Cardiac CT (CCT) is well suited for a detailed analysis of heart structures due to its high spatial resolution, but in contrast to MRI and echocardiography, CCT does not allow an assessment of intracardiac flow. Computational fluid dynamics (CFD) can complement this shortcoming. It enables the computation of hemodynamics at a high spatio-temporal resolution based on medical images. The aim of this proposed study is to establish a CCT-based CFD methodology for the analysis of left ventricle (LV) hemodynamics and to assess the usability of the computational framework for clinical practice.The methodology is demonstrated by means of four cases selected from a cohort of 125 multiphase CCT examinations of heart failure patients. These cases represent subcohorts of patients with and without LV aneurysm and with severe and no mitral regurgitation (MR). All selected LVs are dilated and characterized by a reduced ejection fraction (EF). End-diastolic and end-systolic image data was used to reconstruct LV geometries with 2D valves as well as the ventricular movement. The intraventricular hemodynamics were computed with a prescribed-motion CFD approach and evaluated in terms of large-scale flow patterns, energetic behavior, and intraventricular washout.In the MR patients, a disrupted E-wave jet, a fragmentary diastolic vortex formation and an increased specific energy dissipation in systole are observed. In all cases, regions with an impaired washout are visible. The results furthermore indicate that considering several cycles might provide a more detailed view of the washout process. The pre-processing times and computational expenses are in reach of clinical feasibility.The proposed CCT-based CFD method allows to compute patient-specific intraventricular hemodynamics and thus complements the informative value of CCT. The method can be applied to any CCT data of common quality and represents a fair balance between model accuracy and overall expenses. With further model enhancements, the computational framework has the potential to be embedded in clinical routine workflows, to support clinical decision making and treatment planning. Cardiac CT (CCT) is a preferred imaging modality for the treatment of various cardiovascular diseases and is for example used in the investigation of coronary artery disease, for the measurement of myocardial perfusion, or in the planning of interventions in valvular heart diseases , 2. For in vivo analysis of intraventricular blood flow via medical images includes, for example, the quantification of blood flow kinetic energy   , 26, to ion (BC) , 38. Dooion (BC)  gave a dion (BC)  and Hirsion (BC) .The balancing between model accuracy and complexity marks a central trade-off in the CFD-based investigation of LV hemodynamics. Modeling approaches need to incorporate the most important features to accurately reproduce the intraventricular hemodynamics. At the same time, data requirements, required working hours, computational expenses, and model uncertainties need to be minimized to enable a usability in the clinical routine. Finding an adequate compromise is the subject of this study. We propose a moderate complexity computational framework to compute LV hemodynamics by using CCT image-based, prescribed-motion CFD that requires pre-processing times and computational expenses that are within reach of clinical feasibility. The workflow is largely automated and applicable to arbitrary CCT data of common quality. The technical feasibility is demonstrated by means of four cases, each representing a subcohort with a respective pathological configuration: patients with and without LV aneurysm as well as with severe and no MR.via CCT, the image data is used to segment end-diastolic and end-systolic LV geometries as well as both annuli. In the next step, the segmented data are used to set up LV geometries with 2D valves and to derive the ventricular movement. For the intracardiac flow simulations, adequate physics models and BCs are furthermore posed. As the last step, valuable hemodynamic markers for the analysis of intraventricular flow features are selected before each of the four patient-specific cases is computed and evaluated. The individual steps are addressed in detail in the following.The central workflow of the computational framework is illustrated in n = 125, mean age of 60.6 ± 10.0 years, 16.8 % women) was retrospectively analyzed. Data were collected in the German Heart Center Berlin between November 2005 and January 2016. The patients are grouped into two cohorts: patients without (Cohort I) and with (Cohort II) anterior LV aneurysm. The LV aneurysm was diagnosed by echocardiography and confirmed by CCT. The MR grade was defined echocardiographically. For each cohort, one case without MR and one with severe MR (grade III) were selected. The different cases are denominated via M{MR: 0 = no MR; 1, 2, 3 = grade I, II, III}A{aneurysm: 0 = no; 1 = yes}, resulting in the four cases: M3A1, M3A0, M0A1, and M0A0. The hemodynamics of all cases are investigated, each being representative for its subcohort. The four LVs were chosen such that the end-diastolic volumes (226 to 256 ml) and the reduced ejection fractions (EFs) (23 to 29 %) are comparable. p-value below 0.05 was considered statistically significant.A cohort of heart failure patients after myocardial infarction . All scans were conducted at a tube voltage of 100 kV and an individually adapted tube current, using the scanners exposure control software. A multiphase data set of the whole heart cycle was reconstructed that allows identification of the diastolic phase with the largest left ventricular end-diastolic volume (LVEDV) and the systolic phase with the smallest left ventricular end-systolic volume (LVESV). All images were reconstructed using a standard soft-tissue convolution kernel and a dedicated noise reduction software. The spatial and temporal resolution of the CT images varied. Spatial resolutions of (0.39–0.648 mm) x (0.39–0.648 mm) in-plane resolution and (0.5–1.85 mm) slice thickness were used for segmentation. The temporal resolution ranged from 70 to 140 ms depending on the patient's heart rate. One heart cycle was always resolved by 10 phases.To analyze the LV anatomy as well as to prepare geometric and dynamic boundary conditions for the flow simulations, the LVs were segmented. The segmentations were created using a prototypical software developed earlier on the basis of the MeVisLab platform . A detaivia the MV centers. End-diastolic and end-systolic geometries are cut 1 cm below the most apical points of the AV and MV in the end-diastolic state and are slightly smoothed, preserving the LV volumes. The boundary points of that cutting plane as well as the segmented annuli are used to reconstruct a well-defined LV surface mesh of the end-diastolic geometry as follows and as schematically shown in via a best-fit plane for point clouds  constant in time t and dependent on the position x =  in Euclidean coordinates, can be derived. It is scaled by a time-dependent factor α(t) to obtain a grid velocity vector v that allows the ventricular volume to follow any specified volume curve at a given EF (Equation 2).The ventricular motion is derived from the cut end-diastolic and end-systolic geometries . With twd(x) is computed as follows. During geometry creation, the cut LVs were positioned in the global origin with the negative z-axis pointing toward the apex. From the highest z-coordinate to 1 cm above the lowest z-coordinate, 100 equidistantly distributed planes, being parallel to the x-y plane, are placed into the LV (as shown in The deformation field t) is derived. It is based on a multiplicative approach and realized by forcing the volume flux of the simulation to follow the volume flux BC and results in Equation (3).As the last step, the scaling factor α is the relative volume of the simulated LV, and ξ(Vsim(t), Δt, d(x)) is the differential relative volume flux that a deformation along d(x) over Δt at a specific volume Vsim(t) induces. ξ(Vsim(t), Δt, d(x)) can be obtained by computing the deformation once for α(t) = 1 and equating ξ(Vsim(t), Δt, d(x)) to the resulting volume flux where d(x) and α(t), the grid velocity vector (Equation 2) can be computed.Having obtained D incompressible Navier-Stokes equations with moving mesh for unsteady flow. No body-forces and source terms are added. Therefore, the governing equations for mass (Equation 5) and momentum (Equation 6) conservation in tensor notation read as follows .Therein, −3 and a dynamic viscosity of 0.0035 Pas. The Star-CCM+ internal mesher is used to create a polyhedral volume mesh at a base size of 1 mm with a refinement to 0.25 mm in the valve region. Detailed information about the mesh can be found in the Blood is modeled as Newtonian fluid with a density of 1,050 kgmThe ventricular motion is prescribed as BC at the walls. No-slip BCs are furthermore posed at the walls in terms of the relative movement of the fluid to the wall. For the non-MR cases, physiological pressure BCs are extracted from circadapt  and posevia a quadratic sine function between the halfway opened and the final projected orifices. By varying the pressure drop at these intermediate valve shapes, valve opening and closing as well as the general valve function is mimicked. Common areas of the MV orifice range between 4.0 and 6.0 cm2  is placed in the LA fluid to track the path of blood that flows into the LV in the first cycle. Therewith, a contrast agent washout can be mimicked. For the passive scalar, only convective transport is considered. To extrapolate the washout, an exponential function is used (Equation 8).t is time and B is the coefficient quantifying the washout. In terms of energetic efficiency, the cycle-averaged kinetic energy is regarded. To get a hold of the energetic loss, the dissipation function Φ is used. It is defined as the double-dot product of the stress tensor σ and the gradient of the velocity vector ∇v  at 2.3 GHz on the Emmy system of the North-German Supercomputing Alliance. Concerning the accuracy of the deformation, the mean difference between the imposed and the computed volume curve is below 0.02 ml for all cases. The mean distances between the segmented and the computed end-systolic geometries of the four cases  are between 0.14 and 0.52 mm. The mesh quality shows no degeneration, and a mesh independence study was performed see . As the The intraventricular large-scale flow patterns are qualitatively evaluated by means of streamlines, first cycle diastolic inflowing blood (FCDIB), and Q-criterion. Latter two are provided in video format in the t1). In the non-MR cases, all blood is ejected through the LV outflow tract, whereas in the MR cases blood from the posterior-sided regions regurgitates into the LA. The regurgitating jet impinges on the upper LA wall and causes a chaotic, swirling blood motion in the LA. At the onset of diastole, a jet of blood is accelerated from the LA into the LV (t2). In the MR cases, the jet transports vortex tubes, which are leftovers of the chaotic systolic flow field inside the LA caused by the regurgitation . Vortices are rolled up along a shear layer that forms between the resting and the inflowing blood. Whereas in the non-MR cases, a distinct ring vortex structure is visible at peak diastole, the ring structure does not entirely evolve in the MR cases . Concerning the E-wave jet, its structure is being disrupted in the MR cases, such that by diastasis, it is split into several parts (t3). In cases M0A1, M0A0, and partially M3A1, the jet impinges on the septal wall in mid region of the LVs in diastasis and is partially redirected toward the apex. In case M3A0, the E-wave jet moves along the posterior wall towards the apex. It is decelerated and decomposes without impinging on any wall. At late diastole (A-wave), a second jet at lower velocities rushes into all LVs. Again, vortices are rolled up along the shear layer, being weaker than the E-wave vortices. At the end of diastole, an unstructured flow field is present in all LVs.During systole, blood is accelerated toward the basal LV regions  at t1. Io the LV  at t2. Ial parts  at t3. Ivia the AV, whereas in the MR-cases, 50 % regurgitates back into the LA. The regurgitating blood exceeds velocities of 4.5 m/s in cases M3A1 and M3A0 . The R2 values  for the exponential fits are above 97 % for all cases.The blood in which the passive scalar was placed to track the fluid motion, the FCDIB, enters the LV in diastole of the first cycle and is ejected in the subsequent cycles . The ejeThe ejected fractions of FCDIB per cycle are displayed in In this study, we propose a moderate complexity, generally applicable, and quick to preprocess modeling approach to calculate intraventricular hemodynamics with image-based CFD. The ventricular movement is derived from the segmented end-systolic and end-diastolic geometries and prescribed in an arbitrary Lagrangian-Eulerian formulation at the boundaries. The valves are modeled as 2D orifices, whereat the MV is represented by a projected orifice shape. LA and AO geometries are attached at the annuli and physiological pressure curves, respective mass flow rates are posed as inflow and outflow BCs. This methodology requires only end-diastolic and end-systolic geometries and is currently focused on CCT, which typically has a rather low temporal resolution due to the desired minimization of radiation dose and technical limitations. However, it is applicable in the same manner to MRI and echocardiographic data. To demonstrate the technical and clinical feasibility, the methodology was applied to four cases, each representing a subcohort of a pathological state of heart failure patients after myocardial infarction.We evaluated the intraventricular hemodynamics of the four representative cases in terms of large-scale flow patterns, energetic behavior, and washout. The most noticeable observations were made in the MR cases. In these, no clear ring vortex structure evolves during the diastolic inflow. The E-wave jet is disrupted by the transported vortex tubes and the accompanying swirling motion supposedly prevents a distinct shear layer development, leading to fragmentary vortex formation. In the study of Le and Sotiropoulos , similarvia a straightforward exponential fit function. The resulting fits overestimate FCDIB in the first cycles and underestimate FCDIB in the later ones or vice versa , suggesting a correlation between E-wave jet orientation and washout. Based on this, the question arises as to what determines the inflow orientation. We identify two potentially interesting relationships in this study. First concerns the deformation. In cases M3A1 and M0A1, the strongest deformation appears in septal and inferior regions, e.g., segments 5 and 6  presented in this study are provided as open data in an online repository. The name of the repository and accession number can be found at: The studies involving human participants were reviewed and approved by the Ethics Committee-Charité Universitätsmedizin Berlin (EA2/177/20). The study was performed according to the principles of the Declaration of Helsinki.LG, NS, CK, and TK: conceptualization. LO, AS, NS, and CK: data curation. LO, LT, KV, JB, and LG: formal analysis and methodology. LG and TK: funding acquisition and supervision. LO and AS: visualization. LO, NS, CK, and LG: investigation. LO, KV, and LG: writing original draft. All authors review and editing. All authors contributed to the article and approved the submitted version.This study was funded by the Einstein Center Digital Future and by the DFG grants for the project Nr. 465178743 in frames of the SPP2311.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.


Takotsubo syndrome (TTS) is a transient but severe myocardial dysfunction that has been known for decades and is still to be fully understood regarding its clinical presentations and pathophysiological mechanisms. Cardiac magnetic resonance (CMR) imaging plays a key role in the comprehensive analysis of patients with TTS in acute and follow-up examinations. In this review, we focus on the major advantages and latest evolutions of CMR in diagnosis and prognostication of TTS and discuss future perspectives and needs in the field of research and cardiovascular imaging in TTS.Specific CMR criteria for TTS diagnosis at the time of acute presentation are established. In addition to identifying the typical regional wall motion abnormalities, CMR allows for precise quantification of right ventricular and left ventricular (LV) function, the assessment of additional abnormalities/complications , and most importantly myocardial tissue characterization .CMR enables a comprehensive assessment of the entire spectrum of functional and structural changes that occur in patients with TTS and may have also a prognostic impact. CMR can distinguish between TTS and other important differential diagnoses  with direct consequences on medical therapy. Takotsubo syndrome (TTS), which typically mimics acute coronary syndrome (ACS) with acute occurring symptoms such as angina pectoris or dyspnoea , 2, new Referring to the latest guidelines of the European Society of Cardiology (ESC), TTS is no longer classified as myocardial infarction with non-obstructive coronary arteries (MINOCA)  but rathFurthermore, large registers validate the predominance of 80% of patients being postmenopausal women , 21. UntIn the first period, major adverse cardiac events (MACE) such as acute heart failure, arrhythmias and cardiogenic shock are in frequency and complexity comparable to ST-elevation myocardial infarction (STEMI) with mortality rates of 3.5–5% in hospital , 25, 26 Due to its clinical presentation as STEMI or high-risk non-STEMI, TTS patients mandatorily need coronary angiography for the exclusion of myocardial infarction according to current guidelines , 29. HowTransthoracic echocardiography (TTE) is the image modality of choice in the acute presentation of ACS or TTS to assess amendments of the cardiac function and morphology. For instance, RWMA and RV-involvement  in the acute setting as well as mechanical complications (left ventricular outflow tract obstruction (LVOTO), mitral regurgitation (MR), wall rupture), LV thrombi, pericardial effusion and pulmonary artery pressure in the subacute phase and later course of the disease –35. FurtSubsuming, echocardiographic findings of high-risk TTS patients with adverse in-1hospital outcomes are the following: LVEF < 35% and low cardiac output, RV involvement, LVOTO, MR > 2 +, LV thrombi, pericardial effusion and wall rupture , 39.Notably, the diagnosis of rare TTS-patters beyond apical or midventricular forms is highly challenging and not reliably possible without other imaging modalities. During follow-up, TTE is broadly used to monitor the recovery of LV-function, the regression of RWMA and to detect the occurrence of mechanical complications .Whilst echocardiography being the most accessible and low cost in use and coronary plus ventricular angiography being performed to rule out acute myocardial infarction (AMI) in the acute phase, CMR displays the reference standard for the concise assessment of left ventricular (LV) and right ventricular (RV) volume and functions as well as detection of wall movement abnormalities (RWMA) , 41. FurRecently, specific CMR criteria for TTS diagnosis at the time of acute presentation were established which include the combination of typical RWMAs, oedema and the absence of evidence of irreversible tissue injury (late gadolinium enhancement (LGE)) .Moreover, CMR is a potent alternative if echocardiography generates suboptimal image quality, if urgent information about the ventricular morphology, potential differential diagnosis or complications of acute ischaemic cardiac symptoms are needed.CMR is uniquely suited for the evaluation of patients with TTC as gold standard for functional imaging and its unique ability of myocardial tissue characterisation. Regarding the CMR protocol in patients with suspected TTS Table , we outlIn accordance with the recent published standardized protocols by the Society for Cardiovascular Magnetic Resonance (SCMR), the initial scout should be followed by balanced steady-state free precession (bSSFP) or fast spin echo (FSE) sequences for image acquisition in short axis and long axis  orientations . These pConcerning TTS, one can visualize the typical RWMA of the LV with a major decrease of the ejection-fraction (EF) due to hypokinesia with ballooning of the apical region (82%), the midventricular region 17%), the basal region (1%) or of focal regions in very rare cases  in TTS patients, which commonly has been associated with prolonged hospitalization and higher rate of MACE , 45–47. Stiermaier et al. firstly described a transient reduction of the left atrial (LA) emptying fraction (EF) in the acute phase of TTS, with an LA-EF improvement from 42 to 51% after 3 to 5 months . Hence, Moreover, major complications like LV thrombi, pericardial or pleural effusion and very rare septum or free wall ruptures can easily be detected by the use of CMR . DespiteLatterly, the method of feature-tracking (FT) in CMR has become a promising parameter for the measurement of regional deformation like dyssynchrony and rotational parameters in all four heart chambers, corresponding to speckle tracking echocardiography , 50–52. Notedly, the usage of CMR-FT enabled the identification of several new parameters of prognostic relevance, such as transient myocardial dyssynchrony in the acute setting and preserved systolic torsion in the follow-up. Referring to Backhaus et al., especially patients with the typical apical ballooning, biventricular ballooning, reduced LVEF or malignancies were vulnerable for dyssynchrony, with a non-significant but trend on higher mortality. Additionally, radial- and circumferential strain allowed a reliable discrimination between apical and midventricular ballooning  Fig. 3)3).Fig. However, only few studies investigated the prognostic value of LV- and RV-FT. Accordingly, TTS patients show comparable strain-pattern like STEMI patients but with significantly lower values. Regarding the LV, radial and circumferential strain showed no predictive value, whereas the reduction of global longitudinal strain was identified as a potential parameter for long-term risk stratification . RecentlLatest investigations of both atria via CMR-FT showed at least a transient impairment of the LA reservoir and conduit function in acute TTS with an independent prediction of mortality.Meanwhile, the method of CMR-FT of the LV shows a high intra- and inter-observer reproducibility . CompareSubsuming the outlined potencies of CMR concerning functional changes in TTS-patients, we conclude the following: by performing bSSFP or FSE for cine imaging,  typical The enabling of a multiparametric myocardial tissue characterisation is one of the most advantageous capabilities of CMR to discriminate reversible from irreversible myocardial injury. Therefore, by the usage and absence of late gadolinium enhancement (LGE), one can preclude myocarditis or an ischaemic myocardial infarction (e.g. with spontaneous lysis of thrombus), which is, according to the latest literature, one of the main diagnostic criteria of TTS , 57. ConIn myocarditis, LGE pictures as patchy myocardial necrosis or/and fibrosis. However, focal LGE was detected in TTS-patients once low signal intensity (SI) thresholds of three standard deviations (SD) from a healthy myocardial reference contour were used. These findings are not reproducible when high SI thresholds are applied and fade out within weeks, which reflect their transient character , 58. SomRecapitulated, the absence of LGE at high SI thresholds remains a main diagnostic criterion for TTS, noteworthy that patchy LGE at lower SI might occur in rare cases. Nonetheless, until today no significant differences concerning clinical outcome of TTS-patients without- or with LGE of three SD have been validated in prospective registries , 59 Fig.Fig. 4DOne of the main features of TTS is acute inflammation of unknown mechanisms with an increment of intra- and extracellular fluid causing oedema and cellular injury with troponinaemia. A possible explanation is transient ischaemia or increased myocardial wall movement stress which rarely leads to persisting cellular damage compared to STEMI or myocarditis. Characteristically, in TTS patients, oedema is not limited to one coronary coverage area; it is mostly diffuse and vanishes alongside the recovery of myocardial contractility within weeks. Thus, oedema is a key diagnostic feature for the determination of severity and extent of myocardial stunning .Several CMR techniques for the visualisation of oedema, such as “T2-weighted block blood imaging” (T2bb) with equal suppression of blood and fat, native T1 mapping or T2 mapping, exist. In T2bb a SI ratio  equal to or greater than 1.9 is considered as oedema. Meanwhile, techniques for a more precise and objective assessment such as motion correction algorithms of parametric T1 and T2 mapping with bail out of saturation- and motion artefacts compared to routine T2 sequences gain wide consent  Fig. 5)5).Fig. Noteworthy, the field of mapping techniques for the detection of damaged myocardial areas without additional gadolinium contrast is rapidly developing with a huge variety of pulse sequences. For image acquisition, one should consider the timing of sequences prior to gadolinium application and the measurement of haematocrit within 24 h for the accurate measurement of extracellular volume fraction (ECV).For T1 mapping, modified Look locker inversion recovery (MOLLI) or shortened MOLLI (shMOLLI) are recommended Fig. .Fig. 6TT2 mapping is performed via single-shot bSSFP with different T2 prep times, gradient and spin echo (GraSE) and T2-weighted (T2w) via “black blood T2w short tau inversion recovery” (STIR) .In the acute phase, some small studies suggest significantly higher T1 and ECV values in areas of RWMA in TTS patients which persisted in the follow-up even after normalisation of LVEF. Likewise, T2 values were initially risen but normalised completely . Other sAggregating the stated capabilities of CMR in tissue characterisation of TTS patients, we suggest  the consCMR should be used whenever possible in the acute setting and follow-up for diagnosing and prognostication of TTS patients. The main potencies are the acquisition of valid and detailed information about contractility abnormalities, structural complications and tissue characterisation with absence of LGE and visualisation of oedema as a pathognomonic key feature in TTS. In detail, typical RWMA with ballooning patterns and myocardial oedema as a hint of reversible tissue injury are commonly visualised while LGE as proof of irreversible tissue injury is absent. However, the pathophysiological mechanisms underlying myocardial oedema remain unclear and subtle fibrosis may rarely be seen through LGE in TTS. Additionally, CMR is the validated gold standard for the detection of RV-TS and the detection of biventricular ballooning, which has incremental impact on morbidity and clinical outcome.Additionally, major information for the evaluation of potential differential diagnosis of acute ischaemic cardiac symptoms ((peri-)myocarditis, myocardial infarction) or possible complications  can easily be generated and converted and are important for therapeutic decision making.Notwithstanding the huge number of potential pathophysiological mechanisms underlying TTS, a gratifying explanation is yet to be proven. Further research in all fields including cardiovascular imaging is needed to better understand the pathophysiology and clinical spectrum of TTS. Such better knowledge regarding underlying myocardial and microvascular mechanisms is important before clinical trials with evidence-based therapeutic algorithms for treatment of TTS patients can be performed.Regarding clinical trials with CMR-imaging, promising opportunities for research exist in the wide field of FT and further validation and standardisation of mapping techniques. The occurrence of diffuse fibrosis as detected by T1 mapping techniques and its potential prognostic impact may be future research targets. Moreover, it needs to be assessed if there are specific mapping markers of TTS like specific T1 times and pattern in comparison to other relevant differential diagnosis like myocardial infarction or myocarditis.Most recently the pandemic of “severe acute respiratory syndrome coronavirus type 2” (SARS-CoV-2) as coronavirus disease 2019 (COVID-19) has led to a global health crisis. Myocardial injury emerged as a major predictor for worse outcome , 66 and


Background: Hemispatial neglect is a debilitating consequence of right hemispheric ischemic stroke (RIS), with evidence that patient-level factors influence neglect severity. Study objective: Determine if cardiac function is associated with presence and severity of neglect, independent of infarct size.Methods: Two hundred and eighteen non-demented, RIS with cerebral MRI and echocardiography who completed ≥1 of 4 tests evaluating neglect were included. Age- and sex- adjusted Z-scores defined neglect with severity categorized as no neglect, neglect on one or neglect on ≥2 tests. The dependent variable was presence of neglect (multivariable logistic regression), or neglect severity . The association with left ventricular (LV) structure/function (independent variable) was evaluated using separate nested adjustment models.Results: Patients were on average 61 yo (21–95), female (50%), black (53%), with an ejection fraction of 60% (IQR 20–75%). Fifty eight (27%) had neglect. Each 1 cm increase in LV systolic diameter was associated with a higher relative risk of having neglect on two tests compared to those with no neglect , but not after adjusting for education and DWI volume . Per 1 cm increase in left atrial (LA) diameter, the relative risk of having neglect on 2 tests vs. no neglect was over two times higher (95% CI 1.04–4.77), but lost significance in the final model .Conclusions: We found an association between markers of diastolic dysfunction  and severity of neglect, suggesting that cardiac structure, and function affects not only lesion volume, but also the functional consequences of infarct volume. Hemispatial neglect is a devastating consequence of right hemispheric ischemic stroke (RIS) and is associated with worse outcomes . SeveralThe study was approved by the Johns Hopkins Institutional Review Board, and all patients gave written informed consent. Inclusion criteria were admission to the hospital for acute RIS with diffusion weighted imaging (DWI) and clinically indicated TTE admitted at two academic hospitals . Patients were excluded if they had a cerebral hemorrhage, were non-English speaking, had history of dementia or other neurological disease affecting the brain, uncorrected hearing or visual acuity deficits, ongoing sedation, or were unable to undergo MRI imaging. Patients were approached for written consent while inpatients in the hospital and were evaluated for neglect testing within a time window of 24 h to 5 days from time of RIS. This inclusion criteria reflects that of a parent study, which is an ongoing longitudinal, prospective parent study of the history of neglect in patients with RIS.Neglect was determined using four, well-validated tests: horizontal line bisection, line cancellation, Ogden copy scene and gap detection and scored without knowledge of the study hypothesis, infarct volumes, or TTE findings . Four diZ-scores for neglect were defined based on normative data from 58 individuals of similar age who were admitted with TIA or were preoperative coronary artery bypass graft surgical candidates. These patients were chosen as norms due to the fact that they were felt to best represent the vascular risk factor profile that might influence the left ventricle and its function, but did not have an ischemic stroke. Although, using this population for norms might underestimate neglect , it would not overestimate neglect or effect the correlations evaluated in this study. Neglect was considered as both a binary and a categorical variable. Neglect was defined as having a Z-score of ≥2 on one of any of the four tests. Neglect severity was then categorized for those who completed at least two tests as: no neglect, neglect on 1 or neglect on ≥2 or more tests, as previously reported . The datTTE was obtained during admission at the discretion of the inpatient treatment team, but is fairly routine at the recruiting institution. All TTEs were performed by accredited technicians, with reports generated by board-certified cardiologists, and using the Philips IE33 ultrasound in standard 2D-analysis. The following variables were recorded from each patient's TTE report according to the pre-specified analysis: LV ejection fraction , LV ventricular diastolic diameter (cm), LV systolic diameter (cm), Left atrial (LA) diameter (cm) and mitral E to A ratio. Mitral E and A point velocities are components of the mitral inflow signal to assess diastolic filling.© software or MRICron©. Such techniques have been well-validated for calculating infarct volumes  or severity of neglect as defined above. Pre-specified TTE variables (primary independent variables) were each evaluated descriptively and in univariate analyses in association with the outcome of interest using crude logistic regression models. Subsequent models then explored the association between presence of neglect (multivariable logistic regression), and then severity of neglect  with each specified TTE variable in separate analyses, with the same nested adjustment models. Each of the LV variables were considered as separate independent variables, in separate models and were pre-specified prior to the analysis. Covariates were obtained at the time of consent and were chosen based on the possibility of confounding the association between neglect and the TTE variables. In a sensitivity analysis, the Bonferroni correction was applied to adjust for the potential for multiple comparisons.3. Education was dichotomized into 12th grade and over vs. below 12th grade. LVEF is reported per 10% increase.The nested adjustment models were as follows: Model 1 adjusted for sex, race, and age; Model 2 for Model 1 plus atrial fibrillation, and Model 3 for Model 2 plus education and DWI volume. Age was centered at 65 years old and considered in increments of 10 years. DWI volume was centered at the mean and considered in increments of 10 cmp < 0.05 was considered statistically significant.All statistical analyses were performed using Stata v14.1. Two-sided P-value 0.01).Two hundred and eighteen patients met inclusion criteria  and 212 p-value ≤ 0.01).There was no significant association between any of the TTE variables of interest and presence of neglect . When coWe found an association between markers of diastolic dysfunction  and severity of neglect, defined as more frequent neglect on four standard tests. Our findings are clinically relevant as hemispatial neglect can complicate acute rehabilitation therapy following a stroke, and is frequently associated with other cognitive deficits , so idenApart from the presence of atrial fibrillation, or acute LV thrombus, cardiac findings on TTE do not currently change stroke care. It is important to consider that there may be meaningful information that might be garnered from the TTE that is not currently used in the care of the stroke patient, particularly considering that this test is usually routine for comprehensive stroke centers in order to evaluate the cardiovascular system as recommended by the American Stroke Association guidelines. There were many LV variables that could have been chosen for analysis, including the E/E' ratio and the presence of tricuspid regurgitation. We chose to include those variables that are most generalizable based on those that are most frequently collected on routine stroke echo, and those that have the most evidence behind the association between their function and stroke outcome. We anticipate a time when the cardiac evaluation will be more tailored to the ischemic stroke patient; for example, further evaluating the function of the left atrium in a patient with cardioembolic stroke or embolic stroke of unknown source, while focusing on the LV and diastolic function for a patient with hemispatial neglect, may be informative.Here we show that incremental changes in LV function impact not only infarct volume, but also its functional consequences, measured by severity of neglect. If hemispatial neglect does not recover after a stroke, it is associated with poorer outcomes . As a reWe readily acknowledge limitations to our study. This was a cross-sectional analysis and we cannot comment on causality or mechanism. We required that participants complete at least one test to be eligible, and it may be that those with more severe neglect were unable to complete any tests, or fewer tests, potentially meaning our population had milder neglect. We would anticipate, however, that including those with more severe neglect would strengthen associations, rather than bias toward the null. Furthermore, the number of tests completed was more often constrained by time limitations due to other clinical assessments, rehabilitation, and so on. Even patients with severe neglect were generally able to complete line bisection and line cancellation. When performing a correction for the potential for multiple comparisons, our effect estimates were no longer statistically significant. We chose our independent variables a-priori and ran all estimates in separate models, but it may be that our findings are the result of chance.In conclusion, we have shown the possible importance of diastolic function in outcomes of RIS, specifically hemispatial neglect. Further, study of the possible mechanisms behind this association are needed.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study involving human participants were reviewed and approved by the Johns Hopkins Institutional Review Board in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


An isolated coronary sinus (CS) atrial septal defect (ASD) is defined as a CS unroofed in the terminal portion without a persistent left superior vena cava or other anomalies. This defect is rare and part of the wide spectrum of unroofed CS syndrome (URCS). Recently, several reports have described this finding. The database of New Tokyo Hospital was searched to determine the incidence of this defect. Additionally, to raise awareness of this condition, the findings from five patients with CS ASD who underwent surgical repair at New Tokyo Hospital are discussed.The patients were three women and two men with an age range of 63–77 years. All patients underwent transthoracic echocardiography and computed tomography, and one underwent magnetic resonance imaging. In two patients, the defect was found unexpectedly intraoperatively; left-to-right shunting was apparent in the other three patients preoperatively. The pulmonary-to-systemic blood flow ratio ranged from 1.42 to 3.1 following cardiac catheterization, and oxygen saturation step-up was seen on the right side of the heart. Valvular regurgitation was seen in 4/5 patients with different combinations and degrees of mitral, tricuspid, and aortic valve involvement. Right atrial and ventricular dilation were seen in 4/5 patients; three patients had left atrial dilation. Three patients experienced atrial fibrillation, and one of these also experienced paroxysmal ventricular contractions. All patients underwent surgical repair, and some underwent multiple procedures. One patient who had previously undergone kidney transplantation died approximately 1 year postoperatively; the remaining four patients are currently experiencing good activities of daily living without symptoms.CS ASD (Kirklin and Barratt–Boyes type IV URCS) comprised 1.3% of adult congenital heart surgeries and 0.07% of adult open-heart surgeries at New Tokyo Hospital from 1999 to 2019. At New Tokyo Hospital, cardiac surgery is performed mainly for patients with acquired cardiac disease, and CS ASD is rare. Early diagnosis is important, as well as early surgical repair in symptomatic patients, especially those with blood access shunts, which may overload the heart. The case of a poor prognosis in this series is noteworthy, as similar cases have not been reported previously.The online version contains supplementary material available at 10.1186/s13019-021-01522-x. Unroofed coronary sinus syndrome (URCS) is a rare congenital heart disease , 2. CoroIn general, the prognosis after repair is considered to be favorable, with an uneventful course. Reviewing past reports did not reveal any patients with a poor prognosis after repair of the same type of anomaly. Although some surgeons specializing in congenital heart disease may have the impression that CS ASD is not a concern, especially in hospitals performing surgery mainly for adult patients with acquired heart disease, CS ASD is very rare. The aim of this investigation was to discuss the epidemiology of and clinically important points related to this anomaly by reviewing the surgeries performed for congenital heart disease at New Tokyo Hospital, where surgeries are performed mainly for adult acquired heart disease.All included patients underwent surgical CS ASD repair between January 1999 and December 2019. Upon review of the hospital’s surgical records from the past 20 years, five cases  of CS ASD were identified, and the survival of the patients was confirmed. Their background characteristics are shown in Table Surgical cases of adult congenital heart disease and the number of open-heart surgeries were also investigated. Cases of off-pump coronary artery bypass grafting were included as open-heart surgeries, and patent foramen ovale was excluded from the investigation as a congenital heart disease  from the age of 33 years. Ostium secundum ASD was identified at age 42 at another hospital. He had undergone follow-up for 11 years at another hospital, and when chest X-ray (CXR) showed cardiomegaly with a cardiothoracic ratio (CTR) of 70%, he was referred to New Tokyo Hospital. Transthoracic echocardiography (TTE) showed significant dilation of the right atrium (RA), right ventricle (RV), and left atrium (LA), as shown in Table A 71-year-old woman had undergone regular follow-up to monitor AF. She underwent radiofrequency catheter ablation (RFCA) for frequent paroxysmal ventricular contractions (PVCs) focused on the right ventricular outflow tract (RVOT) in April 2011. Subsequently, she developed dyspnea with New York Heart Association (NYHA) class II heart disease, and she was referred to New Tokyo Hospital for aortic regurgitation (AR) progression in October 2012. Electrocardiography (ECG) showed AF but a stable heart rate of approximately 70 bpm. CXR showed cardiomegaly, with a CTR of 60%, and TTE showed moderate AR, mild-to-moderate MR, and definite dilation of the RA and LA. Although the TTE findings indicated CS dilation measuring 23 mm, no intracardiac shunt was identified preoperatively  for 2 years. Subsequently, she experienced episodes of presyncope. TTE and CT revealed an unroofed CS. She was referred to New Tokyo Hospital to confirm indications for surgical repair. CXR showed no significant signs of heart failure. Her heart rate was stable, with a normal sinus rhythm. TTE showed a large defect between the LA and the CS, measuring 16 mm in width. The Qp/Qs was estimated at 2.1, and severe TR was observed. The RA and RV were definitely dilated Table , with clA 65-year-old man was referred to New Tokyo Hospital with NYHA class II dyspnea. CXR showed an almost normal cardiac size, with a 51% CTR and no other signs of congestion. His heart rate was approximately 70 bpm with a sinus rhythm during ECG. TTE showed a dilated CS orifice measuring 24 mm × 18 mm, and shunt flow was visible at almost the same point, which suggested blood flow from the LA through the unroofed CS to the RA. The Qp/Qs was 2.0, and the RA and RV were definitely dilated , tricuspid annuloplasty (TAP), a biatrial maze procedure, and RA plication. Cardiopulmonary bypass was commenced by ascending aortic cannulation near the aortic arch and both superior vena cava (SVC) and inferior vena cava (IVC) cannulation. Aortic cross-clamping (AXC) was performed with antegrade cardioplegia (CP) through the aortic root. Under cardiac arrest, the secundum ASD was found to measure 30 mm × 40 mm, and an unroofed CS to the LA was identified. A retrograde CP cannula was inserted from the CS directly. After opening the right side of the LA, the mitral valve could be observed. Dilation of the mitral annulus, mild myxomatous degeneration on the leaflets, and a relatively normal subvalvular apparatus were observed. Maze cryoablation, MAP with a 30-mm ring, and TAP with a 36-mm band were performed. Finally, the secundum ASD was closed with an autologous pericardial patch using 5–0 polypropylene (ppp) running sutures. The CS ASD was also closed by direct suturing or the application of an autologous pericardial patch from the left atrial side.On 15 January 2013, the patient in case 2 underwent aortic valve replacement with a 25-mm bioprosthesis, mitral valve repair (plasty) (MVP) with anterior commissurotomy, anterior mitral leaflet thinning by peeling of the thickened intima , MAP witIn 2016, surgery for the repair of preoperatively diagnosed CS ASD was performed for the patient in case 3 on 16 March, that in case 4 on 25 July, and that in case 5 on 4 October, described below.Under general anesthesia and with a median sternotomy, cardiopulmonary bypass was performed between the ascending aorta and both vena cavae. Myocardial protection was achieved with cold-blood CP through the aortic root. After AXC and cardioplegic arrest, the RA was opened. With a trans-interatrial septal approach, the septum was retracted to clearly observe the mitral valve, and the CS defect was identified from the left atrial side. The defect was observed near the mitral posterior commissure Fig. . The uppIn case 3, TAP with a 26-mm band was added. In case 5, MAP was performed with a 28-mm ring, along with valvuloplasty on both the P1–P2 and P2–P3 indentations, TAP with a 30-mm band, and a left atrial maze procedure  and 7314 open-heart surgeries were performed  without other complex congenital anomalies, i.e., case 5 provided novel insights. In case 5, volume overload of the cardiac chambers resulted in AF, annular dilatation of the atrioventricular valves, and atrial functional TR/MR. Furthermore, a blood access shunt for renal dialysis overloaded the patient’s heart. Although renal failure and disuse syndrome cause systemic failure, leading directly to the patient’s death, surgical intervention before the progression of arrhythmia and/or valvular dysfunction is still recommended. Therefore, it is very important to make a true diagnosis as early as possible.Optimal timing for surgical intervention is also very relevant. The indications for the operation in case 4 may be controversial because the Qp/Qs was 1.42 according to the catheter analysis, while a Qp/Qs of 2.0 was determined using echocardiography. Some may suggest that it was too early to decide to perform a surgical intervention in case 4. However, the isolated CS ASD was closed because of dyspnea and dilation of the RA and RV. As noted above, in case 5, the blood access shunt for renal dialysis had been overloading the patient’s heart before the operation for 34 years, which may have been an additional and fatal load for this patient specifically. In contrast to the patient in case 5, the patient in case 1 has lived in very good health for 15 years after the operation, even with renal dialysis, which was introduced due to renal sclerosis 10 years after the repair.It is often difficult to diagnose CS ASD. Notably, the patients in cases 1 and 2 had no preoperative diagnosis of CS ASD. In case 1, because of the large secundum ASD, the echocardiographer might have disregarded other congenital anomalies. Intraoperatively, the initial CP was performed in an anterograde manner from the aortic root, and cannulation for retrograde CP was performed from the CS ostium directly, so blind cannulation injury to the CS roof was impossible. In case 2, preoperative TTE revealed CS enlargement but did not show the defect on the CS roof or the intracardiac shunt. Retrospectively, preoperative computed tomography (CT) was performed only in the axial view, so the defect could have been overlooked. The patient in case 2 had previously undergone RFCA to treat frequent PVCs associated with the RVOT; the catheter was not inserted into the CS, so iatrogenic damage to the roof of the CS caused by the catheter was impossible. TEE, MRI, and three-dimensional CT are quite helpful for diagnosing both CS ASD and other concomitant congenital anomalies , 11–13.In this case series, there were no cases of PLSVC, and each CS roof defect was closed from the left atrial side through a right-side left atrial approach in 2005 and 2013 and a trans-interatrial septal approach in 2016. URCS is a rare congenital heart disease . The atrRepairs were performed from the left atrial side through standard and orthodox approaches, although simple closure of the CS orifice is also indicated for URCS without PLSVC, with permissible right-to-left shunts . There hThere are several limitations to this study. First, this was a retrospective observational study at a single center. Second, over the past 20 years, echocardiography was performed using different equipment in case 1 in 2005 than in the other cases. Third, the surgical approaches were not the same, i.e., the right-side left atrial approach was used in 2005 and 2013, and the interatrial septal approach was used in 2016. Finally, repair was performed from the left atrial side through these two approaches, which was not novel, although standard and orthodox approaches were used. However, the whole interior of the LA could be observed, allowing the type of unroofed CS and other cardiovascular anomalies to be confirmed.In conclusion, CS ASD was very rare at New Tokyo Hospital from 1999 to 2019. There were five adult patients (Kirklin and Barratt-Boyes type IV URCS) who underwent surgical ASD repair in the past 20 years. One of the patients died approximately 1 year after the operation. Reviewing past reports revealed no patients with a poor prognosis after repair of the same type of anomaly. It is very important to make a true diagnosis as early as possible. When CS enlargement is identified, PLSVC and other anomalies must be ruled out. Otherwise, it can be difficult to identify the true diagnosis. In particular, in cases of an isolated CS ASD, there are often almost no symptoms, and the defect can be missed on TTE , 19.Additional file 1: Supplemental Table 1. Number of congenital heart disease and open-heart surgeries performed in the past 20 years. The numbers in parentheses represent the number of concomitant anomalies. The cases were as follows: one case of VSD (type I) with concurrent RVOT stenosis in 2002; one case of secundum ASD with PLSVC in 2003; one case of secundum ASD with sinus venosus ASD and one case of secundum ASD with PDA in 2005; one case of BAV with PDA in 2006; one case of secundum ASD with VSD (type II) and one case of sinus venosus ASD with PAPVR in 2007; one case of sinus venosus ASD with PAPVR and PLSVC in 2008; one case of BAV with PDA in 2009; one case of PDA with CoA in 2010; one case of secundum ASD with PA stenosis in 2012; one case of secundum ASD with PA aneurysm in 2013; one case of BAV with CPAF in 2014; one case of VSD (type II) with a double-chamber RV in 2015; and one case of sinus venosus ASD with concomitant PAPVR in 2017. The details of “others” in Table ASD atrial septal defect, URCS unroofed coronary sinus, VSD ventricular septal defect, I type I VSD, II type II VSD, PAPVR partial anomalous pulmonary venous return, AVSD atrioventricular septal defect, ToF tetralogy of Fallot, BAV bicuspid aortic valve, CoA coarctation of the aorta, PDA patent ductus arteriosus, Ebstein Ebstein anomaly, CPAF coronary artery–pulmonary artery fistula, OHS open-heart surgery, PA pulmonary artery, QAV quadricuspid aortic valve.


Miñana and Núñez wrote an editorial to introduce the contents in a Special Issue of the Journal of Clinical Medicine focused on “Epidemiology, Diagnosis, Pathophysiology, Risk Stratification, and Therapy of Heart Failure with Preserved Ejection Fraction” . Here, tIn patients with heart failure (HF), left ventricular (LV) diastolic dysfunction mainly causes HF symptoms such as dyspnea, irrespective of LV ejection fraction (EF). An elevated LV filling pressure due to LV diastolic dysfunction produces dyspnea at rest and on exercise . Even whThe pathogenesis of HFpEF is multifactorial. It has been recognized that in addition to LV diastolic dysfunction caused by myocardial abnormality, a disorder in the LV-aortic coupling, atrial fibrillation, functional mitral regurgitation, and extracardiac comorbidities such as aging, female sex, hypertension, diabetes, chronic kidney disease, chronic obstructive lung disease, anemia, obesity, and frailty, may contribute to the HFpEF pathophysiology ; howeverInterests regarding HFpEF maybe how to diagnose LV diastolic dysfunction noninvasively and how to treat HFpEF with evidence-based.Noninvasive diagnosis of LV diastolic dysfunction in patients with preserved LVEF should be performed using the American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) recommendations A and B as a standard manner . The ASEIn drug therapy for HFpEF, a couple of drugs have been noticed to have beneficial effects in the HFpEF patients with LVEF approximately <60% ,11. LVs


Our data indicate that PDvol assessed by DECT software technique may be a helpful tool to assess the severity of acute PE when compared to obstruction score and RV/LV diameter ratio.The purpose of the study was to investigate whether Dual Energy CT (DECT) can be used as a diagnostic tool to assess the severity of acute pulmonary embolism (PE) by correlating parenchymal perfusion defect volume, obstruction score and right ventricular-to-left ventricular (RV/LV) diameter ratio using CT angiography (CTA) and DECT perfusion imaging. A total of 43 patients who underwent CTA and DECT perfusion imaging with clinical suspicion of acute PE were retrospectively included in the study. In total, 25 of these patients had acute PE findings on CTA. DECT assessed perfusion defect volume (PDvol) were automatically and semiautomatically quantified. Overall, two CTA methods for risk assessment in patients with acute PE were assessed: the RV/LV diameter ratio and the Modified Miller obstruction score. Automatic PDvol had a weak correlation ( Pulmonary embolism (PE) is a common clinical condition being third on the list of cardiovascular causes of death . Severe Computed tomography angiography (CTA) is considered the first-line imaging modality for suspected acute PE . CTA canDual-energy computed tomography (DECT) has made it possible to simultaneously obtain angiographic CT imaging and pulmonary perfusion maps due to the ability to visualize contrast (iodine) distribution within the pulmonary parenchyma. A number of studies have demonstrated the potential of DECT in the diagnosis of acute PE by manual visualization of wedge-shaped pulmonary perfusion defects ,9,10.Similar to CTA obstruction score, there have been developed scoring systems for perfusion defects using manual measurement on DECT iodine distribution maps ,12. DECTThe aim of this study was to investigate whether PDvol measured by an automatic and semiautomatic DECT software technique can be used as a diagnostic tool to assess the severity of acute PE by correlating PDvol with CTA obstruction score and RV/LV diameter ratio.The study is a retrospective single-center study. The institutional review board at our institution approved the study, and informed patient consent was waived due to the retrospective nature of this study (Ref. No. 20036558).Between August 2019 and January 2021, 107 patients with the clinical suspicion of acute PE received a Dual-energy CTA at our department. A total of 64 were excluded, 46 patients due to underlying lung pathology and 18 patients due to reduced image quality of the DECT or CTA scan that potentially could affect the evaluation of pulmonary perfusion, obstruction score, or RV/LV diameter ratio, e.g., artifacts, insufficient vascular enhancement, metastatic pulmonary neoplasm, pulmonary infection, and pleural effusion. Overall, 43 patients  were finally included. In total, 25 of the included patients were confirmed with acute PE findings on CTA, while 18 patients did not have any CTA findings associated with acute PE .All CT scans were performed on a single source DECT scanner . Tube voltage switched between 80 and 140 kV, and images were acquired in a single breath hold in the caudo-cranial direction from under the diaphragm to the lung apex. A 62 keV virtual monoenergetic dataset for pulmonary CTA series was simulated. A split bolus was injected into an antecubital vein through a power injector: first bolus consist of 35 mL Omnipaque 350mgI/mL,  followed by 15 mL saline solution and second bolus of 15 mL Omnipaque 350 mgI/mL, followed by 30 mL saline solution. Injection flow rate was 5.0 mL/s. A bolus-tracking technique was applied; imaging was automatically initiated 4.6 s after the enhancement level reached the threshold of 120 Hounsfield Units in the region of interest (placed in the pulmonary trunk). Detector collimation was set to 80 mm, gantry rotation time was 0.5 s, pitch value was 1.531, scan field of view was 500 mm, display field of view depended on the patient size, and reconstruction with a slice thickness of 0.625 mm, and an increment of 0.625 mm.One fifth-year radiology resident (SJ) evaluated all CTA studies on a PACS workstation  without any awareness of the initial CTA results and without the knowledge of iodine perfusion maps, PDvol or RV/LV diameter ratio. The presence of filling defects in pulmonary arteries on CTA in patients with relevant clinical suspicion was used to diagnose acute PE. The presence of filling defects in the pulmonary arteries, degree of obstruction and their locations were recorded. The same radiologist reviewed RV/LV diameter ratio 2 weeks after assessing the obstruction scores with the scans in random order.The CTA obstruction score was calculated using the modified Miller (MM) score, as described by Qanadli et al. . This scRV/LV diameter ratio was assessed using the axial (transverse) method . Both riAutomated quantification of TLV and PDvol were assessed using the commercially available image post-processing Dual Energy software  and a GE Healthcare AW workstation .3, PDvol is given both in cm3 and as a ratio in percentage when normalized to TLV (PDvol cm3/TLV cm3). In this study, PDvol normalized to TLV is used for the analyses.The thoracic VCAR application with GSI pulmonary perfusion can be used to visualize pulmonary perfusion by showing colorized iodine overlay of the lung parenchyma and to identify regions with relative perfusion deficit based on the iodine concentration in that region . The sofFurthermore, a semiautomatic approach for quantification of TLV and PDvol was assessed, where the only difference from the automatic quantification method was a manual adjustment of the threshold value. One radiologist (PSU), who had 11 years of clinical experience, blindly adjusted the threshold value based on visual evaluation on the colorized iodine overlay maps  to either) was used to assess agreement between PDvol, CTA obstruction score and RV/LV diameter ratio. Correlation coefficient (r) values were interpreted as follows: < 0.20 (no association), 0.20–0.49 (weak), 0.50–0.79 (moderate), and > 0.80 (strong) [t-test was used to evaluate the difference between the group with confirmed acute PE findings, and the group without acute PE findings. The two tailed p-value < 0.05 was considered statistically significant.Statistical analysis was performed with the use of IBM SPSS Statistics v25 . Pearson correlation coefficient ((strong) . Indepenr = 0.51, p < 0.001)    .Automatic PDvol had a moderate correlation with MM score (< 0.001) , and a w= 0.002) . Semiaut< 0.001) , and a m< 0.001) . RV/LV dr = 0.47, p = 0.02), but a non-significant correlation with RV/LV diameter ratio . Semiautomatic PDvol had a moderate correlation with MM score , and a weak correlation with RV/LV diameter ratio , while RV/LV diameter ratio had a moderate correlation with MM score .Automatic PDvol had a weak correlation with MM score .Automatic PDvol, semiautomatic PDvol and RV/LV diameter ratio were significantly higher in the acute PE group compared with the group without acute PE findings using MM score as the reference  with obstruction score (MM score), axial RV/LV diameter ratio (r = −0.52) and serum troponin I (r = −0.45) [r = 0.33) but no correlation between PDvol and the axial RV/LV diameter ratio using a semiautomatic method to assess perfusion defects [Apfaltrer et al. and Meinel et al., also used automatic or semiautomatic quantification of pulmonary perfusion to assess acute PE severity by correlating pulmonary perfusion with obstruction score and RV/LV diameter ratio ,20. WithSeveral other articles have also reported a moderate to high correlation between perfusion defect score with both obstruction score and RV/LV diameter ratio while using a manual scoring method to assess perfusion defect score ,12,21,22n = 20) with acute PE  had low automatically quantified PDvol (≤2%), despite relative high MM obstruction scores (n = 4) in the group without detectable acute PE (MM score = 0) on CTA had high automatically quantified PDvol of > 10%  with single-photon emission computed tomography (SPECT-CT) in the quantification of relative lobar perfusion [There were several limitations in our study. Interobserver variation in terms of reproducibility could not be measured as one radiologist assessed obstruction score and RV/LV diameter ratio while another radiologist assessed semiautomatic PDvol. No evaluation of experience level was assessed, and the results of this study may therefore only apply for readers with similar experience. We did not compare RV/LV diameter ratio or PDvol to their respective reference standard: echocardiography and lung perfusion scintigraphy. Data were not correlated with patient outcome, clinical or laboratory PE severity parameters. A recent study showed that DECT iodine maps had a strong correlation (erfusion . DECT puerfusion . Our stuIn this small retrospective study, our data indicate that PDvol assessed by automatic and semiautomatic DECT software technique may be a helpful tool to assess the severity of acute PE when compared to obstruction score, while only semiautomatic PDvol may assess the severity of acute PE when compared to RV/LV diameter ratio.


Patients with primary aldosteronism (PA) have cardiac remodeling due to hemodynamic and non-hemodynamic causes. However, component analysis of cardiac remodeling and reversal in PA patients is lacking. We investigated components of cardiac remodeling and reversal after adrenalectomy in patients with aldosterone-producing adenoma (APA).This study prospectively enrolled 304 APA patients who received adrenalectomy and 271 with essential hypertension (EH). Clinical, biochemical and echocardiographic data were collected in both groups and 1 year after surgery in the APA patients. The hemodynamic and non-hemodynamic components of left ventricular (LV) remodeling were represented by predicted left ventricular mass index (LVMI) (pLVMI) and inappropriately excessive LVMI .After propensity score matching, 213 APA and 213 EH patients were selected. APA patients had higher hemodynamic (pLVMI) and non-hemodynamic (ieLVMI) components of LV remodeling than EH patients. In multivariate analysis, baseline pLVMI was correlated with systolic blood pressure (SBP) and serum potassium, whereas ieLVMI was correlated with log plasma aldosterone concentration but not blood pressure. Post-operative echocardiography was available in 207 patents and showed significant decreases in both pLVMI and ieLVMI after adrenalectomy. In multivariate analysis, ΔpLVMI was correlated with SBP, ΔSBP, and pre-operative pLVMI, whereas ΔieLVMI was correlated with Δlog aldosterone-to-renin ratio (ARR) and pre-operative ieLVMI.This study concluded that extensive cardiac remodeling in APA patients occurs through hemodynamic and non-hemodynamic causes. Adrenalectomy can improve both hemodynamic and non-hemodynamic components of LV remodeling. Regressions of pLVMI and ieLVMI were correlated with decreases in blood pressure and ARR, respectively. We investigated cardiac remodeling and reversal after adrenalectomy in 304 patients with aldosterone-producing adenoma (APA) with 271 essential hypertension (EH) through hemodynamic and non-hemodynamic components as predicted left ventricular mass index (LVMI) (pLVMI) and inappropriately excessive LVMI (ieLVMI). APA patients had higher pLVMI and ieLVMI correlated with blood pressure and aldosterone. 207 APA patents showed decreased pLVMI and ieLVMI after adrenalectomy with ΔpLVMI correlated with blood pressure and ΔieLVMI correlated with Δlog aldosterone-to-renin ratio. This study demonstrated improved cardiac remodeling in APA patients through hemodynamic and non-hemodynamic causes after adrenalectomy, which correlated with decreases in blood pressure and ARR, respectively.Primary aldosteronism (PA) is a disease featuring excessive endogenous aldosterone , 2. PrevCardiac remodeling is prognostic and linked to heart failure progression . It maniHypertension plays a key role in the hemostasis of hemodynamics, is a well-known risk factor for LVH , and is Inappropriate left ventricular mass is defined as the ratio between measured and predicted left ventricular mass taking sex, body size, and cardiac workload into account. It represents a non-hemodynamic or neurohormonal cause of LVH, and it has been reported to offer additional prognostic value in patients with LVH , 13. A pIn this study, we compared measured, predicted, and inappropriately excessive left ventricular mass between a prospective cohort of patients with aldosterone-producing adenoma (APA) and EH controls, and evaluated their associations with cardiac remodeling and treatment response after unilateral adrenalectomy. We further investigated the pathogenesis of LVH due to hemodynamic and non-hemodynamic causes.We enrolled patients with PA and EH from October 2006 to January 2016 from National Taiwan University Hospital. The PA patients were all registered in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database . Detailein vitro using a commercially available radioimmunoassay kit . All antihypertensive medications were discontinued for at least 21 days before measuring plasma PRA and PAC as suggested in clinical guidelines. Diltiazem and/or doxazosin were administered to lower elevated blood pressure when clinically indicated.Physiological assessments of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were obtained using a sphygmomanometer according to clinical guidelines. Plasma aldosterone concentration (PAC) was measured using a radioimmunoassay with a commercial kit , and plasma renin activity (PRA) was measured as the generation of angiotensin-I This study was conducted in compliance with the Declaration of Helsinki, and it was approved by the Institutional Review Board of National Taiwan University Hospital . Informed consent was obtained from all individuals before enrollment.The confirmation and diagnosis of PA and further identification of APA were made according to previously published protocols and algorithms , 17. PatA standardized echocardiographic ultrasound system  was used, and transthoracic echocardiographic images were obtained in fundamental imaging modes by experienced and qualified technicians blind to the clinical diagnosis. M-mode measurements, two-dimensional imaging with standard views, and Doppler ultrasonography were acquired in each patient.via the parasternal long axis view according to the guidelines of the American Society of Echocardiography (3 - (LV end-diastolic diameter)3]-13.6]  (Left ventricular (LV) dimensions, septal and posterior wall thickness, and LVEF (M-mode) were measured iography . Echocar3]-13.6] , then inemale=2) . Left veemale=2) . Inapproemale=2) . LVH wasemale=2) . The cutemale=2) . In thisAll continuous variables were expressed as mean ± SD if normally distributed and as median with interquartile range if non-normally distributed. The PA group and EH controls were matched using propensity score matching adjusted for age, sex, SBP, DBP, number of antihypertensive medication types, hypertension history using the Python-based extensions, FUZZY and PSM, in SPSS. All continuous variables were compared across groups using the Student’s t test  or the Wilcoxon rank-sum test , while the paired sample t-test was used if two groups were dependent. Categorical variables were presented as counts and percentages and were compared using the McNemar test. Equality of two proportions was assessed using the Pearson chi-square test. Data of PAC, PRA, and ARR were log-transformed due to non-normality as assessed using the Kolmogorov–Smirnov test. Pearson’s correlation tests were performed to determine correlations between LVMI/pLVMI/ieLVMI and ΔLVMI/ΔpLVMI/ΔieLVMI and clinical parameters. Significant determinants found in the Pearson’s correlation test (p ≦ 0.05) were then examined using a multivariate linear regression test with backward subset selection to identify independent factors predicting LVMI/pLVMI/ieLVMI and ΔLVMI/ΔpLVMI/ΔieLVMI. All statistical analyses were performed using SPSS for Windows version 25.0 . All tests were two-tailed, and a p value of ≤ 0.05 was considered to indicate statistical significance.In this study, we enrolled 304 patients with PA, all of whom had APA, and 271 EH patients. The basic clinical characteristics of the patients are listed in Echocardiographic parameters were then compared between the APA and EH groups before and after propensity score matching Table 2.Regression analysis of factors predicting LVMI/pLVMI/ieLVMI in the study cohort are listed in Among the 304 APA patients, echocardiography data 12 months after adrenalectomy were available in 207, and their clinical and echocardiographic data are listed in Comparison of the changes before and after operation of APA according to clinical cure or clinical non-cure was demonstrated in Regression analysis of factors predicting changes in LVMI/pLVMI/ieLVMI after adrenalectomy among the APA group are listed in There are five findings in this study. First, after propensity score matching for age, sex, SBP, DBP, hypertension duration, and use of antihypertensive, the APA patients had greater LVMI, pLVMI, and ieLVMI, with more LVH compared to the EH patients. Second, LVMI was independently associated with SBP, number of antihypertensive medication types, and log-transformed PAC, while pLVMI (hemodynamic component of LV remodeling) was associated with SBP, and ieLVMI was associated with log-transformed PAC (non-hemodynamic component of LV remodeling). Third, significant regressions of LVMI, pLVMI and ieLVMI and reversal of LVH were observed after adrenalectomy. Fourth, ΔLVMI was associated with SBP, ΔSBP, and Δlog-transformed ARR, while ΔpLVMI was associated with SBP, and ΔSBP and ΔieLVMI were associated with Δlog-transformed ARR. These findings clearly showed the factors associated with hemodynamic and non-hemodynamic component of LV remodeling in PA patients, and the factors associated with the regression of both components after adrenalectomy. Last, the study demonstrates that inappropriately excessive left ventricular mass (ieLVM) could be a novel and promising parameter evaluating aldosterone-induced non-hemodynamic left ventricular remodeling.A previous meta-analysis reported that LVH identified by ECG or echocardiography was highly prognostic and an independent risk factor for cardiovascular outcomes . In addiAn inappropriate increase in LVM, which is referred to as an abnormal (non-compensatory) increase in LVM as opposed to a normal (compensatory) LVM increase, has been reported to be more strongly associated with more metabolic risk factors . PreviouSeveral previous studies have reported differences in LVMI and LVH between PA and EH groups and improvements after surgery or medications. Rossi et al. reported increased LV wall thickness and LVMI with higher percentages of LVH and concentric remodeling in PA patients compared to matched EH controls, and that adrenalectomy markedly reduced LV wall thickness and LVMI in APA patients . Catena To the best of our knowledge, this prospective cohort study includes the largest sample size to date, with 304 PA patients  and 271 EH controls, and 213 matched pairs. The cases were matched using propensity score matching for sex, age, SBP, DBP, number of antihypertensive medication types, and hypertension history, with the aim of eliminating as many confounding factors as possible. The use of ieLVMI is different from previous studies and demonstrated the effect of excessive aldosterone on LVH in addition to adaptation to compensate for hemodynamic load. Our findings may help to improve the prediction of cardiovascular outcomes after eliminating the influence of hypertension. The utilization of LVMI, pLVMI and ieLVMI provided further insight into the pathogenesis of increased LVMI, a process involving mixed etiologies, in which pLVMI represented the hemodynamic component and ieLVMI the non-hemodynamic component. Correlation studies of LVMI/pLVMI/ieLVMI between the patients with APA and EH identified the factors associated with increased LVMI, while correlation studies of ΔLVMI/ΔpLVMI/ΔieLVMI after adrenalectomy identified the factors associated with changes in LV morphology and treatment effect of adrenalectomy. Of note, ΔLVMI was independently correlated with ΔSBP and ΔlogARR. Furthermore, ΔpLVMI was independently correlated with ΔSBP, while ΔieLVMI was correlated with ΔlogARR. These findings emphasize the treatment benefits of adrenalectomy, which both reduces blood pressure and aldosterone by removing the aldosterone secreting source in the adrenal gland, thereby resulting in LVH regression in both hemodynamic and non-hemodynamic pathways. The use of ieLVMI has the advantage of excluding the influence of blood pressure on the left structure. In addition, the exclusive association between ΔieLVMI and ΔlogARR consolidates the pathogenesis of aldosterone-induced neurohormonal LVH, which is independent of the influence of hypertension. Moreover, this shows that the treatment effect of adrenalectomy was not just from treating hypertension.There are several limitations to this study. First, this clinical study showed the association between preoperative and postoperative endocrinological and cardiac structural changes, however the study design cannot elucidate the actual causative role of aldosterone in LV remodeling. Second, our follow-up period was 1 year, and longer follow-up periods are warranted to examine whether there is any further late-onset effect of adrenalectomy. Third, we did not perform the saline load test with plasma aldosterone measurement and fibrinogen level on all the APA patients before and after the operation. Fourth, this study only investigated excess aldosterone and showed that elevated ARR increased LVMI, but the effect on cardiovascular mortality or morbidity was not investigated. Further long-term follow-up studies are needed to investigate the clinical impact of aldosterone excess on cardiovascular outcomes.Extensive cardiac remodeling through hemodynamic and non-hemodynamic causes occurs in APA patients. Adrenalectomy improved both hemodynamic and non-hemodynamic components of LV remodeling. The regression of pLVMI and ieLVMI were correlated with decreases in blood pressure and ARR, respectively. These findings provide further evidence of aldosterone-induced hemodynamic and non-hemodynamic LV remodeling in patients with PA, and the effect of adrenalectomy.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 National Taiwan University Hospital (NTUH) Research Ethics Committee (REC). The patients/participants provided their written informed consent to participate in this study.C-TP: experimental design and manuscript writing. X-MW, C-HT, Y-YC and ZW-C: patient enrollment and experimental design. C-CC and B-CL: diagnosis helping, AVS, and report. C-WL and Y-LC: patient case management and experimental design. L-CL and Y-RC: diagnosis helping, echocardiography, experimental design. C-SH and Y-HL: patient enrollment, experimental design, funding raising, manuscript editing. All authors contributed to the article and approved the submitted version.This study was partially supported by grants from the Ministry of Science and Technology (MOST 106-2314-B-002 -048 –MY3) and National Taiwan University Hospital (NTUH 109-A141). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.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.


N-oxide (TMAO), a gut microbiota metabolite from dietary phosphatidylcholine, is mechanistically linked to cardiovascular disease (CVD) and adverse cardiovascular events. We aimed to examine the relationship between plasma TMAO levels and subclinical myocardial damage using high-sensitivity cardiac troponin-T (hs-cTnT). We studied 134 patients for whom TMAO data were available from the Cohort Of patients at a high Risk of Cardiovascular Events—Thailand (CORE-Thailand) registry, including 123 (92%) patients with established atherosclerotic disease and 11 (8%) with multiple risk factors. Plasma TMAO was measured by NMR spectroscopy. In our study cohort , median TMAO was 3.81 μM (interquartile range [IQR] 2.89–5.50 μM), and median hs-cTnT was 15.65 ng/L (IQR 10.17–26.67). Older patients and those with diabetic or hypertension were more likely to have higher TMAO levels. Plasma TMAO levels correlated with those of hs-cTnT  and were significantly higher in patients with subclinical myocardial damage . After adjusting for traditional risk factors, elevated TMAO levels remained independently associated with subclinical myocardial damage . This study demonstrated that plasma TMAO was an independent predictor for subclinical myocardial damage in this study population.Plasma Trimethylamine- N-oxide (TMAO) is a gut microbiota metabolite from dietary phosphatidylcholine (PC) which present in red meat, egg yolks and liver. Increasing data support the role TMAO in the pathogenesis of cardiovascular disease (CVD)5. Importantly, elevated plasma TMAO levels are correlated with future risk of adverse cardiovascular events, increased CVD prevalence, number of diseased coronary vessels and atherosclerotic burden of coronary artery disease (CAD)7.Trimethylamine-8. Assays to detect circulating high-sensitivity cardiac troponin (either T or I) allow for the robust detection of very low troponin concentrations, an indicator of subclinical myocardial damage (SMD) in asymptomatic patients10. Several studies have shown a link between SMD and future risk of adverse cardiovascular events in stable patients with and without CVD, particularly in the general population14.High sensitivity cardiac troponin is a sensitive and specific biomarker of myocardial damage and has been used in the clinical diagnosis of myocardial infarction in acute coronary syndrome (ACS)Several studies have demonstrated the mechanisms underlying the link between elevated plasma TMAO and CVD pathogenesis/risk of cardiovascular events. We thus sought to examine the relationship between plasma TMAO levels and high-sensitivity cardiac troponin T (hs-cTnT) in stable patients at high risk of cardiovascular events.Overall baseline characteristics of the 134 patients in the study population are shown in Table Baseline characteristics were stratified according to presence of SMD. Overall, there were 77 (57%) patients with SMD (hs-cTnT ≥ 14 ng/L). Those with evidence of SMD were more likely to be male, and a slightly higher percentage used angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB). By contrast, history of hypertension, diabetes, EAD status, and renal function did not differ by SMD status. Interestingly, SMD was significantly associated with higher TMAO levels .Plasma TMAO was strongly correlated with hs-cTnT  Fig. . In univElevated TMAO remained a significant predictor of SMD after multivariate logistic regression analysis, which adjusted for traditional risk factors , EAD status, and ACEI/ARB use  in stable patients at high risk of cardiovascular events (123 [92%] with EAD and 11 [8%] with MRFs). The prevalence of SMD in our study cohort was 57%, despite our including stable patients without evidence of ACS at presentation. The key finding of our study is the strong significant association between fasting plasma TMAO levels and SMD. Furthermore, elevated TMAO was an independent predictor of SMD, even following adjustment for traditional risk factors, EAD status, and ACEI/ARB use.5. This is consistent with several other recent studies in subsets of stable patients with elective coronary angiography, peripheral artery disease, diabetes mellitus, chronic kidney disease, CAD, history of heart failure (HF), and even those without CVD15.TMAO, a gut microbiota-generated metabolite, plays an important role in global metabolism. Recent reports have shown that increased levels of plasma TMAO are associated with adverse cardiovascular outcomes and have a direct mechanistic link to the development of CVD16. Moreover, elevated TMAO can predict the presence of coronary atherosclerotic burden and complexity as defined by SYNTAX score and diffuse lesion characteristics6. These findings were independent of traditional risk factors and were validated by independent cohorts, which were reviewed in a recent meta-analyses17. However, the association between TMAO and evidence of SMD as indicated by higher hs-cTnT, has not been well explored. This was the first study to show elevated plasma TMAO to be an independent predictor of SMD. This is consistent with the gut microbiota TMAO pathway being mechanistically linked with the development of atherosclerosis and adverse prognosis.Interestingly, another previous study found elevated TMAO to be associated with risk of major adverse cardiac events among patients with suspected ACS who were initially negative for cardiac troponin T (< 0.1 ng/mL)18. There is evidence that low hs-cTnT concentration in subjects without clinical setting of ACS indicates an increased risk of future cardiovascular events and may predict poor prognosis19. Low hs-cTnT concentration is a useful biomarker to stratify patients by risk level 13. In stable patients with chronic HF or stable CAD, higher hs-cTnT is associated with increased risk of cardiovascular events12. Previous studies have shown that low hs-cTnT is associated with higher incidence of cardiovascular events, total mortality, and cardiac abnormalities  in the general population12.Detection of circulating hs-cTnT is associated with myocardial damage and is a recommended diagnostic criterion for myocardial infarction in ACSth percentile cut-point for diagnosis of myocardial infarction. Importantly, although we included stable patients without evidence of ACS at presentation, elevated plasma TMAO was associated with SMD. Moreover, while hs-cTnT is often higher in patients with declining of renal function20, elevated plasma TMAO remained an independent predictor of SMD even after adjusting for eGFR and other potentially confounding factors. Therefore, it is conceivable that SMD may occur in with elevated plasma TMAO. This may be a clue to understanding the underlying mechanism through which elevated plasma TMAO is linked to enhanced risk of CVD and poor prognosis.In our study cohort, we defined SMD as hs-cTnT ≥ 14 ng/L, which is the 9923.Previous studies have consistently demonstrated that the TMAO pathway is linked mechanistically to multiple cardiovascular and metabolic processes with CVD pathogenesis including the development of atherosclerotic plaque, promotion of adipose tissue inflammation, alteration in macrophage and endothelial cells, plasma lipid abnormalities, insulin resistance, obesity, and enhanced platelet hyperactivity and thrombosis risk, all of which contribute to SMD due to troponin leak23. Several recent studies have demonstrated that flavin-containing monooxygenase 3 (FMO3), the major host enzyme responsible for converting gut microbiota-generated trimethylamine (TMA) into TMAO, is an important regulator of sterol metabolism, prevents reverse cholesterol transport, and is linked to the development of atherosclerosis24. By contrast, FMO3 knockdown mice had decreased circulating TMAO levels and attenuated atherosclerosis plaque formation25. Moreover, recent studies have found that a high fat diet plus 0.2% TMAO promotes adipose tissue inflammation in mice, which be related to SMD26.TMAO may exhibit direct biological activity in modulating platelet hyperactivity, which increases the risk of thrombus formationOur findings shed light on a potential pathophysiological contribution of gut microbiota in the development of atherosclerosis and to adverse prognosis in patients with high atherosclerotic risk. Further study is needed to determine whether therapeutic strategies that reduce plasma TMAO levels can also improve prognosis in these patients.This study had the following limitations: first, only patients with available TMAO data were included, which may have led to selection bias. Second, despite all subjects being recruited from the outpatient clinic after fasting for at least 8 h, we could not exclude the potential for dietary intake of PC or TMAO within 24 h before blood sampling. Third, because plasma TMAO and hs-cTnT were measured at only one point in time, we were unable to evaluate the prognostic value of changes in these indicators. Finally, a relatively low number of patients with MRFs were included in this study.Fasting plasma TMAO is an independent predictor of SMD in patients with high atherosclerotic risk. These findings are consistent with numerous previous studies that have demonstrated a link between elevated plasma TMAO and atherosclerosis pathogenesis and cardiovascular risk. Further study into the mechanism by which elevated TMAO leads to SMD is warranted.27.The Cohort Of patients at a high Risk of Cardiovascular Events—Thailand (CORE-Thailand) registry is a prospective, multicenter, longitudinal cohort study of Thai patients with high atherosclerotic risk. This includes patients aged 45 years or older with EAD and those with MRFs, as detailed in previous publicationsWe studied 134 patients for whom TMAO data were available. This study was approved by the Khon Kaen University Ethics Committee for Human Research (HE611011) and was conducted in accordance with the Declaration of Helsinki.th generation) assay on a Roche Cobas e411 platform . We defined SMD as hs-cTnT ≥ 14 ng/L, as this is considered the upper limit (the 99th percentile) of the normal range in the healthy population19. eGFR was calculated using the modification of diet in renal disease (MDRD) equation.Informed consent was obtained from all patients and fasting blood samples were collected using EDTA tubes at the time of hospital visit. These were then immediately processed and frozen at − 80 °C until analysis. Plasma TMAO levels were determined using an NMR spectrometer at 400 MHz . The Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence was employed to obtain spectra (recycle delay-90°-t1-90°-tm-90°-acquisition) over 64 scans with four dummy scans. Quantification was achieved using a concentration of a known reference signal (in this case TSP) to determine the TMAO concentration. hs-cTnT was measured using a high-sensitivity (5Continuous data are presented as means (standard deviation) or medians (interquartile range) and compared with a student’s t-test or non-parametric test (Mann–Whitney U Test) as appropriate. Categorical variables are presented as numbers (%) and compared between groups using a chi-square test. The correlations between hs-cTnT and plasma TMAO-associated factors were analyzed using the multicollinearity index. Comparisons among three or more groups were evaluated using one-way analysis of variance (ANOVA) or the Kruskal–Wallis test depending on whether or not the distribution was normal. Univariate and multivariate logistic regression analysis was used to determine independent predictors of SMD. Variables entered into the multivariate model included traditional risk factors , ACEI/ARB use, and EAD status. All analyses were performed using R version 4.0.3. A p value < 0.05 was considered statistically significant.


Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening infiltrative disease in elderly patients. Atrial arrhythmias (AAr) are common in patients with ATTR-CM. However, AAr treatment in these patients is challenging. In this case, a patient diagnosed with wild-type ATTR-CM suffered atrial fibrillation (AF) for ~1 year, according to the data of his self-monitoring and regular electrocardiogram. This AF reverted to normal sinus rhythm a few months after the initiation of tafamidis without administering an antiarrhythmic drug. Tafamidis may be beneficial as alternative antiarrhythmic therapy in patients with ATTR-CM. Atrial arrhythmias (AAr), which include atrial fibrillation (AF), atrial flutter and atrial tachycardia, are common in patients diagnosed with cardiac amyloidosis, especially those with wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) . The maiIn 2018, a 70-year-old man with a history of hypertension presented with leg edema. Echocardiography revealed left ventricular (LV) hypertrophy. The patient’s medications, including diuretics, were adjusted accordingly.In 2019, his leg edema worsened. Coronary angiography did not reveal significant stenosis. Cardiac magnetic resonance (CMR) identified late gadolinium enhancement (LGE) with diffuse subendocardial enhancement in the walls of the left and right ventricles and atria . TechnetIn March 2020, electrocardiography revealed AF for the first time . LaboratThree months after starting tafamidis, his heart rate, measured by self-monitoring, demonstrated a sudden decrease to 50 bpm. Electrocardiography showed that AF reverted to normal SR  without antiarrhythmic drugs and beta-blocker . Normal et al. suggested AF as a sign of ATTR-CM advancement. Ablation therapy was reported to be effective, particularly in the early phase, suggesting that some interventions can revert this complication [Wild-type ATTR-CM has a high prevalence of AAr, including AF, which is extremely high, about 70–90% . Donnelllication . Howeverlication .In the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular-related rehospitalizations in ATTR-CM patients . FurtherIn addition to the current case, we experienced another case of a patient with ATTR-CM complicating with atrial arrythmia. Eighty-year-old man with ATTR-CM demonstrated the recovery of SR spontaneously two months after tafamidis treatment, whose atrial flutter lasted about 1 year.Our two cases share similarities. First, the time from detection of AAr to tafamidis administration was almost the same, i.e. <1 year. Second, SR was restored a few months after the initiation of tafamidis. Two AF mechanisms in cardiac amyloidosis patients have been proposed, increased LV filling pressure leading to atrial wall dilatation and direct amyloid influences in the left atrium that disrupts myocardial conduction. Both mechanisms may make AF treatment in cardiac amyloidosis more difficult. In this case, there were few findings regarding the improvement of heart failure by tafamidis. Therefore, the recovery of SR did not derive from the improvement of heart failure. The effect of tafamidis in these cases was considered to be directly related to atrial electrical arrhythmogenicity.Recent reports suggested amyloid organ deposition consists of a multistep process. It is also known that organ damage occurs at the stage of nonfibrillar TTR before the amyloid deposition in the organ. Nonfibrillar TTR seems to play an important role in enhancing the leakage of circulating TTR into extracellular spaces by affecting endothelial cells of blood vessels . This meThe certifying the impact of a specific therapy on the recovery of SR is generally difficult. There had been little reports about the spontaneous conversion of long-standing AF, which described it as very uncommon phenomenon . FurtherOf course, there is a limitation that the verification of AF persistence is generally difficult. The possibility that it was actually paroxymal AF cannot be completely denied, which, however, is considered to be unlikely.In conclusion, tafamidis may be an effective drug to regain SR. Further research is necessary to support this.EA belongs to the Department, endowed by NIPRO-Corp, Terumo-Corp., Senko-Medical-Instrument-Mfg., Century-Medical, Inc., ONO-pharmaceutical-Co., Ltd Medtronic-JAPAN Co., Ltd, Nippon-Shinyaku Co., Ltd, Abiomed-Inc, AQuA-Inc, Fukuda-Denshi Co., Ltd, and Sun-Medical-Technology-Research Corp. EA got lecture fee from Pfizer Inc. JI got lecture fee and research grant (55026059) from Pfizer Inc.Written consent obtained.Guarantor is Eisuke Amiya.