The clinical implication of new-onset left bundle branch block (LBBB) after transcatheter aortic valve replacement (TAVR) remains controversial. We investigated the impact of new-onset persistent LBBB on reverse cardiac remodeling and clinical outcomes after TAVR.Among 478 patients who had undergone TAVR for symptomatic severe aortic stenosis from 2011 to 2021, we analyzed 364 patients after excluding patients with pre-existing intraventricular conduction disturbance or a pacing rhythm before or during the indexed hospitalization for TAVR. Echocardiographic variables of cardiac remodeling at baseline and 1 year after TAVR were comprehensively analyzed. The primary outcome was a composite of cardiovascular death and hospitalization for heart failure. Secondary outcomes were all-cause death and individual components of the primary outcome.p < 0.001). However, the new LBBB group showed no significant changes in these parameters. During a median follow-up of 18.1 months, the new LBBB group experienced a higher incidence of primary outcomes  and all-cause death . The data were similar after multivariable regression analysis.New-onset persistent LBBB occurred in 41 (11.3%) patients after TAVR. The no LBBB group showed a significant increase in the left ventricular (LV) ejection fraction and decreases in LV dimensions, the left atrial volume index, and LV mass index 1 year after TAVR (all New-onset persistent LBBB after TAVR is associated with insufficient reverse cardiac remodeling and increased adverse clinical events. Transcatheter aortic valve replacement (TAVR) is an effective alternative to surgical aortic valve replacement (SAVR) for symptomatic severe aortic stenosis (AS) in patients with high, intermediate, or low surgical risk –5. Howevn = 77)  before TAVR and patients who had received permanent pacemaker implantation before or during the index hospitalization for TAVR (n = 34). There was no patient with previously implanted intracardiac cardioverter-defibrillator or cardiac resynchronization therapy. The present study also excluded three patients who did not survive immediately after TAVR. Thus, 364 patients were included in the final analysis in this study.A total of 478 consecutive patients who had undergone TAVR for symptomatic severe AS at Severance Cardiovascular Hospital from June 2011 to May 2021 were retrospectively reviewed. We excluded patients with pre-existing intraventricular conduction disturbances  and the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score , 12. TheLBBB was defined as a QRS duration > 120 ms, delayed onset of intrinsicoid deflection in leads V5 and V6, broad monophasic R waves that are usually notched in leads I, V5 and V6, and secondary ST- and T-wave changes opposite in direction to the major QRS deflection . In thisAll echocardiographic studies were performed using commercially available equipment and were reviewed by imaging cardiologists without knowledge of the clinical data. Standard measurements were performed according to current guidelines . LV EF wThe primary outcome was a composite of cardiovascular death or hospitalization for heart failure. Secondary outcomes included all-cause death, cardiovascular death, hospitalization for heart failure, number of hospitalizations for heart failure event, and permanent pacemaker implantation. All clinical outcomes were analyzed according to the Valve Academic Research Consortium-3 consensus .t-test or the Wilcoxon rank-sum test. Time-to-event variables were presented as Kaplan-Meier event rates and were compared using the log-rank test. The total number of hospitalizations for heart failure was calculated and compared using Poisson regression. Multivariable analysis for clinical outcomes was performed using a multivariable Cox proportional hazard regression model. The covariates included in the adjusted models were variables with clinical relevance, such as age, sex, New York Heart failure Association (NYHA) functional class, comorbidities such as chronic lung disease, end-stage renal disease, coronary artery disease, peripheral artery disease, prior cardiac surgery, atrial fibrillation, EuroSCORE II, STS-PROM score, baseline LV EF, RV systolic dysfunction, pulmonary artery systolic pressure and moderate or severe paravalvular regurgitation. The baseline and 1-year echocardiographic parameters were compared using paired t-test or the Wilcoxon signed-rank test as appropriate. Two-way repeated ANOVA was used to determine differences between the baseline and 1-year echocardiographic parameters according to the study groups. Missing data of 1-year echocardiographic data was not imputated. As sensitivity analysis, baseline and 1-year echocardiographic data was compared with multiple imputation of missing data. All the tests were two-tailed, and p-values <0.05 were considered statistically significant. All statistical analyses were performed using R version 4.1.0 .Categorical variables were presented as numbers (percentages) and were compared using chi-squared test or Fisher's exact test. Continuous variables were presented as means ± standard deviation and compared using Student's Of the 364 patients, 41 (11.3%) had new-onset persistent LBBB after TAVR. The baseline clinical characteristics are shown in p = 0.018), a larger LV end-diastolic dimension  and end-systolic dimension , and higher E/e′  than the no LBBB group.The echocardiographic characteristics are summarized in p < 0.001; p = 0.038) at the 1-year follow-up and no significant changes in the LV end-systolic dimension, LV mass index, and LA volume index. The sensitivity analysis with multiple imputation for 1-year echocardiographic data showed similar results (p = 0.408), whereas the no LBBB group showed significant LV EF improvement  1 year after TAVR. However, in patients with a preserved LV EF (>50%), the new LBBB group showed a significantly decreased LV EF  from the baseline while the no LBBB group had a similar LV EF  after TAVR  volume index . The new LBBB group had a higher risk of all-cause death , individual events of cardiovascular death , and hospitalization for heart failure . Furthermore, the new LBBB group had more hospitalizations for heart failure  and PPM implantation than the no LBBB group . There was no post-procedural CRT implantation. After multivariable adjustment, the patients with new-onset LBBB still had a significantly higher risk for adverse clinical outcomes, with the exception of PPM implantation. In Cox multivariate regression analysis, new-onset persistent LBBB, end-stage renal disease, atrial fibrillation, and prior caridac surgery were identified as independent predictors for the composite events of cardiovascular death and hospitalization for heart failure (Patients were followed for a median of 18.1 months (interquartile range: 7.7–30.1). All the clinical outcomes after TAVR and hazard ratios for the adverse clinical events are described in  failure .The major findings of the present study were as follows: 1) new-onset persistent LBBB occurred in 11.3% of patients without significant baseline conduction disturbances; 2) new-onset LBBB was associated with insufficient reverse cardiac remodeling and decline in the LV EF 1 year after TAVR; 3) new-onset LBBB was associated with increased occurrence of hospitalization for heart failure, cardiovascular death, and all-cause death.The incidence of new-onset LBBB in previous studies varies widely because of differences in the inclusion of transient LBBB, timing of measurement, and type of transcatheter valve . GeneralLBBB is associated with a shortening of LV diastole, abnormal septal motion with an associated decrease in the regional ejection fraction and an overall reduction in the global LV ejection fraction . LBBB fuBecause concentric LV hypertrophy and reduced contractility is the main cardiac manifestation derived from pressure overload, the reversal of cardiac remodeling is a critical therapeutic target in patients with severe AS . HoweverLBBB is a significant risk factor for both cardiovascular and all-cause mortality in patients with various cardiovascular diseases . HouthuiThis study has several limitations. First, this study was a single-center retrospective study, which has inherent limitations. Second, the number of subjects with new LBBB was too small for detailed subgroup analysis. Third, this study included subjects with an advanced age and at variable surgical risk, possibly limiting the generalization of our study results to younger patients, who are at a lower surgical risk. Finally, 1-year follow-up echocardiography data were not available for all patients due to the early occurrence of clinical outcomes and the advanced age of the study population. However, we performed the multiple imputation for missing 1-year echocardiographic data and found similar results with main findings.New-onset persistent LBBB following TAVR is associated with insufficient reverse cardiac remodeling and increased adverse clinical events such as all-cause death, cardiovascular death, and hospitalization for heart failure.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Severance Hospital, Yonsei University College of Medicine. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.KK and Y-GK contributed to the conception and design of the work. KK, Y-GK, and CS drafted the manuscript. JR, Y-JL, JS, S-JL, IC, S-JH, C-MA, J-SK, B-KK, and G-RH assisted in data collection and analysis. J-WH, DC, and M-KH contributed to the review and revision of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Excessive trabeculation, often referred to as “noncompacted” myocardium, has been described at all ages, from the fetus to the adult. Current evidence for myocardial development, however, does not support the formation of compact myocardium from noncompacted myocardium, nor the arrest of this process to result in so-called noncompaction. Excessive trabeculation is frequently observed by imaging studies in healthy individuals, as well as in association with pregnancy, athletic activity, and with cardiac diseases of inherited, acquired, developmental, or congenital origins. Adults with incidentally noted excessive trabeculation frequently require no further follow-up based on trabecular pattern alone. Patients with cardiomyopathy and excessive trabeculation are managed by cardiovascular symptoms rather than the trabecular pattern. To date, the prognostic role of excessive trabeculation in adults has not been shown to be independent of other myocardial disease. In neonates and children with excessive trabeculation and normal or abnormal function, clinical caution seems warranted because of the reported association with genetic and neuromuscular disorders. This report summarizes the evidence concerning the etiology, pathophysiology, and clinical relevance of excessive trabeculation. Gaps in current knowledge of the clinical relevance of excessive trabeculation are indicated, with priorities suggested for future research and improved diagnosis in adults and children.  •Current evidence shows that the extent of trabeculated vs compact myocardium in the adult is determined by differential  growth of each myocardial layer. Because trabeculated myocardium does not coalesce to form the compact myocardial wall, the term “left ventricular noncompaction” is inaccurate and use should be discouraged.•Excessive trabeculation, as diagnosed using existing criteria, may be present as a normal variant or as a response to preload conditions.•In adults incidentally found to have excessive trabeculation with normal myocardial function and morphology, clinical management is determined by other cardiovascular symptoms or abnormalities, without regard to trabecular pattern.•In adults diagnosed with hypertrophic or dilated cardiomyopathy where excessive trabeculation is also present, the extent of ventricular trabeculation has not been demonstrated to alter management nor prognosis. Following guidelines developed specifically for those conditions is recommended.•In infants and children, caution is warranted because fewer data are available regarding the etiology and prognosis of excessive trabeculation. Clinical evaluation for occult neuromuscular disease or another genetic/metabolic etiology may be appropriate. Loci associated with lower fractal dimension conferred higher risk of dilated cardiomyopathy and heart failure in both observational and Mendelian randomization analyses. This suggests a potential role of normal trabecular structure in maintaining cardiac output, or alternatively, that observed associations with certain genetic forms of cardiomyopathy and excessive trabeculation may be mediated by the roles that these genes have in development.In the community-based UK Biobank CMR study, left ventricular trabeculation measured in fractal dimension was observed to have ∼20% heritability.For patients in whom so-called noncompaction is diagnosed, causative genetic sequence variations are reported in approximately one-third of individuals, although these estimates are confounded by inclusion bias. Such biases include patient age, family screening, heterogeneity in case ascertainment, variability in content and size of genetic screening panels, and inconsistent interpretation of the pathogenicity of genetic variants.,,,Gene sequence variation associated with so-called noncompaction were recently evaluated in several systematic reviews.,MYH7, MYBPC3, ACTC1, and TTN represented just over two-fifths of the identified sequence variations.MYH7, ACTN2, and PRDM16 were detected in some cases, but such truncating variants have not been identified as causes of more specific cardiomyopathies, suggesting that they may associate more specifically with excessive trabeculation.PRDM16 has been shown to be crucial for normal mural development in mouse models.In 2 of these recent systematic reviews,Due to the aforementioned considerations, contemporary guidelines advocate genetic testing according to the presence of the features of a conventional cardiomyopathy,,,,Excessive trabeculation has been observed in several neuromuscular disorders, including specific genetically determined conditions such as Barth syndrome,,,A retrospective analysis of CMR scans of another large cohort with Duchenne muscular dystrophy showed almost 30% of patients had excessive trabeculation in at least 1 cardiac segment when using Petersen criteria.Reversible excessive trabeculation is known to develop secondarily to increased preload in a sizeable proportion of individuals who are pregnant with otherwise normal hearts. The feature had usually resolved by 12 weeks subsequent to delivery, although with some variability in the regression of the trabecular layer, this being similar to the variation in the reduction of the overall left ventricular mass.,A reversible phenotype of excessive trabeculation has been reported in athletes. This is recognized as a morphologic epiphenomenon related to high cardiac preload demand associated with intensive physical exercise.In a younger (mean age 48 years), community-based cohort of physically active participants involved in the PESA  study, which objectively measured vigorous recreational physical activity, was associated with higher prevalence of isolated excessive trabeculation. This was double in those making up the highest quintile achieving vigorous physical activity compared to those with no vigorous physical activity.At the levels of physical activity reported by individuals who were nonathletic making up the community-based UK Biobank study, there was no evidence to suggest a dose-response relationship between physical activity intensity and the extent of left ventricular trabeculation.Excessive trabeculation has been described in up to one-sixth of patients with β-thalassemia, raising the issue of a differential diagnosis between cardiomyopathy with excessive trabeculation and thalassemic cardiomyopathy.,Chemotherapy-related cardiac dysfunction is now also emerging as being potentially associated with excessive trabeculation.Ultimately, in patients with hemoglobinopathies and other chronic hematologic disorders, the finding of excessive trabeculation should be interpreted as an adaptive response to increased cardiac preload.A number of reports have described a possible association between polycystic kidney disease and a cardiomyopathy said to be caused by excessive trabeculation.Arrhythmias are common in heart failure, in part because of coexistent myocardial fibrosis.,,There are numerous reports on presence of thrombus in the trabecular layer of patients with cardiomyopathy.,,,,Trabeculations have also been suggested to reduce the compliance of the ventricular wall,Zemrak et al,,,Multiple studies have identified the presence of left ventricular dysfunction as the principal mediator for adverse outcomes in the presence of excessive trabeculation.,Few studies have compared the prognosis for patients with cardiomyopathy and excessive trabeculation to that of other nonischemic cardiomyopathies. Among patients with dilated cardiomyopathy, the extent of trabeculation did not influence event-free survival in either unadjusted or adjusted models.The bulk of current evidence suggests that the phenotypic feature of excessive trabeculation has no independent prognostic relevance in otherwise healthy individuals with no clinical suspicion of inherited cardiac conditions or symptoms. In patients with excessive trabeculation and a known cardiomyopathy, in contrast, the risk for major adverse clinical events appears to be associated with the latter and is apparently independent of the coexisting trabeculation  and 2. ILike adults, children with normal ventricular size and function may have excessive trabeculations, frequently representing a normal variant. Congenital heart defects, such as Ebstein malformation and isomerism of the atrial appendages, may coexist with excessive trabeculation and complicate the picture.Using echocardiography, the prevalence of excessive trabeculation fulfilling the criterion for recognition as a potential cardiomyopathy among competitive athletes ranges from around 1%Among athletes, excessive trabeculation is of concern in individuals who have either left ventricular systolic dysfunction or dilation, cardiac symptoms, or abnormal electrocardiographic findings unrelated to training . Alterna,,,Athletes with symptoms, abnormal electrocardiographic findings, or a family history of cardiomyopathy should undergo cardiopulmonary exercise testing, Holter monitoring, and CMR.Controversies remain regarding the clinical significance of excessive trabeculation in both adults and children. For adults, patients who are asymptomatic with excessive trabeculation but normal ventricular function and normal chamber size appear to require little or no long-term follow-up unless other clinical concerns exist, such as family history or electrocardiogram abnormalities. No prospective cohort or registry data are currently available to validate this approach over a 5- or 10-year period. Ongoing collection of outcomes and covariates  in large studies such as UK Biobank may prove beneficial to understanding the independent physiologic impact of excessive trabeculation in these otherwise healthy individuals.For adults with cardiomyopathies combined with excessive trabeculation, questions remain regarding the implications of the trabecular phenotype. As diagnostic and genetic testing has become more sophisticated, the underlying etiology of these and other cases of cardiomyopathy will increasingly be understood. This may result in an ability to make more specific etiologic diagnoses as opposed to a general statement of cardiomyopathy with excessive trabeculation. Large, multi-institutional databases of patients with cardiomyopathy and excessive trabeculation would allow tracking of long-term outcomes, final diagnoses, and potential treatments. Further research to determine whether cardiomyopathy with excessive trabeculation have a different natural history compared to dilated cardiomyopathy without excessive trabeculation may be desirable. Such studies require careful statistical adjustment for confounders, thus increasing complexity.For neonates, children, and adolescents, the research focus is somewhat different. Longitudinal studies of the early development of the myocardium may shed light on the origin of varying phenotypes. Severe malformations of the trabecular layer, poorly developed left ventricular papillary muscles, along with frequent congenital heart disease and sudden death have been suggested as a distinct cardiomyopathy in neonates and young children.This review summarizes the evidence and uncertainties regarding the phenotypic feature of excessive trabeculation and its potential associations with cardiomyopathies . BecauseDr Petersen has received support from the National Institute for Health and Care Research Barts Biomedical Research Centre; and has consulted with Circle Cardiovascular Imaging Inc. Dr Friedrich has received support from the McGill Health Centre Foundation; has served as an advisor to and is a shareholder of Circle Cardiovascular Imaging Inc; and is a founder and shareholder of Area19 Medical Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Myocarditis is an acute or chronic inflammatory reaction of the heart muscle frequently associated with viral infections and post-viral immune-mediated responses. Recently the SARS-CoV-2 virus has been identified as a cause of myocarditis in COVID-19 patients. The role of cardiac MRI in such patients hence has become a subject of concern. Thus, we present a case of post-COVID-19 myocarditis where cardiac MRI was helpful in establishing the diagnosis. Myocarditis is an acute or chronic inflammatory reaction of the heart muscle that can be elicited by a multitude of viral, immune-mediated, or toxic factors A female patient aged 45 years presented to our emergency department with complaints of acute chest pain, dyspnea, palpitation, and arrhythmia in the form of ventricular tachycardia. Her routine tests showed electrocardiographic changes with increased troponin and C-reactive protein levels. Given the possibility of having coronary artery disease based on her clinical scenario, she underwent CT coronary angiography which revealed normal coronary arteries with no evidence of thrombosis or occlusion. She revealed she had recently been diagnosed with COVID-19 two weeks prior. Therefore, the patient was referred for a CMR to look for other possible causes of her cardiac symptoms.Cardiac MRI with contrast was performed for the patient on a 3Tesla platform. The CMR sequences of transverse black blood and bright blood images, vertical long axis, four-chamber, short-axis cine images, left ventricular outflow tract (LVOT) views along with three-chamber cine images were obtained. The short-tau inversion recovery (STIR) images were obtained from the base to the apex of the heart in the short axis. The delayed gadolinium enhancement phase-sensitive inversion recovery (PSIR) sequences were also obtained in short axis, four-chamber, and vertical long-axis views. The imaging findings showed a reduced left ventricular ejection fraction (LVEF) of 38% with hypokinetic anterior and anteroseptal segments of the basal and mid cavity. STIR images showed high signal intensity in the above-mentioned segments suggestive of edematous changes. The corresponding segments of the basal and mid cavity depicted subepicardial delayed gadolinium enhancement (DGE) in the post-contrast study . Mild miMyocarditis- a nonischemic inflammatory disease of the myocardium, is frequently associated with viral infections and post-viral immune-mediated responses Post COVID myocarditis may show either localized or diffuse edematous changes which is a characteristic feature signifying inflammation. The myocardial edema on CMR is seen as a high T2 signal intensity or a global or localized increase in cardiac T2 relaxation time where T2 hyperintensity essentially indicates increased tissue water Myocardial injury is a cardinal feature of myocarditis and LGE imaging is considered among the most essential MRI sequences in the possible myocarditis. The injured or damaged myocardial tissue appears as a hyperintense area in the post contrast images representing the retention of contrast agents. Furthermore, the DGE sequence is also a reliable and useful marker to indicate the fatality associated with myocarditis Both of those CMR findings of myocardial edema and DGE with accompanied T2 hyperintensity were present in our case along with the associated ancillary features such as minimal pericardial effusion and minimal to moderate pleural effusion. CMR in post-COVID-19 patients may reveal a high incidence of diffuse myocardial edema, with a regional increase of T1 and T2 mapping values. However, the overall CMR characteristic features of myocarditis in post-COVID-19 patients and non-COVID-19 individuals may resemble following the globally recognized Lake Louis Criteria Regarding the clinical management of COVID-19-related myocarditis, studies are yet inconclusive to follow a regular treatment option in particular. Nevertheless, intravenous immunoglobulins (IVIG) and corticosteroids in combination have been widely used with an effective outcome so far In conclusion, CMR is a recommended promising tool to address various challenges in the diagnosis of myocarditis and also in post-COVID-19 associated acute myocarditis. Moreover, CMR enables the noninvasive diagnosis of myocarditis providing an excellent diagnostic accuracy with improved acquisition protocol together with the introduction of advanced mapping techniques.Please specify the contribution of each author to the paper, e.g. study design, data collections, data, analysis, writing, others, who have contributed in other ways should be listed as contributors.Dr. Nirmal Prasad Neupane- study design and analysis, Dr. Kritisha Rajlawot – manuscript preparation, Dr. Chandramani Adhikari – manuscript preparation, Dr. Devraj Kandel – Figure collection and preparation, Dr. Irfa Mustafa – Figure collection and preparation.


Heart failure is a clinical syndrome with a complex pathophysiology, multiple comorbidities, frequent decompensation, and hospitalizations. It is associated with significant morbidity and mortality, which implies high costs.This Research Topic presents cardiac imaging novelties in the field of heart failure with the aim of improving management strategies.Heart failure with preserved ejection fraction (HFpEF) is a challenging, incompletely elucidated disease with multiple etiologies and comorbidities. The numerous ongoing studies could help improve the management of this variable population. Cardiovascular imaging, especially echocardiography, plays an important role in this disease, as it represents the first-line imaging modality for diagnosis, stratification, and therapeutic protocols.Del Torto et al. shows the importance of advanced multimodality cardiovascular imaging  for screening and detection of different etiologies in patients with HFpEF. With echocardiography, we assess systolic function and diastolic function of the left ventricle (LV) , as well as additional measures like the velocities in the pulmonary veins and global longitudinal strain (GLS) with speckle tracking echocardiography (STE). CMR is the gold standard for measuring the volume, wall thickness, mass, and ejection fraction for the left and right ventricles. With cardiac CT, on top of coronary anatomy assessment, we can detect valvular calcifications, and assess LV function and the presence and extension of epicardial adipose tissue. Exercise diastolic stress test echocardiography is very important for the assessment of myocardial viability and is recommended to confirm HFpEF in patients with exertional dyspnea. The most studied parameters are mitral E/e' ratio (≥15) and the tricuspid regurgitation velocity (>2.3 m/s), which can indicate an increase in the mean pulmonary capillary wedge pressure (mPCWP) and pulmonary artery systolic pressure (sPAP).The study by Verwerft et al. presents additional echocardiographic parameters for the exercise diastolic stress test, such as peak exercise septal systolic velocity (exercise S' < 9.5 cm/s), which was the best echocardiographic parameter associated with elevated exercise pulmonary artery wedge pressure (PAWP), and mean pulmonary arterial pressure/cardiac output slope (mPAP/CO ≥ 3.2 mmHg/L). A total of 22 patients were included in this study, among which 14 patients presented a value of exPAWP ≥ 25 mmHg. Although invasive hemodynamic exercise testing with the measurement of PAWP is considered the gold standard to rule in or out patients with HFpEF, it is not used much in daily clinical practice because of the limited expertise and the invasive approach of the method. In addition to this problem, the authors wanted to identify additional non-invasive echocardiographic markers for elevated PAWP because of lacking standardized methods when diagnosing HFpEF non-invasively.The study by Wang, Mu et al. introduced a novel echocardiography index based on 3D and tissue Doppler echocardiography for diagnosing and estimating prognosis in HFpEF. This non-invasive index is SVI/S' and is calculated by the ratio between stroke volume indexed by the body surface area (SVI) and tissue Doppler mitral annulus systolic peak velocity (S'). The authors enrolled 104 symptomatic patients with HFpEF who underwent right heart catheterization (RHC). Based on the RHC results, the patients were divided into a HFpEF group (PCWP ≥ 15 mmHg) and non-HFpEF group (PCWP < 15 mmHg) according to the standard cut-off for HFpEF diagnosis. The patients who had a PCWP ≥ 15 mmHg had a low SVI/S' index and showed a poorer prognosis. Also, the non-invasive SVI/S' index was associated with high PCWP measured invasively.Another possible additional assessment of HFpEF patients is by 3D echocardiography. Acute heart failure (AHF) is a life-threatening event that needs a prompt reaction, requiring urgent hospitalization and emergency treatment .Izumo shows the value of transthoracic echocardiography (TTE) in patients with AHF, underlining the fact that it is crucial to determine the etiology. The most used parameter is of course the LV ejection fraction, which reflects the cardiac function and is a valuable diagnostic and prognostic tool. Other relevant parameters are the E/A ratio (a ratio ≥2 indicates elevated LV filling pressures), the E/e' ratio (≥13) by tissue Doppler, the velocity of the tricuspid flow (≥2.8 m/s), and the measurement of the velocity time integral (VTI) in the LVOT tract for the estimation of SV and cardiac output. Also, recent studies have shown that lung ultrasound plays a key role when assessing patients with dyspnea and shock, and that we need to use this tool in addition to TTE.The review by Mazzola et al. included 86 patients with AHF, 31 cases with and 55 cases without concomitant pneumonia, a common association in the acute setting, especially in older patients. Pneumonia can be both a trigger factor or a following complication of AHF and is associated with high in-hospital mortality. The purpose of this study was to assess B-lines with the help of pulmonary ultrasound using an anterolateral and a posterior approach. The evaluation was realized at admission, after 24, 48 h, and before discharge. Lung ultrasound is non-invasive, rapid, provides high specificity and sensibility, and can even detect residual, subclinical pulmonary congestion at discharge which is proven to predict adverse outcomes. The results showed that only the assessment of the anterolateral B-lines is sufficient for monitoring pulmonary congestion when making a diagnosis, and also for prognostic stratification purposes, because the study showed that they can predict rehospitalization in patients with and without concomitant pneumonia.The study by Hedwig et al. focus on the assessment of myocardial work, a novel STE-derived parameter, in patients with advanced HF. The study included 105 patients, all evaluated with the help of echocardiography among whom only 94 underwent cardiopulmonary exercise testing. The test was realized on a bicycle ergometer, including the measurement of peak oxygen uptake (peak VO2) and ventilation-carbon dioxide output relation (VE/VCO2) slope, and was stopped only if the patients were exhausted, had angina or significant ECG changes (ST-segment depression), or if the maximum physical capacity was reached. The calculated parameters by STE were the global work index (GWI) and global constructive work (GCW). The results showed that a value of GWI ≤ 455 mmHg% or a GCW ≤ 530 mmHg% was a powerful predictor of outcome in patients with advanced HF.Ye et al. focuses on patients with HCM and ventricular arrhythmias, evaluating the role of late gadolinium enhancement (LGE)-CMR. The study included 68 patients with HCM who were grouped into two categories: 31 cases with and 37 cases without demonstrated ventricular arrhythmias. The parameters used for assessment were the LV EF, maximal WT, the diameter of the LA, and %LGE measured by standard volumetric methods. All these parameters were associated with a high development of ventricular arrhythmias events. The authors used a novel marker named scar entropy which has been proven to predict adverse cardiac events and all-cause mortality with the possibility to identify arrhythmogenic scars. These findings might be helpful in the future for risk stratification in HCM.Hypertrophic Cardiomyopathy (HCM) is the most common genetic heart disease, often asymptomatic and benign, with mutations in genes encoding sarcomere proteins, characterized by increased wall thickness . The review of Valdés et al. is LV myocardial strain assessed by CMR imaging techniques. The parameters of LV myocardial strain  were analyzed with the feature tracking (FT) method. The fast strain-encoded (fSENC) method was also used but only for GLS and GCS. The results showed that gender had a strong impact on the strain values derived from FT and fSENC, being more predominant in women than men, while the impact of age on strain is still an inconclusive problem. Another important influence on strain is that of temporal resolution, which is affected by heart rate and the number of cardiac phases. Patients with HCM had lower values of global strain because these values decreased with the increase in cardiac mass, and cut-off values were calculated to help discriminate between healthy and HCM patients.The center of interest for Amyloidosis is a systemic disease characterized by amyloid fibrils deposition in the extracellular space. Cardiac involvement is the first cause of mortality and morbidity in these patients, and death usually occurs due to electromechanical dissociation or ventricular arrhythmias. There are several types of cardiac amyloidosis, but the most frequent are the primary amyloid light-chain (AL) amyloidosis, and the transthyretin (ATTR) amyloidosis (either variant due to recognized transthyretin gene mutation or wild-type). Many studies have approached this subject, seeking the optimal treatment and management of these patients.Razvi et al. made a review of current imaging techniques in amyloidosis . Echocardiography is the first-line imaging modality for assessment. The typical features are increased LV WT or biventricular implication, thickening of the valves and the interatrial septum, left atrium enlargement, a “speckled” appearance of the myocardium, diastolic dysfunction, and STE “apical sparing”. CMR offers an accurate morphological and functional evaluation, with a detailed myocardial tissue characterization; the latter feature can be obtained without contrast, thanks to the T1 mapping sequence, or after gadolinium-based contrast administration, with LGE sequence (considered the non-invasive gold standard for diagnosis) and with extracellular volume (ECV) estimation. Bone scintigraphy with the use of Tc-99 m pyrophosphate (PYP) has high positive predictive value and specificity, and it is used for additional information in ATTR. All three imaging techniques are useful and important and should be integrated from diagnosis to treatment response monitoring.Anderson-Fabry disease is an X-linked lysosomal disorder, caused by a lack or a deficit of the enzyme α-galactosidase A (GLA gene). This disease affects the cardiovascular, renal, and nervous systems, and due to the X-linked transmission, men are usually the most affected. The typical signs and symptoms are anhidrosis/hypohidrosis, angiokeratoma, proteinuria, chronic kidney disease, corneal deposits, and gastrointestinal and cerebrovascular problems. The involvement of the cardiovascular system represents the main cause of death, with the majority being sudden cardiac death events, so it is crucial to make an early diagnosis.Citro et al. focuses on this disease by selecting patients from daily hospital practices presenting to the echocardiographic laboratory because of LV hypertrophy and “clinical red flags” . This study was realized in a metropolitan area unexplored before and 30 patients were chosen by specific criteria. Among these patients, three of them (10%) were diagnosed with this disease, and another five were discovered with the help of familiar genetic screening. The interesting finding of this study is that the authors found a completely new mutation gene (mutation c.388A > G (p.Lys130Glu) in exon 3 of the GLA gene) causing a classical phenotype.The study by Left Ventricle Non-Compaction (LVNC) is a genetic disorder defined by excessive trabeculations and deep recesses in the left ventricle. This disease is complex, with numerous mutations in genes encoding cardiac sarcomere proteins. It is associated with LV dilatation and systolic dysfunction and sometimes the right ventricle is also involved.Nemes et al. aims to evaluate by 3D STE the functional and morphological abnormalities of the tricuspid valve annulus in patients with LVNC without right ventricular implication. A total of 21 patients were enrolled, but unfortunately, six of them were excluded because of inferior image quality. The 15 remaining patients were evaluated by a complete and standard 2D echocardiography  and 3D STE. Their results were compared with age and gender-matched healthy patients with negative ECG and echocardiographic findings and with the absence of any disorders. End-systolic and end-diastolic dimensions of the tricuspid annulus were evaluated in 3D echocardiography for the assessment of functional parameters [such as tricuspid annular fractional shortening (TAFS) and tricuspid annular fractional area change (TAFAC)] and morphological parameters . The results showed a significantly dilated end-systolic and end-diastolic tricuspid annulus diameter and area, but with preserved sphincter-like function (TAFAC and TAFS). TAPSE had only a mild correlation with the functional parameters (TAFAC and TAFS).The study by Wang, Chen et al. shows the influence of right ventricular dysfunction on patients with LVNC. A total of 117 patients were included, 53 patients with RV dysfunction, and 64 patients without RV dysfunction. The criteria for dysfunction included the following parameters: TAPSE < 17 mm, tricuspid S' velocity < 10 cm/s, and RVFAC < 35%. The patients were followed up for a period of more than 5 years and the results showed that the group of patients with RV dysfunction and with an impaired RV global longitudinal strain had a higher risk of all-cause mortality.Another study performed by Aortic stenosis (AS) is the second most common valvular heart disease (VHD) with pathological and clinical implications, and is frequently associated with other VHD.Mantovani et al. is on the latter issue. There is a common association between AS and mitral regurgitation (MR) (20–80%); thus, it is crucial to carefully assess the mechanism of MR for the decision of simultaneous surgical management. When assessing the valves, the study observed that vena contracta is a very reliable parameter due to its independence from afterload, and that the effective regurgitant orifice (ERO) predicts HF and correlates with mortality. In patients undergoing transcatheter aortic valve replacement (TAVI) for severe AS, the presence of moderate-severe MR is associated with poor outcomes and a high rate of mortality and rehospitalization. After TAVI, the MR can worsen or improve by at least one grade. Another common association is AS and tricuspid regurgitation, with worse outcomes, more severe symptoms, and increased mortality and hospitalization rates. Studies have shown that the correction of AS improved tricuspid regurgitation in approximatively 15–30% of patients. According to the guidelines, intervention should be considered in two conditions: when dilatation of the annular tricuspid is present and when there are signs of right HF. The association between AS and mitral stenosis can have various etiologies, but the most frequent cause is rheumatic, followed by degenerative. When assessing the mitral valve in these subjects, the pressure half-time (PHT) method and the continuity equation are not reliable parameters because they lead to overestimation. Bi-valvular surgery is suggested when the mitral valve area (MVA) is ≤ 1.5 cm2, and in patients with a high risk of surgical intervention that are not suitable for balloon valvuloplasty, the trans-catheter mitral valve replacement is a new, safe, and efficacious option. The combination between AS and aortic regurgitation (AR) is frequent in the bicuspid aortic valve in rheumatic heart disease. For this assessment, two parameters are indicated: vena contracta and the ERO calculation. The PHT parameter is not reliable, while, in some cases, planimetry might be helpful. When it comes to managing this type of patient, surgery is the first-line therapy and should be done before dilatation and dysfunction of the LV occur.The focal point of the review article by MR is the most common VHD and is classified into two main categories: primary (organic) and secondary . Many studies have focused on this subject, on different aspects of the disease, and on optimal surgical timing.Pastore et al. focuses on the evaluation of the primary MR and on the optimization of the surgical intervention timing. It is crucial to assess the mitral valve anatomy with the help of specific parameters  and to elucidate the mechanism of the regurgitation. Assessment of the patient is done with the help of 2D and 3D echocardiography focusing on the function and volumes of the LV. STE is also very useful because it provides key information about the LV and left atrium longitudinal function. Pre-operative assessment should mandatorily include the evaluation of right ventricular function, the degree of tricuspid regurgitation, and the tricuspid annulus measurement. Even though TTE could provide enough information, assessment of the patient with transesophageal echocardiography (TEE) is still required because it gives better insights into the mechanism and offers additional parameters. TEE is also important in post-operative evaluation to ensure that there are no unfavorable changes and to assess the integrity of the repair.The review by The tricuspid valve (TV), the so-called “forgotten valve”, has caught wider attention in the last few years because of its unique and complex structure and its prognostic relevance. Numerous studies have focused on this issue, trying to discover new modalities to assess the valve, its pathological implications, and to help us better understand the impact on patients.Margonato et al. present in their review an update regarding the clinical burden of tricuspid regurgitation (TR) in the context of LV systolic dysfunction, and the potential benefit of early TV intervention in these patients. At present, the appropriate time of treatment is still debated, because different subtypes and stages of TR imply different treatment options . Moderate TR in patients with LV systolic dysfunction is linked to higher mortality, and the parameters which are usually used are ERO > 0.2 cm2, vena contracta > 5 mm, and regurgitant volume > 20 ml. These findings are important for the surgical management of patients, and a more aggressive strategy has been proven to prevent significant long-term progression of functional TR.The left atrium (LA) plays a very important role in left heart physiology, and cardiovascular imaging has improved its evaluation in different clinical settings in recent years. It has three major functions: it works as a pump (it delivers blood for ventricular filling), as a reservoir (collecting pulmonary venous blood), and as a conduit (helping blood passage from the left atrium to the left ventricle).Carpenito et al. focuses on the central role of LA in patients with HF and provides a contemporary review of this topic. For assessment purposes, the method of choice is the left atrial volume indexed to the body surface area (LAVi) because of its strong prediction in cardiac outcomes and risk stratification. The assessment with M-mode and 2D echocardiography (anteroposterior diameter measurement) has proven to be inaccurate so they are not often used in daily clinical practice. A very important aspect is the dilatation of the LA, which offers a prediction of mortality and hospitalization in patients with HFpEF, especially when it is associated with increased pulmonary pressure. Over LA size, peak atrial longitudinal strain (PALS) by STE is correlated with functional capacity during exertion, is a strong predictor of prognosis, and a severely reduced value (< 12.9%) relates to HF symptoms and adverse cardiac events.The study by The LV is the most assessed chamber in daily clinical practice, with the focus often including LV function and size because they are keystones for cardiac diagnostics and prognosis. Countless studies have focused on this topic with diverse purposes and different available imaging techniques.Airale et al. focuses on the assessment of LV filling pressures using a novel echocardiographic tool named hemodynamic force (HDF) analysis using STE. The final study was composed of 67 patients who were evaluated with TTE and then underwent RHC. The parameter acquired during catheterization was the pulmonary capillary wedge pressure (PCWP) and the results revealed that 33 patients (49.2%) had increased LV filling pressure (PCWP > 15 mmHg). LA volume (LAVi > 34 ml/m2), mitral flow velocities, E/A ratio (>14), mitral annular E' velocity , and TR velocity (>2.8 m/s) were then assessed. HDF analysis was obtained with an off-line analysis and the study focused on the diastolic longitudinal component (DLF) because it is closely linked to the diastolic phase of the cardiac cycle and associated with increased LV filling pressure. Based on the echocardiographic findings and the HDF analysis, the authors assembled a scoring system (PCWP prediction score) which was based on LA enlargement, e' septal, LV ejection fraction, and DLF. The score showed high sensitivity and specificity when applied to the studied cohort.The study of Nemchyna et al. wrote a review about the parameters of LV mechanics with predictive value in patients undergoing surgical ventricular restoration using STE. One hundred and fifty-eight patients were included and evaluated with TTE before the intervention. LV function was assessed using longitudinal parameters measured with the 18-segment model. The authors showed that the basal longitudinal strain (BLS), the end-systolic diameter of the LV, and the fractional shortening, which are parameters of the basal segments of the LV, were strongly associated with outcomes, even more so than global longitudinal strain. Patients with a less impaired BLS had a superior survival rate. Moreover, a preoperatory preserved segmental longitudinal strain was associated with a better improvement in regional wall motion of the LV after surgery.The right ventricle (RV) has a complex asymmetric geometry, with trabeculations and a profound understanding of its morphology and function is essential for comprehending pathophysiological mechanisms. RV systolic function has an important role in the prediction of adverse outcomes and must be assessed routinely.Meng et al. studied RV diastolic dysfunction in 71 patients with chronic thromboembolic pulmonary hypertension who underwent pulmonary endarterectomy. The patients were assessed with echocardiography, RHC, and a 6 min walking test. The results showed that the indexed right atrial area (>8.8 cm2/m2) and the early diastolic strain rate were accurate indices of RV diastolic dysfunction with high sensitivity and specificity.Artificial Intelligence (AI) is a new, innovative application in echocardiography that helps and provides navigation through huge amounts of information, can do several automatic tasks, and even offers new opportunities for research.Machine learning (ML) and deep learning (DL) are branches of artificial intelligence that can serve as diagnostic tools for physicians and can offer alternative pathways in medical management, such as for HF.Schuuring et al. showed another interesting feature of AI, the so-called automated view classification which helps in standardizing views and measurements. It can offer guidance during training by advising how to move the probe in the correct way to get better images and even recognizes views that are incorrect or with an off-axis acquisition. The most performed task was the assessment and quantification of the LV function because it is a crucial parameter in daily clinical practice. Another important solution that AI offers is in the field of VHD because it helps with the sizing of devices in minimally invasive interventions. It is expected that in the future AI will reduce workload, improve the prediction of major adverse cardiac events (MACE) including mortality, and will be a pillar stone in the educational area.The study by In conclusion, the Research Topic included several starting points for the optimization of HF study and management, ranging from cardiomyopathies to novel advanced imaging techniques.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Surgical resection remains a first-line therapy for glioblastoma multiforme (GBM). Increased extent of resection (EOR) of noncontrast-enhancing regions in T2-weighted MRI images (T2-EOR) provides a survival benefit for GBM patients receiving standard radio/chemotherapy. However, whether it also improves immunotherapeutic outcomes remains unclear. We calculated the T2-EOR by comparing the preoperative and postoperative MRI T2 hyperintensity outside the enhancing tumour and correlated the T2-EOR with immunological and clinical outcomes from our published early-phase trial of heat shock protein peptide complex-96 (HSPPC-96) vaccination in treating a cohort of 19 patients with newly diagnosed GBMs (NCT02122822). Patients with higher T2-EOR exhibited shorter progression-free survival (PFS)  and overall survival (OS)  times than patients with lower T2-EOR. T2-EOR was negatively correlated with the levels of tumour specific immune response (TSIR) post-vaccination  and absolute TSIR increase from pre- to post-vaccination . Multivariate Cox regression models revealed that higher T2-EOR represented an independent risk factor for PFS  and OS  in this patient cohort. Taken together, increased T2-EOR deteriorated immunotherapeutic outcomes by suppressing TSIR, suggesting the potential of T2-EOR as an early biomarker for predicting the immunotherapeutic efficacy of HSPPC-96 vaccination. Glioblastoma multiforme (GBM), the most common and deadliest primary malignant brain tumour in adults, presents a great challenge for neurooncologists and neurosurgeons, as the outcomes of GBM patients have not greatly improved over the past two decades . The medThe last decade has witnessed unprecedented progress in cancer immunotherapies, which have already been approved as primary treatment options for a variety of malignancies –16. In gIn this study, we reviewed the clinical and immunological data, as well as the preoperative and postoperative (48-72 hours after surgery) MRI images, of patients in the HSPPC-96 vaccinated cohort . We calcvia subcutaneous injection in 25-μg doses every week for 6 weeks. Cyclophosphamide (400 mg) was given through intravenous injection before each HSPPC-96 vaccination (http://www.chictr.org.cn/enindex.aspx (ChiCTR-ONC-13003309). Written informed consent was obtained from all participants. All the included patients underwent gross total resection of contrast-enhancing regions in the tumour and had a Karnofsky performance status (KPS) scale (range 0-100%) score of ≥ 70% before vaccination . The number of PBMCs responding to tumour lysate, as measured by IFN-γ release, was calculated by subtracting the background number of IFN-γ spots in the negative control well.TSIR was evaluated by the number of stimulated peripheral blood mononuclear cells (PBMCs) in response to autologous tumour lysate in an IFN-γ release ELISPOT assay, as previously reported . In the Preoperative MRI images were obtained within 14 days before surgery, and postoperative MRI images were obtained within 3 days after surgery. The noncontrast-enhancing regions were represented as T2-hyperintense areas outside the contrast-enhancing lesions in T1-weighted images, termed T2-nonenhancing regions. After the T2-nonenhancing regions were manually outlined, the volume was automatically calculated with Neusoft PACS  software, which has been shown to be reproducible and accurate for tumour volume estimation in previous studies , 31.Categorical data were compared using Fisher’s exact test. Continuous data were compared using analysis of variance (ANOVA) or Wilcoxon nonparametric tests. Pearson correlation tests were applied to determine the association between T2-EOR and TSIR indicators. PFS and OS were estimated by the Kaplan–Meier method, and the difference between groups was assessed by the log-rank test. Multivariate Cox regression models were fitted to identify independent risk factors for survival. Statistical significance was set as a 2-tailed p value of less than 0.05. All statistics were analysed using R (version 4.1.2) statistical software.Recent clinical studies have shown the benefits of SpTR of noncontrast-enhancing regions, not just gross total resection of enhancing lesions, for survival outcomes in GBM patients , 10, 13.3 (range 40.57-153.25 cm3) and 45.11 cm3 (range 24.60-154.15 cm3), respectively, resulting in a 40.1% median T2-EOR (range -12.7%-67.8%), as shown in Gross total resection of contrast-enhancing tumour areas was achieved in all patients  compared with those with minimal residual disease   . They su tumour) . In thisAnother possible mechanism is that T2-EOR also represents a change in T2-nonenhancing region before and after surgery and thus could be an indicator reflecting the intensity of the immune response to surgery that would predict immunotherapeutic outcomes. In this scenario, T2-nonenhancing region, representing peritumoural oedema, is positively correlated with the immune response to surgical stress , 39. An Again, given the limited sample size and retrospective design of this study, the current findings should be further confirmed in another larger and carefully designed cohort, although we observed a statistically significant association of T2-EOR with immunotherapeutic efficacy.In conclusion, to our knowledge, our study first revealed a significant association of SpTR or increased T2-EOR with worse immunotherapeutic outcomes in GBM patients, suggesting the potential of T2-EOR as an early biomarker for predicting the immunotherapeutic efficacy of HSPPC-96 vaccination.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Conceptualization, YZ and NJ. Methodology, XC. Software, XC. Formal analysis YZ and XC. Resources, NJ. Data curation, XC and YW. Writing—original draft preparation, XC. Writing—review and editing, YZ and NJ. Visualization, XC and CL. Supervision, YZ and NJ. Project administration, YZ and NJ. Funding acquisition, XH, HG, YZ and NJ. All authors have read and agreed to the published version of the manuscript.This research was funded by National Natural Science Foundation of China , Capital characteristic Clinical Application Project (Z181100001718196), Capital Health Research and Development of Special Grant (2022-2-2047).XH is a co-founder and shareholder of Cure & Sure Biotech Co., LTD, Shenzhen, China, 100070; HG is a shareholder of Cure & Sure Biotech Co., LTD, Shenzhen, China, 100070; Cure & Sure Biotech Co., LTD, Shenzhen, China, 100070 developed the HSPCC-96 vaccine and provided financial support to the vaccine trial (NCT02122822), on which the current study is based.The remaining 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.


Cardiac real-time magnetic resonance imaging (RT-MRI) provides high-quality images even during free-breathing. Difficulties in post-processing impede its use in clinical routine.To demonstrate the feasibility of quantitative analysis of cardiac free-breathing RT-MRI and to compare image quality and volumetry during free-breathing RT-MRI in pediatric patients to standard breath-hold cine MRI.n = 22) received cardiac RT-MRI volumetry during free breathing  in addition to standard breath-hold cine imaging in end-expiration. Real-time images were binned retrospectively based on electrocardiography and respiratory bellows. Image quality and volumetry were compared using the European Cardiovascular Magnetic Resonance registry score, structure visibility rating, linear regression and Bland–Altman analyses.Pediatric patients (P < 0.01). Linear regression revealed good correlations for the ventricular volumes. Bland–Altman plots showed a good limit of agreement (LoA) for end-diastolic volume , end-systolic volume , stroke volume  and ejection fraction .Additional time for binning of real-time images was 2 min. For both techniques, image quality was rated good to excellent. RT-MRI was significantly more robust against artifacts (Compared to standard cine MRI with breath hold, RT-MRI during free breathing with retrospective respiratory binning offers good image quality, reduced image artifacts enabling fast quantitative evaluations of ventricular volumes in clinical practice under physiological conditions.The online version contains supplementary material available at 10.1007/s00247-022-05327-5. The importance of cardiac magnetic resonance imaging (MRI) in pediatric cardiology as a noninvasive diagnostic method has increased substantially over the last few years. Cardiac MRI permits the flexible choice of imaging planes  that is Real-time (RT)-MRI offers unique advantages for the representation of the heart: It provides accelerated imaging by radial data encoding in combination with nonlinear inverse reconstruction –8. Thus,Although cardiac RT-MRI offers tremendous advantages in the qualitative representation of the heart, the lack of quantitative evaluation strategies precludes its current use in clinical practice. The aim of this study was (1) to enable the quantitative analysis of cardiac RT-MRI volumetry in pediatric patients for daily clinical use by combining RT-MRI during free breathing with retrospective binning of images by electrocardiography (ECG) and respiratory bellows and (2) to evaluate ventricular function parameters and image quality by comparing the RT-MRI results to those obtained by standard cine MRI. To this end, we hypothesized that the combination of cardiac real-time MRI during free breathing in pediatric patients with retrospective respiratory binning offers good image quality, reduced image artifacts and quantitative evaluations of ventricular volumes.The study was designed as a descriptive, observational in vivo imaging study of pediatric patients recruited from the Department of Pediatric Cardiology at the University Hospital Duesseldorf and was approved by the local ethics committee . Written informed consent was obtained from the children’s parents or their legal guardians before the study.2 ± 0.4 m2 and used to calculate the left ventricle (LV) and right ventricle (RV) indexed volume results.Body surface was calculated using the DuBois formula with 1.6 mMRI measurements were performed on a clinical 1.5-T MRI scanner . For the measurements, an MR table with an installed 32-channel spine matrix coil  was used, and an 18-channel body coil  was placed around the patients.The clinical cardiac MRI examination included standard cine MRI volumetry  with bSSFP contrast, retrospective gating and segmented k-space-filling Table . RepetitThe clinical cardiac MRI examination was followed by cardiac RT-MRI volumetry with bSSFP contrast (33 ms per image) Table . Slice ohttps://doi.org/10.5281/zenodo.6352262. The individual ECG-derived time after the R-wave was provided by the intrinsic MR scanner software  and included in the DICOM tags from the RT-MR images  based on programming in Python  by adapting published open-source packages . The threshold signal intensity was then determined as the most considerable signal intensity value in the histogram with at least threshold count pixels. Based on the threshold signal intensity, the window width controlling for visual image contrast was calculated as  and the window center controlling for the image brightness was calculated as .The image quality of cardiac RT-MRI and cine MRI was compared by D.K., a pediatric radiologist with 16 years of experience in cardiovascular MRI and L.M.R. (radiologic assistant in the first year) using two established cardiac MRI scores. The European cardiac MRI score was used to rate artifacts  on MR images , 14. Then = 7).The short 3-D module of cvi42 was used to automatically contour the LV endocardial and epicardial contours and the RV endocardial contours at end-diastole and end-systole. L.M.R. performed manual corrections based on a standardized approach at the Children’s University Hospital, University Hospital Duesseldorf, Germany  that wast-test was calculated. The Wilcoxon rank sum test was used in the case of non-normal distributed and ordinal-scaled data, e.g., image quality analysis. Linear regression analyses were performed and Bland–Altman plots were generated to evaluate the agreement between LV and RV function parameters obtained with RT and cine MRI. The intra-rater and inter-rater reliability for the volumetric analysis was determined with the intraclass correlation coefficient for the ICC and was classified as poor (ICC < 0.5), fair (0.5 < ICC < 0.75), good (0.75 < ICC < 0.9) and excellent (ICC > 0.9) [P) was used to determine intra- and inter-rater reliability in the case of ordinal-scaled data, e.g., image quality analysis. The effect size rho was classified as small (0.1–0.3), medium (0.3–0.5) and strong (> 0.5), according to Cohen [P < 0.05 was considered statistically significant.All statistical analyses were performed in SPSS . The Shapiro–Wilk test was used to test for normal distribution. In the case of normal distributed data, e.g., ventricular function parameters, a paired sample C > 0.9) . Spearmato Cohen . A signiTwenty pediatric patients  from the 22 recruited patients were included in the study  central processing unit).P < 0.01) and RT-MRI  for inter-rater reliability. Intra-rater reliability was determined for cine MRI with rho = 0.94 (P < 0.01) and for RT-MRI with rho = 0.97 (P < 0.01). The artifact rating provided strong correlations for cine MRI  and RT-MRI  for intra-rater reliability and for cine MRI  and RT-MRI  for inter-rater reliability.Spearman rho rank correlation showed a strong and statistically significant correlation for the structure visualization analysis for both, cine MRI . RT-MRI was superior in image quality, especially in young patients with breath holding problems .While cine images, especially in younger patients often showed respiratory artifacts on multiple slices (1.5 ± 1.4), respiratory artifacts did not occur in RT-MRI (0.0 ± 0.0). Wilcoxon rank sum test proved the increased incidence of respiratory ghosting on cine MRI statistically significant (P < 0.01)  and cine images (1.8 ± 1.4) but showed a significantly higher artifact extent on the cine images ( ± 1.3 anP < 0.01).The overall evaluation of the artifact rating demonstrated that RT images were significantly less affected by artifacts than cine images , the left ventricular end-systolic volume indexed to body surface area (LV-ESVi), the left ventricular stroke volume indexed to body surface area (LV-SVi) and the left ventricular ejection fraction (LV-EF) Fig. .Fig. 4Li2 ± 2.7 ml/m2), LV-ESVi (LoA = 0.4 ml/m2 ± 1.9 ml/m2), LV-SVi (LoA = -0.5 ml/m2 ± 2.3 ml/m2) and LV-EF (LoA = -0.5% ± 1.6%) , LV-ESVi (P = 0.34), LV-SVi (P = 0.30) and LV-EF (P = 0.21) , the right ventricular end-systolic volume indexed to body surface area (RV-ESVi), the right ventricular stroke volume indexed to body surface area (RV-SVi) and the right ventricular ejection fraction (RV-EF) Fig. .2 ± 3.4 ml/m2), RV-ESVi (LoA = 0.6 ml/m2 ± 2.0 ml/m2), RV-SVi (LoA = -2.6 ml/m2 ± 3.3 ml/m2) and RV-EF (LoA = -2.1% ± 2.8%)  Fig. .Nevertheless, the differences for the RV-EDVi, RV-ESVi, RV-SVi and RV-EF between cine MRI and RT-MRI were greater compared to the LV volume results Table  with lowt-tests proved the differences between both methods statistically significant with lower values on average for RT-MRI in RV-EDVi (P = 0.02), RV SVi (P < 0.01) and RV-EF (P < 0.01). No significant differences were found for the RV-ESVi (P = 0.18) (Table Paired sample 8) Table .The results for the ICC were good to very good (ICC = 0.86–1.00) for the left and right ventricular EDVi, ESVi, SVi and EF evaluation from the cine MRI and RT-MRI for inter- and intra-rater reliability Table .This study demonstrates the feasibility of studying cardiac volumetry with RT-MRI during free breathing in pediatric patients. Implementing user-friendly, time-saving software for RT-MRI postprocessing enabled us to integrate this method in everyday clinical practice. Retrospective respiratory binning guaranteed image stabilization and high image quality. Thus, quantitative volume evaluation was enabled from data acquired under physiological conditions from almost all patients in the study. Cardiac function could not be analyzed in one patient because of an unusable respiratory bellows signal.Although the benefits of RT-MRI are well known, the lack of quantitative evaluation strategies that offer fast post-processing comparable to standard cine MRI precludes its current use in clinical practice. We were able to reduce the time for post-processing by implementing a user-friendly GUI. Thus, the additional net time required was reduced to 2 min.At present, cine MRI with slice per slice data acquisition and repetitive breath holding is the clinical standard for the examination of cardiac volumetry. In cases where breath holding is impossible due to preexisting conditions or patient age, cine MR images may be acquired during free breathing, which is associated with significantly poorer image quality. For patients with heart or lung diseases, and especially for children, breath holding is a major disadvantage that reduces the patient’s comfort , inducesIn our study, problems with breath holding often resulted in respiratory ghosting on cine images, reducing image quality. This has been demonstrated in previous studies . In our RT-MRI provided a significantly better robustness against metallic artifacts. This can be explained by a more rapid data acquisition with radial (i.e. frequency-encoding) trajectories in comparison to cine MRI with a Cartesian phase-encoding scheme –8. MetalCompressed sensing techniques are commonly used for accelerated imaging techniques and already used in RT cine cardiovascular MRI, thereby improving temporal resolution while reducing image quality . MathemaLV and RV volumes showed good correlations between the RT images acquired during free breathing and binned corresponding to a low lung volume and cine images with a slice per slice acquisition in end-expiratory breath holding. No significant differences were found between either technique for the LV-EDVi, LV-ESVi, LV-SVi and LV-EF. This is in line with other comparative MR studies , 29. HowPrevious RT-MRI studies during free-breathing demonstrated that even with calm breathing, respiration influences cardiac function , 10, 30.The influence of breathing on RV function can be explained by heart–lung interactions , 32. TheIn our study, we observed lower values for RV-EDVi, RV-SVi and RV-EF derived from RT volumetry, acquired during free-breathing and binned corresponding to a low lung volume in comparison to results from cine MRI during end-expiratory breath holding. Differences in RV function between the same respiratory phase during breath holding and free-breathing have been described in a previous RT-MRI study , highligEven though our study demonstrates the feasibility of cardiac RT-MRI volumetry during free breathing in pediatric patients, some limitations must be considered:First, our study included pediatric patients ages 5 to 17 years. Future studies will have to demonstrate the feasibility of RT-MRI during free breathing to reduce the need for sedation or even anesthesia in preschool children and to enable cardiac volumetry testing in neonates and infants in combination with sleep and feed studies.Second, respiratory bellows do not provide quantitative data for lung volume and breathing depths. Thus, the heart position varied in images with equal respiratory bellows values resulting in greater movement from image to image in RT-MRI. MR-compatible spirometry could provide quantitative information on respiratory flow in future studies .Third, the poor quality of the respiratory bellows made it necessary to define the end-expiratory breathing class very broadly and the class was solely defined based on absolute respiratory bellows values without consideration of respiratory flow. This resulted in less image stabilization and the respiratory influence on cardiac volumes was probably underestimated.Fourth, volumes were obtained from 2-D short axis stacks. In the future, volume determinations of 3-D data sets might provide results that are even more precise. Previous studies have already demonstrated the feasibility of real-time 3-D flow MRI .Fifth, temporal resolution of RT-MRI with b-SSFP contrast at 1.5 T is limited to 33 ms. In small children with faster heart rates, the limited temporal resolution could be insufficient. Using spoiled fast low-angle shot (FLASH) contrast at 3 T would provide a temporal resolution of even 20 ms, i.e. 50 frames per s, that could provide sufficient temporal resolution for faster heart rates in infants.Sixth, minor differences in pixel size may have resulted in minor differences between RT and conventional MR images.In comparison to cardiac cine MRI with breath holding, the combination of free-breathing RT-MRI with retrospective respiratory binning using a custom user-friendly software program provides good image quality, fewer image artifacts and, most importantly, offers a reliable clinical tool for the accurate quantification of ventricular volumes during preserved physiological conditions in pediatric patients.Supporting Video: Image Quality: The first part of the video shows a heart cycle in a midventricular slice from standard cine MRI during end-expiratory breath holding and the corresponding free-breathing RT-MRI with retrospective respiratory binning in a 15-year-old patient (patient 10) with good breath holding. The second part of the video demonstrates a heart cycle in a midventricular slice from standard cine MRI in a 5-year-old patient (patient 19.) with breath-holding problems and the corresponding RT-MRI acquired during free breathing and binned retrospectively corresponding to a low lung volume. Supplementary file1 (MP4 15543 KB) Supporting Video: Metallic Artifacts: The video shows metallic artifacts from sternal wires on a midventricular slice from standard cine MRI during end-expiratory breath holding and on the corresponding midventricular slice from RT-MRI acquired during free breathing and binned retrospectively corresponding to a low lung volume. The higher artifact extent on cine MRI is obvious.Supplementary file2 (MP4 9489 KB) Below is the link to the electronic supplementary material.


Background: Congenital heart pathology has a significant burden regarding morbidity and mortality in the pediatric population. Several transcatheter interventions and devices have been designed as an alternative to surgical repair. Percutaneous interventions have been proven to yield good results in most cases but with less stress and trauma than that attributed to surgical treatment, especially in frail pediatric patients. We aimed to review the literature and to investigate the feasibility and efficacy of transcatheter interventions and implantable devices for congenital heart disease management in children. Methods: We performed a search in Scopus and MEDLINE databases using prespecified keywords to retrieve clinical studies published between 2000 and 2021. Results: This article provides an up-to-date review regarding the applicability of interventional techniques in simple inter-atrial or inter-ventricular defects, and in challenging congenital defects, such as hypoplastic left heart syndrome, tetralogy of Fallot, or coronary artery fistula. Furthermore, we reviewed recent indications for defibrillator and cardiac resynchronization therapy, and new and promising devices currently being tested. Conclusion: Transcatheter treatment represents a feasible and efficient alternative to surgical repair of congenital heart defects. Novel devices could extend the indications and possibilities of percutaneous interventions in pediatric patients with congenital heart diseases. About 0.8–1.2% of all children born each year worldwide suffer from congenital heart defects, with isolated ventricular septal defect being the most frequent type. Moderate and severe forms of disease account for up to 6 in 1000 cases .Percutaneous device treatment opened an entirely new era for congenital heart defect children, including those with isolated heart defects , aortic coarctation, isolated inter-ventricular and inter-atrial communications), and those with complex heart disease (hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (ToF)). Percutaneous device treatment refers to transcatheter management of congenital heart defects using approved devices. One study investigated device failure associated with ventricular septal defect closure and found that 7.6% of cases treated in this manner encountered device failure . No assoAmplatzer devices have been successfully used for atrial septal defect closure since 1997, proving to be safer than surgical interventions ,9. PDA iThe safety and benefit of balloon atrial septostomy has been proven in the transposition of great arteries and could also prove beneficial in both types of atrioventricular valve atresia and in total anomalous pulmonary venous return with no or restrictive foramen ovale . InterveSome important barriers in pediatric transcatheter treatment innovations have been described . One of We aimed to review the literature and to investigate the feasibility and efficacy of transcatheter interventions and contemporary implantable devices for congenital heart disease management in children. Consequently, we provide an updated narrative review integrating various percutaneous treatment techniques and devices used in pediatric interventional cardiology.Several types of devices are routinely used by pediatric cardiac interventionists while others are seldom used, as they do not have such a wide applicability in children  17]. De. De17]. These devices are used for their approved indications but also in an off-label manner. For instance, radiofrequency perforation wires are approved for atrial septostomy but are also used for atretic valve perforation. Embolization coils are used to occlude small patent ductus arteriosus off-label  while dilation balloons, approved for valvar pulmonary stenosis treatment, are also used for stenotic aortic valves, stenotic conduits, or aortic coarctation. A cutting balloon can be used not only for desobstruction of a dialysis fistula but also for atrial septostomy or pulmonary artery stenosis treatment while stents can be placed off-label in a stenotic conduit, a stenotic pulmonary or even systemic vein, a coarctation site, a stenotic pulmonary artery branch, or can be used to keep patent ductus arteriosus in an open state . These oAlthough pulmonary valve atresia with intact ventricular septum is a relatively rare congenital heart disease, these patients are at an increased mortality risk, even after surgical intervention (52% in the first year) . DiffereMost studies in the literature reported similar techniques of pulmonary valve perforation and balloon valvulotomy. A 4F (or 5F) right coronary catheter was advanced towards the infundibular area in one study. Afterward, different guidewires were used to perforate an atretic pulmonary valve: the stiff end of a 0.014-inch guidewire, 0.018-inch, or 0.024-inch radiofrequency guidewires . In patiEarly data supported percutaneous pulmonary valvulotomy in patients with a well-formed right ventricular infundibulum, pulmonary valve annulus ≥ 7 mm, and tricuspid valve annulus ≥ 11 mm . In addiPediatric patients with PDA and favorable anatomy for interventional treatment can be referred for percutaneous closure in the first year of life ,27. In tThe early available Amplatzer-type devices were not indicated in patients with low body weight. However, the Amplatzer Piccolo Occluder could be used even in patients ≥ 700 g and was approved by the Food and Drug Administration in 2019 . Due to Usually, when an Amplatzer device is considered for PDA closure, ductus arteriosus is crossed from the venous side towards the aorta. In most studies, the device size was 1–2 mm greater than the narrowest diameter of ductus arteriosus. The device is positioned in the descending aorta through a long sheath. Initially, the distal disc should be opened and placed on the ductal aortic side. After confirming the proper position of the system, the occluder device could be delivered . Nit-OccPercutaneous balloon angioplasty with or without stent implantation represents an alternative to surgical intervention, even in infants . BalloonIn selected patients for percutaneous treatment, venous and arterial femoral access should be performed . The proTypically, a 1–2 mm larger balloon than the diameter of the pre-stenotic aorta is used for percutaneous angioplasty. Before stent deployment, some authors recommend testing stenosis distensibility by inflating the balloon at low pressure (<4 atm). The stent might not fully expand in highly fibrotic stenosis after the first intervention. Once patients grow, additional balloon inflations could be performed to expand the stent further .Although the immediate success rate is high (97% even in low-weight children), some complications should be addressed . In a prCongenital coronary artery fistula (CAF) is a rare condition in the general population, with a 0.002% reported incidence . BesidesEven though the right coronary artery was the most common origin site, CAFs can emerge from the left main, left anterior descending, or circumflex coronary arteries, as documented in one study . CAFs weDifferent techniques of CAF occlusion have been described, highlighting the anatomical variations : antegrade venous approach (long CAF), retrograde arterial approach , arterio-arterial circuit approach (CAF draining in the left atrium or ventricle), and arterio-venous circuit approach (CAF draining in the right atrium or ventricle) . AccordiIsolated ventricular septal defect (VSD) constitutes the most frequent form of congenital heart disease, with an incidence of 2–5% in newborns. However, although the incidence is high, most small VS  close spontaneously within 1 year. Percutaneous correction is reserved for pediatric patients with hemodynamically significant VSD, including left heart volume overload or pulmonary to systemic flow ratio ≥ 2 . Neverthp < 0.05 for all), with a reduced risk of significant complication ..63].ToF is a common and complex congenital heart disease, with surgical treatment being the standard of care . PercutaIn patients with ductus-dependent pulmonary flow, ductus arteriosus percutaneous stenting can be performed as an initial palliative intervention . DiffereWhen a femoral venous approach is chosen, a catheter is advanced from the right heart towards the aortic arch across the VSD. Different catheters can be exchanged to obtain a good position near the ductal ampulla required for stent passage . Rarely,Other interventions for ToF involve right ventricular outflow tract (RVOT) obstruction management. In one study, the authors reported successful implantation of two Melody valves in a pediatric patient with TOF and acquired double RVOT with good clinical outcomes during long-term follow-up (7 years) . PercutaPercutaneous treatment for HLHS constitutes a palliative intervention before surgical correction. The transcatheter intervention aims to delay the surgical intervention, as open-heart surgery might have worse outcomes .As a first step, the palliative intervention includes pulmonary artery flow restriction and ductus arteriosus stenting to obtain satisfactory pulmonary and systemic blood flows. A hybrid approach and a full percutaneous technique were described in this setting ,70.In one study investigating the hybrid approach, pulmonary artery banding was achieved through median sternotomy. Afterward, a 0.018-inch guidewire was used to cross the ductus arteriosus and was placed in the distal descending aorta. A sinus-SuperFlex stent, 1–2 mm larger than the ductus arteriosus measured diameter, was implanted. The authors reported an 83% survival rate during 137 days .A relatively new entirely percutaneous technique was described and investigated in clinical studies enrolling HLHS patients. In this regard, a venous femoral access site is obtained, as reported in one study. Modified Micro Vascular Plug (MVP) devices were used as flow restrictors in the pulmonary arteries. The modified MVP replaced surgical pulmonary banding, avoiding inherent surgical risks. The ductus arteriosus was then crossed using a guidewire, and a Formula stent was deployed . A similBalloon atrial septostomy constitutes a palliative intervention before lung transplantation in patients with pulmonary arterial hypertension and patients with HLHS, tricuspid, or pulmonary valves atresia. However, balloon atrial septostomy is efficient if performed in neonates or children aged < 6 weeks ,73,74. OA venous access site  should be obtained. Several available catheters can be used to cross foramen ovale: the Miller catheter, Rashkind balloon catheter, Fogarty balloon catheter, and NuMED septostomy catheter . The balEven though balloon atrial septostomy is highly efficient, some complications can occur: balloon rupture or embolization, mispositioned balloon, cardiac perforation, vascular access site injury, or stroke .In the last two decades, deep venous thrombosis (DVT) and embolism have been reported more frequently in children. DVT might occur secondary to oncologic therapy, intensive care unit stay, or trauma in children. In this context, inferior vena cava (IVC) filter placement could replace anticoagulant therapy in selected patients (including children in whom anticoagulation is contraindicated) and could be performed as an adjunctive therapy. Some authors used IVC filters in patients considered for local thrombolysis for DVT or prior to high-risk surgical interventions ,77.One study investigated the long-term efficacy and complications related to Greenfield IVC filters in 15 children. During 16 years of follow-up, none of the patients developed pulmonary embolism. Mild femoral venous reflux was observed in three patients but without venous obstruction . NotablyBefore IVC filter implantation, a venous access site  should be obtained. Using a catheter positioned in the infrarenal IVC, a guidewire is advanced and placed distally. After confirming the position, the IVC filter is deployed . PotentiThe first pediatric pacemaker implant was performed in November 1960 by Dr. Zoll and Dr. Frank in a child who had developed complete heart block following a ventricular septal defect repair procedure . NowadaySome of these centers also perform biventricular pacing and implantable cardioverter-defibrillator (ICD) implants. ICDs are implanted in children for the primary or secondary prevention of life-threatening arrythmia . ChildreThese children, with complicated intracardiac anatomy, are better suited for epicardial pacing. In a study performed by Rico-Mesa et al., the most frequent complications associated with intracardiac pacing or defibrillation were hematoma, infection, and pneumothorax, followed by venous occlusion, embolism, or death . The samBiventricular assist devices do not have clear implantation indications and guidelines in children; however, they seem to improve systolic function in children with cardiomyopathies or congenital heart diseases by 12.8 ± 12.7%, thus delaying heart transplantation indication . ChildreThe CAM (Carnation Ambulatory Monitor) is an ECG monitor that can store 7 days’ worth of continuous stripe. The monitor is small, and it attaches to the patient’s sternum to capture high-resolution ECGs that can be uploaded to a web page afterwards. This device is already available for clinical use .Children undergoing open heart surgery could soon benefit from the VentriFlo True Pulse pump, an extracorporeal blood pump that is able to provide a complete stroke volume while using a flexible membrane and valves. This device has already obtained its patent .Another novel and promising device is the LEAP valve, a prosthetic heart valve that “grows with the child” by expanding up to twice its initial size. This device is still undergoing ex vivo tests and has not yet reached the animal testing phase .Its main competitor seems to be PolyVascular, another expandable polymer valve, which is also not yet available for use .Another great help in terms of mechanical circulatory support seems to be the NuPulseCV intravascular ventricular assist system, which is inserted in the subclavian artery. The main benefits of this system are that it is minimally invasive and can be used in a long-term manner. This device is already in its human testing phase, which begun in adults in 2016 and is currently still recruiting .ExGraft is an expendable radiopaque synthetic vascular graft that accommodates the child’s growth and reduces the need for repeated surgery. This device is currently available in the European Union .The FloWatch pulmonary artery banding device has long surpassed its testing phase. Its previous version was used between 2002 and 2012. The new version of this device is telemetry controlled to allow calculated amounts of blood to flow through the pulmonary artery .Children suffering from end-stage kidney disease could benefit from The Arteriovenous Fistula Eligibility (AFE) system use. This is an external blood pump that stimulates venous dilation and improves the likelihood for successful placing of an arteriovenous fistula, and has not yet undergone human studies .Arterial lines and inflatable cuffs could soon be replaced by the Boppli blood pressure monitor, which monitors blood pressure in a noninvasive, continuous, and comfortable manner. The device looks like a watch and is not yet available for use .Novel devices that can be applied to pediatric cardiology patients are being developed every day. In 2018, The Pediatric Device Innovation Symposium revealed several gems :The CAM This paper opens the pathway to future research related to pediatric cardiology. Future work should not only include a thorough follow-up on the novel devices discussed here but also on new interventional technique development and detailed research on nanotechnologies applicable to newborn, infant, and pediatric cardiac malformations.Pediatric cardiology is currently a rapidly growing subspecialty. Children with more or less complex heart pathologies are now benefitting from increasingly complex and less invasive procedures thanks to the interventional cardiology branch. Simple conditions, such as atrial or ventricular communications, coarctation of the aorta, or patent ductus arteriosus, can be easily managed in a percutaneous manner. Furthermore, Blalock–Taussig shunts can now be closed in children developing pulmonary over-circulation-related heart failure symptoms, right ventricular outflow obstruction encountered in Fallot tetralogy can be interventionally managed, and inferior vena cava filters can be placed in selected patients. Implantable cardioverter-defibrillators have clearer use guidelines while cardiac resynchronization is usually reserved for dilated cardiomyopathies, as a bridge to transplantation.


Arterial hypertension affects ≈ 1 billion people worldwide. It is associated with increased morbidity and mortality and responsible for millions of deaths each year. Hypertension mediates damage of target organs including the heart. In addition to eliciting left ventricular hypertrophy, dysfunction and heart failure, hypertension also causes left atrial remodeling that may culminate in atrial contractile dysfunction and atrial fibrillation. Here, we will summarize data on the various aspects of left atrial remodeling in  hypertension gathered from studies on patients with hypertension and from spontaneously hypertensive rats, an animal model that closely mimics cardiac remodeling in human hypertension. Analyzing the timeline of remodeling processes, i.e., distinguishing between alterations occurring in prehypertension, in early hypertension and during advanced hypertensive heart disease, we will derive the potential mechanisms underlying left atrial remodeling in  hypertension. Finally, we will discuss the consequences of these remodeling processes for atrial and ventricular function. The data imply that left atrial remodeling is multifactorial, starts early in hypertension and is an important contributor to the progression of hypertensive heart disease, including the development of atrial fibrillation and heart failure. High blood pressure  poses a worldwide clinical and socioeconomic burden affecting ≈ 1 billion people and is responsible for millions of deaths each year ,3. ArterIn humans, essential or primary hypertension is, by far, the most common form of arterial hypertension, accounting for >90% of cases. The cause of primary hypertension is currently unknown. However, risk factors are known, such as age, male sex, smoking, high sodium intake, obesity or a positive family history . Thus, eAF is the most common sustained arrhythmia. It is associated with increased morbidity and mortality, mainly resulting from thrombus formation in the LA appendage and subsequent stroke, as well as from impairment of LV function caused by reduced LV filling and irregular LV activation ,11. HF i1) receptor blockers (ARB), β-adrenergic receptor blockers (or β-blockers), Ca2+ channel blockers (or Ca2+ antagonists) and diuretics  and slowing of CaT decay with the development of heart failure. SR Ca2+ load was increased, but fractional SR Ca2+ release greatly diminished in heart failure. Increased propensity for proarrhythmic Ca2+ alterations  was also observed. These alterations of atrial myocyte Ca2+ handling were associated with reduced expression of α1C (Cav1.2), RyR2 and calsequestrin and progressively decreasing expression of SERCA2a, indicating severe impairment of SR Ca2+ handling. Interestingly, in heart failure, phosphorylation of RyR2 (and PLB) was decreased at sites predominantly phosphorylated by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and unchanged at sites predominantly phosphorylated by PKA. This is in clear contrast to ventricular Ca2+ handling remodeling observed in most heart failure models (including humans and SHR), which exhibit increased phosphorylation of RyR2 at both CaMKII and PKA sites i and prolonged CaT decay impair atrial (myocyte) relaxation. Even if CaT amplitude is maintained , this might not suffice for efficient LV filling in the presence of elevated LV end-diastolic pressure (LVEDP). In addition, CaT alternans will cause alternating degrees of LV filling. The structural, electrical, CaIn line with these considerations, several studies indicated atrial contractile dysfunction in hypertensive patients as well as in SHR. In SHR with LV hypertrophy (15 weeks of age), the peak early filling rate of LV was unchanged, but the peak late filling rate was reduced by 25%, suggesting impaired atrial filling of LV . ContracNevertheless, in animal models and in patients with chronic hypertension and structural remodeling, impaired LA contractile function is a consistent finding. What might be the consequences of reduced LA contractility? Since LA contraction contributes to LV filling and cardiac output, reduced LA function will impair LV function and reduce cardiac output. While this might go unrecognized and not matter much in a healthy heart, it might be critical for cardiac function in a diseased heart with already compromised LV function. In line with this, in hypertensive patients with increased risk for LV diastolic dysfunction, reduced LA contractile function was a predictor for adverse cardiac outcomes and death . Similar2+ handling may serve as the trigger initiating the first episodes of AF. In addition, neurohumoral activation  and acute atrial stretch might also trigger AF via increasing the propensity of spontaneous Ca2+ release events in atrial myocytes i i . Thus, td [Na+]i ,162,163.In summary, LA remodeling in hypertension results in LA contractile dysfunction and AF, which can cause LV dysfunction and heart failure .