To explore the characteristics of myocardial textures on coronary computed tomography angiography (CCTA) images in patients with coronary atherosclerotic heart disease, a classification model was established, and the diagnostic effectiveness of CCTA for myocardial ischaemia patients was explored.This was a retrospective analysis of the CCTA images of 155 patients with clinically diagnosed coronary heart disease from September 2019 to January 2020, 79 of whom were considered positive  and 76 negative  according to their clinical diagnoses. By using the deep learning model-based CQK software, the myocardium was automatically segmented from the CCTA images and used to extract texture features. All patients were randomly divided into a training cohort and a test cohort at a 7:3 ratio. The Spearman correlation and least absolute shrinkage and selection operator (LASSO) method were used for feature selection. Based on the selected features of the training cohort, a multivariable logistic regression model was established. Finally, the test cohort was used to verify the regression model.A total of 387 features were extracted from the CCTA images of the 155 coronary heart disease patients. After performing dimensionality reduction with the Spearman correlation and LASSO, three texture features were selected. The accuracy, area under the curve, specificity, sensitivity, positive predictive value and negative predictive value of the constructed multivariable logistic regression model with the test cohort were 0.783, 0.875, 0.733, 0.875, 0.650 and 0.769, respectively.CCTA imaging texture features of the myocardium have potential as biomarkers for diagnosing myocardial ischaemia.The online version contains supplementary material available at 10.1186/s12872-021-02206-z. Coronary atherosclerotic heart disease (CHD), also referred to as coronary heart disease, is one of the leading causes of death and disability worldwide –3. It isCoronary CT angiography (CCTA) is a non-invasive imaging technique that can clearly display the anatomy of the coronary arteries. In addition, it has advantages in evaluating coronary artery stenosis, atherosclerotic plaque, calcification, and cardiac function ) –7. ThereRecently, radiomics has shown great potential for various cancers in terms of pathological classification, the assessment of tumour metastasis, clinical outcomes and gene expression –13. RadiAll patients with a diagnosis of myocardial ischaemia with available CCTA images between September 1, 2019, and January 1, 2020, at Xiamen Cardiovascular Hospital Xiamen University in Fujian Province were retrospectively included in this study. The diagnosis of myocardial ischaemia was based on clinical diagnosis and/or single photon emission computed tomography (SPECT) imaging findings. To ensure that the corresponding clinical and imaging data of the included patients were suitable for the purposes of our research, we established the following inclusion criteria: (1) The interval between CCTA image acquisition and myocardial ischaemic diagnosis was less than two weeks. (2) The absence of a combination of other heart diseases, a history of coronary artery bypass grafting or coronary stent implantation, as these conditions may affect the results. Finally, a total of 79 patients with clinically diagnosed myocardial ischaemia were enrolled. The study also included 76 age-matched healthy controls with CCTA scans performed during the same time period.The following patient information was collected: demographic data, including sex, age and weight; clinical data, including history of hypertension, history of hyperlipidaemia, history of diabetes, smoking status, clinical characteristics and myocardial enzymes; and imaging data, including electrocardiography and CCTA.In this study, myocardial ischaemia was diagnosed based on stress SPECT imaging and/or the patient’s clinical characteristics, electrocardiogram and myocardial enzymes Fig. . The diaThe stress SPECT scan was performed with a D-SPECT Cardiac Scanner System . The patient received an intravenous injection of adenosine disodium triphosphate  at a rate of 0.14 mg/kg.min, which was completed continuously within 6 min. Three minutes after the start of the injection, the patient received a simultaneous bolus injection of 99mTC-MIBI  at a dose of 24.0 mCi via another intravenous channel. Approximately 1 h later, the patient underwent stress-gated myocardial tomography.All patients received a CCTA scan on an empty stomach with a 560-slice multi-slice spiral cardiovascular CT device . The scan range was from the tracheal crest to the bottom of the heart. The scanning parameters were as follows: tube voltage 120 kVp; tube current 50 mA; CT rotation time 0.24 s; and reconstruction layer thickness 0.5 mm. The contrast agent was injected from a vein through a high-pressure syringe , and scanning started 5 s after reaching the trigger threshold. The contrast medium used was iohexol injection  with the following injection programme: duration of coronary drug injection 12 s; heart rate ≥ 75 beats/min; every additional 5 beats/min, the rate was increased by 0.2 ml/s, and the amount of medicine was increased similarly. A 30 ml dose of saline was injected at the same rate as the contrast. The CCTA scans were performed in accordance with the 2016 Society of Cardiovascular Computed Tomography (SCCT) guidelines for the performance and acquisition of coronary computed tomographic angiography, and the scan parameter settings followed the "as low as reasonably achievable" (ALARA) principle . The conThe CCTA images were imported into CQK software  for automatic myocardium segmentation and feature extraction. A radiological expert with 10 years of experience verified the segmentation results. A total of 387 features were extracted from the three-dimensional segmented myocardium, including histogram parameters 42 features), grey level cooccurrence matrix features (144), Haralick feature s(10), grey level run-length matrix features (180) and grey level size zone matrix features (11). The corresponding formula and meaning of each feature are detailed in Additional file  featuresThe dataset was randomly assigned in a 7:3 ratio to either a training cohort or a test cohort. All images in the training cohort were used to train the predictive model, while those in the test cohort were used to independently evaluate the model performance. Before the analyses, variables with zero variance were excluded. Then, missing and outlier values were replaced by the median, and finally, the data were standardized.Feature selection was performed by using Spearman correlation analysis (SPM) and the least absolute shrinkage and selection operator (LASSO). A Spearman correlation coefficient between two features of ≥ 0.9 was considered to indicate a relevant correlation, and only one of the two features was selected randomly to reduce feature redundancy. The LASSO method was used to further select features with penalty parameter tuning that was conducted by tenfold cross-validation based on minimum criteria. Finally, we obtained the optimal feature subset. A multivariable logistic regression model was constructed based on the optimal feature subset from the training cohort. Multivariable logistic regression is a machine learning method that analyses the relationship between multiple variables and two-classification dependent variables and solves the problem of binary classification (0 or 1). Then, the optimal features from the test cohort were imported into the constructed model to verify its discriminative performance. To visualize and validate the multivariable logistic regression model, we built a radiomics nomogram.For the sample size of test cohort, Shein-Chung Chow and colleagues  introducLet the positive and negative groups be where U test was utilized for comparisons between two groups. Categorical variables are expressed as frequencies (percentages) and were compared with the chi-square test.In this study, the patients were divided into a myocardial ischaemia group and a normal myocardial blood supply group. Continuous variables with a normal distribution are expressed as the mean ± standard deviation, and Student's t-test was utilized for comparisons between two groups. Continuous variables with nonnormal distributions are expressed as medians (interquartile ranges), and the Mann–Whitney http://www.r-project.org/). A two-tailed p-value < 0.05 indicated statistical significance. The SPM method and multivariable logistic regression model were performed with the “stats” package in R software, and the LASSO method was performed with the “glmnet” package. Receiver operating characteristic (ROC) curves were generated to determine the performance of the machine learning model with the “pROC” package, and the accuracy (ACC), sensitivity, specificity and area under the curve (AUC) were calculated with the “ReprotROC” package. The nomogram was generated with the “rms” package.All statistical analyses for the present study were performed with R software  and 76 patients with normal myocardial blood supply . There were 59 and 47 male patients in the positive group and negative group, respectively, with p = 0.086.A total of 155 patients were included in this study. For each patient, 387 features were extracted. After using SPM, 68 features remained. Then, 14 features were selected by utilizing the LASSO method *VoxelValueSum + (0.404)*histogramEntropy + (− 0.228)*skewness + (0.440)*Correlation_AllDirection_offset7_SD + (0.096)*GLCMEntropy_angle45_offset7 + (0.065)*HaralickCorrelation_angle90_offset7 + (1.625)*RunLengthNonuniformity_AllDirection_offset7_SD + (0.942)*ShortRunEmphasis_AllDirection_offset4_SD + (1.508)*ShortRunEmphasis_angle45_offset7 + (0.820)*ShortRunLowGreyLevelEmphasis_AllDirection_offset1_SD + (− 0.241)*ShortRunLowGreyLevelEmphasis_AllDirection_offset7_SD + (− 0.531)*SizeZoneVariability + (− 0.252)* LowIntensitySmallAreaEmphasis.The selected 14 CCTA features were utilized to construct the multivariable logistic regression model for the diagnosis of myocardial ischaemia.The ACC, AUC, specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of the diagnostic myocardial ischaemia model with the training cohort were 0.835, 0.914, 0.733, 0.959, 0.957, and 0.746, respectively; with the test cohort, these values were 0.717, 0.827, 0.684, 0.741, 0.650 and 0.769, respectively (Table The patients were randomly divided at a ratio of 7:3. There were 60 positive and 49 negative patients in the training cohort and 19 positive and 27 negative patients in the test cohort. The ratio of the training cohort to the test cohort is close to 1:1, at which the logical regression model performs well. The event-per-predictor ratio was 7.78 since there were a total of 14 predictors in our model. An event-per-predictor ratio greater than 5 is recommended in logistic regression models according to the rule of thumb . TherefoIn our study, the sample sizes in the training cohort were This proof-of-concept study shows that the combination of radiomics and machine learning algorithms can help in the diagnosis of myocardial ischaemia from CCTA images. The extracted information quantifying the spatial and textural properties of CCTA images may generally be invisible to the naked eye. The constructed imaging biomarkers have the potential to objectify our interpretation of CCTA images and increase the diagnostic accuracy for myocardial ischaemia.At present, the gold standard for myocardial ischaemia diagnoses consists of stress tests, such as stress SPECT/PET or stress CMR. However, stress tests may pose potential risks to patients with suspected CHD. Clinically, myocardial ischaemia is conventionally diagnosed based on comprehensive information including the patient’s history, clinical characteristics, and electrocardiography. In this article, we grouped patients based on SPECT findings and clinical diagnoses.CCTA is a non-invasive vascular imaging technique commonly used to observe coronary narrowness and plaques from anatomical structures and is routinely used to track suspicious CHD. Many methods also exist for evaluating coronary function based on CCTA, such as CT blood FFR-CT –20, coroRadiomics offers a large number of high-throughput mathematical objectives for describing different lesion characteristics, especially parameters that are invisible to the naked eye or cannot be quantified through routine analysis, such as texture and shape. It has been widely reported that radiomics can provide more information on the diagnosis and prognosis of various diseases than conventional approaches –13. In tOne of the characteristics of this paper is the use of deep learning technology for the segmentation of the myocardium, which decreases the subjective differences among doctors and reduces the duration of manual analysis. In addition, three-dimensional segmentation allows an overall assessment of the myocardium. Furthermore, a large number of extracted high-order features provide multidimensional parameters for the diagnosis of ischaemia by CCTA.This article has some limitations that should be acknowledged. First, the size of the data is small, despite the average statistical power of 0.895, and the generalizability of the results still needs to be validated with an external, central dataset. Second, we excluded patients with other heart diseases to reduce their impact on the model. However, this may have led to potential selection bias, which should be considered in subsequent studies. Third, the model incorporates only the radiomics features from CCTA images; clinical indicators could be further combined to increase the effectiveness of the diagnosis. Since the main focus of this paper was to explore the effectiveness of CCTA, the value of combining clinical indicators will be explored in a future study. Finally, this study is limited to the prediction of myocardial ischaemia, and in future studies, we will further explore the value of myocardial textures in predicting other conditions such as heart failure and heart deposits.In conclusion, this paper develops a multivariable logic regression model based on CCTA images for diagnosing myocardial ischaemia. These results will add value to CCTA research and facilitate a more accurate diagnosis for these patients.Additional file 1: Table 1. The contrast media injection protocol.Additional file 2: AK software radiomics parameter description.


Serial crystallography (SX) using X-ray free-electron lasers (XFEL) and synchrotron X-rays is an emerging X-ray crystallography technique to determine the structure of macromolecules at room temperature or near-physiological temperature with minimal radiation damage . This teIn an SX experiment, a large number of crystals are serially delivered to an X-ray interaction point via various sample delivery techniques, such as injectors injector , syringeIn SX technology, a “hit” denotes a diffraction pattern with the minimum number of detectable Bragg peaks . As onlyh, k, and l)  . SubsequThe hit rate and indexing rate provide information about the crystal density and crystal quality, respectively, used during data collection and aid in calculating the amount of data sufficient for determining the crystal structure or changing the experimental parameter. This information aids in utilizing the beamtime efficiently. Meanwhile, SX researchers and journal reviewers/editors often evaluate and compare the hit rate and indexing rate numbers of independent SX experiments. However, the hit rate and indexing rate of independent SX experiments cannot be compared because the rates can represent distinct values depending on the experimental results or program parameters. Moreover, the hit rate and indexing rate can be increased or decreased easily by altering the settings of the data processing program. Accordingly, I believe the hit rate and indexing rate are just statistics that cannot be compared with independent experiments.The hit rate is an important statistic for determining the data acquisition efficiency and planning beamtime utilization in experiments. For example, when the crystal hit rate is low during data collection, researchers can replace the sample with fresh crystals or increase the crystal density, which may increase the hit rate and yield more hit images containing the diffraction pattern for the remaining beamtime. Meanwhile, although obtaining a large number of hit images is important to increase the SX data collection efficiency, when the crystal hit rate is high with intense multiple crystal diffraction patterns during data collection, researchers may decrease the density of the crystal sample. This reduces the hit rate, but it offers the advantage of avoiding the incorrect indexing of the Bragg peaks and the incorrect signal-to-noise ratio (SNR) related to the background noise.Crystal density is calculated based on the sample delivery method  and X-ray properties  to obtain an appropriate hit rate. The crystals are delivered continuously to an X-ray location to collect diffraction data. In an ideal experiment, new crystals  would be delivered continuously at every X-ray exposure point, resulting in a 100% hit rate. However, providing crystals precisely each time both spatially and temporally through which X-rays are transmitted is experimentally impossible. The collected SX data include the diffraction image in which X-rays pass through the crystal and the image information in which the crystal is not hit. In addition, unwanted diffraction from salt crystals and the sample delivery material may occur experimentally during data acquisition. This unwanted diffraction can be sorted as a Bragg peak and processed as a hit image by the filtering program, leading to an increase in the hit rate.Programs such as Cheetah , NanoPeaThe hit images including the Bragg peaks are indexed, integrated, and scaled to provide the final three-dimensional structural information. The accurate indexing of crystal diffraction patterns in the first data processing step is essential to provide an accurate structure factor. In general, higher indexing rates provide better data statistics in terms of using more diffraction patterns. Factors affecting the indexing rate include the quality of the acquired image, optimization of the detector geometry, indexing program used, and technical skills. In terms of data quality, the following factors can decrease the indexing rate: 1) several space groups of crystal forms existing in the crystal sample, 2) Bragg peaks with low SNR levels, 3) salt peaks or unwanted intensities, and 4) mis-indexing because of multicrystal diffraction patterns.Information about the detector geometry, including the X-ray energy, crystal-to-detector distance, and detector specifications is essentially required to index the diffraction patterns from hit images in the SX experiment. The indexing efficiency varies based on the accuracy of the detector geometry information. For example, segmented detectors consist of several small detector modules tiled together, such as Cornell-SLAC Pixel Array Detectors (CSPAD) , multi-pdials. index in DIALS .In the SX experiment, the hit rate and indexing rate can be used to evaluate the sample quality, data collection strategy, and beamtime efficiency during data collection and processing. However, these rates can be increased or decreased according to the processing parameters used. Hence, hit rate and indexing rate cannot be used to analyze the SX experimental results.


The relation of the second heart sound (S2) amplitude with exercise level was less significant. BiVHF resulted in amplitude reduction of S1. LVHF resulted in reverse splitting of S2 and an amplitude reduction of only the left-sided heart sound components, whereas RVHF resulted in a prolonged splitting of S2 and only a mild amplitude reduction of the right-sided heart sound components. In conclusion, our hemodynamics-driven mathematical model provides fast and realistic simulations of heart sounds under various conditions and may be helpful to find new indicators for diagnosis and prognosis of cardiac diseases.We propose a novel, two-degree of freedom mathematical model of mechanical vibrations of the heart that generates heart sounds in CircAdapt, a complete real-time model of the cardiovascular system. Heart sounds during rest, exercise, biventricular (BiVHF), left ventricular (LVHF) and right ventricular heart failure (RVHF) were simulated to examine model functionality in various conditions. Simulated and experimental heart sound components showed both qualitative and quantitative agreements in terms of heart sound morphology, frequency, and timing. Rate of left ventricular pressure (LV dp/dtTo the best of our knowledge, this is the first hemodynamic-based heart sound generation model embedded in a complete real-time computational model of the cardiovascular system. Simulated heart sounds are similar to experimental and clinical measurements, both quantitatively and qualitatively. Our model can be used to investigate the relationships between heart sound acoustic features and hemodynamic factors/anatomical parameters. Among various vital signals used for diagnosis and prognosis of cardiac diseases, heart sounds are not employed precisely because physicians subjectively assess their auscultatory findings. On the other hand, recorded heart sounds are also difficult to quantitatively relate to different cardiac conditions given the complex nature of their generation. We therefore employed cardiovascular modeling and developed a novel hemodynamics-driven mathematical model for heart sound generation to unravel the relationships between heart sounds and other vital signals. Simulated and experimental heart sound components showed qualitative and quantitative agreements in terms of heart sound morphology, frequency, and timing, not only during normal conditions, but also during simulated exercise and heart failure. Our model can be used to understand generation of heart sounds in more details and may be helpful to find new diagnostic indicators and treatment methods of cardiac disorders. Previous studies have proposed various theories about the genesis of heart sounds including sudden tension in otherwise loose valve membranes , sudden In the present study, we propose a novel mechanical vibration model of heart sound generation based on Rushmer’s theory  and implThe research protocol for the animal experiments were approved by the Central Committee for Animal experiments (CCD) in The Netherlands and the Animal Experimental Committee of Maastricht University.Fig 1A). According to basic physiological and physical properties, closure of atrio-ventricular and ventriculo-arterial valves is induced by retrograde blood flow and a reversal of the pressure gradients. Abrupt cessation of retrograde blood flow at the moment of actual valve closure causes a vibration in the column of blood and the surrounding viscoelastic structures, , giving rise to the heart sounds. The first heart sound (S1) comprises of a mitral (M1) and tricuspid (T1) valve component whereas the second heart sound (S2) comprises of an aortic (A2) and pulmonary (P2) valve component. A two degree of freedom system  was used to simulate the mechanical vibration of each heart sound component [Table 1) [A module to model the first and second heart sounds by hemodynamic factors was developed in CircAdapt , a lumpeomponent . Blood momponent  in whichTable 1) –11. SpriTable 1) .A force (f(t)) corresponding to the real-time pressure difference across the valve is applied to the vibratory mass at the time of backward flow towards the valve. Eq  shows thx(t)prox and x(t)dis, we used a numerical approach that involved four constants of integration. In order to have a pure vibration excited by the driving force, we assumed the initial velocity and displacement of the masses Because the analytical solution of Eq  for the S1 Text for a complete description of the applied method):A numerical approach with central difference method was applied to solve the final equation below  and during exercise for the normal heart as well as for hearts with biventricular, left ventricular or right ventricular heart failure . The diameter and wall mass of cardiac chambers and large blood vessels were adapted to the level of exercise as defined previously . ExercisLV and RV myocardial active stress were reduced from normal condition 100% to 50% at steps of 10% resulting in five heart failure conditions. For BiVHF this was done for all walls, for LVHF for the left ventricular free wall and septum, and for the RVHF for the right ventricular free wall.Heart sounds were obtained from open-chest sacrifice experiments of five pigs (weight: 64 ± 1 kg) Following atrioventricular block induction by radiofrequency ablation, atrio-biventricular pacing was imposed with a fixed atrial to ventricular pacing delay (150 ms). The data-acquisition system consisted of a custom made triaxial accelerometer located on the anterior RV base to obtain heart sounds, ECG leads as well as pressure- and volume catheters. Data were recorded on custom made data acquisition systems (IDEE Maastricht University / Maastricht Instruments BV). Data were sampled with 1000 Hz. A second-order Butterworth bandpass filter of 40–250 Hz was applied to the accelerometer signal. The displacement obtained by integration of the filtered accelerometer signal was used to compare with our CircAdapt-simulated heart sounds. S1 and S2 localizations in the displacement signal were identified with reference to ECG lead II.Simulated heart sounds were compared with phonocardiograms (PCG) of normal human subjects, recorded on the chest and available in PhysioNet dataset, an open access heart sound database, collected for an international competition . The accFig 2. The left panel shows simulation results. Heart sound components generated in the left side of the heart  preceded the ones  from the right side (15ms delay between M1 and T1 and 6ms between A2 and P2). Left sided components also had higher intensity than the components generated in the right heart. The delay in the simulated heart sounds with respect to pressure crossover and valve closure was in line with previous reports on clinical data as well as with our animal experimental data presented in the right panel [Heart sounds and their relationship with cardiovascular hemodynamics in resting condition are presented in ht panel –23. S1 oFig 3 shows the frequency spectrum of the simulated heart sound after transmission through the thorax in comparison with the recordings of the PhysioNet dataset. Simulated heart sounds and the mean of apical phonocardiographic recordings showed similar magnitude-frequency distributions with dominant frequencies roughly between 10 and 200 Hz. In LVHF, the depressed contractility of the LV caused a significant decrease in magnitude and rate of rise of left ventricular pressure, resulting in lower amplitude of M1. A2 had a lower amplitude because of not only lower Ao-LV pressure difference at the time of backward flow towards the valve but also because of higher end systolic LV volume. Enhanced blood mass and lower driving force together generated smaller A2 amplitude. Similar amplitude reduction was noticeable for T1 and P2 in RVHF. Additionally, simulated LVHF was accompanied with increased end diastolic LV volume and, hence, with a prolonged LV contraction in LVHF, causing a delayed A2 and consequently fusion and even reverse splitting of S2 [Simulated heart sounds and corresponding pressures for normal condition (reference) as well as severe left (LVHF) or right (RVHF) ventricular heart failure  are presented in ng of S2 .Fig 5A demonstrates the relationship between the amplitude of the first heart sound and heart rate / cardiac output. Results of the simulations for the normal heart were in line with the observation on young healthy subjects in a clinical study by Bergman et al. [max) increased and, consequently the magnitude of S1 [2:0.99, p<0.001), whereas S2 amplitude did not change significantly with exercise. n et al. . With inde of S1 . The ampFig 6 compares the experimental data of diverse  conditions  by Sakamoto et al. [max and S1 amplitude . Heart failure caused a reduction in dP/dtmax and consequently a reduction in S1 amplitude. Hence, while the relation between S1 amplitude and LV dp/dtmax remained linear during heart failure, it shifted to the left. This leftward shift was proportional to the severity of simulated heart failure.o et al.  and the  Positive intervals indicate reverse splitting of S2, and negative intervals indicate normal splitting. Whereas reverse splitting in LVHF was related to both cardiac output and LVHF severity, the splitting interval did not depend on RVHF severity. Splitting was the largest in resting condition when the level of heart failure (both left and right) severity was the highest.A2-P2 splitting interval for left and right heart failure on various exercise levels is shown in We present a novel mechanical vibration model of heart sound generation implemented in CircAdapt, a lumped-parameter real-time computational model of the cardiovascular system . To the The model replicated not only the observed abovementioned linear relationships, but also paradoxical experimental findings, like the unchanged S2 amplitude during exercise, indicating the appropriate physics and physiology implemented in the model.max. Although right-sided generated heart sound components contribute less to S1 and S2 than their left-sided equivalents, superposition of the waves can cause constructive or destructive interference on final S1 or S2 that depends on timing of the components in various conditions.The energy content of a mechanical vibration is proportional to the amplitude squared. This energy represents hemo-mechanical energy of the heart contraction transformed into vibrations. Since lower amplitudes of S1 signify lower energy contents of the wave, we propose to use S1 amplitude as a proxy for cardiac contractility or dp/dtWe found that heart sounds generated from the same left ventricular stroke volume but with different contractility levels can have different S1/S2 amplitude, which is in agreement with studies on various cardiac conditions . AdditioThe experimental data of the patients with coronary artery disease showed a smaller increase of S1 amplitude during exercise as compared to normal controls. A similar trend was seen in the simulated data for high degrees of BiVHF. Additionally, normal conditions with different cardiac outputs showed a continuous increasing trend in both experimental and simulation results .Previous studies have simulated aortic and mitral components of heart sounds. However, these studies focused on one valve and one heart sound component at a time, and the heart sound model was not integrated in a complete model of cardiovascular system capable of simulating various cardiac conditions ,12,27–29The good agreement between model simulations and experimental data indicates the correctness of the theory and assumptions, on which the model is based. We assumed that not only valve closure but also the surrounding structures are involved in heart sound generation. While our system is simple, it is realistic for real-time simulation of cardiovascular hemodynamics and mechanics, including heart sounds, and can be executed with different conditions. Our model provides the flexibility to manipulate hemodynamic and anatomical variables in order to obtain the resulting heart sounds corresponding to different cardiovascular conditions and to assess the effective pathophysiological factors. Our model can be used to investigate the relationships between acoustic features  of heart sounds on the one hand and hemodynamic factors , anatomical parameters  on the other hand. Because our model enables to assess the four heart sound components  separately before they are contaminated with noise from different sources, better understanding about amplitude and timing of each component and their relationship with the corresponding hemodynamic factors can be obtained. This is almost impossible in real recordings because recorded heart sound components are vulnerable to sensor types/recording techniques and are already affected by acoustic interactions of cardiac structure in terms of interference, attenuation, reflection, and absorption. Finally, our model can be used for teaching auscultation.Similar to other reported heart sound models ,12,27–29In conclusion, our hemodynamics-driven mathematical model provides fast and realistic simulations of heart sounds under various conditions and may be helpful to find new indicators for diagnosis and prognosis of cardiac diseases.


A cardiopatia chagásica (CC) é uma condição de progressão lenta, cujo principal achado histopatológico é fibrose. Avaliar se a fibrose cardíaca aumenta ao longo do tempo e se correlaciona com aumento no tamanho do ventrículo esquerdo (CE) e redução na fração de ejeção (FE) na CC crônica. Estudo retrospectivo que incluiu 20 indivíduos  com CC crônica que se submeteram a dois exames de ressonância magnética cardíaca (RMC) com realce tardio com gadolínio em um intervalo mínimo de quatro anos entre os exames. Volume, FE e massa de fibrose do ventrículo esquerdo (VE) foram determinados por RMC. Associações da massa de fibrose na primeira RMC com alterações no volume do VE e FE ventricular esquerda na segunda RMC foram testadas por análise de regressão logística. Valores p<0,05 foram considerados significativos. Os pacientes foram classificados em: A  e B1 . O tempo médio entre os dois estudos de RMC foi de 5,4±0,5 anos. Fibrose do VE (em % massa do VE) aumentou de 12,6±7.9% para 18,0±14,1% entre os exames de RMC . A massa de fibrose cardíaca no basal associou-se com uma diminuição > cinco unidades absolutas na FE ventricular esquerda da primeira para a segunda RMC . A massa de fibrose do VE foi maior e aumentou entre os dois estudos de RMC no grupo de pacientes que apresentaram diminuição na FE entre os testes. Mesmo pacientes em estágios iniciais da CC apresentam um aumento na fibrose do miocárdio ao longo do tempo, e a presença de fibrose do VE no basal está associada a uma diminuição da função sistólica do VE. Trypanosoma cruzi , que infecta cerca de 10 milhões de pessoas em todo o mundo1 e de 1 a 3 milhões de pessoas no Brasil.2 Entre os pacientes com doença de Chagas crônica, 20 a 40% apresentam a forma cardíaca da doença – cardiopatia chagásica (CC) –2 e cerca de 2% dos pacientes, a cada ano, irão evoluir da forma indeterminada para a forma cardíaca.3A doença de Chagas é causada pelo protozoário 5Estudos histopatológicos de amostras de miocárdio obtidas de pacientes com CC revelaram uma cardiomiopatia fibrosante crônica leve, com contínua substituição de fibras miocárdicas por áreas de fibrose e hipertrofia compensatória de miócitos remanescentes, o que poderia estar correlacionado com progressão da CC, remodelamento cardíaco e disfunção sistólica do ventrículo esquerdo (VE).6 A massa de fibrose correlaciona-se diretamente com a classe funcional e inversamente com a fração de ejeção do VE.7 Ainda, fibrose identificada por RMC associa-se com arritmias ventriculares,8 especialmente na presença de duas ou mais áreas contíguas de fibrose transmural.9 Estudos longitudinais relataram que a massa de fibrose foi um preditor independente do desfecho combinado de morte cardiovascular, taquicardia ventricular sustentada,10 e mortalidade por todas as causas.11O exame de ressonância magnética cardíaca (RMC) permite a identificação e a quantificação não invasiva de fibrose cardíaca e de anormalidades da motilidade da parede cardíaca, e a avaliação da função sistólica do VE em pacientes com CC.8 e em 43,7% dos pacientes no estágio A da CC,8 com função sistólica de VE normal  na ecocardiografia bidimensional. Por outro lado, em pacientes com estágios mais avançados da forma cardíaca, fibrose cardíaca é detectada em 89%-100% dos pacientes.9 Assim, a RMC pode identificar o envolvimento cardíaco precoce na doença de Chagas e a prevalência de pacientes com fibrose cardíaca aumenta com a gravidade das doenças.Ainda, a RMC pode identificar áreas de fibrose em aproximadamente 20% dos pacientes com a forma indeterminada de doença de Chagas,Assim, nosso objetivo foi avaliar se a fibrose cardíaca aumenta ao longo do tempo, e se correlaciona com piora da função e geometria do VE. Nós avaliamos retrospectivamente um grupo de pacientes em estágios iniciais da CC que se submeteram a dois exames de RMC com um intervalo mínimo de quatro anos entre os testes.Este foi um estudo retrospectivo que incluiu uma amostra de conveniência composta de pacientes adultos com doença de Chagas crônica acompanhados regularmente no ambulatório de doença de Chagas.2 forma indeterminada (sem evidência de envolvimento cardíaco), forma cardíaca [evidência de alterações típicas de CC no eletrocardiograma (ECG)], forma digestiva (evidência de megacólon ou megaesôfago), ou forma cardiodigestiva. A forma cardíaca foi classificada em estágio A , estágio B , estágio C (IC sintomática), ou estágio D .Os critérios para a classificação da doença de Chagas seguiram o consenso brasileiro de doença de Chagas:8Foram incluídos no estudo todos os pacientes com CC em estágio A ou B1 submetidos a dois exames de RMC pela técnica do realce tardio com gadolínio, com fibrose cardíaca detectada na primeira RMC, e teste negativo para doença arterial coronariana no teste ergométrico com esteira no momento basal. A maioria dos pacientes incluídos haviam participado de um estudo anterior.Dados epidemiológicos e clínicos, incluindo comorbidades, sintomas, ecocardiograma, ECG, Holter 24 horas, e exames de sangue, foram obtidos por análise de prontuários médicos.® GE, versão 3.6, como descrito anteriormente.8 O segundo exame foi realizado em um aparelho Siemens Avanto de 1,5 T , ou um aparelho Siemens Verio 3,0 T . As imagens do VE foram obtidas durante pausa respiratória de 15 segundos, a fim de minimizar artefatos causados por movimentos respiratórios. Imagens do eixo longo e do eixo curto do VE foram obtidas por sequências desencadeadas por ECG nos mesmos locais. Análises da função sistólica do VE e do ventrículo direito foram realizadas por cine-RMC, usando o protocolo de imagens de precessão livre em estado estacionário e o diâmetro diastólico do VE, volume diastólico e sistólico do VE, massa ventricular esquerda, fração de ejeção do VE. Volume diastólico do ventrículo direito, e fração de ejeção foram determinados. Os músculos papilares foram considerados como parte da cavidade do VE para o cálculo do volume e da massa do VE. As imagens foram adquiridas a partir de cortes de 8mm e espaçamento de 2mm até o ápice do VE. Utilizou-se uma sequência de pulso gradiente eco com inversão-recuperação para avaliação de realce tardio do miocárdio (RTM) em eixos longo e curto do VE. A presença, local, e padrão da fibrose foram determinados qualitativamente. A massa da fibrose foi calculada usando o programa ReportCard®GE versão 3.6 na primeira RMC, e o programa CVI42  na segunda RMC. O cálculo da massa de fibrose baseou-se na detecção semiautomática de áreas hiperintensas compatíveis com fibrose no eixo curto nas sequências de RTM. O pesquisador tinha liberdade em delimitar a área de fibrose. Foi adotado um limiar de sinal ≥3 desvios padrões (DPs) acima do sinal médio do miocárdio de referência para se determinar o volume de cicatrização para os dois programas utilizados para o cálculo da massa de fibrose. RTM segmentar foi analisado utilizando-se o modelo de divisão do VE em 17 segmentos.12 O padrão de cicatrização foi classificado como: 1) transmural, se houvesse qualquer área de cicatriz com ocupação >50% da espessura da parede, em menos de oito segmentos; 2) focal, se a área de cicatrização não fosse transmural e fosse identificada em menos de oito segmentos; e 3) difusa, se as áreas de cicatrização estivessem presentes em mais de oito segmentos, independentemente da presença de áreas transmurais.10 Fibrose em segmentos individuais foi classificada como subendocárdica, medial, subepicárdica, ou transmural.O primeiro exame de RMC foi realizado em um aparelho GE HDxt de 1,5 Tesla (T) , e analisado utilizando o programa ReportCardAs análises da primeira RMC foi realizada por dois observadores, e as análises da segunda RMC por dois observadores diferentes, que desconheciam os resultados do primeiro exame.2 no volume diastólico do VE, e um aumento > 10mL/m2 no volume sistólico do VE foram considerados eventos nessa análise. Valores p menores que 0,05 foram considerados significativos.Os cálculos foram realizados utilizando o programa estatístico MedCalc 12.5.0.0. As variáveis contínuas foram expressas em média ± DP, e as variáveis categóricas em valores absolutos e porcentagens. Todas as variáveis contínuas passaram o teste de normalidade (teste de KolmogorovSmirnov), permitindo o uso de testes paramétricos. Os dados entre a primeira e a segunda RMC foram comparados pelo teste t de Student pareado. A associação entre a massa de fibrose na primeira RMC e alterações na estrutura e função do VE da primeira para a segunda RMC foram testadas por análise de regressão logística. Uma diminuição superior a cinco unidades na fração de ejeção do VE, um aumento > 10mL/mVinte pacientes foram incluídos no estudo. Todos apresentavam CC; 65% no estágio A e 35% no estágio B1 da doença na primeira RMC. Doença digestiva associada esteve presente em 35% dos participantes. Observou-se uma igual distribuição de sexos, a maioria dos pacientes nasceu na região nordeste do país, era de etnia branca, apresentava ensino fundamental completo, e era hipertensa   . NenhumEm relação ao ECG, todos os pacientes estavam em ritmo sinusal, e as principais alterações no ECG foram bloqueio de ramo direito, hemibloqueio anterior esquerdo, e alterações primárias da onda T   . NenhumNa ocasião da segunda RMC, três pacientes evoluíram do estágio A para o estágio B1; um paciente progrediu do estágio B1 para B2, e um paciente progrediu do estágio B1 para C. Nenhum paciente apresentou algum evento clínico compatível com síndrome coronária aguda durante o acompanhamento.O tempo médio entre os exames de RMC foi de 5,4 ± 0,5 anos. A proporção de segmentos do VE com áreas de cicatrização no primeiro e no segundo exames de RMC está apresentada na O padrão de fibrose foi classificado como focal em 13 pacientes (65%) e transmural em sete pacientes (35%) na primeira RMC. Sessenta e dois das 340 paredes  do VE apresentaram fibrose cardíaca com a distribuição: ínfero-lateral basal (55%), apical (30%), apical lateral (30%), apical inferior (25%), apical anterior (25%), ínfero-lateral medial (25%), ínfero-basal (20%), apical septal (20%), ântero-lateral medial (20%), ântero-lateral basal (15%), ântero-septal basal (10%), ínfero-septal medial (10%), anterior basal (5%), ínfero-septal (5%), anterior medial (5%), inferior medial (5%), e ântero-septal medial (5%). O padrão de fibrose foi classificado como parede medial em 37 segmentos, transmural em 23 segmentos, subepicardial e parede medial em um segmento, e subendocardial e parede medial em um segmento.Na segunda RMC, o padrão de fibrose apresentado pelos pacientes foi classificado como focal em 13 pacientes (65%), transmural em três pacientes (15%), e difuso em quatro pacientes (20%). O número de paredes com áreas de fibrose aumentou para 102 de 340 paredes (30%) e a frequência de paredes com áreas de fibrose foi: ínfero-lateral basal (75%), inferior basal (50%), ínfero-lateral medial (45%), apical lateral (40%), ântero-lateral basal (35%), ântero-lateral medial (35%), ântero-septal basal (30%), apical (30%), apical inferior (25%), apical anterior (25%), apical septal (25%), ínfero-septal medial (20%), inferior medial (20%), ínfero-septal basal (15%), anterior medial (15%), ântero-septal medial (15%), e anterior basal (10%). O padrão de fibrose foi classificado como mesocárdico em 74 segmentos, transmural em 25 segmentos, mesocárdico e subepicárdico em um segmento, e mesocárdico e subendocárdico em dois segmentos.Em relação à função e tamanho do VE, os valores médios do volume sistólico do VE e da massa do VE foram maiores, e a fração de ejeção do VE foi menor no segundo exame de RMC em comparação à primeira RMC. O diâmetro diastólico do VE médio, o volume médio do ventrículo direito, e a fração de ejeção do VE média não mudaram significativamente da primeira para a segunda RMC   .A massa de fibrose média em porcentagem da massa do VE aumentou 43% da primeira RMC para a segunda RMC   . Em rel2 no volume diastólico do VE e sete apresentaram aumento superior a 10 mL/m2 no volume sistólico final do VE. A massa de fibrose cardíaca em porcentagem da massa ventricular esquerda detectada na primeira RMC mostrou uma associação univariada significativa com uma redução maior que cinco unidades na fração de ejeção do VE  da primeira para a segunda RMC. Não houve associação significativa univariada ou multivariada entre sexo, idade, massa de fibrose do VE na primeira RMC e mudanças maiores que 10mL/m2 no volume diastólico ou sistólico do VE da primeira para a segunda RMC  longitudinal e circunferencial do VE.16 Fibrose do miocárdio associou-se independentemente com mortalidade por todas as causas em um estudo retrospectivo,11 e com a ocorrência do desfecho combinado de morte cardiovascular e taquicardia ventricular sustentada em um estudo prospectivo.10Pacientes com doença de Chagas com fibrose cardíaca apresentam menor fração de ejeção do VE e maior volume e massa do VE, e maior dimensão do átrio esquerdo que pacientes sem fibrose cardíaca.9 Após um acompanhamento médio de 5,4 anos, a prevalência de fibrose cardíaca aumentou em quase todos os segmentos, mais pronunciadamente nos segmentos basais. Houve uma piora no padrão de fibrose cardíaca, uma vez que, em quatro pacientes, o padrão de fibrose mudou de transmural para difusa. Isso reforça a natureza progressiva do dano cardíaco causado pela doença de Chagas.Na primeira RMC, fibrose foi mais comumente observada nos segmentos ínfero-lateral e apical, como mostrado anteriormente na doença de Chagas.17 podem ter um importante papel na patogênese da doença de Chagas. Mudanças no equilíbrio entre MMP e suas atividades inibitórias podem ser importantes para remodelação cardíaca.18 Em camundongos infectados por T. cruzi , tratamento com inibidores de MMP-2/MMP-9 induziu uma redução na inflamação do miocárdio e aumento na sobrevida.19 Em pacientes com doença de Chagas crônica, níveis séricos de MMP-2 e MMP-9 são maiores nos pacientes com as formas indeterminada e cardíaca em comparação a controles.21 Contudo, os níveis séricos de MMP-2 foram mais altos em pacientes com a forma cardíaca que a forma indeterminada,22 ao passo que os níveis de MMP-9 foram maiores nos pacientes com a forma indeterminada que a forma cardíaca.22 Portanto, um equilíbrio entre MMP-2 e MMP-9 parece ser importante na progressão da doença de Chagas.23Nossos dados mostraram que a massa de fibrose do miocárdio aumenta ao longo do tempo, o que pode estar relacionado com uma miocardite fibrosante de progressão lenta, com alterações na matriz extracelular que leva à remodelação cardíaca e IC. De fato, as enzimas envolvidas na modulação da matriz extracelular [metaloproteinases (MMP) 2 e 9], presentes na patogênese de várias doenças cardiovasculares,8 Em um estudo prévio,24 a variabilidade interobservador para a técnica de quantificação de fibrose baseada no limiar de sinal versus miocárdio de referência , que nós usamos para avaliar fibrose do VE, foi -1,2% .24 Em nosso estudo, seis pacientes apresentaram uma diminuição na massa de fibrose no VE em porcentagem da massa do VE, que variou de 1,56 a 7,48%, todos dentro dos limites do intervalo de confiança de 95% para a variabilidade interobservador. Por outro lado, dos 11 pacientes que apresentaram um aumento na massa de fibrose do VE, em porcentagem da massa do VE, sete apresentaram um aumento acima do limite do intervalo de confiança de 95% descrito para a variabilidade interobservador. Três outros pacientes apresentaram uma diferença inferior a um porcento entre os exames. Assim, todos os pacientes com uma diferença entre exames maior que a variabilidade do teste mostraram um aumento na massa de fibrose do VE e corresponderam a 35% da população estudada. Assim, acreditamos que a variabilidade intraobservador e entre observadores não causou viés em nossos resultados.Limitações deste estudo incluem seu delineamento retrospectivo, pequena amostra de conveniência, e o fato de os exames de RMC terem sido realizados em equipamentos de diferentes fabricantes, e analisados por diferentes especialistas, sem uma avaliação da variabilidade interobservador. No entanto, a concordância entre os observadores para massa de fibrose cardíaca do grupo que realizou a primeira RMC foi excelente, como já demonstrado previamente.Quanto à exclusão de pacientes com doença arterial coronariana prévia, um resultado negativo no teste ergométrico com esteira não exclui a possibilidade de uma oclusão total de um ramo coronariano. No entanto, os pacientes negaram a existência de eventos clínicos prévios compatíveis com síndrome coronariana aguda. Ainda, os pacientes não foram submetidos a um segundo teste ergométrico ou à angiografia coronária antes da segunda RMC para excluir possível doença arterial coronariana. Contudo, nenhum paciente apresentou qualquer evento clínico compatível com doença arterial coronariana durante o acompanhamento do estudo.Neste estudo retrospectivo que incluiu pacientes em estágios iniciais da CC, a fibrose miocárdica aumentou ao longo do tempo, e a fibrose do VE no basal associou-se a uma diminuição da função sistólica do VE. Esse importante achado deve ser confirmado em estudos prospectivos. A fibrose cardíaca deve ainda ser mais estudada como um índice prognóstico para a evolução da doença de Chagas e eventos cardiovasculares. Trypanosoma cruzi that infects around 10 million people worldwide1 and 1 to 3 million people in Brazil.2 Among those patients with chronic Chagas disease, 20 to 40% have the cardiac form or Chagas heart disease (CHD)2 and around 2% of patients will progress each year from the indeterminate to the cardiac form.3Chagas disease is caused by the protozoan 5Histopathological studies of myocardial specimens obtained from patients with CHD revealed a low-grade chronic fibrosing cardiomyopathy with a continuous replacement of myocardial fibers by areas of fibrosis and compensatory hypertrophy of remnant myocytes, which would be correlated to CHD progression, cardiac remodeling and left ventricular (LV) systolic dysfunction.6 Fibrosis mass correlates directly to functional class and inversely to the LV ejection fraction.7 Moreover, fibrosis identified by cardiac MRI is associated to ventricular arrhythmias,8 especially in the presence of two or more contiguous areas of transmural fibrosis.9 Longitudinal studies found that fibrosis mass was an independent predictor of the combined end-point of cardiovascular death, sustained ventricular tachycardia,10 and all-cause mortality.11Cardiac magnetic resonance imaging (MRI) allows the non-invasive recognition and quantification of cardiac fibrosis, the identification of global and segmental wall motion abnormalities, and aneurysm and intracardiac thrombi, as well as evaluation of LV systolic function in patients with CHD.8 and in 43.7% of patients at the stage A of CHD,8 who have normal global and segmental LV systolic function on two-dimensional echocardiography. On the other hand, in patients with more advanced stages of the cardiac form, cardiac fibrosis is detected in 89-100% of the patients.9 Therefore, cardiac MRI can identify early cardiac involvement in Chagas disease and the prevalence of patients with cardiac fibrosis increases with the severity of the disease.Furthermore, cardiac MRI can identify areas of fibrosis in around 20% of the patients with the indeterminate form of Chagas diseaseTherefore, we aimed to evaluate if cardiac fibrosis progresses over time and if it correlates with worsening of LV function and LV geometry. For that, we retrospectively evaluated a group of patients at early stages of CHD, who underwent two cardiac MRI tests with a minimum interval of four years between them.This is a retrospective study that included a convenience sample composed of adult patients with chronic Chagas disease regularly followed at the institutional outpatient Chagas disease clinic.2 indeterminate form (no evidence of cardiac involvement), cardiac form , digestive form (evidence of megacolon or megaesophagus), or cardiodigestive form. Cardiac form was classified into stage A (no symptoms of heart failure [HF] with isolated changes in the ECG), stage B , stage C (symptomatic HF), or stage D (end-stage HF).The criteria of Chagas disease classification followed the Brazilian consensus on Chagas disease:8All patients with CHD at stages A or B1 who underwent two cardiac MRI tests with late gadolinium enhancement (LGE) protocol within a minimum interval of four years, with cardiac fibrosis detected at the first MRI, and negative test for coronary artery disease on treadmill exercise testing at baseline were included in this study. Most patients included in this study were part of a previous study.Epidemiological and clinical data, including comorbidities, symptoms, echocardiogram, ECG, 24-hour Holter monitoring, and blood tests, were obtained by analysis of medical records.®GE software, version 3.6, as previously described.8 The second cardiac MRI was performed using a Siemens Avanto 1.5 T scanner  or a Siemens Verio 3.0 T scanner . LV images were obtained during a 15-s breath hold to minimize artefacts due to breathing movements. LV long-axis and short-axis images were obtained by two ECG-triggered pulse sequences at the same locations. LV and right ventricular (RV) systolic function were analyzed by cine-CMR using steady-state free precession protocol. End-diastolic LV diameter, end-diastolic and end-systolic LV volumes, LV mass, LV ejection fraction, end-diastolic RV volume and ejection fraction were determined by the Simpson’s method. Papillary muscles were regarded as part of the LV cavity for calculation of LV volume and mass. Images were acquired with 8-mm slice thickness and 2-mm slice spacing up to the LV apex.The first cardiac MRI was performed in a GE HDxt 1.5 Tesla (T) MRI scanner  and analyzed using the ReportCard®, Guerbet, Aulnay Sous Bois, France) using an inversion-recovery prepared gradient-echo sequence for myocardial delayed enhancement (MDE) protocol in the long- and short-axis projections. The presence, location and pattern of fibrosis were qualitatively determined. Fibrosis mass was calculated using the ReportCard®GE software version 3.6 in the first cardiac MRI and using the CVI42 software  in the second cardiac MRI). Calculation of fibrosis mass was based on semi-automatic detection of hyperintense areas compatible with fibrosis on short-axis MDE sequences. The researcher was free to edit the limits of the area of fibrosis. Signal threshold of ≥ 3 standard deviations (SDs) above the mean signal of the reference myocardium was applied to determine the scar volume for both software programs used for fibrosis mass calculation. LV fibrosis mass was defined in absolute values and as percentage of the LV mass. Segmental MDE was analyzed using LV 17-segment model.12 Scar distribution patterns were classified as follows: 1) transmural, if there was any area of scar that occupied >50% of the wall thickness but in no more than eight segments; 2) focal, if the scar area was not transmural and identified in no more than eight segments; and 3) diffuse, if the scar areas were present in more than eight segments, regardless of the presence of transmural areas.10 Fibrosis in individual segments was classified as subendocardial, midwall, subepicardial, or transmural.In order to evaluate myocardial fibrosis, images were acquired 10 to 20 min after intravenous bolus of 0.1mmol/kg of gadolinium-based contrast  allowing the use of parametric tests. Data between first and second cardiac MRI were compared using paired Student’s t-test. Associations between fibrosis mass at the first cardiac MRI and changes on LV structure and function between first and second cardiac MRI were tested using logistic regression analysis. A decrease >5 units in LV ejection fraction, an increase >10 mL/mA total of 20 patients were included in this study. All patients had CHD and 65% were at stage A and 35% at stage B1 of the disease at the time of the first cardiac MRI. Associated digestive disease was present in 35% of the participants. There was an equal gender distribution, most patients were born in the northeast region of Brazil, were white, had elementary schooling, and had hypertension   . No parRegarding ECG, all patients at baseline were in sinus rhythm, and the most common ECG changes were right bundle branch block, left-anterior hemiblock, and primary T wave changes   . No parAt the time of the second cardiac MRI, three patients progressed from stage A to B1, one patient progressed from stage B1 to B2, and one patient progressed from stage B1 to C. No patient presented any clinical event compatible with acute coronary syndrome during the study follow-up.The mean time between the cardiac MRI studies was 5.4 ± 0.5 years. The proportion of the LV segments with areas of scar at the first and second cardiac MRI is depicted in Fibrosis pattern was classified as focal in 13 patients (65%) and transmural in seven patients (35%) at the first cardiac MRI. Sixty-two out of 340 walls (18.2%) showed cardiac fibrosis with the following distribution: basal inferolateral (55%), apex (30%), apical lateral (30%), apical inferior (25%), apical anterior (25%), mid inferolateral (25%), basal inferior (20%), apical septal (20%), mid anterolateral (20%), basal anterolateral (15%), basal anteroseptal (10%), mid inferoseptal (10%), basal anterior (5%), basal inferoseptal (5%), mid anterior (5%), mid inferior (5%), and mid anteroseptal (5%). The fibrosis pattern was classified as midwall in 37 segments, transmural in 23 segments, subepicardial and midwall in one segment, and subendocardial and midwall in one segment.At the second cardiac MRI, the fibrosis pattern presented by the patients was classified as focal in 13 patients (65%), transmural in three patients (15%), and diffuse in four patients (20%). The number of walls with areas of fibrosis increased to 102  and the frequency the walls with areas of fibrosis were: basal inferolateral (75%), basal inferior (50%), mid inferolateral (45%), apical lateral (40%), basal anterolateral (35%), mid anterolateral (35%), basal anteroseptal (30%), apex (30%), apical inferior (25%), apical anterior (25%), apical septal (25%), mid inferoseptal (20%), mid inferior (20%), basal inferoseptal (15%),mid anterior (15%), mid anteroseptal (15%), and basal anterior (10%). The fibrosis pattern was classified as midwall in 74 segments, transmural in 25 segments, subepicardial and midwall in one segment, and subendocardial and midwall in two segments.Regarding LV size and function, mean values of end-systolic LV volume and LV mass were greater, and the LV ejection fraction was lower at the second cardiac MRI compared to the first cardiac MRI. Mean end-diastolic LV diameter and volume, and the right ventricular volume and ejection fraction did not change significantly from the first to the second cardiac MRI   .The mean fibrosis mass in % of LV mass increased 43% from the first cardiac MRI to the second cardiac MRI   . Regard2in end-diastolic LV volume, and seven subjects showed an increase >10 mL/m2in end-systolic LV volume. Cardiac fibrosis mass in % of LV mass detected at the first cardiac MRI showed a univariate significant association, with a decrease of >5 units in LV ejection fraction  from the first to the second MRI. There was no univariate or multivariate significant association between sex, age, LV fibrosis mass at the first cardiac MRI and the changes in end-diastolic or end-systolic LV volume > 10 mL/m2from the first to the second cardiac MRI , present in the pathogenesis of several cardiovascular diseases,8 In a previous study,24 the interobserver variability for the signal threshold versus reference myocardium (STRM)-based scar quantification technique, which we used to evaluate LV fibrosis, was -1.2% (95% CI -8.8 to 9.2%).24 In our study, six patients had a decrease in LV fibrosis mass in % of LV mass, that ranged from 1.56 to 7.48%, all within the 95% CI described for the interobserver variability. On the other hand, from the 11 patients who presented an increase in LV fibrosis mass in % of LV mass, seven showed an increase above the 95% CI described for the interobserver variability. Three other patients had a difference less than one percent between exams. Therefore, all patients with a difference between exams above the test variability showed an increase in LV fibrosis mass and corresponded to 35% of the studied population. Therefore, we believe that our results were not biased by intra or inter-observer variability.This study is limited by its retrospective design, a small convenience sample, and by the fact that the cardiac MRIs were performed in machines of different vendors and analyzed by different experts, without an assessment of interobserver variability. However, the interobserver agreement for cardiac fibrosis mass of the group that performed the first cardiac MRI was previously described as excellent.Regarding exclusion of patients with previous coronary artery disease, a negative treadmill exercise test result does not exclude the possibility of complete occlusion of a coronary branch. However, patients denied previous clinical events compatible with acute coronary syndrome. Patients also did not undergo a second treadmill exercise test or coronary angiography before the second MRI to exclude coronary artery disease. However, no patient presented any clinical event compatible with coronary artery disease during the study follow-up.In this retrospective study that included patients at an initial stage of CHD, myocardial fibrosis increased over time and LV fibrosis at baseline was associated with a decrease in LV systolic function. This important finding should be confirmed in prospective designed studies. Cardiac fibrosis must also be further studied as a prognostic index for Chagas disease progression and cardiovascular events.


Methods: A total of 71 consecutive adult patients ) referred for CMR examination with concomitant irregular heart rate  during scanning were prospectively enrolled. For each patient, two cine sequences were systematically acquired: first, the reference prospectively triggered multi-breath-hold Cineref sequence including a short-axis stack, one four-chamber slice, and a couple of two-chamber slices; second, an additional single breath-hold CSrt sequence providing the same slices as the reference technique. Two radiologists independently assessed ARA and image quality  for both techniques. Results: The mean heart rate was 71.8 ± 19.0 (SD) beat per minute (bpm) (95% CI: 67.4–76.3 bpm) and its coefficient of variation was 25.0 ± 9.4 (SD) % (95% CI: 22.8–27.2%). Acquisition was significantly faster with CSrt than with Cineref (Cineref: 556.7 ± 145.4 (SD) s (95% CI: 496.7–616.7 s); CSrt: 23.9 ± 7.9 (SD) s (95% CI: 20.6–27.1 s); p < 0.0001). A total of 599 pairs of cine slices were evaluated (median: 8 (range: 6–14) slices per patient). The mean proportion of ARA-impaired slices per patient was 85.9 ± 22.7 (SD) % using Cineref, but this was figure was zero using CSrt (p < 0.0001). The European CMR registry artifact score was lower with CSrt (median: 1 (range: 0–5)) than with Cineref (median: 3 (range: 0–3); p < 0.0001). Subjective image quality was higher in CSrt than in Cineref (median: 3 (range: 1–3) versus 2 (range: 1–4), respectively; p < 0.0001). In line, edge sharpness was higher on CSrt cine than on Cineref images (0.054 ± 0.016 pixel−1 (95% CI: 0.050–0.057 pixel−1) versus 0.042 ± 0.022 pixel−1 (95% CI: 0.037–0.047 pixel−1), respectively; p = 0.0001). Conclusion: Compressed sensing real-time cine drastically reduces arrhythmia-related artifacts and thus improves cine image quality in patients with arrhythmia.Background and objective: Cardiac magnetic resonance (CMR) is a key tool for cardiac work-up. However, arrhythmia can be responsible for arrhythmia-related artifacts (ARA) and increased scan time using segmented sequences. The aim of this study is to evaluate the effect of cardiac arrhythmia on image quality in a comparison of a compressed sensing real-time (CS Cardiac magnetic resonance (CMR) is a major imaging modality for the assessment of left and right ventricular volumes and mass ,2,3. Morref) acquisitions [Decreasing the amount of measured data is a simple way to reduce acquisition time. In recent years, compressed sensing was established as a powerful method to drastically reduce scan time ,12,13,14isitions .rt) could reduce ARA, our study aimed at evaluating its image quality as compared to the reference multi-breath-hold segmented bSSFP cine (Cineref) in patients suffering from cardiac arrhythmia.Various CMR studies have evaluated real-time CS cine sequences in 1.5 and 3 Tesla magnetic resonance scanners showing promising results for the assessment of left and right ventricles, including in patients with atrial fibrillation ,19,20,21RR) was greater than 10% while scanning. The CVRR was calculated as the ratio of the standard deviation to the mean of RR intervals’ durations which were obtained from digital imaging and communications in medicine (DICOM) fields. Patients under 18 years old, grown-up congenital heart disease, stress CMR, patients undergoing ECG retrogated CMR and patients with sinus rhythm were excluded. A graphic illustration of the study design is provided in From January 2019 to December 2019, 71 adult patients referred to our cardiovascular radiology department for CMR with concomitant arrhythmia during scanning were enrolled. Irregular HR was defined when the coefficient of variation of RR intervals  and one right ventricular (RV) two-chamber slice, one four-chamber slice and a LV short-axis stack covering both ventricles with an 8 mm slice thickness and a 2 mm gap. Regarding the prospectively gated Cineref sequence, 20 phases of the cardiac cycle were acquired and the number of views per frame was set to reach this sampling rate. In single-shot CSrt cine imaging, the data acquisition was performed in a single heartbeat. The acquisition was triggered by the R peak on the ECG. With adaptive triggering, the acquisition was stopped with the next R peak, which allowed capturing the complete cardiac cycle. However, for multi-slice acquisition it could lead to a variation in the number of cardiac phases acquired between different slices as the temporal resolution was fixed. Temporal interpolation was applied to generate an additional dataset with a fixed number of cardiac phases (n = 20). This dataset was used to quantify cardiac function using a dedicated post-processing software that required a fixed number of cardiac phases. To evaluate the CSrt sequence in clinical conditions, 40 iterations were used to perform image recovery to maintain an acceptable reconstruction time. An additional phase contrast imaging (PCI) flow sequence was acquired on the aortic root. Segmented Cineref and CSrt cine sequences parameters are available in CMR studies were performed on a 1.5 T scanner . Every patient underwent two series of cine images: first, the reference prospectively triggered and segmented multi-breath-hold CineImage quality was evaluated in both groups using four indicators. First, the subjective overall image quality was evaluated using a subjective 4-point Likert scale . Secondly, an objective image quality assessment was carried out based on standardized criteria adapted from the European CMR registry “LV-Function cine SSFP” section (referred to below as “EuroCMR score”)  (p. 3). Third, the proportion of short-axis slices affected by ARA in each stack of both sequences was calculated, referred to as ARA rate. ARA were defined as a blurring of all or a part of the LV wall borders .−1) reflecting the spatial resolution, was measured on paired Cineref and CSrt four-chamber slices at end-diastole, accordingly to the literature [Finally, the edge sharpness (ε) of the boundary between myocardium and blood pool, which is the spatial frequency  from 30 randomly selected patients to evaluate the interobserver agreement and performed the same assessment regarding subjective quality, EuroCMR score and ARA rates. In the case of mismatch between the two readers, a radiologist with 15 years of experience (FP) performed the quality assessment with the two others to reach consensual scores which were used instead of those set by the first and less experienced observer. Mismatches were defined by discrepancies greater than or equal to 2 points regarding subjective quality score and EuroCMR score, or by a 20% difference in ARA rates. The edge sharpness assessment was automated and was not evaluated for interobserver agreement. Finally, semi-automated segmentation of LV endocardium and epicardium, and manual segmentation RV endocardium were performed on the same workstation with both cine sequences for each patient. LV stroke volume was also measured on PCI sequence.Images from both sequences were anonymized before transfer to a clinical workstation . A radiologist with 4 years of experience (PEA) performed the image quality assessment according to the above-cited indicators. Image sets were randomly evaluated in each group. The same observer (PEA) first performed the quality assessment of the reference Cinet-test was used for ARA rates, edge sharpness comparisons, and ventricular functional parameters comparison. An analysis of variance (ANOVA) was used to compare LV stroke volumes assessed by cine segmentation and PCI flow sequence. Intraclass correlation coefficient and kappa test were applied to assess the interobserver agreement [p < 0.05 were considered statistically significant. Statistical analysis was performed using MedCalc software .Categorical data were represented as numbers (percentages), continuous variables as mean ± standard deviation (SD) ) in case of normal distribution and median (range: minimum–maximum) in other cases. Sequences were compared using the Wilcoxon signed-rank test regarding the overall subjective quality score and the modified EuroCMR score. Paired Student’s greement . Values n = 41/71; 57.7%, women: n = 30/71; 42.3%). Patients were referred for initial work-up or follow-up of coronary artery disease , heart rhythm disorder , dilated cardiomyopathy , infiltrative cardiomyopathy , heart valve disease , myocarditis , hypertrophic cardiomyopathy , and heart failure . The mean HR was 71.8 ± 19.0 beats per minute (bpm) (95% CI: 67.4–76.3 bpm) and 38.0% of the patients (n = 27/71) demonstrated a mean HR above 75 bpm, meaning the 49 ms temporal resolution of the CSrt cine provided less than 16 frames of the cardiac cycle per slice. The mean CVRR was 25.0 ± 9.4% (95% CI: 22.8–27.2%). Arrhythmia was caused by atrial fibrillation , ventricular hyperexcitability , and conduction disorders . Demographic data are summarized in The mean age of the population was 59.5 ± 20.1 (SD) years (95% CI: 54.7–64.2 years) with a male predominance (rt was significantly faster than Cineref (Cineref: 556.7 ± 145.4 (SD) s (95% CI: 496.7–616.7 s); CSrt: 23.9 ± 7.9 (SD) s (95% CI: 20.6–27.1 s); p < 0.0001). A total of 599 short-axis cine slices were acquired with each sequence. A median number of 8 (range: 6–14) cine slices was acquired twice for each patient, depending on cardiac morphology. To acquire the same slices, CSrt cine (median: 1 (range: 0–5)) was significantly better than for the Cineref sequence (median: 3 (range: 0–3); p < 0.0001)    . Interobp < 0.0001) for the CSrt sequence with a median score of 3 (range: 1–3). A 0.85 interobserver agreement was reached. The Cineref sequence provided a median score of 2  with an intraclass coefficient of 0.82  cine slices from n = 70/71 (98.6%) patients, with a 0.90 interobserver agreement. One mismatch was encountered between the readers . The mean proportion of impaired slices per patient was in 85.9 ± 22.7 (SD) %. No ARA could be depicted using the CSrt sequence.ARA using Cinert sequence provided a higher edge sharpness coefficient at end-diastole (εCSrt = 0.051 ± 0.016 pixel−1 (95% CI: 0.048–0.055 pixel−1)) than the Cineref (εCineref = 0.040 ± 0.018 pixel−1 (95% CI: 0.036–0.044 pixel−1)) (p = 0.0001). A similar finding was observed at end-systole (εCSrt = 0.054 ± 0.016 pixel−1 (95% CI: 0.050–0.057 pixel−1); εCineref = 0.042 ± 0.022 pixel−1 (95% CI: 0.037–0.047 pixel−1); p = 0.0001). The CSrt sequence in patients with irregular HR. Previous studies in non-selected patients confirmed that real-time CS cine imaging is a reliable alternative to segmented multi-breath-hold SSFP for the assessment of both ventricles’ volumes and function in addition to reducing acquisition time [rt in patients suffering from heart rhythm disorders. However, no CSrt set was rated as excellent because of the smooth boundaries rendered by the interpolation process which are mandatory for post-processing. Indeed, since the temporal resolution of the CS sequence is fixed, a variable number of frames will be acquired from one cycle to another in the case of arrhythmia. For segmentation to be achieved, post-processing tools require all cine slices to display the same number of frames per cycle. Consequently, a standardization is performed to display 20 frames per cycle on all slices. This prospective monocentric study based on a 71-patient cohort is, to our knowledge, the widest and most comprehensive study to evaluate the CSion time ,18,19,20rt and Cineref sequences allowed similar image quality [rt cine. Of note, this sequence still provided non-null EuroCMR scores since the slices were identically located on both sequences; accordingly, most of the wrap-around or metallic artifacts were reproduced on the CSrt acquisition. We previously showed on a small sub-group of 25 patients suffering from arrhythmia that CS quality . HoweverOur results are in line with the previous study by Goebel et al. on 20 patients with atrial fibrillation . This strt images reflected the faster signal variation along a distance and a better delineation of the image boundaries. We evaluated the edge sharpness both at end-diastole, when the myocardium is supposed to be relatively still, and at end-systole. This metric, regardless of the non-linearity of the reconstruction process, is more suitable than the SNR or its reciprocal to evaluate image quality [The higher edge sharpness of CS quality . The ESF quality ,25,28. rt provided significantly lower LV end-diastolic volume (−3.6 ± 7.2 mL) than measured on Cineref, which was already observed in previous studies [ref should be considered with caution in a population with arrhythmia. Indeed, irregular heartbeats induce variable ventricular preloads and contractions, making the real reference values impossible to determine. Moreover, since CSrt demonstrated a better image quality than Cineref that was impaired by ARA, one may consider the segmentation to be more reliable on CSrt.Regarding volumetric evaluation in patients suffering from arrhythmia, CS studies ,20. As frt sequence allowed a dramatic reduction in scan time. Not only was acquisition faster, but the ARA reduction avoided repeating the acquisition of non-diagnostic slices [Besides the image quality improvement, the single breath-hold CSc slices . The worc slices .rt cine, 10 stacks were still considered as non-diagnostic. Indeed, iterative reconstructions occasionally failed or were not completely achieved on this prototype sequence. Nevertheless, such failures are now rare since the release of the final version of the sequence. Moreover, ECG-related issues occurred when R peaks were occasionally missed, which made the system consider two consecutive heartbeats as one single cycle. The corresponding slices then display a double heart cycle which could not be used for post-processing and was ranked as non-diagnostic. Special attention should be paid to skin preparation before ECG electrode placement.Although the overall subjective image quality was improved with CSrt to other types of real-time sequences. To our knowledge, no such evaluation has been published and further study would be required for comparison.Other fast real-time sequences, such as radial acquisition, have previously been reported ,31. Our rt cine displayed smoother boundaries than Cineref sequence. Consequently, observers could recognize the type of sequence they were evaluating. However, paired CSrt and Cineref stacks from the same patients were separated, randomized, and assessed during different sessions.A methodological limitation of our study is the impossibility to perform blinded evaluation of the sequences since CSRR in HR may be encountered, and some slices may display undersampled heart cycles. In our study, 38% of the patients demonstrated a mean HR above 75 bpm for whom the undersampling of the cardiac cycle should be considered cautiously during interpretation, especially for volume segmentations. Nevertheless, it must be balanced by the reduction of ARA provided by CSrt. Regarding the sampling of heart cycles for the assessment of ventricular volumes and mass, the fixed temporal resolution leads to variable sampling rates from shorter cycler to longer ones. As a consequence, in the case of HR faster than 60 bpm, the recommended 20 frames per cycle could not be acquired ,10. Howert sequence drastically reduces arrhythmia-related artifacts and improves image quality in patients with irregular heart rate. This rapid imaging technique allows practitioners, in daily practice, to improve quality, workflow and accessibility of CMR for patients with challenging cardiac conditions. In addition to reducing acquisition time, CS


Atrial fibrillation (AF) is a major cause of cardiovascular morbidity and mortality. To early detect and to avoid AF-related complications, several cardiac imaging modalities and approaches aim to quantify the severity of the underlying atrial cardiomyopathy . However, most established cardiac imaging modalities just incorporate single components of atrial remodeling and do not reflect the complete multifactorial process, which may contribute to their limited predictive value. Echocardiography-derived PA-TDI duration is a sophisticated echocardiographic parameter to assess total atrial conduction time and directly reflects both electrical and structural changes to the atria. Therefore, PA-TDI duration provides a more comprehensive quantification of the extent of atrial remodeling than other imaging modalities. In this article we review the role of PA-TDI duration as a marker of atrial remodeling and summarize the available data on PA-TDI duration to identify patients at risk for AF, as well as to guide AF management. Moreover, we discuss how to assess PA-TDI duration and provide recommendations on the implementation of PA-TDI duration into routine clinical care. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and affects more than 6 million people in Europe . AF is oQuantification of the extent of atrial remodeling is considered the key to predict the development and progression of AF, the response to AF treatment and the risk for AF related complications. However, most imaging modalities that are used to quantify atrial remodeling fail to capture more than one clinical manifestation of this process, thereby limiting their predictive value.Echocardiography derived total atrial conduction time is a marker of atrial remodeling that reflects both morphological  and electrical (conduction velocity) manifestations . Total aHere, we review the role of the PA-TDI duration as a marker of atrial remodeling and summarize the available data on PA-TDI duration to detect patients at risk for AF, to guide AF treatment and monitor the effect of risk factor modification on the left atrial substrate. Importantly, we discuss how to assess PA-TDI duration and provide recommendations on the implementation of PA-TDI duration into routine clinical care.. The PA-TDI duration is measured during sinus rhythm as the time interval from the onset of the P-wave in lead II of the surface ECG  to the peak A’-wave on the tissue Doppler tracing of the LA lateral wall .The PA-TDI duration is measured from ECG-gated pulse-wave TDI recordings of the apical four-chamber view using two-dimensional transthoracic echocardiography. Settings are optimized for the highest framerate as possible . A region of interest marker is placed at the LA lateral wall just above the mitral annulus providing the tracing of the mechanical activation in that area Fig. . The PA-R = 0.911, p < 0.001) [p < 0.01).The use of PA-TDI duration to estimate total atrial conduction time has been validated by Merckx et al. using P-wave duration (PWD) on the signal-averaged ECG as the ‘gold standard’ (< 0.001) . PWD in Histological validation of PA-TDI duration to assess atrial remodeling was provided by Müller et al. who demonstrated the correlation between PA-TDI duration and the degree of atrial fibrosis inside the right atrial appendage, one of the hallmark processes involved in atrial remodeling . In addip < 0.001). Furthermore, after effective treatment with continuous positive airway pressure therapy, which is one of the mainstay treatment options for obstructive sleep apnea patients [The PA-TDI duration is strongly influenced by factors that play a role in atrial remodeling Fig. . In a grpatients , the PA-patients . This obThe PA-TDI duration shows a close correlation to conventional echocardiographic indices of atrial remodeling. Weijs et al. demonstrated that PA-TDI duration is associated with left atrial dilatation  . HoweverAF is associated with a higher cardiovascular morbidity and mortality, and timely identification of AF may help to avoid complications and improve outcome –35. TherPost-operative AF (POAF) is the most common sustained arrhythmia after cardiac surgery and is associated with an increased morbidity and mortality as well as prolonged in-hospital stay . Pre-opeAntiarrhythmic drugs, electrical cardioversion and catheter ablation are the cornerstones of rhythm control therapy of AF. Despite significant advancement of these therapies, AF recurrence rates are high . Age, coAF predisposes patients to a fivefold increased risk of ischemic stroke . Thus, iEchocardiography is commonly used to quantify atrial remodeling by measurement of LA size and function. LA size and function have proven to be an important predictor of AF related outcome –40. HoweA more sophisticated echocardiographic parameter that does not rely on volumetric measurements to quantify atrial remodeling is LA strain. LA strain uses Speckle tracking tissue deformation analysis to assess global LA function and has proven to be an independent predictor of AF related outcome . HoweverMeasurement of PA-TDI duration is angle-independent and the TDI-tracings have a high temporal resolution . Moreover, the PA-TDI duration can be measured directly on the echo machine and does not require time-consuming offline post-processing and has a low intra- and interobserver variability.p < 0.0001). Most likely, this could be explained by a different time delay between the ECG-signal and the echo-signal across the two systems [The PA-TDI duration can be assessed on each echocardiographic machine with the ability to record TDI with ECG-gating. Therefore, this technique is widely available and easy to introduce into clinical practice. However, there are some challenges that need to be overcome. Currently, no normal values for PA-TDI duration have been established. There seems to be a large variation in values for PA-TDI duration across the different studies Table A–D. Alth systems . In addi systems , 12, 28.Quantification of atrial remodeling is considered the key to predict the development of AF, the response to rhythm control therapies and the occurrence of AF related complications. The PA-TDI duration is an echocardiography-derived parameter that can be used to quantify the severity of atrial remodeling . The advPA-TDI duration is very closely related to PWD, as both parameters are indices of the total atrial conduction time. However, whereas PWD reflects the time interval between the earliest and latest atrial electrical activation, PA-TDI duration reflects the time interval between earliest atrial electrical activation and the latest atrial mechanical contraction. Theoretically, PA-TDI duration, therefore, provides a more comprehensive assessment of atrial remodeling than PWD. Practically, measurement of PA-TDI duration is less time-consuming than PWD derived from signal-averaged ECG , and hasHeart rate can have an important impact on cardiac physiology, for example on the QT-time. The impact of heart rate on PA-TDI duration has not been investigated extensively. Chao et al. found a weak correlation of − 0.270 between PA-TDI duration and heart rate, meaning that roughly 7% of variation in PA-TDI duration can be related to the heart rate . However2DS2-VASc score may benefit from anticoagulation therapy. Carefully designed clinical trials are needed to evaluate these potential applications of PA-TDI duration.Assessment of PA-TDI duration as a routine echo-lab parameter may substantially improve risk stratification and management of AF. The simple, quick and inexpensive measurement of PA-TDI duration enables its integration into everyday clinical practice. As PA-TDI duration reflects different aspects and dynamics of atrial cardiomyopathy, this parameter may be useful: (1) to identify patients at risk for AF; (2) to guide and monitor individualized rhythm-control therapy; and (3) to identify which patients with low CHAThe PA-TDI duration is an easy and fast-to-measure echocardiographic parameter that combines information about parts of the structural, electrical and functional changes to the atria to reflect the different and dynamic facets of atrial remodeling. Assessment of PA-TDI duration, as part of an integrated diagnostic work-up, has a potential role to improve risk stratification and management of AF in clinical practice.


Parenting behaviours—including the extent to which parents are protective, hostile, or caring—likely impacts whether a child develops a sense of vulnerability that carries forward into adulthood. Ideas of vulnerability are a contributory factor to the occurrence of paranoia. Our aim was to assess whether there is an association between specific parenting behaviours and paranoia.We examined cross-sectional associations of parenting and paranoia in an epidemiologically representative cohort of 10,148 adolescents  and a second dataset of 1286 adults in Oxfordshire. Further, a network analysis was conducted with paranoia, parenting behaviours, and cognitive-affective variables . Overprotectiveness, verbal abuse, physical abuse, and amount of care were assessed in mothers and fathers separately.p < 0.001, CI 2.47–6.85). Network analyses revealed high interconnectivity between paranoia, parenting behaviours, and cognitive-affective variables. Of the parenting variables, paranoia most strongly interacted with paternal abuse and maternal lack of care.Nearly all parenting variables were significantly associated with paranoia, with parental verbal and physical abuse showing the largest associations. For example, the odds of reporting paranoia was over four times higher for those in the adult sample reporting a lot of paternal verbal abuse, compared to those reporting none (OR = 4.12, There are associations between participants’ self-reported experiences of parental behaviours and paranoia. Despite being associated with paranoia, cognitive-affective variables did not appear to mediate the relationship between parenting and paranoia, which is surprising. What might explain the link therefore remains to be determined. Paranoia exists on a spectrum of severity in the general population: many people have a few paranoid thoughts and a few people have many –3. It isIn a theoretical model, it is hypothesised that negative self-beliefs lead to feeling inferior, apart, and vulnerable, and that paranoia builds upon these concerns . NegativHow might the beliefs about the self and others form in the first place? Childhood physical abuse, sexual abuse, and other victimisation experiences have been associated with paranoia and may plausibly partly exert influence via beliefs about the self and others , 20. ParHow might parenting behaviours link to paranoia? Perhaps the experience of overprotection could lead a child to develop schemas about the world as dangerous and themselves as vulnerable, to explain the protection. Similarly, experiencing low care from parents could lead a child to develop the kinds of negative self-beliefs that paranoia builds upon, e.g., that they are unworthy of care and therefore inferior to others. Finally, negative beliefs about the self and others are often developed in the context of adverse interpersonal experiences . ExperieIn this paper, we examine associations in two samples  between parenting, cognitive affective processes, and paranoia. The aim was to use the first sample as an initial test of the model, with the second sample used to explore the relationships in greater detail with more robust measures included. We also make use of a network analysis to conceptualise the interplay between these variables , 31. NetOur hypotheses were as follows. First, that regression analysis would show positive associations between maternal and paternal overprotectiveness and paranoia and between maternal and paternal abuse and paranoia, and negative associations between amount of maternal and paternal care and paranoia in both participant groups. Second, these associations would be apparent when analysing variables as part of a network. Third, within the network, cognitive-affective variables such as levels of anxiety and self-esteem would provide a mediating pathway between paranoia and parenting behaviours.www.hcp.med.harvard.edu.ncs. The new survey was administered via Qualtrics, an online questionnaire platform.Associations between parenting behaviour and paranoia were first tested in the National Comorbidity Survey Replication Adolescent Supplement (NCS-A)  and thenn = 4962) of the sample were male, 51.1% (n = 5186) female.The NCS-A sample included 10,148 adolescents aged 13–17 years old. 9244 adolescent students were selected from a representative sample of 320 schools in the same nationally representative sample as the National Comorbidity Survey-Replication (NCS-R) (response rate 74.7%). The remaining 904 participants were from the same households of those that took part in the National Comorbidity Survey-Replication (response rate 85.9%). The mean age was 15.18 years (SD = 1.51) and 48.9% (. The mean age of this survey group was 41.54 years (SD = 15.95). Data on participant gender were not collected for the first 207 participants. Of the remaining 1024 participants, 23.7% (n = 243) were male and 76.3% (n = 781) female. It is typical for online surveys to receive a considerably higher response rate from women ; ‘pushed, grabbed or shoved, threw something, slapped or hit’ [physical abuse (List B)]; ‘kicked, bit or hit with a fist, beat up, choked, burned or scalded, threatened with a knife or gun’ [severe physical abuse (List C)].The Oxfordshire participant group completed the same measures of paranoia and parental behaviour described for the NSC-A dataset, as well as the following measures:a > 0.95) across both mild and severe ends of the paranoia spectrum [Participants completed the Green et al. Paranoid Thoughts Scale—Part B (GPTS-B) . This isspectrum . Test–respectrum .The Measure of Parenting Style (MOPS)  was usedAlthough two of the subscales were named differently from the parenting questions included in the NCS-A dataset , they were taken in our study to be measuring the same constructs. This was justified upon Parker et al.’s descriptions of both over-protection and care described above . The abuα  > 0.85 and a near-perfect correlation with the long form of the scale when using total scores (r > 0.96) [The self-compassion scale-short form (SCS-SF) was used . The sca > 0.96) .α  = 0.9) [Participants were given the Compassion Scale , a 24-it  = 0.9) .α  = 0.85) [The Patient Health Questionnaire-4 (PHQ-4)  is a bri = 0.85) . The two = 0.85) .The Rosenberg Self-Esteem Scale  is a higThe NCS-A data were analysed using the Statistical Package for the Social Sciences . The datFirst, identical logistic regressions as above were conducted using the same measures of parenting and paranoia as were included in the NSC-A dataset. Second, simple regressions were conducted for the more in-depth measures of parenting and paranoia completed by the Oxfordshire participant group.Network analysis with the measures from the Oxfordshire survey was conducted in R, version 3.6.1 . A netwoUsing the package qgraph, a Gaussian graphical model was fitted . A regulTwo separate network models were constructed to show the shortest path between paranoia and every other variable, and between the parenting variable found to have the strongest edge with paranoia and every other variable using Dijkstra’s algorithm . The shon = 2302) of participants in the NCS-A participant group endorsed the paranoia item “People often make fun of me behind my back”. In the Oxfordshire group, 18% (n = 226) endorsed the paranoia item. Table Twenty-three per cent . Despite previous research finding stronger associations between reported paternal behaviour and schizophrenia, than maternal behaviour and schizophrenia , this waThe network analysis revealed a highly interconnected network, though with the parenting and cognitive-affective variables clearly clustering separately. After controlling for all other variables, the strongest associations between reported parenting behaviours and paranoia were between maternal indifference and paranoia, and between paternal abuse and paranoia. Janssen et al.  suggest There are a number of limitations to the study. First, demographic confounds such as socio-economic status and cognitive variables such as IQ were not tested. Previous studies assessing the relationship between early-life adversities and symptoms of psychosis have found that these variables are associated with paranoia . True asFinally, the biggest limitation is that the studies were cross-sectional, limiting causal inference. It cannot be determined whether these parental behaviours contribute to the development of paranoia, whether paranoia impacts parental relationships and thus parental behaviours, whether paranoia biases report of parental behaviours, or whether a confounding variable can explain the associations. However, regarding the possibility that paranoia biases the report of parental behaviours, it has been shown that patient reports of early experiences do tend to be unaffected by current symptoms, accurate when judged against reports of siblings, and stable over long periods, including times of acute illness versus remission –64. MoreBradford Hill  argues t