility of LASr in therapeutic decision-making regarding rhythm control [Another relevant clinical implication of LASr in the general population is represented by AF prediction . Individ control . LA defo control .Despite all promising clinical applications of LA parameters mentioned above, few studies validated LASr role in CKD. Two studies included in our systematic review reported reliable correlations between LASr and MACE or  mortality.One of them evaluated the link between LASr and long-term CV outcomes (3.9 ± 2.7 years) in patients with CKD stage 3–4 . AlthougThe other study evaluating LASr and MACE correlations showed similar results, as LAGS was associated with an increased risk of MACE . NeverthThese data support the utility and feasibility of LASr parameters in clinical practice for an accurate CVD risk stratification of CKD patients (even in the early stages). Furthermore, LASr could be integrated into future prediction models and other clinical and imagistic variables, as it could detect CKD patients at high risk even better than LVGLS.A “softer” CV outcome associated with LASr is exercise capacity. Only LASr was significantly associated with exercise capacity among echocardiographic measures in a final prediction model, with an excellent predictive power for achieved METs . Moreovep < 0.001). Conversely, LAVI and LVMI were higher in the presence of diastolic dysfunction (p < 0.05).Moreover, LA deformation imaging was associated with LV diastolic dysfunction even in patients with ESKD and preserved LV ejection fraction . A graduS-S, LAS-E, LAS-A); each of them being associated with estimated PCWP.Finally, an attractive application of LA deformation imaging is represented by LV filling pressures estimation. Patients with ESKD, hemodialysis, and preserved LV ejection fraction, showed a strong correlation between LASr and estimated PCWP . This stThe main limitations of the LASr technique are represented by echocardiographic image quality, inter-observer variability, the necessity of software, and the learning curve. Probably, the necessity of dedicated software makes LA deformation imaging less available nowadays. Moreover, a different software application could be a source of variability . Data reIn the era of personalized medicine and novel imagistic techniques, LASr constitutes a promising marker for CV events prediction and risk evaluation in CKD settings. Critical clinical applications of LASr in CKD include detecting patients at high risk of MACE, CV mortality, and all-cause mortality to individualize the follow-up strategy or therapeutic regimen. AF prediction using LASr holds critical practical implications so that anticoagulant therapy could be initiated promptly. The inclusion of LASr in the future clinical models might improve the prediction power; however, more prospective studies are needed.


The optimum cutoff value of log NT-proBNP for predicting CC was 6.04 pg/mL. Log NT-proBNP ≥ 6.04 pg/mL  was an independent predictor of good CC. CC development was higher in patients with a pre-TIMI flow of 0 or 1 than those with a pre-TIMI flow of 2 or 3 . The incidence of left ventricular (LV) dysfunction (< 50%) was greater in patients with a pre-TIMI flow of 0 or 1 . The release of NT-proBNP was greater in patients with LV dysfunction . The incidence of good CC was greater in patients with log NT-proBNP levels ≥ 6.04 pg/ml . The association between NT-proBNP and collateral formation was not influenced by pre-TIMI flow and LV function. NT-proBNP appears to reflect the degree of collateral formation in the early phase of STEMI and might have a new role as a useful surrogate biomarker for collateral formation in patients undergoing primary PCI.There is insufficient information on the relationship between the N-terminal pro-brain natriuretic peptide (NT-proBNP) level and collateral circulation (CC) formation after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction. We analyzed 857 patients who underwent primary PCI. The serum NT-proBNP levels were measured on the day of admission, and the CC was scored according to Rentrop’s classification. Log-transformed NT-proBNP levels were significantly higher in patients with good CC compared to those with poor CC (6.13 ± 2.01 pg/mL versus 5.48 ± 1.97 pg/mL, The online version contains supplementary material available at 10.1007/s00380-021-01866-3. The coronary collateral circulation (CC) is thought to provide blood for the ischemic myocardium and an interconnecting network to alleviate the burden of myocardial ischemia –3. It isN-terminal pro-brain natriuretic peptide (NT-proBNP) is secreted from the myocardium due to increased myocardial wall stress . RecentlThis observational study included 857 consecutive patients who underwent primary PCI after STEMI and were enrolled in the Korean Acute Myocardial Infarction registry (KAMIR). The KAMIR is a Korean, prospective, open, observational, multicenter, online registry of AMI with support of the Korean Society of Cardiology that was initiated in November 2005; details of the KAMIR have been published previously . The stuThe flow diagram of the study is shown in Fig. AMI was diagnosed based on a characteristic clinical presentation, serial changes on electrocardiogram indicating infarction, and an increase in cardiac enzyme levels . STEMI wCoronary CC data were collected at baseline through standard angiography, with six views of the left coronary artery and two views of the right coronary artery and used for the interpretation of collateral vessels. CC was scored according to Rentrop’s classification . A gradet test was used to perform all comparisons between the baseline variables and the continuous variables, and the Pearson Chi-square test was used to compare the categorical variables. Patients were categorized into two groups according to the presence of coronary CC: poor collateral circulation (n = 693) and good collateral circulation (n = 164). Univariate analyses were performed to determine the predictors for good CC. A logistic regression analysis model was used to compute the odds ratios (ORs) and 95% confidence intervals (CIs) of independent predictors of good collateral circulation. Variables with p values < 0.05 on univariate analysis were entered into the multivariate logistic regression model, namely the presence of preinfarction angina, pre-thrombolysis in MI (TIMI) flow grade of 0 or 1, multivessel disease, left anterior descending artery (LAD) as a culprit vessel, symptom-to-door time > 6 h, and log-transformed NT-proBNP. We estimated the receiver-operating characteristic (ROC) curves and the areas under the ROC curves (AUC) of NT-proBNP to identify the optimum cutoff value in the corresponding logistic models. The serum levels of NT-proBNP were compared within the collateral grade categories 0, 1, and 2/3, and with the analysis of variance according to the symptom-to-door time, presence of preinfarction angina, pre-TIMI flow of 0 or 1, and multivessel disease. For all analyses, a 2-sided p value < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software .Data are shown as mean ± SD for continuous variables, and percentages for categorical variables. Student’s p = 0.038) and symptom-to-door time > 6 h (p = 0.009). Log-transformed NT-proBNP levels were significantly higher in patients with good CC compared to those with poor CC . Among the angiographic findings, patients with good CC had a greater prevalence of multivessel disease (p = 0.022), pre-TIMI flow grade of 0 or 1 (p < 0.001), and a lower prevalence of LAD-related MI (p < 0.001) (Table p for trend)  were men. Overall, 429 (50.1%) had angiographic evidence of CC, including 265 (30.9%) with grade 1 and 164 (19.1%) with grade 2 or 3  was an independent predictor of good CC, in addition to a pre-TIMI flow grade of 0 or 1  and LAD-related MI  was an independent predictor of good CC after adjusting for confounding variables , and the optimum cutoff value was 6.04 pg/mL   . High NT-proBNP levels were more common in patients with LV dysfunction . Good CC was greater in patients with high NT-proBNP levels .Good CC was greater in patients with a pre-TIMI flow of 0 or 1   . However, BNP is also strongly correlated with the severity of myocardial ischemia, and an elevated level of BNP is, therefore, positively associated with good CC . Therefore, in the novel concept, BNP is a strong stimulator for angiogenesis reflecting myocardial ischemia, and as a result, good CC would be developed immediately after STEMI.Our research has several limitations that should be considered. First, because this was an observational study, we cannot completely exclude the possibility of residual confounding factors, although we attempted to control for selection bias with multivariate statistical methods. Therefore, our results should only be regarded as hypothesis generating. Second, we assessed coronary collateralization by Rentrop’s score instead of the collateral flow index. However, Rentrop’s score was used extensively in previous studies investigating the collateral development in humans and was shown to be a well-documented and reproducible method to assess coronary collateral vessels. Therefore, these limitations should not undermine the strength of this study.In conclusion, the serum level of NT-proBNP was increased markedly in patients with good CC. Although the precise mechanisms by which NT-proBNP is synthesized and released remain to be elucidated, the serum level of NT-proBNP appears to reflect the degree of collateral formation in the early phase of AMI.Supplementary Figure. Conventional concept (A) versus novel concept (B) regarding BNP and collateral formation immediately after STEMI. (TIF 83 kb)Below is the link to the electronic supplementary material.


ESM was completed up to ten times daily for 1 week. Patients experienced marginally greater paranoia than relatives  and significantly greater paranoia than controls , but controls and relatives did not differ . Patients were more often alone  and experienced greater paranoia when alone than when in company . In relatives this was reversed  and in controls non-significant . The time-lagged association between being in social company and subsequent paranoia was non-significant and paranoia did not predict the likelihood of being in social company over time (both p’s = 0.68). All groups experienced greater paranoia in company of strangers/distant others than familiar others  and being with familiar others was associated with lower paranoia over time . Patients are frequently alone. Importantly, social company appears to limit their paranoia, particularly when being with familiar people. The findings stress the importance of interventions that foster social engagement and ties with family and friends.Social isolation has been suggested to foster paranoia. Here we investigate whether social company  and its nature  affects paranoia differently depending on psychosis risk. Social interactions and paranoid thinking in daily life were investigated in 29 patients with clinically stable non-affective psychotic disorders, 20 first-degree relatives, and 26 controls ( Individuals with non-affective psychosis frequently experience chronic social isolation , 2. ParaIt is clear that paranoia fluctuates in intensity throughout the day , 10. ChaHowever, the study failed to differentiate paranoia levels between the different groups; healthy controls comprised only 56% of the low paranoia group, ‘acutely paranoid patients’ formed only 74% of the high paranoia group and the groups did not differ in terms of their real-life social engagement either. Myin-Germeys et al.  examinedIn this study, we aimed to investigate the relationship between social company , its nature  and paranoia across the psychosis continuum. We included individuals with a diagnosis of non-affective psychosis, controls without a family history of psychosis, and for the first time healthy first-degree relatives with a family history of psychosis. Any associations between social context and paranoid thinking in relatives are unconfounded by factors that are secondary to the clinical disorder, such as stigma or antipsychotic medication use. Thus, including relatives can help to identify whether specific mechanisms are associated with the familial vulnerability to psychosis.We used ESM to investigate the association between social interactions and paranoid thinking in daily life. We hypothesized that: (1) patients would be alone more often and generally would experience greater paranoia than controls, and that relatives would occupy an intermediate position; (2) in patients paranoia would be greater when alone than when in social company; (3) in patients being alone would predict greater paranoia over time and that reversely greater paranoia would be associated with a higher likelihood of being alone over time (in line with a hypothesized safety mechanism); (4) all groups would show less paranoia in the company of familiar compared to less familiar others; (5) in patients being with familiar but not less familiar others would be associated with lower levels of paranoia over time.Eighty-two participants were enrolled in three groups: individuals with a diagnosis of a non-affective psychotic disorder, healthy first-degree relatives of individuals with non-affective psychosis, and controls without a personal or family history of psychosis. Inclusion criteria for all participants were: age between 18 and 65, sufficient command of the English language to understand the ESM application and testing material, estimated Intelligence Quotient > 70. Additional inclusion criteria for patients were: a diagnosis of a non-affective psychosis according to ICD-10 criteria , stable Participants completed a demographic questionnaire containing questions concerning, e.g., gender, age, nationality/ethnicity, living status and medication.Participants received an iPod with an ESM application (app) and were instructed to carry the iPod with them at all times or used their own iPhone with the app. Participants completed a short questionnaire on the device up to ten times daily when alerted by a beep. Beeps appeared pseudo-randomly between 8.00 am and 10.30 pm, for 7 consecutive days, to achieve a representative impression of a week in the participants’ lives. The ESM questionnaire contained either 30 or 34 items depending on the answer to the item ‘I am on my own’, branching into different questions when individuals were alone or not. Our main analyses focused on ‘paranoia’, ‘being in social company vs. alone’, and the ‘nature of company’.α = 0.79), as previously used  and a combined category (2) ‘distant relation & strangers’  and (stranger(s), other), because patients were rarely in company of distant relations, such as colleagues  and negative affect , which have been suggested to account for the association between paranoia and social company . Specifically, patients had significantly higher odds of being alone than controls  and relatives , while the odds of being alone did not differ significantly between relatives and controls . Male gender was associated with significantly higher odds of being alone . When gender was added to the model the difference between patients and controls became smaller and trended towards significance . The effect for patients vs. relatives became smaller, but remained significant . The groups differed marginally significantly in their levels of paranoia . Patients experienced marginally significantly greater paranoia than relatives  and significantly greater paranoia than controls , but controls and relatives did not differ significantly , see Table On average, patients were alone at the time of 68.5%, relatives at 44.8% and controls at 56.2% of their completed beeps. Time spent alone differed significantly between the groups . Specifically, patients experienced significantly greater paranoia when alone than when being in social company . Relatives showed the reversed pattern, with lower paranoia when alone than when being in social company  and in controls the association was not significant .There was a significant group-by-being alone vs. in social company interaction on concurrent paranoia  and no significant main effect of being in social company vs. alone on paranoia within 180 min later . The main effect of group was marginally significant . Lagged analysis showed no significant group-by-paranoia interaction  and no main effect of paranoia at the previous time on the odds of being alone within 180 min later . The main effect of group was significant .Lagged analysis also showed no significant interaction of group-by-being in social company vs. alone on paranoia within 180 min later . The main effect of nature of company on concurrent paranoia was significant . In all groups, paranoid thinking was greater in company of strangers/distant relations than in company of close relations.The group-by-nature of company interaction on concurrent paranoia (X2(2) = 1.61, p = 0.44]. The main effect of group was not significant . However, the lagged main effect of nature of company on paranoia within 180 min later was significant , showing that across all groups being with close others was associated with reduced paranoia over time.The lagged analysis showed no group-by-nature of company interaction on paranoia within 180 min later  or negative affect . When in social company vs. alone all groups showed significantly higher positive  and significantly lower negative affect . There were no significant main effects of group for either positive or negative affect . Participants reported significantly higher positive  and significantly lower negative  affect in company of close vs. strangers/distant relations. Table There were no significant interactions between group and being in social company vs. alone and group and the nature of social company on positive affect [The present study is the first to investigate the associations between real-life social contact and paranoid thinking across the psychosis continuum. Our findings show that patients are most frequently alone and that being alone, compared to being with others, is associated with higher levels of concurrent paranoid thinking specifically in patients. Across all groups, social contact with familiar people was associated with lower paranoid thinking than being with less familiar people or strangers. These findings highlight the importance of social contact for mental wellbeing and relief from symptoms.In line with extensive literature on social functioning in individuals with psychosis our findings showed that patients were alone significantly more often than first-degree relatives and controls , 19, 20.Our findings suggest that patients’ tendency to be alone frequently is not entirely driven by safety behaviours, but that it may be due to other factors, such as for instance the lack of opportunity for social interaction through leisure or work. The majority of patients (79.3%) were not engaged with work (paid or voluntary) or study, compared to only 16.7% of the controls and 21.1% of the relatives. Also, individuals in the patient group were more than twice as likely to live alone compared to relatives and controls. Finally, less social contact could be the consequence of other factors that have been linked to a diagnosis of non-affective psychosis, such as poor social (cognitive) skills and theory of mind , difficuThe current data did support our hypothesis about the sensitivity to the nature of social company, i.e., social context or familiarity, in individuals with a diagnosis of non-affective psychosis. Similar to relatives and controls, patients reported more paranoia when they were in company of strangers or less familiar others, compared to familiar others. This pattern seems adaptive, given that one has to be more cautious of the intentions of less familiar people. In line with Myin-Germeys et al. , our resSocial isolation is often chronic in individuals with a psychotic disorder  and has


Stress cardiomyopathy (Takotsubo syndrome) is a reversible syndrome stemming from myocardial injury leading to systolic dysfunction and is usually noted in the setting of a stressful event, be it an emotional or physical trigger. While the exact pathophysiology behind stress cardiomyopathy is yet unknown, there is ample evidence suggesting that neurocardiogenic mechanisms may play an important role. Although historically stress cardiomyopathy was generally thought to be a relatively benign condition, there is growing recognition of the cardiovascular complications associated with it despite its reversibility. Our review aims to shed light onto key cardiovascular imaging modalities used to diagnose stress cardiomyopathy while highlighting the role that imaging plays in assessing disease severity, identifying complications, dictating treatment approaches, and in short-term and long-term prognosis. Takotsubo syndrome, also known as stress cardiomyopathy (stress CM), apical ballooning syndrome, or broken heart syndrome, is increasingly recognized as an important cause of acute reversible myocardial injury and acute systolic dysfunction . The oriStress CM was initially thought to be a relatively benign, reversible condition, but as prevalence has increased it has become apparent that it is often associated with significant morbidity and mortality . There iIn an era where the application of multimodality cardiovascular imaging has been increasing, our review will aim to highlight the diagnosis of stress CM with a particular focus on imaging.Stress CM is defined as a syndrome of transient and acute LV systolic and diastolic dysfunction usually related to a profound emotional or physical stress within the prior 5 days , 5. The Multiple diagnostic criteria have been proposed: the most commonly used are the Heart Failure Association of the European Society of Cardiology diagnostic criteria for Takotsubo Syndrome , the Int2-adrenoceptors are more frequently expressed in an apical than the basal segment of the LV, while a reverse distribution is present for norepinephrine β1-adrenoceptors and sympathetic and sympathetic nerve terminals of the neuro-cardiac axis, which are dense at the base but not the apex  with variable severity and in most cases recovers as the myocardial stunning resolves . The degLeft ventricular EF has been found to be an independent predictor of major cardiovascular complications and can help identify stress CM patients at higher risk particularly in those aged >75 years . ElderlyAssessment of LV longitudinal strain may have an important prognostic value in the acute phases of stress CM. Decreased global longitudinal strain (GLS) in patients with stress CM was found to correlate with higher in-hospital mortality .LV diastolic dysfunction is common in stress CM . Global The mechanism of MR in stress CM is not completely understood. Systolic anterior motion of the anterior mitral leaflet (SAM) has been reported in 40–50% of patients with stress CM and may be associated with significant MR  Figure . MR in sLVOTO, diagnosed by echocardiogram, may result from basal hypercontractility with or without systolic anterior motion of the anterior mitral leaflet causing dynamic obstruction of the LV outflow tract (LVOT), and is seen in as many as 12.5–25% of cases , 34. SigElectrocardiographic signs of RV strain warrant special attention with regards to evaluation of RV function in stress CM.The prevalence of RV involvement has been reported to be around 14% in one study; however, this may be an underestimation due to difficulty imaging the RV . In patiPer the updated American Society of Echocardiography guidelines (2018) and European Association of Cardiovascular Imaging (2017) guidelines, contrast echocardiography is a recommended tool to evaluate for the presence of an LV thrombus in situations where it is not detected on non-contrast echocardiography . HoweverCine CMR sequences allow for more detailed assessment of LV and RV function, ventricular wall motion abnormalities, and possible complications of stress CM , 39. WhiAdditionally, CMR allows for more quantitative assessment of RV function. RV involvement has been assessed by CMR in multiple studies: patients with RV dysfunction were older, had with longer hospital stays, had more frequent preceding stressful events, had significantly more pleural effusions, and had a lower LV EF compared to those that did not have RV involvement , 42.Recently, CMR post-processing techniques called feature/tissue tracking CMR (FT-CMR) have been developed that enable strain analysis for the quantification of myocardial deformation. A study by Stiermaier et al. evaluated 141 patients with stress CM and found that reduced global circumferential (GCS) and global longitudinal strain (GLS) were associated with the apical ballooning variant while reduced global radial strain (GRS) was associated with the basal ballooning variant . AdditioIn the setting of myocardial injury, tissue inflammation may increase resulting in localized myocardial edema . ChangesBy employing the black blood T2-weighted (fast spin echo) triple-inversion recovery (IR) sequence, fat, and flowing blood can be suppressed allowing the contrast signal to differentiate between normal myocardium and edematous tissue . This prThe pattern of edema in stress CM classically overlaps with the dysfunctional ventricular regions noted on the cine CMR sequence and does not correspond to territories served by epicardial vessels that would generally be seen in ACS . The sigIt is important to note, however, that T2-weighted triple IR can be prone to artifacts from various factors such as arrhythmias, blood pooling, or breathing motion artifact. Therefore, studies investigating techniques that use motion correction algorithms such as extracellular volume (ECV) mapping and parametric T1 or T2 mapping have shown to improve diagnostic accuracy and provide further quantitative evidence in evaluating myocardial edema , 45–47. Although the pathophysiology of myocardial inflammation in stress CM is not well-known, increased myocardial edema on imaging may indicate a direct inflammatory process from the syndrome, a secondary effect stemming from elevated sympathetic drive, or microvascular ischemia associated with stress CM , 48, 49.The use of gadolinium-mediated myocardial enhancement has been used to delineate areas of myocardial scarring or replacement fibrosis stemming from myocardial injury and inflammation. Conventionally, when using LGE to delineate areas of fibrosis in patients with a history of myocardial infarction or myocarditis, a threshold of 5 standard deviations (SDs) above the signal intensity seen in remote, unaffected tissue is used to define significant enhancement. In areas affected by myocardial infarction, the LGE pattern is generally predominant in the subendocardial tissue and can spread transmurally depending on the extent of injury, while in myocarditis the distribution tends to dominate in the sub-epicardial region (updated Lake Louise consensus criteria) . PreviouThere are various theories as to what causes the delayed enhancement, with some studies suggesting a delayed washout of contrast due to the presence of myocardial inflammation and interstitial edema. Other studies have used immune-histological evidence to show that affected areas in stress CM have increased collagen-1 which could be indicative of a fibrotic process , 53. PerWithin 1–3 min of gadolinium administration, EGE can be accessed via a high T1 inversion time. This technique is essential for the identification of LV thrombus. Thrombi are characterized by having no gadolinium uptake and are seen as a hypodense mass  in contrast to the gray myocardium. Important CMR parameters are summarized in Recent studies have reported a role for nuclear imaging findings in the diagnosis of stress CM. Single photon emission computed tomography can assess cardiac stunning using 201 Thallium or 99m Technetium-labeled radiopharmaceuticals and 123I-metalodobenzyl-guanidine (I-123 MIBG) . In addiThe evaluation of stress CM by I-123 MIBG scintigraphy demonstrates a defect in MIBG uptake at the level of the apex. Semi-quantitative measures also demonstrate a reduction in H/MR and an increase in washout . The useCardiac multi-detector computed tomography (MDCT) is a comprehensive imaging modality that is used to assess cardiac function as well as coronary artery lesions . MDCT caAlthough the hallmark of stress CM is that myocardial function returns to normal within weeks, many patients endure complications related directly to stress CM or comorbid medical conditions and can have significant morbidity and mortality in the inpatient setting .Systolic heart failure is the most common complication encountered by these patients in the acute setting, with an incidence ranging between 3 and 46% , 61, 62.Formation of an LV thrombus is a relatively rare but significant complication associated with stress CM, particularly with the apical ballooning variant. Studies have shown an incidence between 2 and 9.2% of patients –68. In tAs cardiac arrhythmias are important potential complications of stress CM that could arise in the acute setting, patients need to be monitored closely via telemetry and serial ECGs in order to evaluate for abnormal rhythms and a prolonged QT interval. Atrial fibrillation can occur in ~4.5–25% of patients and is the most common arrhythmia seen in stress CM patients –71. RareTo date, there have been no large randomized controlled trials investigating various therapies that are commonly used for the treatment of acute heart failure in stress CM. The primary goal of therapy is to address any acute complications that arise, prophylactically treat to minimize risks of certain complications such as thromboembolism, and closely follow the patient throughout the course of the disease until full recovery and/or normalization of cardiac function. In determining the course of therapy, it is important to delineate the pattern of cardiomyopathy and identify certain features such as the presence of LVOTO that may require adjustment in medication regimen .In a patient with normal cardiac output, the standard of treatment involves use of diuretics in order to achieve euvolemia and afterload reduction with arterial vasodilators  , 74. In 2+ sensitizer) as a potential alternative inotropic agent . Presenting in an unstable condition  or having other non-cardiac acute co-morbidities were also associated with a higher risk of in-hospital mortality. In analyzing long-term outcomes, some studies have shown a higher mortality in patients with stress CM compared to a general age and gender-matched population while others have shown no differences in the long term (In-hospital mortality rates for stress CM have ranged between 2 and 5% , 83–85. ong term , 88.Data on recurrence have been limited but current evidence reports a recurrence rate of around 2–4% per year and up to as high as 20% in 10 years , 88, 89.As featured comprehensively in this review, cardiovascular imaging plays a vital role in stress CM and offers many facets of benefits ranging from the initial diagnosis to long-term outcomes. Echocardiography and certain sequences in CMR enable us to differentiate between variants of stress CM, characterize severity of left ventricular dysfunction and identify prognostic features such as LVOTO, mitral regurgitation and RV involvement that often drive our course of therapy. Additionally, several CMR sequences such as feature/tissue tracking, T1/T2 mapping are useful in providing qualitative and quantitative evidence of myocardial injury and degree of inflammation on a cellular and tissue level that can then be translated into prognostic information. As we begin to understand that stress CM is not a benign condition and can often have serious complications in the acute and chronic setting similar to more common cardiac pathologies such as ACS, there is a strong call for further large scale trials in order to investigate and refine our diagnostic and therapeutic approach to this disease.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Balaenoptera physalus) song is comprised of relatively simple 20 Hz pulses produced at regular intervals. The timing of these intervals, in addition to the presence and frequency of overtones, appears to be unique to each population. The purpose of this study was to characterize Western Antarctic Peninsula fin whale song and describe temporal pattern variations in song type and occurrence. Recordings were collected in the area from 2001–2004 and again 2014–2016. One song type was identified with a primary inter-pulse interval (IPI) of approximately 14 s and secondary IPI of 12.5 s. This song occurred in three pattern variants: singlet, doublet, and long triplet. The interval between pulses increased by 1.5 s between recording periods while the frequency of the overtones decreased from 89 Hz to 86 Hz. Song was never recorded in August and while it was recorded at other times in some years, it was consistently present in recordings from April through June across all years. While multiple pattern variants were present each year, singlets were generally the most prevalent variant. Doublets and triplets occurred from February through June, with highest levels of variants in February. In later years the triplet variant presence increased and in 2016 it comprised 53% of recorded song bouts. Further research is needed to understand the reasons why song changes over time and to examine the feasibility of using song to delineate and identify populations.Song is produced by a variety of terrestrial and marine animals and is particularly common among baleen whales. Fin whale ( Auditory signals are used throughout the animal kingdom to communicate with conspecifics. Sound allows individuals to convey information across great distances and in environments with poor visibility . When thSongs can be innate or learned from conspecifics , 13. SocMegaptera novaeangliae) songs are arguably the most complex [Balaenoptera musculus) produce relatively simpler songs combining pulsed and tonal units [B. physalus) songs appear the least complex as they consist of simple pulses [Several baleen whale species produce species-specific low-frequency songs which vary in their complexity. Humpback whale  [Baleen whale song has been observed to undergo change over time. In some species, such as the humpback whale, song changes over the course of a season and these accumulated innovations can render the song entirely unrecognizable from the original within years , 25, 29.ticetus) , and finticetus) , 35. In ticetus) , 35, 36 ticetus) , 37. In Fin whale song is comprised of a series of short 1 s notes or pulses that are centered around 20 Hz and are referred to as 20 Hz pulses or 20 Hz notes , 38. TheThe highly productive waters in the Southern Ocean support large aggregations of krill, creating an important feeding ground for a variety of marine mammals and birds –45. One Fin whales typically undertake annual migrations from low-latitude breeding grounds in winter to high-latitude feeding grounds in summer , althougPassive acoustic recorders were deployed off the coast of the WAP from 2001–2003 and 2014–2016. Previous studies have analyzed seasonal fin whale acoustic presence using recordings from 2001–2003 . EarlierDuring all deployments the data were recorded with 16-bit A/D quantization. The ARPs had an effective bandwidth of 250 Hz. Deployments from 2014–2016 had higher sampling rates, resulting in an effective bandwidth of 100 kHz. These HARP recordings were decimated by a factor of 100 to create a dataset with an effective bandwidth of 1 kHz for easier review. In 2014 and 2015 recordings were duty-cycled with recording periods of 5 min out of every 6 and 10 out of 13.5 min, respectively, but data were recorded continuously in all other years .Triton [th of the month. This protocol allowed for a minimum of two whale observations per month, although if multiple song sequences were present in a given day it was not important for our analysis whether they were produced by a single or multiple animals. Data from the selected date were manually reviewed for presence of clearly identifiable fin whale songs. Identifiable song was defined as periods of fin whale 20 Hz pulses visible in 1 hour LTSA view that revealed a clear and consistent IPI pattern upon closer inspection via spectrogram. When evidence of song was found, these periods were examined using 120 s spectrograms with a frequency range of 0–150 Hz with 0.1 s time and 1 Hz frequency resolution. Periods of intense 20 Hz pulse production, when individual songs could not be identified, were excluded from analysis. For the purposes of this analysis, song was defined as periods of patterned 20 Hz pulses that persisted for two minutes or longer, in keeping with the protocol used for previous fin whale song analyses [Recordings were spectrographically visualized using the custom MATLAB  software program Triton . Long-teanalyses , 29. A sAfter a day was fully reviewed, inter-pulse intervals (IPIs) were calculated as the difference in start time between one 20 Hz pulse and the next one. Each song bout was then categorized as either a singlet, doublet, or triplet. We defined a singlet as a song containing a single, consistent IPI value. A doublet contained two distinct, alternating IPI values whereas a triplet had two distinct IPI values that can be produced in a consistent pattern of long-long-short (long triplet) or long-short-short (short triplet) . In the Each day analyzed was manually annotated to determine song type based on the distribution of IPI values. If a song contained a single-mode IPI it was considered a singlet. A song with a bimodal IPI distribution was considered a doublet or triplet based upon prevalent patterning of those IPI values. For each song variant present, the median and first and third quartile IPIs were calculated for each distinct IPI mode. IPI values were characterized by median instead of mean due to the non-normal distribution of IPI values. To determine whether IPI values changed over time, median IPI values were compared across years using a nonparametric Kruskal-Wallis test; years were compared post-hoc using the Dunn method  and adjuBased on its IPI values and associated overtone frequency, there was one fin whale song type detected in the WAP with overtones present below 90Hz. The primary ‘long’ IPI value was approximately 14 s, two seconds longer than the secondary ‘short’ IPI which was about 12 s during the latter part of the study. Singlet, doublet, and long triplet variants were all observed . We consSong was recorded in all months except August, however it was only present in all recordings from April through June (S1). Recordings from 2016 contained the only observations of song from October through December and song was only present in January on January 31, 2003. The lack of song in February 2002 and March 2001 could be due to shorter recording effort during this time. Song was present in July in 45% of recordings and in September during 30% of recordings. The singlet variant was generally the most common IPI variant throughout the year and song was most complex February through May . DoubletThe singlet variant was prevalent during 2001–2003 and 2014–2015 . Data frPrevious research of fin whale 20 Hz pulses in WAP characterized the song as a series of pulses with a duration of less than 1 s that sweep from 28 Hz down to 15 Hz  and are The IPI of the song lengthened by 0.1 s annually while overtone frequency decreased by 0.2 Hz per year. Similar changes in fin whale songs have been reported in other ocean basins , 35–37. Whales could be compensating for increasing anthropogenic noise. Baleen whales have been observed to alter calling behavior in response to changing noise conditions , 63, howIn addition to shifts in overtone frequency and IPI length, changes in song complexity were also observed. While variants were present each year of recording, there was a shift in variant occurrence. Singlet song tended to be prevalent, however in later years the proportion of triplet song variants increased, with the highest proportion occurring in 2016. Since song is presumed to serve a reproductive function , 11, it The song in this area was relatively stable within each year, with no observable change in IPI values over the course of one singing season. This contrasts with the observations of other studies, which have found some populations of fin whales change IPIs during a single year , 37, 42.When fin whales arrive in Antarctica in austral spring, September through November, song is almost entirely comprised of the singlet variant. This remains true in early summer, December and January. This tendency to favor singlets abruptly changes in February, when all three song variants appear and no one variant constitutes more than 50% of pulses. The presence of all three song variants persists through May, although singlet song returns to dominance in April. Triplet song persists in June, but by July only singlet song remains. No evidence of song was found in August. It is interesting to note that song is most complex, i.e. contains the greatest level of variants, in February while previous studies have found peaks in acoustic presence in May , 55–57.The offset between peak song complexity and peak song production suggests that the complexity of song in this time cannot be explained solely by an increased number of singers. Given this fact, and the differing seasonality trends of the three variants, it is unlikely that the three variants are the result of different individuals that sing one variant type exclusively. It appears more probable that individuals switch between variants depending on context. The mechanisms driving variant use are not yet known. Perhaps these different variants serve unique functions within the population; others have posited that intra-annual changes in song might serve the purpose of conveying changes in prey abundance or other environmental factors , 42. SeaThe song of WAP fin whales remained relatively stable over the course of this study. The decrease in song frequency by 3 Hz over 15 years, which averages a change of -0.2 Hz/year, agrees with previous reports of declining fin whale song frequency from the North Pacific and measured by the frequency of the 20 Hz pulse , 35. OthThe frequency of overtones has been used to separate different populations of Antarctic fin whales , 39. TheA migratory link between the WAP and Chilean waters has been proposed previously based on the presence of overtones at approximately 85 Hz, which matches closely the overtone observed in more recent recordings in this study , 75, 76.To better understand the migratory patterns and population structure of Antarctic fin whales, recording effort and analysis should be increased in the southern hemisphere. Further recording effort and acoustic analysis should be performed in Eastern Antarctica and Australia and New Zealand to characterize song and determine whether migratory linkages can be made. Additionally, the deployment of acoustic tags throughout the Southern Ocean on male fin whales, equipped with satellite tracking, would enable researchers to track movement and calling behavior of individual whales . In someThe use of passive acoustic monitoring methods is especially attractive in environments as challenging as Antarctica , 50. TheThe data presented here represent the first known detailed description of the WAP fin whale song. The 20 Hz pulses of this song are accompanied by overtones below 90 Hz. The primary long IPI of the song is 2 s longer than the secondary short IPI. While the song had a primary IPI of approximately 14 s and secondary IPI of 12.5 s, the IPI lengthened by 1.5 s and overtone frequency decreased by 3 Hz between 2001–2003 and 2014–2016 recording periods. Three variants of the song were recorded, with singlet song being most common. Song was most complex, i.e. contained the most variants, in early austral autumn. The song remained relatively stable over this 15-year period, which makes fin whale song an attractive tool to indicate population identity. Further research is needed to examine long-term trends in song variant preference and to observe whether IPI and overtone frequency drift persist. In addition, extending recording effort to other potential fin whale aggregations sites such as Eastern Antarctica, Chile, Australia, and New Zealand would allow for better understanding of migratory pathways in the southern hemisphere. The use of acoustic tags would allow for individual tracking and behavioral and environmental data may provide valuable clues to potential drivers of song preference. Genetic analysis of fin whales, in combination with acoustic recordings from the southern hemisphere, would allow us to test whether fin whales singing the same song can be considered a distinct population.S1 Data(XLSX)Click here for additional data file.


Aortic stenosis (AS) is characterised by a long and variable asymptomatic course. Our objective was to use cardiovascular magnetic resonance imaging (MRI) to assess progression of adverse remodeling in asymptomatic AS.Participants from the PRIMID-AS study, a prospective, multi-centre observational study of asymptomatic patients with moderate to severe AS, who remained asymptomatic at 12 months, were invited to undergo a repeat cardiac MRI.2/m2) were included. There was small but significant increase in indexed left ventricular (LV)  and left atrial volumes , with a decrease in systolic  and diastolic  function, but no overall change in LV mass or mass/volume. Late gadolinium enhancement increased  but markers of diffuse interstitial fibrosis did not change significantly . There was also a significant increase in the levels of NT-proBNP .Forty-three participants with moderate-severe AS (mean age 64.4 ± 14.8 years, 83.4% male, aortic valve area index 0.54 ± 0.15 cmThere is progression in cardiac remodeling with increasing scar burden even in asymptomatic AS. Given the lack of reversibility of LGE post-AVR and its association with long-term mortality post-AVR, this suggests the potential need for earlier intervention, before the accumulation of LGE, to improve the long-term outcomes in AS.• Current guidelines recommend waiting until symptom onset before valve replacement in severe AS.• MRI showed clear progression in cardiac remodeling over 12 months in asymptomatic patients with AS, with near doubling in LGE.• This highlights the need for potentially earlier intervention or better risk stratification in AS. Aortic stenosis (AS) is the commonest valve lesion requiring surgery in the developed world, with increasing prevalence with ageing populations . It is cCardiovascular magnetic resonance imaging (MRI) has provided valuable insights into the remodeling patterns in AS . SeveralStudying the changes in remodeling at an earlier stage of disease may provide important insights into the pathophysiology of disease progression . The aim2, peak pressure gradient > 36 mmHg, or mean pressure gradient > 25 mmHg), asymptomatic, and ability to perform bicycle exercise test. Exclusion criteria were absolute contraindications to MRI/adenosine/contrast, previous cardiac surgery, left ventricular ejection fraction (LVEF) < 40%, persistent atrial flutter/fibrillation, other severe valve disease, previous heart failure, planned AVR or comorbidity limiting life expectancy, or precluding AVR. Those who remained asymptomatic at 12 months on clinical review and direct questioning were invited for a repeat MRI and blood sampling. The UK national research ethics service approved the study (11/EM/0410) and written informed consent was obtained from all participants.Asymptomatic patients with moderate to severe AS were recruited as part of the multi-centre, prospective ‘PRognostic Importance of MIcrovascular Dysfunction in asymptomatic patients with AS’ (PRIMID-AS) study between April 2012 and October 2013 , 13. TheA trans-thoracic echocardiogram was performed at baseline by an accredited sonographer according to international guidelines . All imacvi42 version 5 (Circle Cardiovascular Imaging). Papillary muscles were excluded from the myocardial mass. LGE was quantified using > 5SD above the mean signal intensity of normal myocardium [Patients underwent comprehensive multi-parametric 3T cardiac stress MRI including long- and short-axis cine, pre- and post-contrast T1 mapping, adenosine stress first-pass perfusion imaging, and LGE, at baseline and 12 months, using identical imaging protocol, as previously described . T1 mappocardium . ECV wasocardium  using haocardium . To accoocardium . MPR wasocardium .Qualitative LGE assessment was performed by 2 assessors  and non-infarct pattern LGE was graded as 0 = no enhancement, 1 = mild insertion point enhancement, 2 = subtle enhancement in 1 region outside insertion point, 3 = bright scar in 1 region/diffuse enhancement in multiple regions, and 4 = clear scar in multiple regions  was measured using our in-house non-competitive assay that employs the quantitative sandwich enzyme immunoassay technique, and has excellent correlation with the Roche Elecsys assay.Blood samples were collected in EDTA tubes and centrifuged within 4 h at 2000p < 0.05 considered statistically significant. Normally distributed data are expressed as mean ± standard deviation. Non-parametric data are expressed as median (interquartile range). Continuous variables were compared between baseline and follow-up visit using paired sample t tests or the Wilcoxon signed-rank test. McNemar test was used for categorical variables. Linear regression was used to explore the univariate associations of baseline MRI parameters/echocardiographic Doppler data/ NTproBNP levels with absolute change in the LV remodeling parameters: LV end-diastolic volume index (LVEDVI), LV mass index (LVMI), LV mass/volume, LVEF, left atrial volume index (LAVI) and LGE.Statistical analysis was performed using SPSS 24.0 software , with 2/m2. Bicuspid morphology was present in 40%.Forty-three subjects  were included (Table p = 0.05). These were associated with a small but significant decrease in LV and RV EF, albeit remaining within the normal range. The longitudinal peak diastolic strain rate also decreased significantly. There was a borderline significant increase in LVMI (p = 0.058) but no significant change in LV mass/volume.There was no significant change in patients’ weight, blood pressure, or heart rate between baseline and follow-up. MRI data is shown in Table n = 1), the qualitative grade of LGE increased in 39%  , and decreased by one grade in 3 patients . The total amount of LGE(g) doubled over 12 months. There was no significant change in the measures of diffuse interstitial fibrosis: ECV or iECV. There was a decrease in stress and rest MBF, but no change in the MPR.Significant non-infarct pattern LGE  was present in 11 patients at baseline, and 20 at follow-up, with subendocardial infarction in an additional 9 patients at both visits and no new infarctions at follow-up. Excluding those with infarct pattern LGE and with missing follow-up LGE imaging .There was a significant increase in levels of NT-proBNP at 12 months  was present in 36% of all patients at baseline and increased to 57% at 12 months. A recent meta-analysis showed LGE to be present in 49.6% of patients with AS . LGE is Baseline LGE was positively associated with change in LGE, which is similar to the previous finding of LGE progressing fastest in those with more LGE at baseline . CoronarBoth rest and stress MBF decreased, but there was no change in MPR. MBF is quantified per gram of myocardium, and therefore, this most likely represents an increase in non-metabolically active fibrotic burden within the myocardium. In this asymptomatic cohort, with exclusion of those who develop symptoms, perfusion falls but remains balanced. Combined with the findings of MPR being a predictor of symptom onset in the original PRIMID study, this suggests that a separation of the rates of decline in rest and stress MBF may be a key step in symptom onset in AS. This hypothesis will of course need to be tested in a separate and larger cohort.Our data highlights the potential need for earlier intervention or development of anti-fibrotic therapy to optimise long-term outcomes in AS. Recent data suggests the non-inferiority of TAVR in lower risk (but still symptomatic severe) AS , 27. TheThese patients were a subset of those who remained asymptomatic and were not referred for surgery, and comprise a relatively small cohort, although poorly studied previously. T1 mapping data was not available in all patients, and only measured on a single mid-ventricular slice, whilst LGE was measured using a full short-axis stack. Lack of repeat echocardiography for assessment of AS severity at follow-up is another limitation. However, planimetry AVA on CMR has been shown to be a reliable and reproducible technique, with close agreement with AVA on transoesophageal imaging and AS severity on cardiac catheterisation –30.Asymptomatic patients with moderate to severe AS demonstrate unequivocal progression in adverse cardiac remodeling within 12 months, with a significant increase in focal myocardial fibrosis. Further studies are required to determine whether earlier intervention in asymptomatic AS is associated with improved long-term outcomes.