Domestic pigs are widely used in cardiovascular research as the porcine circulatory system bears a remarkable resemblance to that of humans. In order to reduce variability, only clinically healthy animals enter the study as their health status is assessed in entry examination. Like humans, pigs can also suffer from congenital heart disease, such as an atrial septal defect (ASD), which often remains undetected. Due to the malformation of the endocardial cushion during organ development, mitral valve defects  are sometimes associated with ASDs, further contributing to hemodynamic instability. In this work, we report an incidental finding of a hemodynamically highly relevant ASD in the presence of incompetent mitral and tricuspid valves, in an asymptomatic, otherwise healthy juvenile pig. In-depth characterization of the cardiac blood flow by four-dimensional (4D) flow magnetic resonance imaging (MRI) revealed a prominent diastolic left-to-right and discrete systolic right-to-left shunt, resulting in a pulmonary-to-systemic flow ratio of 1.8. Severe mitral (15 mL/stroke) and tricuspid (22 mL/stroke) regurgitation further reduced cardiac output. Pathological examination confirmed the presence of an ostium primum ASD and found a serous cyst of lymphatic origin that was filled with clear fluid partially occluding the ASD. A large mitral cleft was identified as the most likely cause of severe regurgitation, and histology showed mild to moderate endocardiosis in the coaptation area of both atrio-ventricular valves. In summary, although not common, congenital heart defects could play a role as a cause of experimental variability or even intra-experimental mortality when working with apparently heathy, juvenile pigs. Due in part to their good availability, acceptable cost, and relatively easy handling, domestic (farm) pigs are often used in research . The simIn order to diagnose and delineate congenital heart defects in large laboratory animals as well as in the clinic, multiple imaging modalities can be used, with echocardiography as a primary screening tool . FurtherGlaesserella parasuis and porcine circovirus at the age of 3 and 6 weeks, whereas sows are vaccinated against Parvovirus and Erysipelothrix rhusiopathiae. Additionally, sows are vaccinated against E. coli 5 and 3 weeks prior to giving birth. Upon arrival at our facility, all pigs are clinically assessed by observation  and only if further indicated by physical examination as it often induces additional stress to newly arrived animals. Following an unremarkable entry examination, a 30 kg female pig (Swiss White large “Edelschwein”) ~10–12 weeks old, was included in an acute study as part of a scientific project investigating the use of hyperpolarized 13C urea for magnetic resonance perfusion imaging under the license ZH152/2013. After 10 days of habituation, the animal was anesthetized for the imaging procedure as part of the experimental protocol. General anesthesia was induced by intramuscular application of ketamine (15 mg/kg), azaperone (2 mg/kg) and atropine (0.05 mg/kg), deepened with intravenous propofol (1 mg/kg) for orotracheal intubation and maintained with isoflurane (2–3%) in 100% oxygen under volume controlled, positive pressure ventilation . The animal was subjected to functional and phase contrast MRI  on a clinical grade 1.5 T Philips Ingenia scanner . Upon completion of the imaging procedure, the animal was euthanized with an i.v. overdose of pentobarbital  while still in deep anesthesia; according to the study protocol. The heart was harvested and preserved in 10% neutral buffered formalin for pathological analysis. Following macroscopic examination, tissue blocks of the left and right atria, left and right ventricular free walls, and the septum were prepared and histological sections of the affected regions were made. Tissue blocks were routinely processed and embedded in paraffin wax prior to haematoxylin and eosin staining of 2 μm sections. Consecutive sections were additionally stained with reticulin, elastic van Gieson and trichrome stains or mounted onto positively charged glass slides and stained for Factor VIII-related antigen (FVIIIra) and CD31 using immunohistochemistry.All pigs entering the research facility are provided by the same supplier and screened under the national surveillance program for classical and African swine fever, foot and mouth disease, Aujeszky's disease, porcine reproductive and respiratory syndrome (PRRS) and swine vesicular disease. While still at the supplier, piglets are vaccinated against Functional MRI showed a clear defect in the atrial septum and a moderately enlarged right ventricle . Analysi2) with a diastolic L-R shunt (930 mL/min).Furthermore, MRI examination revealed an elevated ratio of pulmonary-to-systemic flow (Qp/Qs = 1.8), supporting the presence of a hemodynamically relevant ASD  and is also known as incomplete AVSD or endocardial cushion defect.AVSDs account for ~3% of congenital cardiac defects in humans and are also highly associated with both Noonan and Down syndrome . The mosDiastolic L-R shunting as described in this case could be attributed to hemodynamic effects caused by differences in ventricular stiffness and compliance, whereas the small systolic R-L shunt could be due to pulmonary hypertension and severe tricuspid regurgitation. Diastolic MR is a rare event and often indicates diastolic left ventricular dysfunction or AV block . FurtherCysts associated with ASD are rare but have been reported in patients previously. However, they were often either tumorous (myxoma) in origin or blood cysts usually filled with necrotic tissue and thrombus material , 20. ValHence, congenital septal and related valvular defects in humans as well as in pet and farm animals are quite similar in anatomical appearance and corresponding hemodynamic effects. Although important, diagnosis of such cardiac disease could be quite challenging in large laboratory animals. Specialized imaging techniques such as functional and phase contrast MRI, besides echocardiography, can be applied. However, such MRI procedures require general anesthesia with multiple breath holds and are lengthy. Nevertheless, modern acquisition sequences and hardware are available that can significantly shorten the scan time and hence increase safety and ‘comfort' of large animals used for scientific purposes , 24.Domestic  pigs are widely used in studies of human heart disease and therapy, mainly due to the similarity in heart development, physiology, and anatomy. These similarities also extend to congenital heart defects, such as ASD. Although having a strong impact on cardiac function, such defects are often not apparent upon clinical examination prior to the study and their diagnosis often require specialized imaging procedures like echocardiography or magnetic resonance. Easier to perform, jet less specific diagnostic methods, like cardio-pulmonary auscultation, might be successfully used with well-adapted and/or trained (mini-) pigs, however they are quite challenging in a setting of entry examination of farm pigs not used to human handling. Although echocardiographic equipment is widely available in the laboratory animal setting, examinations still require pigs to be sedated. Transthoracic as well as transoesophageal echo-imaging windows are quite restrictive in porcine and a comprehensive echocardiographic examination requires experience and adapted imaging protocols . On the in vivo or detailed pathological post-mortem examination.Hence, congenital heart defects should be considered as a possible cause of inter-animal variability or even mortality when working with healthy-appearing juvenile domestic pigs in scientific projects. However, the detection of such defects is challenging and requires specialized imaging procedures The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Cantonal Veterinary Office Zurich.NC, MW, and CS: conceptualization, imaging procedure, animal handling, data reconstruction, data analysis, and preparation and review of manuscript. AM and LG: pathology data acquisition, data analysis, and preparation of the manuscript. SN and ME: data analysis, data interpretation, and review of manuscript. All authors contributed to the article and approved the submitted version.This work was partially funded by grants from the Swiss National Science Foundation (PZ00P2_174144 and CR23I3_166485) and Olga Mayenfish foundation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Sirs:A 19-year-old female patient presented to the emergency department with fever, tachycardia, dyspnea, and abdominal pain. She was diagnosed with an ovarian germ cell tumor 1 month previously. Chemotherapy had been initiated including cisplatin, etoposide, and bleomycin 2 weeks before. Transthoracic echocardiography showed normal left ventricular (LV) and right ventricular function prior to chemotherapy.On admission, physical examination and electrocardiogram did not show relevant pathologies. Heart rate was 120 beats per minute (sinus rhythm), blood pressure was 101/58 mmHg, and temperature was 38.5 °C. Laboratory analyses revealed markedly elevated C-reactive protein  and procalcitonin , and severe leukocytopenia . A transthoracic echocardiogram showed severely impaired systolic LV function and LV dilatation, and preserved systolic right ventricular function . There was moderate to severe mitral regurgitation. Chest X-ray demonstrated pulmonary congestion and a left-sided pleural effusion.The patient’s status rapidly deteriorated and she developed severe cardiogenic shock  requiring high-dose vasopressors and inotropes. NT-pro BNP level was 29,390 ng/L, hs-Troponin T level was 66 ng/L. The patient was urgently transferred to the catheterization laboratory. Coronary angiography revealed normal coronary arteries. Endomyocardial biopsies (EMB) from the LV were obtained and an Impella CP micro-axial flow-pump  was inserted for LV unloading [Escherichia coli and Streptococcus salivarius. High-dose corticosteroids were given for 3 consecutive days, but without significant clinical benefit.The patient was intubated and mechanically ventilated due to progressive respiratory failure despite rapid stabilization of hemodynamics on mechanical support. Levosimendan was administered to gradually reduce vasopressors and inotropes. After 19 h on Impella support, inotropes were weaned and early intravenous heart failure treatment was started using the short-acting β-blocker landiolol due to its almost neutral effect on blood pressure. Antibiotic treatment was applied due to bacteremia with 2. Macrophages (CD11b + /Mac-1 +), CD45R0 T Memory cells, and perforin-positive cytotoxic cells (CD3 +) were analyzed and showed increased infiltrations.Histologic, immunohistologic, molecular, and virological analyses of the EMBs Fig.  were perBased on the clinical course, persistently reduced LV function and evidence of actively replicating B19V an antiviral therapy with tenofovir disoproxil (245 mg once daily) was initiated. Following step-wise reduction of pump-flow, the Impella pump was removed on day 8. Oral heart failure therapy was started including a beta-blocker, an angiotensin-converting enzyme inhibitor, and a mineralocorticoid-receptor antagonist. The patient remained in stable clinical condition. LV function steadily improved and was mildly reduced at discharge on day 17. On 3 month follow-up, LV function was completely normalized . There were no signs or symptoms of heart failure. No major adverse events occurred. NT-pro BNP level dropped to 167 ng/L. On 4 month follow-up, cardiac magnetic resonance imaging demonstrated the absence of late gadolinium enhancement and myocardial edema  indicates B19V transcriptional activity. In contrast to latent infection (solely DNA genomes), expression of B19V viral RNA in the myocardium has been demonstrated to be of clinical significance , 5. TreaAcute viral myocarditis with cardiogenic shock early after chemotherapy is a rare and life-threatening entity. EMB can unveil the underlying pathology and guide diagnosis and specific therapy. Tenofovir disoproxil on top of guideline-recommended heart failure therapy demonstrated a safe and effective specific treatment option in this case of B19V-induced acute myocarditis.Supplementary file1 Supplemental Video 1: Transthoracic echocardiogram at ICU admission  showing a severely reduced systolic LV function and LV dilatation (AVI 876 KB)Supplementary file2 Supplemental Video 2: Transthoracic echocardiogram at 3 months follow-up  showing full recovery of systolic LV function. (AVI 1868 KB)Below is the link to the electronic supplementary material.


Left ventricular (LV) involvement in diabetic cardiomyopathy has been reported; however, only limited data exist on right ventricular (RV) involvement. Therefore, our purpose was to investigate RV systolic dysfunction and its association with LV longitudinal myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) and preserved LV ejection fraction (LVEF).We studied 177 T2DM patients with preserved LVEF and 79 age-, sex-, and LVEF-matched healthy volunteers. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), and RV systolic function was assessed as RV free-wall strain, and predefined cutoff values for subclinical dysfunction were set at GLS < 18% and RV free-wall strain < 20%, respectively.2 = 6.2) with the addition of conventional echocardiographic parameters  and a further improvement with the addition of GLS .RV free-wall strain in T2DM patients was significantly lower than that in normal controls . RV free-wall strain in T2DM patients and LV longitudinal dysfunction was similar compared to that in T2DM patients without . Furthermore, multivariate logistic regression analyses showed that GLS was independently associated with RV systolic dysfunction as well as mitral inflow E and mitral e′ annular velocities ratio . Sequential logistic models evaluating the association of RV systolic dysfunction in T2DM patients showed an improvement in clinical variables (χRV subclinical systolic dysfunction was observed in T2DM patients with preserved LVEF and was associated with LV longitudinal myocardial dysfunction. Our findings may provide additional findings for the management of T2DM patients.The online version contains supplementary material available at 10.1186/s12933-021-01404-5. Type 2 diabetes mellitus (T2DM) has come to be considered as an important contributor to the development of various types of heart failure (HF) , 2. LeftThe role of right ventricular (RV) systolic function has been increasingly recognized, and there is a growing body of evidence that RV systolic function is a powerful predictor of mortality in patients with various types of HF –12. Seve2; (4) uncontrolled hypertension with blood pressure > 180/100 mmHg; (5) more than moderate valvular heart disease; and (6) atrial fibrillation. The diagnosis of T2DM was based on World Health Organization criteria [A total of 177 asymptomatic patients with T2DM and preserved LVEF  without coronary artery disease who were admitted to Kobe University Hospital between June 2013 and March 2020 were retrospectively studied. The mean patient age was 61 ± 13 years, 83 patients (47%) were women, and the mean LVEF was 66% ± 5% . All enrolled patients underwent an exercise stress screening test, such as a treadmill exercise or stress myocardial perfusion scintigraphy during hospitalization, and patients with an ischemic response were excluded. The preliminary exclusion criteria were as follows: (1) history of coronary artery disease; (2) previous history of open-heart surgery or congenital heart disease; (3) severe renal dysfunction defined as a glomerular filtration rate < 30 mL/min/1.73 mcriteria . For comAll patients with T2DM and normal controls underwent transthoracic echocardiography. All echocardiographic data were obtained using a commercially available echocardiographic system . Digital routine grayscale two-dimensional cine loops from three consecutive heartbeats were obtained at end-expiratory apnea from standard parasternal and apical views. The sector width was optimized to allow for complete myocardial visualization while maximizing the frame rate. Standard echocardiographic measurements were obtained in accordance with the current guidelines of the European Association of Cardiovascular Imaging .Two-dimensional speckle-tracking strain analysis was performed for each patient using dedicated software  to evaluate LV longitudinal myocardial function and RV systolic function. LV longitudinal myocardial function was assessed as GLS, and longitudinal speckle-tracking strain was calculated using an automated contouring detection algorithm, and manual adjustments of the region of interest were performed, if necessary. Longitudinal strain results for the individual clips were visualized in a color-coded format and combined in a bull’s eye plot. GLS was then determined as the average peak longitudinal strain of 18 LV segments and was expressed as an absolute value . RV systt-test or the Mann–Whitney U test, as appropriate. Proportional differences were evaluated using Fisher’s exact test. The initial univariate logistic regression analysis to identify univariate determinants of RV systolic dysfunction  was followed by a multivariate logistic regression model using stepwise selection, with the P-values for entry into the model set at < 0.50. Sequential logistic models were performed to determine the incremental benefit of GLS in relation to RV systolic dysfunction using clinical variables, including age, sex, dyslipidemia, and estimated glomerular filtration rate (eGFR), and echocardiographic parameters, including LVEF, mitral inflow E and mitral e′ annular velocity ratio (E/e′), and left atrial volume index. A statistically significant increase in the global log-likelihood χ2 of the model was considered to represent an incremental predictive value. For all steps, a P-value < 0.05 was considered statistically significant. All analyses were performed using commercially available software .Continuous variables are expressed as mean values with standard deviation for normally distributed data and median values with interquartile range for non-normally distributed data. Categorical variables are expressed as frequencies and percentages. The parameters of the two subgroups were compared using Student’s 2 vs. 22 ± 4 kg/m2, P < 0.0001), higher systolic blood pressure , increased heart rate , and higher prevalence of hypertension (107 (60%) vs. 6 (8%), P < 0.0001) and dyslipidemia (105 (59%) vs. 6 (8%), P < 0.0001), while echocardiographic data showed that patients with T2DM were more likely to have a larger left atrial volume index , LV mass index , and E/eʹ  and a smaller GLS  and RV free-wall strain  compared to normal controls.The baseline clinical and echocardiographic characteristics of the 177 patients with T2DM and 79 normal controls are summarized in Table 2 vs. 25 ± 6 kg/m2, P = 0.02) and triglyceride , and lower high-density lipoprotein cholesterol  compared to those with LV longitudinal dysfunction without RV systolic dysfunction.RV free-wall strain in patients with T2DM was significantly lower than that in normal controls as shown in Fig. 2 = 6.2), showed an improvement with the addition of LVEF, E/eʹ, and left atrial volume index  and a further improvement with the addition of GLS .The incremental benefits determined using sequential logistic models to identify the association between RV systolic dysfunction and clinical variables are shown in Additional file Figure The findings of our study indicate that subclinical RV systolic dysfunction was observed in asymptomatic patients with T2DM and preserved LVEF without coronary artery disease, and LV longitudinal myocardial function was also highly associated with RV systolic function in such patients.LV systolic dysfunction due to left-sided HF is believed to be the most common cause of RV systolic dysfunction, which is independently associated with poor outcomes in various types of HF patients –12. CurrT2DM is considered an independent predictor of mortality and contributes to the development of HF, even in patients with preserved LVEF in the absence of significant coronary artery disease and hypertension , 25. ThuHF is a global public health problem, and the number of hospitalized patients due to HF is increasing, which is one of the most important issues for the management of HF , in whatThis was a single-center retrospective study, and was a cross-sectional study design so that there was only small evidence of the relationship between T2DM and RV dysfunction. Thus, prospective multicenter studies with larger patient populations and longitudinal data are needed to further assess our findings. Furthermore, the assessment of GLS and RV free-wall strain after treatment of T2DM was not part of this study because only a small number of patients were available for follow-up.RV subclinical systolic dysfunction was observed in asymptomatic patients with T2DM and preserved LVEF without coronary artery disease and was associated with LV longitudinal myocardial dysfunction. Our findings may provide additional findings for the management of T2DM patients.Additional file 1. The incremental benefits determined using sequential logistic models to identify the association of RV systolic dysfunction, showing that one model, based on clinical variables including age, gender, dyslipidemia, and eGFR, showed an improvement with the addition of LVEF, E/e′ and left atrial volume index and a further improvement with the addition of GLS.


Background: Changes in physical activity (PA) after implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillators (CRT-D) implantation were unknown. The association of PA changes with new-onset atrial fibrillation (AF), cardiac death and all-cause mortality was unclear in patients at high risk of sudden cardiac death.Methods: Patients receiving ICD/CRT-D implantation from SUMMIT registry were retrospectively analyzed. Changes in PA were considered from baseline status to 1 year after implantation. New-onset AF was defined as the first atrial high-rate episode ≥1% of the daily AF burden detected after implantation.Results: Over a mean follow-up of 50.3 months, 124 new-onset AF events (36.2%), 61 cardiac deaths (17.8%), and 87 all-cause deaths (25.4%) were observed in 343 patients with ICD/CRT-D implantation. PA at 1 year after implantation was increased compared with PA at baseline , and PA at 1 year was improved in 210 patients (61.2%). Per 1% decrease in PA was associated with 12.4, 18.3, and 14.3% higher risks of new-onset AF, cardiac death and all-cause mortality, regardless of different baseline characteristics. Patients with decreased PA had 2-fold risks of new-onset AF  as high as those with unchanged/increased PA. Decreased PA was an independent risk factor for cardiac death  and all-cause mortality .Conclusion: PA decrease after ICD/CRT-D implantation is associated with a higher incidence of new-onset AF, resulting in worsened outcomes in cardiac death and all-cause mortality. Atrial fibrillation (AF) is a common cardiac arrhythmia with an increasing prevalence . It was Physical activity (PA) can predict the outcomes of different diseases –12. PA cTo date, few studies have assessed changes in PA after ICD/CRT-D implantation. In the present study, early changes in PA from baseline to 1 year after implantation were evaluated in patients with ICD/CRT-D implantation. Dual-chamber ICDs can provide quantitative and continuous daily PA and AF burden data using a remote home monitoring system, enabling accurate detection of PA changes and new-onset AF . This stThe Biotronik Home Monitoring System Safety and Efficacy in Cardiac Implantable Electronic Device-implanted Patients (SUMMIT) registry is a prospective, observational, and multicentre study in China. We performed a retrospective analysis using the archived home monitoring transmission data from SUMMIT registry and evaluated the association of changes in PA with the incidence of new-onset AF, long-term cardiac death, and all-cause mortality. The present study, which conformed to the Declaration of Helsinki, was approved by all participating institutions. All patients provided written informed consent before entering this study.Patients who underwent ICD/CRT-D implantation between May 2010 and May 2015 were included when the following criteria were met: (1) ICD or CRT-D was implanted in accordance with the current guideline's recommendations; (2) continuous home monitoring transmission started immediately after implantation; (3) data related to AF daily burden and PA were available; (4) patients were aged ≥18 years at implantation; and (5) life expectancy was >1 year after device implantation. Patients were excluded when (1) AF, atrial flutter (AFL) or atrial tachycardia (AT) was diagnosed using ICD-10 codes  before enrolment; (2) patients were lost to follow-up; (3) remote monitoring transmission data was missing or incomplete; or (4) patients were diagnosed with a malignant tumor or scheduled for heart transplantation.The Biotronik remote home monitoring system can transmit and store data from implantable devices to service centers every day. Data on daily AF burden and PA were collected for each patient. Daily AF burden was expressed as a percentage of the time with atrial high-rate episodes (AHREs) > 180 beats in a 24-h period, where 1% indicated a total of 14.4 min of AHREs per day, which is the minimum daily AF burden. Similar measurement algorithms were previously shown to have a sensitivity and specificity of 95% for AHREs and AF burden detection , 21.Continuous PA was recorded using a Biotronik accelerometer sensor. PA was defined as a percentage of total daily duration recorded when rates were higher than basic rates, where 10% indicated 2.4 h of daily PA, with a resolution of 2 s. PA at baseline was the average daily value detected during the first 30–60 days after ICD/CRT-D implantation, as recommended by previous studies , and PA The primary endpoint was new-onset AF. New-onset AF was defined as the first AHRE ≥1% of the daily AF burden, whether symptomatic or not, detected after ICD/CRT-D implantation , 20.The secondary endpoints were cardiac death  and all-cause mortality. The date and cause of death was based on the death certificate. Routine follow-ups were conducted via telephone or clinics. If data transmission was disrupted, the clinical research coordinator immediately confirmed the patient's conditions by contacting the family members.Baseline data for the enrolled patients were derived from medical records during hospitalization, including age at implantation, sex, body mass index (BMI), ICD or CRT-D implantation, New York Heart Association (NYHA) class, echocardiographic characteristics (left ventricular ejection fraction [LVEF] and left ventricular end diastolic diameter [LVEDD]), comorbidities , stroke, dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], ischemic cardiomyopathy [ICM], valvular disease, prior myocardial infarction [MI], percutaneous coronary intervention [PCI], and pre-implant syncope], and medication .n = 114, mean = −2.85%, range [−12.9 to −0.4%]), PA unchanged group , and PA increased group .Changes in PA were considered from baseline to 1 year after ICD/CRT-D implantation. All enrolled patients were divided into three groups based on the tertiles of changes in PA, including PA decreased group , and categorical variables are presented as frequencies and percentages. Clinical characteristics were compared across decreased PA, unchanged PA, and increased PA groups using one-way analysis of variance for continuous variables and a chi-square test for categorical variables. Clinical outcomes, including new-onset AF, long-term cardiac death, and all-cause mortality, were calculated and compared using chi-square test.Considering the competing risks, cumulative incidence function and Fine and Gray model were used in the survival analysis of detected new-onset AF between different groups of PA performance. Kaplan-Meier survival curves and cox proportional hazards regression models were performed to evaluate the association of changes in PA with cardiac death and all-cause mortality. In the multivariate analysis, model 1 was adjusted for age at implantation and sex. Model 2 was adjusted for additional confounders, including BMI, LVEF, LVEDD, ICD or CRT-D implantation, NYHA class, hypertension, DM, DCM, ICM, prior MI, PCI, and ACEI/ARB, diuretics, and aldosterone antagonist usage. Model 3 was adjusted for the above-mentioned confounders and baseline PA.P-values < 0.05 were considered statistically significant. Statistical analyses were conducted using SPSS Statistics version 23.0  and R version 4.0.3 .Subgroup analysis was performed to explore the effects of changes in PA on the incidence of new-onset AF in patients with different baseline characteristics using Fine & Gray model. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to show the impact. n = 520), unavailable or incomplete monitoring data (n = 75), <1 year survival after device implantation (n = 40), and diagnosis of AF and/or AFL before enrolment . Finally, a total of 343 patients were included in the study.A total of 1,015 patients with ICD/CRT-D implantation were retrospectively analyzed. Patients were excluded due to lack of data on AF daily burden (P = 0.008). PA was improved at 1 year in 210 patients (61.2%), compared with baseline PA. Changes in PA across PA decreased, PA unchanged, and PA increased groups were −2.85 ± 2.63, 0.98 ± 0.79, and 5.29 ± 2.93%, respectively. The average age at implantation was 62.53 ± 13.54 years, and male patients were dominant in the cohort study (77.6%). The mean LVEF and LVEDD were 39.08 ± 14.57% and 62.07 ± 13.37 mm, respectively. About half of the patients (51.0%) underwent CRT-D implantation. Significant differences between the groups were observed for baseline PA (P < 0.001) and PA at 1 year (P < 0.001), in addition to sex (P = 0.042), and PCI (P = 0.039). No significant differences were observed for other baseline characteristics. Overall, PA at 1 year after ICD/CRT-D implantation was significantly higher than PA at baseline . For the secondary endpoints, 61 (17.8%) cardiac deaths and 87 (25.4%) all-cause mortality events occurred. In 124 patients who experienced new-onset AF, 44 death events (35.5%) were observed, which was significantly higher than the incidence of mortality  in the remaining 219 patients who did not experience new-onset AF. Patients in PA decreased group had higher risks of cardiac death  and all-cause mortality  than those in PA unchanged and PA increased groups. The average follow-up time was 50.28 ± 17.75 months. A total of 124 new-onset AF events (36.2%) were detected. The incidence of new-onset AF was significantly higher in the PA decreased group than in PA unchanged and PA increased groups , cardiac death (P = 0.007), and all-cause mortality (P = 0.010) in PA decreased group, compared to PA unchanged/increased group , and PA decreased group was associated with a higher incidence of new-onset AF  than PA unchanged/increased group. After adjusting for additional confounders, including BMI, LVEF, LVEDD, ICD or CRT-D implantation, NYHA class, hypertension, DM, DCM, ICM, prior MI, PCI, ACEI/ARB, diuretics, and aldosterone antagonist usage in model 2, and the above-mentioned factors and baseline PA in model 3, PA decrease remained an independent risk factor of new-onset AF. Per 1% decrease in PA at 1 year could result in 12.4% higher risks of new-onset AF , and patients with decreased PA had 2-fold risks of new-onset AF  as high as those with unchanged/increased PA.Changes in PA were inversely associated with the incidence of new-onset AF in patients who underwent ICD/CRT-D implantation . In FineP = 0.008) and all-cause mortality , compared to unchanged/increased PA, in multivariate Cox regression model 1, adjusted for age at implantation and sex. After adjusted for age at implantation, sex, BMI, LVEF, LVEDD, ICD or CRT-D implantation, NYHA class, hypertension, DM, DCM, ICM, prior MI, PCI, prior AF and ACEI/ARB, diuretics, and aldosterone antagonist usage, changes in PA remained an independent predictor for cardiac death and all-cause mortality in model 2. After further adjusting for baseline PA in model 3, the results remained consistent for cardiac death and all-cause mortality. Per 1% decrease in PA contributed to 18.3% and 14.3% higher risks in cardiac death  and all-cause mortality , respectively. Compared to patients with unchanged/increased PA, the risks of cardiac death  and all-cause mortality  increased 2.4 times and 1.8 times, respectively, in patients with decreased PA.Regarding the long-term cardiac death and all-cause mortality, PA decrease was shown as independent risk predictors . Decreas2 or ≥24 kg/m2), device type (ICD or CRT-D), and LVEF (<35% or ≥35%) (P = 0.200).Subgroup analysis was performed using Fine and Gray model 3 to evaluate the association of new-onset AF with changes in PA based on different baseline characteristics, including baseline PA (low level <10.2% or high level ≥10.2%), age at implantation (<60 years old or ≥60 years old), BMI (<24 kg/mor ≥35%) . ChangesP = 0.117) although it was not statistically significant. In patients with high baseline PA levels, decreased PA resulted in significant higher incidence of new-onset AF, compared to unchanged/increased PA (P < 0.001). However, no significant difference was shown between the PA decreased group and PA unchanged/increased group among patients with low baseline PA levels (P = 0.761).Considering the potential effects of PA at baseline on new-onset AF, the effects of changes in PA was evaluated among patients with high PA at baseline (PA at baseline >10.2%) and low PA at baseline (PA at baseline <10.2%) using cumulative incidence function . PatientIn a cohort study of 343 patients, time-varying changes in PA and new-onset AF were detected using continuous remote monitoring system. Overall, PA at 1 year after ICD/CRT-D implantation was significantly higher than PA at baseline, and PA at 1 year was improved in 210 patients (61.2%). Early changes in PA from baseline to 1 year after implantation were inversely associated with the incidence of new-onset AF, especially among patients with high levels of baseline PA. Additionally, PA decrease at 1 year after implantation remained an independent risk factor of long-term cardiac death and all-cause mortality at 4.2 years.Some studies have clarified the association of activity performance with AF episodes, hospitalisations, and death among different populations , 15–18. P = 0.008), and PA increase was observed in 210 patients (61.2%) with an average value of 3.44 ± 3.00%. This finding was consistent with previous published studies, which showed that PA at 3 and 6 months after CRT implantation were generally higher than baseline PA of patients with HF  over a follow-up period of 4.2 years was reported, which was comparable to the incidence of newly AHREs (30.1%) detected among patients with HF . After aThere are several limitations in the present study. First, the sample size was small, which might limit the analysis of PA changes in low baseline group; Second, the study participants were patients with high risks of sudden cardiac death, so further studies are needed to determine if the association of early changes in PA with new-onset AF can be generalized to other patient populations. Third, due to the limitation of the home monitoring system, AHREs with <1% of total AF burden over a 24-h period cannot be detected. However, the measurement algorithms in this analysis were previously shown to have a sensitivity and specificity of 95% for AHREs and AF burden detection .PA decrease at 1 year was associated with a higher risk of new-onset AF, regardless of baseline characteristics. Moreover, PA decrease was an independent predictor for long-term cardiac death and all-cause mortality in patients at high risk of sudden cardiac death.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Fuwai Hospital (the chief institute) and all other participating organizations . The patients/participants provided their written informed consent to participate in this study.XS and SZhao performed the conception or design of the work. XS, KC, WH, YS, WX, FW, XF, YD, ZL, and SZhang contributed to the acquisition, analysis, and interpretation of data for the work. XS drafted the manuscript. SZhao critically revised the manuscript. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Right ventricular (RV) free wall fibrosis is an important component of adverse remodeling with RV dysfunction in pulmonary hypertension (PH). However, no previous reports have compared cardiovascular magnetic resonance (CMR) findings and histological analysis for RV free wall fibrosis in PH. We aimed to assess the feasibility of CMR T1 mapping with extracellular volume fraction (ECV) for evaluating the progression of RV free wall fibrosis in PH, and compared imaging findings to histological collagen density through an animal study.Among 42 6-week-old Wistar male rats, 30 were classified according to disease duration  and 12 were used to control for aging (4 and 8 weeks after the baseline). We obtained pre and post-contrast T1 maps for native T1 and ECV of RV and left ventricular (LV) free wall for six animals in each disease-duration group. Collagen density of RV free wall was calculated with Masson's trichrome staining. The Kruskall-Wallis test was performed to compare the groups. Native T1 and ECV to collagen density were analyzed with Spearman’s correlation.P = 0.244, 0.504 and 0.331, respectively). However, the values significantly increased according to disease duration . Significant correlations were observed between native T1 and collagen density , and between ECV and collagen density for the RV free wall  in PH. However, there was no significant difference in native T1 and ECV values for the LV free wall according to the disease duration from the baseline .The mean values of native T1, ECV and collagen density of the RV free wall at baseline were 1541 ± 33 ms, 17.2 ± 1.3%, and 4.7 ± 0.5%, respectively. The values of RV free wall did not differ according to aging (We observed significantly increased values for native T1 and ECV of the RV free wall without significant increase of the LV free wall according to the disease duration of PH, and findings were well correlated with histological collagen density.The online version contains supplementary material available at 10.1186/s12968-021-00755-y. In pulmonary hypertension (PH), the right ventricle (RV) is compromised by high pressure, which leads to RV cavity dilatation, dysfunction, and fibrosis. Because RV performance is an indicator of disease severity and a predictor of survival in PH, there is great interest in new imaging techniques that allow early detection of RV involvement –3. AlthoWhile left ventricular (LV) fibrosis is readily evaluated with CMR using late gadolinium enhancement (LGE) imaging and T1 mapping with the extracellular volume fraction (ECV) –8, thereAll experiments were approved by the Animal Care and Use Committee of our institution, and we performed experiments according to the National Institutes of Health guidelines. A total of 46 6-week-old Wistar male rats were used. A single subcutaneous injection of monocrotaline (40 mg/kg)  was used to induce PH , 17. Ani2; section thickness, 2 mm; number of slice, 8—9; and cardiac phase, 25. Pre-contrast T1 maps were acquired in the short axis planes using a respiratory navigated Look-Locker inversion recovery imaging [2; section thickness, 1.5 mm; slice gap, 1.5 mm; acquisition duration, 16 heart beats; number of slice, 3; and relaxation duration, 5000 ms. The RV myocardial thickness of normal Wistar male rats was approximately 0.6 mm in diastole and 0.9 mm in systole. The relative spatial resolution was 0.2 × 0.2 mm2. Post-contrast T1 maps were obtained with the same protocol 15 min after administration of the contrast agent . T1 maps were generated by applying three-parameter non-linear least square fitting on a pixel-by-pixel basis for the motion-corrected phase-sensitive inversion recovery images and then Look-Locker correction [All CMR images were acquired through a 9.4 T small animal CMR scanner  with an 86-mm volume transmit coil and a 4-channel phased-array surface coil. CMR was performed under spontaneous ventilation with anesthesia by inhalation of 2% isoflurane. Cine images in the short-axis planes were acquired using a self-gated fast low-angle shot sequence  with the following parameters: TR/TE, 5/2.3 ms; flip angle, 10°; field of view, 40 × 40 mm; pixel size, 0.32 × 0.32 mm imaging  (Additio imaging . Scanninrrection .2). The ejection fraction (EF) was calculated with the following equation: (end-diastolic volume − end-systolic volume) × 100/end-diastolic volume (%). The ECV was measured using pre- and post-contrast T1 maps as follows: (ΔR1m/ΔR1b) × (1 − hematocrit) × 100 (%), for which R1m is R1 in the myocardium, R1b is R1 in the blood, and ΔR1 is the change in T1 relaxivity before and after the contrast agent was administered. T1 measurements were performed on the middle third of the RV free wall, septum and LV lateral wall right at the midway between the apex and base of the LV on short axis plane. When measuring the middle third of RV free wall, the inner junctional points of both ventricles were used as positional reference points to match the imaging findings with the histologic findings . Two radiologists (Y.J.H. and H-J.L. with 10 and 12 years of experience in cardiovascular imaging) reviewed the images in consensus and were blinded to disease duration. From the short-axis cine images, the end-diastolic and systolic volumes of both ventricles were calculated by multiplying the areas enclosed by the endocardial contours by slice thickness. The end-diastolic volume indices (EDVI) were calculated by dividing the end-diastolic volume by body surface area  , and the pixel numbers of the myocardial tissue and collagen were counted using a macro written in ImageJ  based on the thresholding algorithms , 23. ColP value < 0.05 was considered statistically significant.All statistical analyses were performed with commercially available software SPSS Statistics . Continuous variables are expressed as means ± standard deviations using 2 significant figures, and the Kruskall-Wallis test was performed to estimate significant differences among the groups (from baseline to 8 weeks) for continuous variables. Then for variables with significant differences on the Kruskall-Wallis test, the Mann–Whitney U test was further performed to analyze the differences between the baseline and each disease-duration group, and the differences between two sequentially adjacent disease-duration groups. Because our study was based on an exploratory data analysis with animal experiments, we did not use the Bonferroni correction for multiple testing. Correlations of native T1 and ECV to collagen density of the RV free wall were analyzed with Spearman’s correlation. A P < 0.001). The mean hematocrit level for ECV calculations was 53.8 ± 2.0% at baseline, and increased according to age and disease duration (P < 0.001), with 6 weeks and 8 weeks showing significantly increased levels compared to the baseline . The mean heart rate was not significantly different according to age and disease duration (P = 0.648).Baseline characters are summarized in Table 2 and 10.4 ± 0.9 ml/m2, and of RVEF and LVEF were 67.6 ± 2.0% and 66.3 ± 2.2%, respectively. The mean values of RVEDVI increased and the mean values of LVEDVI decreased according to disease duration (P < 0.001 for both)  , and the values did not show significant differences between 4 and 6 weeks ; However, significant differences were observed between 6 and 8 weeks (P = 0.004 and 0.025). For LVEDVI, significant differences were observed at 6 weeks compared to the baseline (P = 0.004), and no significant differences were observed between 6 and 8 weeks (P = 0.180). For LVEF, significant differences were first observed at 4 weeks compared to the baseline (P = 0.037). In addition, no significant differences were observed between 4 and 6 weeks (P = 0.055), but a significant difference was observed between 6 and 8 weeks (P = 0.030).The results of cardiac function are described in Fig. P < 0.001 for the RV and inferior SIP, 0.006 for the septum, and 0.001 for the anterior SIP, respectively) except for the LV (P = 0.349). Significant differences were first observed at 6 weeks for the RV and septum , and further significant differences were observed between 6 and 8 weeks (P = 0.004) for the RV, but not for the septum (P = 0.223). For the anterior SIP and inferior SIP, the first significant difference was observed at 4 weeks , but no further significant differences were observed between 4 and 6 weeks , and between 6 and 8 weeks .The results of myocardial native T1 are described in Fig. P < 0.001 for the RV and inferior SIP, 0.020 for the septum, and 0.001 for the anterior SIP, respectively) except for the LV (P = 0.240). The first significant difference compared to the baseline was observed at 6 weeks for the RV and septum . Additional significant differences between 6 and 8 weeks were observed for the RV (P = 0.009), but not for the septum (P = 0.818). For the mean ECV values of the anterior SIP and inferior SIP, significant differences were first observed at 4 weeks compared to the baseline , but with no significant differences between 4 and 6 weeks , and between 6 and 8 weeks .The results of ECV are described in Fig. P < 0.001) and showed similar patterns with native T1 and ECV of the RV free wall. The first significant increase was observed at 6 weeks (P = 0.002) and another significant increase was observed between 6 and 8 weeks (P = 0.002). In addition, significant correlations were observed between native T1 and collagen density , and between ECV and collagen density for the RV free wall . . However, there were no significant differences for mean hematocrit levels and heart rates . For cardiac function, there were no significant differences between RVEDVI and LVEDVI  as well as between RVEF and LVEF . When characterizing myocardial tissue, native T1 values  and ECV values  of both ventricles showed no significant difference at baseline, 4 weeks, and 8 weeks. In addition, no significant differences were observed for collagen density in the RV according to age (P = 0.331).The results of the normal control study are described in Additional file The major finding of our study was the significant increase observed in native T1 and ECV values of the RV free wall without significant increases in the LV free wall according to disease duration, and the results were well correlated with collagen density on histopathological analysis. In addition, similar patterns of increase were observed in native T1, ECV and collagen density of the RV free wall with first significance at 6 weeks compared to the baseline and then further significance between 6 and 8 weeks. Through the normal control study, we found that no significant difference was observed in the native T1 and ECV values of both ventricles according to age. T1 mapping with ECV has been associated with diffuse myocardial fibrosis or infiltrates of LV through histological validation . HoweverFurthermore, we observed significant increase in native T1 and ECV values of the interventricular septum including SIPs as well as the RV free wall according to disease duration in animal models. Interestingly, these increases in the values of each section fluctuated from time to time, rather than gradually increasing linearly with time. For the anterior SIP and inferior SIP, significant increase in fibrosis was detected relatively early at 4 weeks with significant changes in both ventricular functions, and thereafter, no further significant changes were observed. Both ventricular functions did not show significant changes between 4 and 6 weeks, but did show significant changes between 6 and 8 weeks. In contrast, significant increases in fibrosis were observed for the RV and septum relatively late at 6 weeks, and further significant progression was noted for the RV at 8 weeks. From these findings, we hypothesized that early changes in the RV function were due to exposure to increased afterload, and that mechanical stress associated with structural changes of the paradoxical septal motion caused fibrosis in the SIPs . AfterwaWhile prior studies showed modest increase in the fibrosis of the RV free wall in human PH patients than in controls , 27, we Our study has limitations. First, we did not perform a longitudinal observation because frequent administration of anesthesia for CMR scanning often leads to the death of animals with PH, and that would have impeded the progress of our study. However, because the effect of monocrotaline has been reported to be constant throughout time in previous reports , the serWe observed the sequential progression of RV free wall fibrosis with time to time variations in an animal model with PH using CMR native T1 mapping and ECV; findings well correlated with histological analysis. As described previously, RV free wall fibrosis is a highly dynamic process, which can be reversed after lung transplantation or pulmonary endarterectomy. Therefore, further studies are needed to determine whether the T1 mapping technique can be used to evaluate the reversibility of RV free wall fibrosis. In addition, the T1 mapping technique needs to be developed further for humans with larger scales of investigation before we can determine the clinical value of the T1 mapping technique for RV free wall fibrosis. New technical developments and subsequent findings might provide new perspectives on PH and help clinicians develop more management strategies for PH patients in the future.Additional file 1: Fig. S1. The pulse sequence diagram for respiratory navigated Look-Locker Imaging (NALLI). Table S1. Cardiac function according to disease duration. Table S2. Myocardial native T1. Table S3. Myocardial extracellular volume fractions (ECV). Table S4. Results of the normal control study


Cardiac remodeling in rheumatic mitral stenosis (MS) is complex and incompletely understood. The objective of this study was to evaluate cardiac structural and functional changes in a cohort of patients with rheumatic MS using cardiovascular magnetic resonance (CMR).This retrospective study included 40 patients with rheumatic MS, consisting of 19 patients from India, 15 patients from China, and 6 patients from Mexico (median (interquartile range (IQR)) age: 45 years (34–55); 75% women). Twenty patients were included in the control group. CMR variables pertaining to morphology and function were collected. Late gadolinium enhancement (LGE) sequences were acquired for tissue characterization. Statistical analyses were performed using the Kruskal–Wallis test and the chi-square test.p < 0.001), lower right ventricular (RV) ejection fraction (44% (40%–52%) vs 64% (59%–67%), p < 0.001), higher RV end-diastolic volume (72 (58–87) mL/m2 vs 59 (49–69) mL/m2, p = 0.003), larger left atrial volume (87 (67–108) mL/m2 vs 29 (22–34) mL/m2, p < 0.001), and right atrial areas (20 (16–23) cm2 vs 13 (12–16) cm2, p < 0.001). LGE was prevalent in patients with rheumatic MS (82%), and was commonly located at the RV insertion sites. Furthermore, the patient cohorts from India, China, and Mexico were heterogeneous in terms of baseline characteristics and cardiac remodeling.Compared to the control group, patients with MS had lower left ventricular (LV) ejection fraction (51% (42%–55%) vs 60% (57%–65%), Our findings demonstrated that biventricular dysfunction, right and left atrial remodeling, and LGE at the RV insertion sites are underappreciated in contemporary rheumatic MS. Further studies are needed to elucidate the prognostic implications of these findings.The online version contains supplementary material available at 10.1186/s12968-022-00853-5. Rheumatic heart disease is the most common cause of mitral stenosis (MS), and remains a major cause of valve disease globally, occurring predominantly in developing countries –4. ProgrWhile echocardiography is typically the noninvasive modality of choice in the evaluation of patients with rheumatic MS due to its availability and low cost, cardiovascular magnetic resonance (CMR) imaging is a promising tool to provide more detailed characterization of morphologic and functional changes that occur in response to MS. CMR has the unique ability to precisely quantify chamber size and function due to its high spatial resolution, and can also provide tissue characterization through late gadolinium enhancement (LGE) imaging and parametric mapping. Prior studies have shown that CMR can improve the evaluation and prognostication of patients with other valve diseases, such as aortic stenosis, mitral regurgitation, and tricuspid regurgitation, through more accurate assessment of cardiac remodeling and tissue characterization –11. HoweIn this study, we assembled a cohort of patients with rheumatic MS who underwent CMR at one of three endemic countries on two continents, and characterized the cardiac structural and functional changes in this population.We studied consecutive patients with symptomatic rheumatic MS referred for CMR in China between 2013 and 2019 , India between 2018 and 2020 , and Mexico between 2012 and 2020  (n = 76). Patients in India underwent CMR as part of a part of a study protocol, patients in Mexico underwent CMR as part of either a study protocol or preoperative evaluation, and patients in China underwent CMR as part of a preoperative evaluation. We excluded patients with prior balloon valvuloplasty, prior cardiovascular procedures, prior myocardial infarction, or greater than moderate concomitant valvular disease as assessed by echocardiography. The control group was derived from a cohort in India that underwent CMR for the evaluation of coronary artery disease (CAD). These patients did not have any abnormalities on rest imaging or stress perfusion imaging, did not have any known cardiovascular conditions, and did not have a history of prior percutaneous coronary intervention or coronary artery bypass graft surgery. This study received approval from each hospital’s respective Institutional Review Board, and patients gave written informed consent for the study.The following CMR scanners were utilized in this study: (1) India: 1.5 T , (2) China: 3 T , and (3) Mexico: 1.5 T . At all three sites, after acquiring localizers, electrocardiogram gated standard balanced steady-state free precession cine images with 8 to 14 short-axis and 3 long-axis planes  were obtained. The parameters were as follows: (1) India: Repetition time (TR)/Echo time (TE) 4.4–5.4/1.1–1.2 ms; slice thickness: 8 mm; flip angle: 66–67 degrees; in-plane spatial resolution: 1.4–1.7 × 1.7–2.3 mm; (2) China: TR/TE, 2.8 /1.2 ms; slice thickness: 8 mm; flip angle: 38 degrees; in-plane spatial resolution: 1.6 × 2.0 mm; (3) Mexico: TR/TE 3.7–3.9/1.8–1.9 ms; slice thickness: 8 mm; flip angle: 60 degrees; in-plane spatial resolution: 1.6–1.7 × 1.6–1.7 mm. Ten to 20 minutes after the administration of a gadolinium contrast agent, segmented two-dimensional LGE images were acquired using routine inversion recovery sequences with the following parameters: (1) India: TE 1.1 ms; slice thickness: 8 mm; flip angle: 40 degrees; field of view: 274 × 319 mm; in-plane spatial resolution: 1.2 × 2.1 mm; (2) China: TE 1.2 ms; slice thickness: 8 mm; flip angle: 40 degrees; field of view: 225 × 300 mm; in-plane spatial resolution: 2.1 × 1.6 mm; (3) Mexico: TE 3.0 ms; slice thickness: 10 mm; flip angle: 25 degrees; field of view: 360–460 × 360–460 mm; in-plane spatial resolution: 1.3–1.6 × 1.6–2.1 mm. All studies included in the analysis were judged to be of good quality. CMR studies from India and Mexico were analyzed at the coordinating center  by two investigators. CMR studies from China were analyzed locally due to export restrictions, but LGE images were virtually reviewed together with the coordinating center. Measurements of biventricular volumes and function, LA volume (using biplane area-length method) and emptying fraction, right atrial (RA) maximal area, and mitral valve area (MVA) by planimetry were performed, and inter-observer and intra-observer variability analyses were conducted. Papillary muscles were included in the LV cavity, not in the LV mass. Native T1 measurements and quantification of extracellular volume fraction (ECV) were performed on a portion of CMR studies from India (n = 18) and China (n = 9). Wall motion abnormalities were assessed by reviewing cine images, and LGE images were analyzed for the presence and location of LGE. CMR studies from India and Mexico were analyzed using suiteHEART . CMR studies from China were analyzed on Qmass  at the time of the CMR were obtained from the medical record. N-terminal pro brain natriuretic (NTpro-BNP) levels were available for the cohort from India. MVA, as determined by pressure half-time (PHT), tricuspid regurgitation peak velocity for determination of pulmonary artery systolic pressure and other concomitant valve diseases were extracted from the transthoracic echocardiogram report from the study performed closest to the time of the CMR. Severe MS was defined as MVA ≤ 1.5 cmNon-normally distributed continuous variables are shown as median (interquartile range) and analyzed using the Kruskal–Wallis test. Categorical variables are shown as total counts with percentages and analyzed using the chi-square test. All statistical analyses were performed with JMP Pro .p = 0.03). The control group was derived from a cohort in India that underwent CMR for the evaluation of CAD, and patients in the control group had higher rates of CAD, diabetes mellitus, and hypertension. The MS cohort reported a higher burden of symptoms, including dyspnea on exertion, palpitations, and angina. Echocardiography data for the calculation of MVA by PHT was available for the majority of the overall cohort . Within the context of this limitation, most patients in the MS cohort were classified as severe MS, as indicated by the median MVA by PHT of 0.85 cm2 (IQR: 0.73 to 1.10 cm2) and median MVA by CMR planimetry of 1.17 cm2 (IQR: 0.89 to 1.56 cm2). The patients in the MS cohort had the following breakdown of coexistent mitral regurgitation: none (12/40 [30%]), trace (7/40 [17.5%]), mild (11/40 [27.5%]), mild-moderate (1/40 [2.5%]), and moderate (9/40 [22.5%]).The final study cohort consisted of 40 patients, including 19 patients from India, 15 patients from China, and 6 patients from Mexico . Patients in China had higher rates of atrial fibrillation, and patients in Mexico had higher rates of hypertension. Furthermore, there was a higher burden of dyspnea on exertion in the India and Mexico groups, and a higher burden of angina in the China and Mexico groups. There were no significant differences in MVA by PHT or CMR planimetry between the three groups.Characteristics of the MS cohort, stratified by country, are shown in Table The CMR findings in the MS cohort and the control group are shown in Table p = 0.001), and RV ejection fraction (RVEF) (44% (IQR: 40% to 52%) vs 64% (IQR: 59% to 67%), p < 0.001). RV volumes were greater in the MS cohort (end-diastolic volume index (RVEDVI) of 72 (IQR: 58 to 87) mL/m2 vs 59 (IQR: 49 to 69) mL/m2, p = 0.003), and there was no difference in LV end-diastolic index (LVEDVI) between the two groups. LV global longitudinal strain (GLS) was worse (less negative) in the MS cohort (− 16% (IQR: − 18% to − 14%) vs − 20% (IQR: − 22% to − 18%), p < 0.001). Pulmonary artery systolic pressures (PASP) by transthoracic echocardiography were mildly to moderately elevated in the MS cohort. In the MS cohort, there was a weak negative correlation between PASP and RVEF  and PASP and RV stroke volume (SV)/end systolic volume (RVESV) , but no correlation was observed between PASP and RV diastolic or systolic volumes.Compared to the control group, the MS patient cohort had significantly lower LV ejection fraction (LVEF) (51% (IQR: 42% to 55%) vs 60% (IQR: 57% to 65%), 2 vs 29 (IQR: 22 to 34) mL/m2, p < 0.001), and LA emptying fraction was significantly lower in the MS group (20% (IQR: 13% to 30%) vs 61% (IQR: 51% to 65%), p < 0.001). RA size was larger in the MS group (20 (IQR: 16 to 23) cm2 vs 13 (IQR: 12 to 16) cm2, p < 0.001). There were no significant correlations between MVA by echocardiography, biatrial or biventricular size/function, or PASP  mL/mp < 0.001). In the MS group, the two patterns of LGE observed were 1) enhancement at the inferior RV insertion site (79%) and 2) enhancement at the superior RV insertion site (13%). There were no patients with subepicardial or subendocardial LGE. One patient in the control group exhibited midmyocardial enhancement at the inferior RV insertion site. There were no patients with wall motion abnormalities in either group. One patient in Mexico underwent endomyocardial biopsy at the RV insertion site that revealed myocardial fibrosis . The China and India cohorts had a mildly reduced median LVEF of 48%, while the Mexico group had a normal median LVEF of 63%. RV function was reduced across all three groups, and biventricular volumes were similar in the three cohorts. There was also no difference in LV GLS between the India and Mexico cohorts.The CMR findings in the MS cohort, stratified by country, are shown in Table 2) compared to the India (80 (IQR: 59 to 98) mL/m2) and Mexico (80 (IQR: 68 to 98) mL/m2) cohorts, but LA emptying fraction was similar in all groups. RA maximal areas were similar across the three cohorts.Indexed LA volumes were significantly greater in the China cohort (median: 109 (IQR: 90 to 153) mL/mp = 0.43). Patients with LVEF ≤ 50% had similar ECV when compared to patients with LVEF ≥ 50% (ECV: 28.5% (IQR: 25.6% to 30.2%) vs 28.0% (IQR: 23.5% to 29.7%), p = 0.41).The prevalence of LGE was similar across all three MS cohorts. There was no difference in the frequency of midmyocardial enhancement at the inferior RV insertion point, but midmyocardial LGE at the superior RV insertion point was more commonly observed in the China group. In the India cohort, the median native T1 time (at 1.5 T) (n = 18) was 990 ms (IQR: 964 to 1029 ms). In the China cohort, the median native T1 time (at 3 T) (n = 9) was 1275 ms (IQR: 1236 to 1340 ms). The median ECV in both cohorts was 28.3% (IQR: 24.5% to 29.9%), and there was no difference in ECV between the India and China groups (27.3% (IQR: 23.3% to 30.4%) vs 28.9% (IQR: 28.1% to 29.4%), p < 0.001) and RVEDVI , and significant negative correlations with RVEF , RV SV/ESV , LVEF , and LA emptying fraction   Table .Table 4COverall, 22/38 (58%) patients with MS ultimately underwent a mitral valvuloplasty or valve replacement . The characteristics of patients, stratified by whether a mitral valve procedure was performed, are described in Additional file In this study of a cohort of patients from China, India, and Mexico with rheumatic MS who underwent CMR imaging, we assessed detailed cardiac structural and functional changes that occurred in response to MS. We found that biventricular and biatrial remodeling was common in this population. We also identified a high prevalence of nonischemic fibrosis at the RV insertion points in the overall cohort, but no significant elevation in native T1 or ECV. In addition, we found notable differences in cardiac structure and function between patients from the three countries.As MS progresses and becomes more severe, the resistance to blood flow through the narrowed mitral valve orifice results in LA pressure elevation leading to LA enlargement and functional decline, pulmonary hypertension, and ultimately RV dilation and dysfunction . AccordiInterestingly, in the overall cohort, LV function was more reduced among MS patients, as assessed by LVEF and GLS. Although the LV was traditionally thought to be spared from adverse hemodynamic consequences due to MS, LV dysfunction in patients with MS has been recognized , 17.The not be a significant cause of subsequent myocardial dysfunction in MS patients. Given the burden of RV dilation and dysfunction in this cohort, it is possible that LV dysfunction is a result of abnormal septal motion and altered RV-LV interactions. In addition, biventricular dysfunction could be a consequence of a tachycardia-mediated cardiomyopathy in the setting of atrial fibrillation. Additional work is required to understand the mechanisms and prognostic implications of LV dysfunction and LGE in this cohort. The indexed LV volumes were at the lower limits of normal, possibly due to reduced preload or reduced filling, but this requires additional study [Our CMR study provides the opportunity to better understand the mechanisms related to LV dysfunction in MS. We found LVEDVs were similar in the MS and control groups, and we did not identify segmental wall motion abnormalities in the MS cohort. LGE imaging showed evidence of inferior and superior RV insertion site fibrosis, which has not been shown previously, and was likely due to RV remodeling in the setting of pulmonary artery hypertension –26. Impoal study .There were several key differences between the China, India, and Mexico cohorts. The India cohort was younger than the China and Mexico cohorts, suggesting that advanced valvular disease and subsequent heart failure symptoms developed more rapidly in this cohort. Prior studies have noted that patients in endemic regions tend to present with more rapidly progressive valve disease, possibly due to recurrent bouts of carditis . FurtherThis study should be interpreted in the context of its strengths and limitations. Strengths include the careful selection of patients with rheumatic MS without concomitant valve disease and cardiovascular conditions, who underwent CMR across three countries. We were able to identify a sizable cohort of patients meeting our stringent criteria, despite the limited access and availability of CMR in these countries. In addition, tissue characterization was performed in the majority of CMR studies.Our study has a number of limitations. Only patients undergoing preoperative CMR were included which reflect a selection bias. Despite this limitation, these patients represent a cohort of patients with symptomatic rheumatic MS. Native T1 mapping was not available on all scans. T2 mapping was not performed, and acute inflammation and edema could not be assessed. However, in general, MS is a late finding in patients with rheumatic heart disease, and patients are typically decades past the acute inflammatory carditis/valvulitis stage. Finally, outcome data are not available and therefore associations of imaging parameters with clinical outcomes could not be performed.In this multicenter international study of patients with symptomatic rheumatic MS, we found that biventricular and biatrial remodeling, including reduced biventricular function and nonischemic fibrosis at the RV insertion sites. In addition, the patient cohorts from India, China, and Mexico were heterogeneous in terms of baseline characteristics and ventricular remodeling, possibly due to differences in disease progression and access to care. These findings further our understanding of the cardiac structural and functional changes in rheumatic MS, and demonstrate the value of CMR imaging in the evaluation of this population. Further studies are needed to understand the prognostic implications of these findings.Additional file 1. Additional tables.


Functional mitral regurgitation (FMR) can be subclassified based on its proportionality relative to left ventricular function and end-diastolic volume. FMR proportionality could help identify responders to transcatheter edge-to-edge mitral valve repair (MitraClip) in terms of residual FMR and/or clinical improvement.This single-centre retrospective cohort study evaluated the feasibility of determining FMR proportionality in symptomatic heart failure patients with reduced left ventricular function who were treated with MitraClip for ≥ moderate-to-severe FMR. Baseline proportionate (pFMR) and disproportionate FMR (dFMR) were distinguished. Patient characteristics and MitraClip procedural outcomes were described.n = 26) or pFMR (n = 10). Conduction disorders were numerically increased in dFMR. All cases requiring > 2 clips were in the dFMR group and absence of FMR reduction occurred more frequently with dFMR.From an overall cohort of 81 eligible FMR patients, 23/81 (28%) had to be excluded due to missing transthoracic echocardiogram parameters, 22/81 were excluded based on FMR severity. The remaining cohort, of 36/81 patients (44%), could be classified into dFMR  contains supplementary material, which is available to authorized users. As opposed to degenerative mitral regurgitation, treatment of functional mitral regurgitation (FMR) remains subject to debate . FMR is Two randomised controlled trials, COAPT  and MITRGrayburn et al. devised a conceptual framework based on FMR proportionality and disproportionality to the dimensions and function of the left ventricle . The hypThis retrospective study aimed to evaluate the feasibility of the FMR proportionality concept in clinical practice as it has only been scarcely evaluated in a real-world MitraClip context , 10. FurWe retrospectively determined FMR proportionality at baseline in all consecutive heart failure patients with reduced left ventricular ejection fraction (LVEF) who were treated with MitraClip for ≥ moderate-to-severe FMR at the Erasmus University Medical Center. Decision to treat was based on multidisciplinary heart team consensus.Reasons for excluding patients from analysis were previous mitral valve repair or replacement, heart transplant or untreated significant coronary artery disease requiring revascularisation. Every patient signed informed consent for the clip procedure and use of related data in a dedicated database for study purposes. The study did not fall under the scope of the Medical Research Involving Human Subjects Act per Erasmus Medical Center Institutional Review Board.The main study objective was to classify baseline FMR as proportionate or disproportionate. Patient and procedure characteristics were described per dFMR and pFMR cohort. Degree of post-procedural FMR reduction (≥ 1 grade) and residual FMR at discharge were recorded.FMR aetiology and severity were evaluated by transthoracic echocardiogram (TTE) using an integrated approach of multiple qualitative and quantitative parameters including left atrial and ventricular size, jet features, pulmonary artery pressures, effective regurgitant orifice area , and regurgitant volume (RegVol). RegVol was calculated from the effective regurgitant orifice area or alternatively the volumetric method, if the effective regurgitant orifice area was unavailable and in absence of aortic regurgitation , 12. ReaSevere FMR was considered proportionate when the regurgitation was in line with expected RegVol based on left ventricular size and function derived from the Gorlin hydraulic orifice equation . Using lContinuous variables are presented as mean ± standard deviation for normally distributed data, or as median with interquartile range [IQR] if non-normal. Time-to-event data of one-year mortality and heart failure related hospitalisation is reported using the Kaplan-Meier method. Statistical analyses were performed with SPSS 25.0 .We evaluated all patients who received MitraClip in our centre between 2011 and 2019 Fig. . Of noteBaseline patient demographics, electrocardiographic and echocardiographic data are reported in Tab. n = 9). Heart failure related hospitalisation rate within 1 year after MitraClip was 25.7% (n = 8). During follow-up, New York Heart Association (NYHA) class improved in 69% of patients .Median follow-up was 464 days (IQR 181–935). One year mortality was 26.5%  dFMR was characterised by conduction disorders and more severe left ventricular dysfunction, 2) dFMR may require more clips, and 3) absence of FMR reduction occurred more frequently with dFMR.Our data seem to confirm that focal left ventricular remodelling and/or dyssynchrony are fundamental mechanisms that underlie dFMR development. There was a higher prevalence of either cardiac resynchronisation therapy implantation or QRS ≥ 150 ms with dFMR. Prolonged QRS duration marks ventricular dyssynchrony , 18, whiAll cases with > 2 clips were in the dFMR group and in spite of using more clips, dFMR reduction appeared less. This finding may result from more extensive mitral regurgitation at baseline. However, clipping does not correct cardiac dyssynchrony, which is associated with residual mitral regurgitation after surgical repair .The retrospective nature of our analysis holds inherent selection bias. To determine FMR proportionality, multiple quantitative echocardiographic parameters are required, each associated with measurement inaccuracies. Importantly, FMR severity in clinical practice is graded using a multi-parametric approach including quantitative and qualitative parameters and is often based on multiple echocardiography studies that may reveal dynamic mitral regurgitation. Standardised comprehensive TTE acquisition protocols and experienced imaging specialists seem essential. This study sample was not powered to make any statistical comparison and should be considered as descriptive and hypothesis generating. We believe our study adds perspective to the application of the concept of mitral regurgitation proportionality in clinical practice and warrants further study. A multicentre initiative is ongoing to complement these single-centre observations.Important limitations in terms of imaging acquisition affected the translation of the FMR proportionality concept to a real-world data set. We did observe different demographic and FMR response patterns in patients with proportionate and disproportionate FMR that warrants further investigation.Appendix I. Determining FMR proportionalitySupplementary Table 1. NYHA functional class during follow-up


To determine the ability of conventional spin echo (SE) T2 and ultrashort echo time (UTE) T2* relaxation times to characterize pathology in cadaveric meniscus samples.n = 17), intrasubstance degenerated (n = 33), or torn (n = 4) using a modified arthroscopic grading system. Using a 3-T MR system, SE T2 and UTE T2* values of the menisci were determined, followed by histopathology. Effect of meniscal pathology on relaxation times and histology scores were determined, along with correlation between relaxation times and histology scores.From 10 human donors, 54 triangular  meniscus samples were harvested. Meniscal pathology was classified as normal (p < 0.0001) and torn (p = 0.0002) menisci compared to that in normal. In contrast, the respective mean SE T2 values were 27.7 ± 9.5 ms, 25.9 ± 7.0 ms, and 35.7 ± 10.4 ms, without significant differences between groups . In terms of histology, we found significant group-wise differences (each p < 0.05) in fiber organization and inner-tip surface integrity sub-scores, as well as the total score. Finally, we found a significant weak correlation between UTE T2* and histology total score , unlike the correlation between SE T2 and histology .Mean ± standard deviation UTE T2* values for normal, degenerated, and torn menisci were 3.6 ± 1.3 ms, 7.4 ± 2.5 ms, and 9.8 ± 5.7 ms, respectively, being significantly higher in degenerated (UTE T2* values were found to distinguish normal from both degenerated and torn menisci and correlated significantly with histopathology. Meniscal injury is one of the most common intra-articular knee derangements . As a weSeveral quantitative MR techniques have been studied in the meniscus, with T2 mapping , 14 reprThe purpose of this study was to further elucidate the ability of quantitative MRI to characterize meniscal pathology in ex vivo specimens. We sought to investigate T2 and UTE-T2* measures of meniscal integrity using a modified arthroscopic classification as well as histopathologic grading as reference standards in cadaveric donor tissues.n = 10) and lateral menisci (n = 8) were harvested from intact donor knee joints. Triangular pieces (n = 54), 5-mm thick, were harvested from the anterior horn, body, and posterior horn of each meniscus . There were 5 males, 3 females, and 2 unknown sexes. Age range was 60 to 87 years with a mean age of 79 years. Medial .MR imaging was performed on a 3 T GE Signa HDX system  in a 1″ diameter solenoid coil. Samples were mounted in an MR-compatible device with meniscal circumferential fibers oriented parallel to BFor morphologic examination, imaging protocol consisted of a proton density–weighted non-fat-suppressed turbo-spin echo sequence Fig.  TR = 25 and non Quantitative imaging protocol consisted of a 2D spin echo multi echo T2 mapping (SE T2) sequence based on Carr-Purcell-Meiboom-Gill acquisition Fig.  to C TR to G (raRegions of interest (ROIs) were manually drawn for the entire meniscus sample by one individual (AST) with 4 years of experience Fig. . In caseMeniscus samples were classified as normal, intrasubstance degeneration (degenerated), or torn using a modified arthroscopic grading system  consistiMeniscus samples were processed for histology by fixation in Z-fix  for 3 days, dehydration in graded ethanol, and embedded in paraffin. Sections (5-um thick) were stained with hematoxylin and eosin (H&E)  to evaluMeniscus histopathology was based on a published grading system Table  29], ev, ev29], p = 0.07) and UTE T2* (Shaprio-Wilk p = 0.001) data were somewhat skewed in distribution, the data were log-transformed prior to performing ANOVA. Tukey’s test was used for subsequent pairwise comparisons. Power analysis was performed using the G*Power software [Descriptive statistics on cadaveric donors are reported. Effect of region  on the observed frequency of different meniscal pathology was evaluated using chi-square test. To determine the effects of meniscal pathology on quantitative MR properties, analysis of variance (ANOVA) was performed to compare mean relaxation times of the normal, degenerated, and torn samples. Normality of MR data was first checked with Shapiro–Wilk test. Since both SE T2 .To determine effects of meniscal pathology on histology scores, Kruskal–Wallis test  was usedp = 0.24), compared to anterior regions, both the body (p = 0.0004) and posterior (p = 0.0008) regions had a greater frequency of degenerated samples.Gross specimen examination and morphologic MR grading diagnosed 17 (31% of 54 samples) meniscus samples as normal, 33 (61%) intrasubstance degeneration (degenerated), and 4 (7%) torn, all extending to the meniscal surface. The distribution of pathology by region of meniscus is presented in Table p < 0.0001; power = 0.99), as well as pairwise differences between normal and degenerated menisci (p < 0.0001) and between normal and torn menisci (p = 0.0002). In contrast, no significant differences in mean SE T2 values were observed between groups . Regional variation (in pooled samples regardless of pathology) showed no significant difference in SE T2 (p = 0.5) or UTE T2* values (p = 0.08). Two-way ANOVA could not be performed due to incomplete distribution of pathology in the three anatomic regions.Mean and standard deviation of SE T2 values Fig.  for normp < 0.05), while the fiber organization  compared to the normal samples. However, there was no statistically significant difference between the groups in the histology total score .Histology images Fig.  showed gion Fig.  of degenRs2 = 0.05 and p = 0.09. In contrast, between UTE T2* and histology total scores  but weak positive correlation with a Rs2 = 0.13. When correlated vs. histology sub-scores, we found a significant (p = 0.002), weak, and positive correlation (Rs2 = 0.18) between UTE T2* and fiber organization, and a nearly significant weak positive correlation vs. surface integrity of the inner rim . All other correlations with sub-scores were not statistically significant.We found no correlation between SE T2 values and histology total scores Fig. , with a res Fig. , we founIn this study, quantitative MRI using SE T2 and UTE T2* techniques was used to evaluate cadaveric human menisci with modified arthroscopic classification of pathology and compared against histology. Spin echo T2 (SE T2) relaxation times of the meniscus were unable to distinguish normal from (intrasubstance) degenerated or torn menisci. These results conflict with a previous work by Rauscher et al., which demonstrated increased meniscal T2 values in patients with clinically mild or severe OA compared to that in healthy controls . SimilarIn contrast to SE T2, our UTE T2* relaxation times were able to distinguish normal from both degenerated and torn menisci. These results are consistent with previous studies, which found UTE T2* mapping capable of detecting subclinical meniscal degeneration in ACL-injured patients without meniscal tears compared to that in uninjured subjects , 22. GivHistology results further supported higher sensitivity of UTE T2* technique to meniscal pathology compared to SE T2. We found that, while the histology sub-scores generally worsened from normal-to-degenerated-to-torn menisci, the most marked changes were in the collagen fiber organization Fig. . Fiber oPotential clinical applications of quantitative MRI of the meniscus have focused on the post-operative knee. For example, Chu et al. demonstrated normalization of elevated UTE T2* values in intact menisci two years following ACL reconstruction . The rel0. As a result, absolute relaxation times are not generalizable. However, all specimens underwent a constant experimental procedure, and therefore, the relationships between measured values are expected to remain valid.There are several limitations to this study. First, our study specimens were obtained from cadaveric donors. While this may have affected tissue hydration, it would be expected to have a negligible effect on comparative results as it would impact all specimens. Samples were previously frozen, which is known to impact tissue microstructure through enlargement of collagen fibrils , though In conclusion, UTE T2* values were found to distinguish normal from both degenerated and torn menisci and correlated significantly with histopathology. This noninvasive technique may provide an advantage over arthroscopy, which is limited to the examination of meniscal surface areas. Detection of intrasubstance meniscal abnormality may ultimately allow for improved monitoring of disease as well as earlier non-operative treatment.