There is paucity of studies applying fat suppressed (FS) technique to T2 mapping to overcome chemical shift artifacts. The purpose of the study is to difference between FS T2 and conventional T2 mapping and reproducibility of FS T2 mapping in the femoral articular cartilage.Eighteen patients who had normal-looking femoral cartilage and underwent knee MRI with conventional T2 and FS T2 mapping were included. T2 values of each mapping were measured by two readers independently from nine regions in the medial femoral condyle (MFC) and lateral femoral condyle (LFC). Each anatomical region was divided by lines at ± 10°, 30°, 50°, 70°, 90°, and 110°. Comparisons of T2 values between conventional and FS T2 mapping were statistically analyzed. The T2 values between FS and conventional T2 mapping in the anterior, central and posterior femoral condyles were compared.p < 0.001). The differences in the T2 values between the two maps were significantly different among the three divisions of the LFC (p = 0.009) and MFC (p = 0.031). The intra-class correlation coefficients indicated higher agreement in the FS T2 map than in the conventional T2 map (0.943 vs. 0.872).The overall femoral condyle T2 values from the FS T2 map were significantly lower than those from the conventional T2 map (48.5ms vs. 51.0ms, The T2 values of knee femoral cartilage are significantly lower on FS T2 mapping than on conventional T2 mapping. FS T2 mapping is a more reproducible method for evaluating knee femoral cartilage. Magnetic resonance (MR) imaging is a widely used imaging modality for assessing morphological changes in articular cartilage. However, this modality has limitations in assessing compositional and ultrastructural changes , 2, whicChemical shift artifacts are a potential source of error on T2 mapping, occurring at the bone-cartilage interface and cartilage-intraarticular fat tissue interface. This can affect the measurement of the T2 relaxation time and the thickness of articular cartilage, especially on 3T MR imaging and for knee joints , 14. TheThe review board of Seoul national university hospital approved this retrospective study and the requirement for patient informed consent was waived. All methods were carried out in accordance with guidelines and regulations of committee on ethics. From April 2015 to August 2016, we included patients who had normal-looking femoral articular cartilage and underwent a knee MR imaging protocol with a conventional T2 mapping sequence and an FS T2 mapping sequence at the same time. In total, eighteen patients  were included in the study. Among the 18 patients, 4 (22.2 %) had normal knee structures, 5 (27.8 %) had a medial meniscus (MM) tear, 2 (11.1 %) had an anterior cruciate ligament (ACL) tear, 2 (11.1 %) had a combination of MM and ACL tears, 1 (5.6 %) had discoid meniscus and 4 (22.2 %) had cartilage defects other than at the femoral condyles (patella and trochlear groove).MRI examinations were performed using a 3T MR system  with a dedicated knee coil. The protocol consisted of routine clinical sequences followed by two sagittal T2 mapping sequences. Routine knee MR imaging consisted of turbo spin-echo proton density weighted images , turbo spin-echo T2-weighted imaging  and turbo spin-echo T1-weighted sagittal imaging.After completion of the routine knee MR imaging, two sagittal conventional and FS T2 mapping sequences were performed using following protocols. T2 maps were generated using inline calculation software  with a mono-exponential fitting from multi-slice, multi-echo source images with five different echo times . Frequency encoding was in the feet-to-head direction. The parameters used for the T2 mapping sequences are as follows: repetition time, 2000 msec for conventional T2 maps and 2300 msec for FS T2 maps; field of view, 159 mm A research assistant under the supervision of a musculoskeletal radiologist (with 17 years of experience) and a musculoskeletal radiologist (with 5 years of experience) measured the T2 relaxation time on conventional and FS T2 mapping. The T2 relaxation times were measured at nine anatomical regions  in the mid-sagittal image of the medial femoral condyle (MFC) and in the mid-sagittal image of the lateral femoral condyle (LFC). Each anatomical region in the MFC and LFC was divided by lines at ± 10, 30, 50, 70, 90, and 110 degrees relative to a vertical line bisecting the femoral condyle width and connecting the two most protruding points of the femoral condyle. Regions of interest (ROIs) for the T2 values were drawn in all regions along the bone-cartilage interface and cartilage surface to include the full thickness of the cartilage. The T2-weighted sagittal source image that most clearly depicted cartilage with high tissue contrast was selected among the multi-echo time source images for ROI segmentation over the cartilage. ROIs were independently and manually drawn on conventional and FS-T2 weighted source image using segmentation tool in PACS workstation. After then, ROIs were transferred to the conventional and FS T2 maps in a copy-and-paste manner, respectively . The central division was defined as the cartilage in contact with the meniscus and corresponded to -30° to 50° in the LFC and − 50° to 50° in the MFC. The anterior division was defined as the cartilage anterior to the central division, and the posterior division was defined as the cartilage posterior to the central division. Interreader and intrareader agreement for the T2 values measured on conventional and FS T2 mapping was assessed with the intraclass correlation coefficient (ICC). Additionally interreader agreement for ROI cross-sectional area also assessed with ICC. The degree of agreement was interpreted as excellent if the ICC was above 0.75, as fair-to-good (moderate) if the ICC was between 0.40 and 0.75, and as poor if the ICC was less than 0.40. The SPSS 25.0 software package  was used for statistical analyses in our study, and a p-value of < 0.05 was considered to indicate statistical significance.p < 0.001). In the LFC and MFC, the mean T2 values of the FS T2 map were also lower than those of the conventional T2 map  .The mean T2 relaxation values of the conventional and FS T2 map in the MFC and LFC are summarized in Table p = 0.020), -30° ~ -10° (p = 0.001), -10° ~ 10° (p = 0.040), and 30° ~ 50° (p = 0.044) regions. Most of the differences were shown in the central division of the LFC. Similarly, the mean FS T2 values were lower than the conventional T2 values in the anterior and central divisions of the MFC. However, the posterior division of the MFC showed higher FS T2 values than conventional F2 values. Significant differences between the two T2 maps were found in the − 50° ~ -30° (p = 0.001) and 90° ~ 110° (p = 0.04) regions.In the LFC, the mean T2 relaxation values of the FS T2 map were lower than those of the conventional T2 map in most regions, except for the 50° ~ 70° region. The differences between conventional T2 mapping and FS T2 mapping were significant in the − 70° ~ 50°   for the overall cartilage T2 value. The intra-reader agreement for the T2 values of both demonstrated perfect agreement. The ICC indicated also indicated higher agreement in the FS T2 map than in the conventional T2 map (0.945 vs. 0.986).2 vs. 7.26 ± 4.53 mm2, p = < 0.001).Additionally, the ROI cross-sectional areas for each region showed higher interreader agreement in the FS T2 map than in the conventional T2 map (0.910 vs. 0.894). The mean cross-sectional area of the ROI was larger on FS T2 mapping than on conventional T2 mapping . The discrepancy with our results might result from the different fat suppression techniques implemented. LIBRE-Iso3DGRE applies water excitation with a novel lipid-insensitive binomial off-resonant radiofrequency excitation pulse, and our study applied the CHESS technique, which is commonly used in musculoskeletal MR imaging [Colotti et al.  applied  imaging . In addiWe demonstrated better reproducibility with FS T2 mapping than with conventional T2 mapping in terms of the T2 values and ROI areas. Although their changes in the T2 value on FS T2 mapping do not match our results, Colotti et al.  also sugSeveral limitations of this study need to be mentioned. First, the study sample was small and excluded patients with chondral abnormalities on MRI. Further investigations with larger study populations, including patients with chondral abnormalities, need to be conducted. Second, our radiologist and research assistant performed manual segmentation; automatic segmentation was not used in our study. The manual segmentation technique is widely used in current T2 mapping studies. To minimize the effects of manual segmentation, we defined the ROI based on the angle and anatomical landmarks and used the mean values of the two independent measurements for statistical analysis. Further study comparing conventional and FS T2 maps is warranted using automated segmentation method for determination the boundary of articular cartilage. Third, we measured full-thickness cartilage T2 values and did not take into account zonal variation. The effect of chemical shift artifacts depends on the depth of the articular cartilage, which could affect the FS T2 mapping results when the cartilage layers are considered. It is difficult to obtain consistent T2 values from layer by layer due to the spatial resolution of the imaging technique and the thin cartilage thickness. Moreover, evaluation of full-thickness cartilage T2 values may be more practical and reliable in the clinical setting. Fourth, the magic angle effect and partial volume artifacts might have affected the T2 value. Our results showed a bimodal distribution of T2 values in the MFC and LFC with peaks at approximately ± 55°, as in previous T2 mapping studies affected by the magic angle effect , 20. TwoThe T2 values of knee femoral cartilage are significantly lower on FS T2 mapping than on conventional T2 mapping. Additionally, FS T2 mapping is a more reproducible method for evaluating knee femoral cartilage.


Persistent dyspnea and reduced exercise capacity is common in pulmonary embolism (PE) survivors. Although improved right ventricular function after pulmonary rehabilitation has been demonstrated in chronic thromboembolic pulmonary hypertension, it is still unknown whether a similar effect also occurs in other patients with dyspnea after pulmonary embolism.The aim of this study was to explore potential effects of a pulmonary rehabilitation program on cardiac structure and function as assessed with cardiac magnetic resonance (CMR).Twenty-six PE survivors with persistent dyspnea were included. Right and left ventricular assessment with CMR was performed before and after an eight-week pulmonary rehabilitation program.Dyspnea as measured by the Shortness of Breath Questionnaire improved significantly after rehabilitation: 15 (IQR: 7–31) versus 8 (IQR: 3–17). Absolute right ventricular global longitudinal strain by CMR was reduced from 19% to 18% (95% CI of difference: 0–3 percent points), and absolute RV lateral strain from 26% to 24% (95% CI of difference: 1–4 percent points). Right ventricular mass was reduced after rehabilitation from 49 g to 44 g (95% CI of difference: 2–8 g).Although there was a substantial improvement in dyspnea after rehabilitation, we found only a minor reduction in absolute right ventricular longitudinal strain and right ventricular mass. No other CMR parameter changed. We therefore suggest that rehabilitation effect of in this patient group was not primarily mediated by cardiac adaptions. Although small studies have suggested a benefit of exercise training on patients with dyspnea following PE The aim of this study was to quantify any cardiac alteration after pulmonary rehabilitation in people with dyspnea following PE, as assessed with CMR. Our hypothesis was that cardiac function improved after rehabilitation, as measured by right and left ventricular myocardial strain.22.1clinicaltrials.gov - NCT03405480) This is a sub-study of the ongoing PeRehab study  and all participants signed an informed written consent form prior to inclusion.2.2Patients were identified from the Østfold Thrombosis Registry (TROLL), which has included all venous thromboembolism (VTE) patients diagnosed at Østfold Hospital in Norway since 2005.The inclusion criteria were as follows: (1) age 18–75 years; (2) diagnosed acute PE  by computed tomography pulmonary angiography (CTPA); (3) 6–72 months since diagnosis of PE; (4) persistent dyspnea emerged after the PE episode .After acquiring informed consent, patients were subjected to clinical evaluation (interviews and a self-completed questionnaire) to determine the presence or absence of dyspnea. If dyspnea was confirmed, the extent of dyspnea was graded using the modified Medical Research Council (mMRC) dyspnea scale which uses five statements to describe the patient’s respiratory disability  Exclusion criteria included CTEPH, severe cardiac and pulmonary disease, heart failure with reduced or preserved ejection fraction (EF) according to European Society of Cardiology (ESC) guidelines Patients with established diagnosis of CTEPH were excluded. All eligible patients underwent echocardiography at the first study visit. Patients who had (1) echocardiographic findings consistent with high probability for pulmonary hypertension according to ESC pulmonary hypertension guidelines Dyspnea before and after rehabilitation was assessed with the Shortness of Breath Questionnaire (SOBQ) scale PE clot burden was assessed by Mean Bilateral Proximal Extension of the Clot (MBPEC) based on CTPA images at diagnosis 2.3Patients performed an outpatient pulmonary rehabilitation program for one hour twice weekly for eight weeks Based on previous findings of optimal musculature adaptions in resistance training, the resistance training was performed with high load and few repetitions, i.e. 5 repetition maximum (RM) per set to avoid dyspnea 2.4CMR was performed before and after the rehabilitation program on one single Siemens 1.5 T Aera magnet  according to established recommendations Endo- and epicardial contours were manually drawn in end-diastole and end-systole on short axis images to measure left and right ventricle (LV and RV) volumes and mass. Contours were refined to minimize the difference between LV and RV stroke volumes. RV mass was measured from end systolic images. LV and RV long axis and short axis mean systolic strain were calculated with feature tracking.Two myocardial regions of interest were manually drawn on short axis T1 maps to measure mean T1 times: LV septum and lateral wall. T1 time of blood was measured from LV cavity. The reported T1 value of each region was the mean of the measured T1 on the basal and mid-ventricular slice. Hematocrit measurement was obtained immediately before CMR.All CMR post-processing was performed in Segment version 3.1  2.5Continuous variables were reported by means and standard deviations (SD), or by medians and interquartile ranges (IQR), as appropriate. Paired continuous variables were compared prior and after rehabilitation with Wilcoxon signed-rank test. Proportions were compared with Fisher’s exact test. Confidence intervals (CI) of differences were calculated from 2000 bootstrap replications.A two-tailed alpha of 5% was considered significant. Missing values were not imputed. All statistical analyses were performed using Stata version 16.1 .3Twenty-six patients were recruited between January 1st 2018 and December 31st 2019. All patients completed the planned rehabilitation program.2. Median time since PE was 2.6 years (IQR: 1.6–4.3 years).Six patients (23%) had perfusion defects on V/Q scintigraphy, of whom one patient had echocardiographic findings suggestive of pulmonary hypertension. This patient was referred to RHT, upon which CTEPH was excluded  20 mmHg, pulmonary capillary wedge pressure (PCWP) 13 mmHg, pulmonary vascular resistance (PVR) 1.1 Wood).Following rehabilitation, there was a significant reduction in dyspnea as assessed with the SOBQ: Median SOBQ score was 15 (IQR: 7–31) before, versus 8 (IQR: 3–17) after rehabilitation (p = 0.001). There was no significant change in heart rate.CMR parameters before and after rehabilitation are displayed in 4To the best of our knowledge, this is the first study to describe CMR findings after pulmonary rehabilitation in patients with persistent dyspnea after PE. Despite a substantial reduction of patient-reported dyspnea, there were only minimal changes in RV functional parameters. Although statistically significant, the reduction of absolute RV strain was only 1–2 percent points. The difference is within 1SD and in our experience within the margin of uncertainty for strain measurements. We also found a modest reduction in RV mass of 5 g.In contrast to our findings, an absolute RV global longitudinal strain increase (difference = 3 pp) measured by speckle tracking echocardiography has been demonstrated after four weeks of high intensity exercise training in a group of elderly patients with heart failure with preserved EF meta-analysis that included 14 studies and 329 non-dyspneic participants concluded that absolute RV strain was reduced after prolonged exercise while the LV is unaffected Previous studies have demonstrated reduced RV function after high intensity exertion We found a reduction in RV mass after rehabilitation. However, it must be emphasized that RV mass is difficult to assess due to the thin and trabecular RV wall. This finding must therefore be interpreted with caution. In a study of 23 untrained men, RV mass increased with 2.7 or 1.4 g after 6 months of endurance or resistance training, respectively Dyspnea is a non-specific subjective symptom and associated with common diseases such as COPD or CAD. Thus, we considered it important to assess whether undiagnosed/latent COPD or CAD could potentially explain the results. All included patients underwent comprehensive clinical examinations including spirometry and echocardiography prior to inclusion. Patients with diseases associated with dyspnea were excluded including patients with COPD and heart failure. Only three patients were diagnosed with LGE compatible with chronic myocardial infarction after CMR, and only one patient had previously diagnosed (but asymptomatic) coronary artery disease. Of note, our findings of mean left ventricular absolute LV GLS = 16% is below the previous reported normal range (LV: 19%-21% Physical deconditioning is an adaption after a long period with inactivity. However, deconditioning has many facets and is therefore difficult to measure. Although only SOBQ improvement was reported in the present study, it has to be emphasized that the effects of rehabilitation are not limited to improvement of dyspnea or to the increase in exercise capacity. Dyspnea and reduced exercise capacity are considered multifactorial and impaired skeletal muscle function may play a central role in the development of these symptoms rather than cardiopulmonary dysfunction 4.1First, this was a single site study with a limited number of patients. Second, there was no control arm or reference group; however, our patients acted as their own controls. Third, the effect of rehabilitation as measured by change in SOBQ was prone to confirmation bias. Forth, RHT was only performed in patients with echocardiographic findings consistent with CTEPH. With RHT of all patients with perfusion defects on V/Q scintigraphy, we could have excluded CTEPH with more confidence. This was not accepted for ethical reasons.Fifth, we cannot rule out that a rehabilitation program of longer duration or with a larger weekly amount of exercise could have resulted in more pronounced changes in CMR parameters.Finally, the patients were included up to 6 years after the PE event, which may have led to a heterogeneous study population. Dyspnea is common in the general population 5Despite a substantial, positive effect on dyspnea after pulmonary rehabilitation, we found only a slight reduction in absolute RV longitudinal strain and a modest reduction in RV mass after rehabilitation. Therefore, we suggest that the clinical effect of pulmonary rehabilitation in this patient group was not primarily mediated through cardiac adaptions.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Zhang et al. reported right ventricular (RV) function in 215 mechanically ventilated patients with septic shock [The authors dissociated RV systolic dysfunction, defined by echocardiography as a tricuspid annular plane systolic excursion (TAPSE) below 16 mm or an RV fractional area changes below 35%, from RV failure defined by RV dilatation and elevated central venous pressure (CVP) , the conIn different statements, experts proposed to define RV failure as a status associating “significant” RV dilatation to maintain an adequate cardiac output, when possible, with systemic congestion which may be assessed by CVP . They moReasons for this apparent absence of validation of physiology are not obvious. RV dilatation is defined using echocardiography when the RV/LV end-diastolic area is > 0.6 and systemic congestion when CVP is ≥ 8 mmHg. Applying such a definition, Vieillard-Baron et al. found a 42% incidence of RV failure in mechanically ventilated septic patients  and ZhanOperationally, patients found to have RV dilatation and elevated CVP need to be assessed for evidence of pulmonary hypertension and volume overload. To the extent that systemic arterial pressure can be sustained greater than pulmonary artery pressures by either using systemic vasopressors or selective pulmonary vasodilators  without the presence of systemic hypoperfusion , diuresis should be cautiously started to reverse RV dilation and improve RV systolic and diastolic function.Finally, because of the absence of gold standard to define RV failure and of the very specific physiology of the right ventricle which includes initial dilatation with increases in CVP, defining RV failure at bedside with the best sensitivity and specificity is still a challenge. Current published papers are not clear and precise enough to give intensivists the most accurate definition. It should be elucidated in future studies, as it is now well-known that RV function is crucial to evaluate at the bedside to optimize respiratory and circulatory management of critically-ill patients.


Sleep disordered breathing (SDB) is known to cause left atrial (LA) remodeling. However, the relationship between SDB severity and LA dysfunction is insufficiently understood and may be elucidated by detailed feature tracking (FT) strain analysis of cardiac magnetic resonance images (CMR). After myocardial infarction (MI), both the left ventricle and atrium are subjected to increased stress which may be substantially worsened by concomitant SDB that could impair consequential healing. We therefore analyzed atrial strain in patients at the time of acute MI and 3 months after.s]; [SRs]), conduit  and booster function  were measured in two long-axis views. SDB was defined by an apnea-hypopnea-index (AHI) ≥15/h. Interestingly, LA εs and εe were significantly reduced in patients with SDB and correlated negative with AHI as a measure of SDB severity at both baseline and follow-up. Intriguingly, patients that exhibited a reduced AHI at follow-up were more likely to have developed improved atrial reservoir and conduit strain . Patients with improved SDB (ΔAHI < −5/h) exhibited a mean improvement of LA reservoir strain of +7.2 ± 8.4% whereas patients with SDB deterioration (ΔAHI> + 5/h) showed a mean decrease of −5.3 ± 11.0% (p = 0.0131). Similarly, the difference for LA conduit function was +4.8 ± 5.9% (ΔAHI < −5/h) vs −3.6 ± 8.8% (ΔAHI> +5/h). Importantly, conventional volumetric parameters for atrial function  did not correlate with AHI at baseline or follow-up.40 patients with acute MI underwent CMR and polysomnography (PSG) within 3–5 days after MI. Follow-up was performed 3 months after acute MI. CMR cine data were analyzed using a dedicated FT software. Atrial strain (ε) and strain rate (SR) for atrial reservoir ([εOur results show that LA function measured by CMR strain but not by volumetry is impaired in patients with SDB during acute cardiac injury. Consistent with a mechanistic association, improvement of SBD at follow-up resulted in improved LA strain. LA strain measurement might thus provide insight into atrial function in patients with SDB. Sleep disordered breathing (SDB) is a highly prevalent disease, especially in patients with heart failure , 2. SDB Research is often focused on cardiac ventricular function, however, emerging evidence indicates that LA function plays an important role in cardiovascular performance and that LA dysfunction is associated with adverse cardiovascular outcome such as a higher risk for cardiovascular events , new onsHowever, currently there is no data on atrial strain and the influence of SDB during acute myocardial ischemia. We therefore investigated the influence of SDB on atrial strain by CMR in patients presenting with acute MI and at 3-month follow up. Interestingly, at each time point atrial function was decreased in patients with SDB. However, the change in SDB severity from baseline to follow-up correlated with the change in atrial strain function, suggesting a close causal connection between SDB severity and atrial function.We performed a sub-analysis of a prospective observational study in patients with acute MI that were enrolled at University Medical Center Regensburg  between March 2009 and March 2012. Details of the study design have been published previously .Key inclusion criteria for this sub-analysis were as follows: patients (age 18–80 years) with a first acute MI and PCI treated at the University Hospital Regensburg within 24 h after symptom onset were eligible for inclusion. Exclusion criteria were previous MI or previous PCI, indication for surgical myocardial revascularization, cardiogenic shock, contraindications for CMR, and severe comorbidities . The study protocol was reviewed and approved by the local institutional ethics committee  and is in accordance with the Declaration of Helsinki and Good Clinical Practice. A written informed consent was obtained from all patients prior to enrolment.n = 18) or follow-up (n = 7), missing polysomnography at follow-up (n = 1), or unfeasible LA strain analysis (n = 8). Only patients with complete baseline and follow-up data were included. The final sub-analysis included 40 patients, who were divided into two cohorts depending on AHI at baseline (AHI < 15/h [n = 16] and AHI≥15/h [n = 24]) and AHI at follow-up (AHI < 15/h [n = 24] and AHI≥15/h [n = 16]) , 74 patients were eligible for the prospective observational study which involved an evaluation of cardiac function and SDB severity at the time of MI (baseline) and 3 months later (follow-up). Thirty four patients were excluded from this sub-analysis due to missing CMR at baseline (n = 16]) .All patients underwent polysomnography using standard polysomnographic techniques  as described before , 28, 29.−1). The number of Fourier lines per heartbeat was adjusted to allow the acquisition of 25 cardiac phases covering systole and diastole within a cardiac cycle. Calculation of cardiac volumes and ejection fraction was performed commercially available software . LV volumes and LV ejection fraction were measured in the serial short axis slices . Atrial volumes were analyzed in the long axis views.CMR studies were performed 3–5 days after the MI on a clinical 1.5 Tesla scanner  using a phased array receiver coil during breath-hold and that was ECG-triggered. Cine short-axis and long-axis slices were obtained with a steady-state–free precision gradient-echo sequence . LA borders were manually traced in the 2- and 4-chamber long-axis views using LV end-diastole as the reference phase. If necessary, manual adjustments were performed to obtain optimal wall tracking.1-L0)/L0, where L0 is the resting/reference length (LV end diastole) and L1 is the change of atrial myocardial length throughout the cardiac cycle. LA strain was analyzed for total strain , passive strain , and active strain  , peak early negative strain rate , and peak late negative strain rate   . Strain unction) .T-test for continuous variables and the Chi-square or Fisher's exact test for categorial variables. Linear regression models were calculated to assess the correlation of AHI and strain as well as with various volumetric and functional LA parameters. Scatter plots with regression lines were used to visualize the relationships between variables. All reported p-values are two-sided . P-values < 0.05 were considered statistically significant. Statistical analysis was performed in SPSS  and Graphpad Prism .Unless indicated otherwise, descriptive data are expressed as means ± SD or as frequencies and percentages of each category. Groups were compared using Student's 2, p = 0.006), increased nt-pro BNP levels at discharge (p = 0.005), increased left ventricular (LV) mass index (p = 0.001). LV ejection fraction was reduced in patients with SDB without reaching statistical significance (p = 0.062). Of the 16 patients with no SDB at baseline, two worsened and had SDB at follow-up. Of the 24 patients with SDB at baseline, 10 improved and had no SDB at follow-up. At follow-up, patients with SDB had increased nt-pro-BNP-levels (p = 0.028), impaired renal function (p = 0.012), decreased LV ejection fraction (p = 0.002), and increased values for LV mass index (p = 0.036) as well as LV end-diastolic volume , patients with SDB exhibited significantly lower LA strain and strain rate as a measure of LA reservoir and conduit function . There wWe then tested if strain analysis could provide a more detailed evaluation of atrial function than conventional volumetric LA parameters. Intriguingly, there was no correlation of LA area and AHI  possiblyWe then sought to evaluate the time course of the association between SDB severity and left atrial function from baseline to the 3-month follow-up as this might provide insights into the causal relationship between SDB and LA function. Therefore, we performed two analyses for the follow-up data. First, we stratified patients for AHI measured at baseline to evaluate the intra-individual development of SDB and strain over time. Interestingly, the association between SDB and reduced atrial function being it LA reservoir or conduit  was subsA possible explanation for the different association of LA strain with AHI at baseline and follow-up may result from a different frequency of apnea events during both time points. In fact, there was a significant reduction in mean AHI from baseline to follow-up .p = 0.08 and B = −0.1834 for εs; p = 0.08 and B = −0.1316 for εe, p = 0.0131)  .Our data shows that the measurement of atrial strain by feature tracking analysis of CMR imaging provides a more sensitive and robust marker for atrial function than conventional volumetric LA parameters. At the time of MI and at the 3-month follow-up, atrial function was decreased in patients with SDB. Moreover, the change in SDB severity from baseline to follow-up correlated with the change in atrial strain function, suggesting a close causal connection between SDB severity and atrial function.Ischemic damage in MI mainly involves both ventricles depending on the culprit lesion. Atrial damage in MI may mostly be secondary to the impaired ventricular function and systemic effects during MI such as increased activation of the sympathetic nervous system and of inflammatory pathways. However, direct hypoxic damage in the atria may be present more frequently than is generally suspected, as histopathological studies have reported the incidence of concomitant atrial infarction in 0.7% to 42% of cases . Atrial Currently, assessment of the LA function is routinely performed by volumetric measurement of LA size or volume . HoweverOur group has shown that SDB is associated with reduced LV ejection fraction and that SDB negatively affects cardiac remodeling in this cohort. There was a clinically relevant reduction in the severity of SDB in patients whose LV ejection fraction improved in the 12 weeks following myocardial infarction whereas the AHI was unchanged in patients whose LV ejection did not improve . The salIn accordance, the magnitude of the time-dependent change in AHI from initial investigation to follow-up correlated with the magnitude of atrial function . UnfortuThere are some circumstantial factors that have to be considered when comparing the measurements for AHI and atrial strain at baseline and follow-up. First, MI leads to acute heart failure and abrupt changes in LV hemodynamics which instantly affect atrial function. Reduced LV ejection fraction results in reduced displacement of the atrioventricular plane which is a major contributor to passive LA reservoir function. Thus, reduced LV ejection fraction contributes to reduced LA reservoir function. Reduced LV ejection fraction and forward heart failure elevate atrial pressure which also affects atrial function. This notion is supported by our observation of increased nt-pro-BNP levels for patients with SDB and reduced atrial strain at baseline . Second,Despite these considerations, our data shows a moderate correlation of AHI and LA function at two different points in time, thus strongly suggesting that SDB is connected to LA dysfunction in the acute and chronic setting of cardiac disease.All CMR cine data were captured in three different planes in the two- and four chamber views. For the calculation of strain, the plane best depicting atrial geometry was chosen. However, the strain analysis was performed on cine images that were originally intended to provide optimal quantification of the left ventricle. Thus, the geometry of the atria might not be optimally represented, and the strain be miscalculated. This was the case in eight patients which have therefore been excluded from the analysis. A selection bias toward less severe cases may occur due to the exclusion criteria which excluded severe lung disease and treated SDB.Our results show that LA function measured by CMR strain analysis is impaired in patients with SDB both chronically and during states of acute cardiac injury such as MI. Correlation between AHI and strain values was more robust at follow-up suggesting that disruptive factors may obscure the relationship of SDB and atrial dysfunction in states of acute cardiac injury. Interestingly, conventional volumetric parameters of atrial function such as LA area and LA volume index did not correlate with AHI at baseline or follow-up. LA strain measurement thus provides additional insight into atrial function at acute and chronic cardiac injury and SDB.“Sleep-disordered breathing and especially obstructive sleep apnea are highly prevalent and clinically relevant cardiovascular risk factors. As they result in impaired cardiac and particularly atrial function, it is crucial to identify patients at risk with polysomnography. Our group has recently shown that the magnitude of the ECG parameter P-wave terminal force in lead V1 is associated with the apnea-hypopnea index and may thus serve as a readily available parameter to identify patients that should be screened for SDB by polysomnography . TreatmeThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study involving human participants was reviewed and approved by Ethikkommission an der Universität Regensburg. The patients/participants provided their written informed consent to participate in this study.MW and SW designed this post-hoc analysis. KD, OH, FP, SB, and MA enrolled participants and acquired the data. MW, JP, SL, CF, KD, OH, FP, and SB analyzed the study data. MW wrote the initial draft of the manuscript. All authors were involved at all stages of the critical revision of the manuscript, read and approved the final manuscript, and meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors.MW, SL, and CF are supported by the local ReForM-program. SW is funded by DFG grants WA 2539/7-1 and 8-1. LM is funded by DFG grants MA 1982/7-1. SW and LM are also supported by the DFG SFB 1350 grant . MA received grant support from the Else-Kroener Fresenius Foundation (2018_A159). CF received a grant from the German Heart Foundation/German Foundation of Heart Research .MA received lecture and consulting fees from ResMed, Philips Respironics, Boehringer-Ingelheim, NRI, Novartis, JAZZ pharmaceuticals, Bayer, Inspire and Bresotec and grant support from ResMed Foundation, ResMed, and Philips Respironics outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The murine transverse aortic constriction (TAC) model is frequently used to investigate molecular mechanisms underlying heart failure. However, limited data is available regarding the expression of mRNAs and circRNAs in murine heart failure progression induced by pressure overload.Transverse aortic constriction was used to induce pressure overload for 2, 4, and 8 weeks in mice. Echocardiographic measurements in B-mode and M-mode, as well as blood flow Doppler data were collected in mice without (sham) and with  pressure load. Hearts were excised and morphology, cardiomyocyte size, and fibrosis were determined. RNA sequencing, circRNA microarray, functional mRNA enrichment analysis, hub gene identification, target miRNA interaction, and competitive endogenous RNA (ceRNA) network construction were conducted.Heart weight, cardiomyocyte hypertrophy, and fibrosis gradually increased over time in the hearts with pressure overload. The 2W-post-TAC hearts displayed concentric hypertrophy, thickened left ventricular walls, and increased EF and FS. The 4W-post-TAC hearts were characterized by preserved EF and FS, dilated atria, and increased left ventricle (LV) systolic volume. The 8W-post-TAC hearts presented with ventricular and atrial dilation, increased LV systolic and diastolic volume, reduced EF and FS, and increased ejection time (MV ET). mRNA expression analysis suggested that cardiac remodeling, immune response dysregulation, and metabolic disorder were the key cellular events in heart failure progression. Depression in chemotaxis and mitochondrial function were predicted in 4W- and 8W-post-TAC myocardia, respectively. A ceRNA network analysis demonstrated that the circRNAs targeted the expression of genes enriched in metabolism dysregulation in the 2W-post-TAC hypertrophic hearts, while they targeted genes enriched in cardiac remodeling in the 4W-post-TAC EF-preserved hearts and in the suppression of oxidative phosphorylation and cardiac contraction in the 8W-post-TAC EF-reduced hearts.Our work empirically demonstrates that distinctive features of heart failure, including ventricular hypertrophy, heart failure with preserved EF (HFpEF), and heart failure with reduced EF (HFrEF) are present in the murine pressure overload models. The three stages of heart failure vary in terms of mRNA and circRNA expression, as well as ceRNA regulation in a manner consistent with their structural, functional, and pathological differences. Despite the improved preventative and therapeutic strategies, the prevalence of heart failure continues to increase worldwide. Hypertension represents a key risk factor of heart failure . In factAortic constriction was reported as early as the 1950s to induce hypertension in rodents . Among sThe established mechanisms of pressure overload-induced heart failure include the dysregulation of hormonal peptides , signaliIn the present study, we explored the expression of mRNAs and circRNAs in the three stages of heart failure in TAC mice and identified distinct pathological features during heart failure progression. We found that HFpEF serves as the transition from hypertrophy to HFrEF. We analyzed mRNA and circRNA expression at three distinct heart failure stages and elucidated the circRNA-based regulation in heart failure. Our findings suggest that the ceRNA network can be an effective target for heart failure therapy.N = 9). Heart structure and function at each stage were assessed by echocardiography, histological examination (N = 5/group), RNA sequencing, and circRNA microarray analyses  was applied. The mice in each group  were anesthetized with isoflurane and set in the supine position. Horizontal parasternal long axis B-mode images of the heart were obtained by placing the probe on the chest midline and pointing it toward the right shoulder. The probe was rotated clockwise by 90° to acquire images of the parasternal short-axis B-mode in the papillary muscle plane. The M-mode images were acquired at the same position as those of the B-mode recording. The structural indices included interventricular septum thickness at end-systole and diastole , left ventricular posterior wall thickness at end-systole and diastole , left ventricular internal dimension at end-systole and diastole , atrial area at long-axis cross-section, and aortic root diameter. The function indices included cardiac output (CO), ejection fraction (EF), and short axis fractional shortening (FS).A mitral inflow Doppler tool was used to evaluate cardiac diastolic function. The probe was placed on the lateral thoracic wall to obtain a four-chamber view of the heart apex. The Doppler sampling volume cursor was then moved to the mitral valve cusp and the early diastolic blood flow peak E-wave velocity (MV E), the late diastolic blood flow peak A-wave velocity (MV A), isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT), and ejection time (MV ET) were measured.Pathological examinations were conducted to evaluate tissue damage, cardiomyocyte size, and cardiac fibrosis as previously described . HematoxHematoxylin and eosin staining was performed as follows: (1) sections were dewaxed with xylene, (2) dehydrated with an ethanol concentration gradient series, (3) stained with hematoxylin solution , (4) differentiated with HCl in ethanol, (5) stained with alcohol-soluble eosin , and (6) dehydrated and mounted. For the WGA staining, fluorescein-labeled WGA  was added to the tissue sections, which were incubated at room temperature (20–25°C) in the dark for 10 min. After staining, the sections were washed twice with phosphate-buffered saline (PBS) and mounted with 4′,6-diamidino-2-phenylindole .For Masson’s trichrome staining, the dewaxed sections were fixed in Bouin’s solution  overnight and stained with Weigert’s hematoxylin  and Biebrich scarlet-acid fuchsin solution  for 3–5 min. Then 1% (w/v) phosphomolybdic acid was applied to the sections to wash out excess stain; sections were then incubated in Aniline blue  for ∼5 min, dehydrated, and mounted. Pathological changes in pressure overload hearts were identified microscopically . The cardiomyocytes were measured with ImageJ 1.52a .GSE182985).1mRNA sequencing was used to profile gene expression at the hypertrophic, HFpEF, and HFrEF stages in murine pressure overload hearts, as previously described . Total RP < 0.05 was applied as the cutoff for differentially expressed gene (DEG) identification. DEGs with log2 (fold change) > 1 were considered upregulated while those with log2 (fold change) < −1 were downregulated. Six DEG datasets were defined: one upregulated and one downregulated dataset each for 2W-post-TAC vs. sham, 4W-post-TAC vs. sham, and 8W-post-TAC vs. sham.The original reads of the genes in the samples from the 2W-post-TAC, 4W-post-TAC, and 8W-post-TAC were compared against those of the sham group. Fold changes between paired groups were log2-transformed. 2 A significant BP term included ≥3 candidates, P ≤ 0.05, ≥1.5 enrichment factor, or a limiting-network interactome consisting of 3–500 candidate proteins  of the BP term reflected its relatively higher degree of gene enrichment. Each DEG in the interaction network was displayed in the modules according to its biological processes.Gene Set Enrichment Analysis (GSEA) was used to predict the potential roles of DEGs in LV hypertrophy, HFpEF, and HFrEF of TAC mice. The six sets of upregulated and downregulated DEGs were uploaded to the web-accessible gene annotation and the Metascape analytical tool.proteins . The higThree DCRs in each heart failure stage were subjected to Quantitative PCR (qPCR) to verify their expression. The protocol was carried out as previously described . The pri3 to construct a protein-protein interaction (PPI) network. In this manner, the types and intensities of the interactions between proteins encoded by the DEGs were established. The CytoHubba plug-in of Cytoscape4 including the maximal clique centrality (MCC) scoring method was used to capture the essential nodes in the PPI network (A protein-protein interaction (PPI) network analysis was performed to identify hub genes. This analysis consisted of two steps and elucidated the altered expression and roles of genes in structural and functional remodeling in 2W, 4W, and 8W pressure overload myocardia. Total DEGs for each comparison pair  were uploaded to the Search Tool for the Retrieval of Interacting Genes/Proteins database (STRING 11.0) network . The topP ≥ 95% for the 3′-UTR miRNA-binding sites, and at least one occurrence of the miRNA in TargetScan, miRDB, or miRTarBase.The miRNAs targeting the mRNAs were then predicted. In the present study, a newly updated miRWalk database with the Python Django framework was used to predict miRNAs. This framework incorporates datasets from TargetScan , miRDB (release 5.0), with validated information from miRTarBase v. 7.0 . For datGSE182912. The array images were imported into the database followed by quantile intensity normalization of chips and samples in an Arraystar’s analysis package of R .Arraystar mouse circular RNA array V2  was used to profile circRNA expression in murine hearts during remodeling and dysfunction progression. After isolation, the total RNAs were digested with RNase R  to remove linear RNAs and enrich circular RNAs. The latter were further amplified and transcribed by random priming into fluorescent cRNA . The labeled cRNA concentration and activity in pmol Cy3/μg cRNA were measured. One microgram of each labeled cRNA was fragmented, heated, and assembled onto the Arraystar Mouse circular RNA Array V2 . The arrays were hybridized, washed, fixed, scanned with an Agilent scanner , and analyzed with Agilent feature extraction software v. 11.0.1.1 . Microarray data were uploaded to the gene expression omnibus (GEO) database (see text footnote 1) under accession No. P < 0.05 was the cutoff for DECR definition. DEGs with log2 (fold change) > 1 were considered upregulated while those with log2 (fold change) < −1 were considered downregulated. The top 40 DECRs (20 upregulated and 20 downregulated) associated with each heart failure stage  were selected to predict circRNA-miRNA interactions.The datasets of the 2W-, 4W-, and 8W-post-TAC arrays were compared against that of the sham array in the circRNA microarray data analyses. Fold changes in circRNA expression of each pair  were then determined. Differentially expressed circRNAs were designated “DECRs”. The Arraystar miRNA database with the datasets from TargetScan [4] and miRanda [5] was used to predict the circRNA-miRNA interactions. TargetScan can be searched for conserved 8mer, 7mer, and 6mer sites matching the seed region of ≥1 miRNA  as well To understand the potential regulatory mechanisms of circRNAs after predicting mRNA–miRNA and circRNA–miRNA pairs, miRNAs common to both interaction pairs were selected, and the networks were combined and displayed. Below are the steps involved in constructing the circRNA–miRNA–mRNA network.First, the miRNA groups were defined. (1) Based on the predictions of the mRNA–miRNA interactions, the miRNAs degrading the upregulated or downregulated mRNAs were designated “mRNA up” and “mRNA down”, respectively. That is, the six miRNA groups were “mRNA up” or “mRNA down” for 2W-post-TAC, 4W-post-TAC, and 8W-post-TAC. (2) Based on predictions of the circRNA-mRNA interactions, miRNAs sponged by upregulated or downregulated circRNAs were designated “circRNA up” and “circRNA down”, respectively. Thus, the six miRNA groups were “circRNA up” and “circRNA down” for 2W-post-TAC, 4W-post-TAC, and 8W-post-TAC.The predicted miRNAs  associated with each heart failure stages  were uploaded to the TBtools program  and subjt-tests were used to identify significant differences between pairs of means. P < 0.05 was considered statistically significant.For the echocardiographic and pathological examinations, the data are presented as means ± SEM. Raw data for the sham and the 2W-post-TAC, 4W-post-TAC, and 8W-post-TAC groups were uploaded to GraphPad Prism 8.0 . Significant differences among multiple data groups were analyzed by one-way ANOVA followed by Tukey’s multiple comparisons test . Graphs showing each individual data point were plotted. For the mRNA sequencing and circRNA microarray, In this study, TAC surgery was used to induce left ventricular pressure overload, while heart structure and function were monitored at 2, 4-, and 8-weeks post TAC surgery. Echocardiography revealed that the peak flow velocity at the ascending aorta and diameter of the aortic root were increased significantly after TAC surgery . The heaP = 0.0786) in the 8W-post-TAC group  were found to be enriched in cardiac remodeling, metabolism, and functional regulators . AugmentDuring the HFrEF stage, augmented immune response was one of the predominant biological processes comprising lymphocyte differentiation, regulation of inflammatory responses, interleukin-13 production, regulation of TNF superfamily cytokine production, positive regulation of immune response, regulation of cytokine production. Other enhanced processes included cardiac remodeling  and lipid catabolic process . In contMyh7 and Pdk4 was upregulated and that of Ucp1 was downregulated in the hypertrophic stage  were randomly selected to verify their expression using qPCR. We found that the results from GSEA and qPCR verification were consistent. The expression of ic stage ; the expegulated  in the HEF stage . The expEF stage .Furthermore, the top 40 hub genes were identified by PPI network analysis in the three stages of heart failure . PathwayIn summary, mRNA expression identification demonstrated that cardiac remodeling and dysregulation of immune response and metabolism were the key events in all three stages of heart failure. Enrichment analysis of hub genes revealed that metabolism downregulation was the central event in the hypertrophic stage, cardiac remodeling was predominant in the HFpEF stage, and impairment in oxidative phosphorylation and cardiac muscle contraction was predicted in the HFrEF stage.Adcy1; adenylate cyclase 1), mmu_circRNA_012321 , mmu_circRNA_19564 , mmu_circRNA_19565 (Adrb3), mmu_circRNA_20588 (Adcy1), mmu_circRNA_20588 (Adcy1), mmu_circRNA_30572 (Adcy1), mmu_circRNA_30572 (Gng2), mmu_circRNA_31249 (Adrb3), mmu_circRNA_35970 (Adcy1), and mmu_circRNA_35970 (Gng2). The mRNAs encoding proteins related to metabolism or metabolic regulation were targeted by mmu_circRNA_017591 , mmu_circRNA_017591 (Elovl6), mmu_circRNA_017591 (Elovl6), mmu_circRNA_19562 , mmu_circRNA_19564 (Scd1), mmu_circRNA_19565 (Scd1), mmu_circRNA_20586 (Elovl6), mmu_circRNA_20586 , mmu_circRNA_22074 , mmu_circRNA_30211 , mmu_circRNA_31249 (Scd1), and mmu_circRNA_32699 (Pdk4). In addition, mmu_circRNA_017591 targeted Mmp9, encoding protein matrix metallopeptidase 9. Adipokines  and  were targeted by mmu_circRNA_20588 and mmu_circRNA_35970, respectively. The chromosomal location, classification, and corresponding linear transcripts of the circRNAs in the hypertrophic hearts are listed in After analyzing the interactions between the hub gene miRNAs and mRNAs and predicting the interactions between the circRNAs and miRNAs , the miRCol11a1; collagen type I alpha 1), mmu_circRNA_009396 , mmu_circRNA_19411 , mmu_circRNA_19411 (Ctsk), mmu_circRNA_20769 , mmu_circRNA_24514 , mmu_circRNA_27257 (Col6a2), mmu_circRNA_30224 , mmu_circRNA_35285 , mmu_circRNA_36719 (Col6a1), mmu_circRNA_39297 , mmu_circRNA_39297 , mmu_circRNA_42790 , mmu_circRNA_42790 , circRNA_43263 , and mmu_circRNA_45033 (Col6a2). In addition, circRNA_30224 and mmu_circRNA_36719 targeted Fstl1, encoding protein cytokine follistatin-like 1. The chromosomal location, classification, and corresponding linear transcripts of the circRNAs in the HFpEF hearts are listed in For the 4W-post-TAC HFpEF stage, 318 and 7 miRNAs were predicted in the “mRNA up” and “mRNA down” groups, respectively, and 91 and 85 miRNAs were predicted in the “circRNA up” and circRNA down” groups, respectively . The ceRIrf4; interferon regulatory factor 4), mmu_circRNA_007653 , mmu_circRNA_34414 (Irf4), mmu_circRNA_37478 , and mmu_circRNA_43368 . In addition, a circRNA, mmu_circRNA_20784 was found to target Uqcrq, encoding mitochondrial protein ubiquinol-cytochrome c reductase complex III subunit VII. The chromosomal location, classification, and corresponding linear transcripts of the circRNAs in the HFrEF hearts are listed in For the 8W-post-TAC HFrEF stage, 50 and 42 miRNAs were predicted in the “mRNA up” and “mRNA down” groups, respectively, and 92 and 76 miRNAs in the “circRNA up” and “circRNA down” groups, respectively . The ceROverall, there are distinct circRNA-based ceRNA networks in hypertrophy, HFpEF, and HFrEF. circRNAs were predicted to regulate cardiac metabolism, remodeling, and mitochondrial function/cardiac contraction in hypertrophy, HFpEF, and HFrEF, respectively, induced by pressure overload.In the present study, we characterized the morphological, functional, and pathological changes occurring in murine heart failure progression and identified distinct hypertrophic, HFpEF, and HFrEF stages in pressure overload hearts. After pressure overload, heart weight, cardiomyocyte hypertrophy, and fibrosis gradually increased over time. Typically, in the early hypertrophic stage, hearts displayed concentric hypertrophy, thickened left ventricular walls, increased EF and FS, and reduced MV E and MV ET. The HFpEF stage was characterized by preserved EF and FS, dilated atria, increased LV systolic volume, and reduced MV E. The advanced HFrEF stage typically presented with ventricular and atrial dilation, increased LV systolic and diastolic volume, reduced EF and FS, and increased MV ET. In the biological process enrichment analysis of mRNAs, we found that pressure overload induced cardiac remodeling, immune response dysregulation, and metabolic disorder. Contractile regulation of the heart was interfered with in the hypertrophic and HFpEF stages. The long-term pressure overload led to mitochondrial dysfunction. The ceRNA network showed that circRNAs predominately targeted metabolism in the hypertrophic stage, while targeting predominately cardiac remodeling in the HFpEF stage, and mitochondrial oxidation and cardiac muscle contraction in the HFrEF stage. Our results showed that circRNA-based ceRNA networks were crucial to heart failure phenotypes induced by pressure overload. The distinct regulatory roles of the circRNA-based ceRNA network in the three heart failure stages are summarized in Here, we applied the conventional open-chest technique to induce pressure overload. Though it has been slightly modified in recent years , the opeHypertensive myopathy is classified into four categories based on its progression. In Degree I, isolated LV diastolic dysfunction occurs with no LV hypertrophy. In Degree II, LV diastolic dysfunction occurs with concentric hypertrophy. In Degree III, clinical heart failure is observed . In Degree IV, dilated cardiomyopathy with heart failure and reduced ejection fraction occurs . AccordiFurthermore, based on the foregoing morphological, functional, and pathological changes, we propose that the 4W-post-TAC mice can serve as a model for HFpEF. The United States, Japan, and various European nations have recently adopted similar guidelines for heart failure diagnosis and treatment. They classified heart failure as reduced ejection fraction , mid-range EF , or preserved EF  . In clinHypertensive heart failure results from interactions among mechanical loading and modifications of the cardiomyocyte phenotypes, the extracellular matrix, and intracellular signaling regulation. The major features of pressure overload-induced remodeling include myocyte hypertrophy, interstitial fibrosis, and collagen degradation . Interst+) supply inhibits inflammatory activation in heart failure  cycle and oxidative phosphorylation. Mitochondrial function is linked to cardiac contraction, cell growth, cell death, and inflammation  can be found below: The animal study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the Guangdong Laboratory Animals Monitoring Institute (No. IACUC2017015).FY, XL, and WT designed and initiated the project. WT performed the animal surgery. XL, SZ, HC, LK, and JW were responsible for cardiac imaging evaluation, pathological analysis, or animal care. XL and FY performed bioinformatics analysis, results interpretation, and manuscript preparation. WP, CZ, PB, and YZ provided critical comments during experiment design and manuscript preparation. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Systemic amyloidosis is a rare, heterogenous group of diseases characterized by extracellular infiltration and deposition of amyloid fibrils. Cardiac amyloidosis (CA) occurs when these fibrils deposit within the myocardium. Untreated, this inevitably leads to progressive heart failure and fatality. Historically, treatment has remained supportive, however, there are now targeted disease-modifying therapeutics available to patients with CA. Advances in echocardiography, cardiac magnetic resonance (CMR) and repurposed bone scintigraphy have led to a surge in diagnoses of CA and diagnosis at an earlier stage of the disease natural history. CMR has inherent advantages in tissue characterization which has allowed us to better understand the pathological disease process behind CA. Combined with specialist assessment and repurposed bone scintigraphy, diagnosis of CA can be made without the need for invasive histology in a significant proportion of patients. With existing targeted therapeutics, and novel agents being developed, understanding these imaging modalities is crucial to achieving early diagnosis for patients with CA. This will allow for early treatment intervention, accurate monitoring of disease course over time, and thereby improve the length and quality of life of patients with a disease that historically had an extremely poor prognosis. In this review, we discuss key radiological features of CA, focusing on the two most common types; immunoglobulin light chain (AL) and transthyretin (ATTR) CA. We highlight recent advances in imaging techniques particularly in respect of their clinical application and utility in diagnosis of CA as well as for tracking disease change over time. This insoluble fibrillar material is derived from a variety of normally soluble precursor proteins which misfold and self-assemble with abnormal cross beta-sheet conformation that is typically stable and resistant to proteolysis  is an under-recognized cause of restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF) (Transthyretin (ATTR) amyloidosis is categorized into hereditary and wild-type amyloidosis on the basis of sequencing of the  (HFpEF) , 18. Aut (HFpEF) , 20. Des (HFpEF) , 21. Whi (HFpEF) . Recent  (HFpEF) . Clinica (HFpEF) , 21.TTR gene and although there is considerable overlap, there is a reasonably strong association between the specific mutation and the predominant clinical phenotype with certain mutations giving rise to predominant ATTR-CM, others predominant ATTR-PN, and the majority associated with a mixture of neuropathy and cardiomyopathy  have been proven to be prognostic indicators in CA , 30. TheDiastolic function is frequently severely impaired in patients with advanced disease with an E/e' which is often significantly elevated, reflecting diastolic dysfunction and raised filling pressures . AmyloidAmyloid infiltration of the cardiac valves is usually associated with regurgitant physiology of the mitral and tricuspid valve. Chacko et al. demonstrated the association between significant mitral or tricuspid regurgitation and a poor prognosis in ATTR-CM. Coexistence of cardiac amyloidosis and aortic stenosis independently conferred a significant reduction in survival in patients with ATTR-CM  , 34. TheBoth ventricular and atrial blood stasis have been demonstrated in studies to be substrate for intracardiac thrombi . Atrial A recent study looked to develop a scoring system using specific echocardiographic parameters to identify patients who were likely to have cardiac amyloid. Boldrini et al. studied two cohorts of patients; one with systemic AL amyloidosis, and one with a hypertrophic phenotype. These two cohorts represented two key clinical scenarios; the first being a patient with systemic AL amyloidosis in whom cardiac involvement must be confirmed or excluded in order to guide chemotherapeutic decisions, and the second being a patient with a hypertrophic phenotype in whom CA must be confirmed or excluded as the cause. Relative wall thickness, longitudinal strain, TAPSE, E/e' and septal apical-to-base ratio were identified as variables that had diagnostic performance in identification of cardiac amyloid see . These vCardiac magnetic resonance imaging has revolutionized the field of cardiac imaging, particularly in cardiac amyloidosis. CMR provides highly accurate, and detailed characterization of cardiac tissue and morphology, and is instrumental in distinguishing between cardiac amyloidosis and other hypertrophic phenocopies. The expansion of extracellular volume that results from amyloid fibril deposition within the myocardial extracellular space is accurately visualized using the administration of gadolinium-based contrast agent Gd-DTPA (gadolinium diethylenetriamine penta-acetic acid). “Late gadolinium enhancement” (LGE) on CMR gives rise to a characteristic, almost pathognomonic distribution; it is typically diffuse, subendocardial and/or transmural on CMR , 37. ThiMyocardial T1 mapping, a pixel-based reconstruction of measured longitudinal relaxation times, complements the use of LGE in the role of CMR in CA. In addition to its diagnostic utility, it can be used to monitor and track myocardial amyloid infiltration and therefore disease severity . In contWhilst T1 mapping is a sensitive marker for CA, it is a composite signal of both the extra and intracellular space. However, by administering gadolinium contrast, the ratio of pre and post contrast T1 maps can be used in conjunction with the patient's haematocrit level to isolate a signal to the extracellular space, and the extracellular volume (ECV) maps can be quantifiably measured . ECV mapChacko et al. recently demonstrated that ECV measurements during routine CMR can also quantify the burden of extracardiac amyloid, specifically splenic and hepatic amyloid in systemic AL amyloidosis patients . Not onlT2 mapping serves to complement T1, LGE, and ECV methods in CMR and is a sensitive method to detect myocardial oedema found in a number of cardiac pathologies, both ischaemic and inflammatory. Examples would include acute myocardial infarctions, stress cardiomyopathies/Takotsubo's and myocarditis . T2 relaIn summary, CMR is a sensitive, accurate and reproducible imaging modality in the diagnosis and monitoring of patients with both AL and ATTR CA. It has also been shown to have utility in the quantification of extracardiac (hepatic and splenic) AL amyloid burden, which previously could only be assessed with SAP scintigraphy at two centers globally.99mtechnetium-labeled-pyrophosphate (Tc-PYP) for bone scintigraphy and myocardial uptake in patients with proven CA was first demonstrated 1983  was shown by Rapezzi et al. to be highly sensitive for ATTR-CM and specific for CA generally  with echocardiography, CMR and biochemical investigations has enabled the diagnosis of ATTR amyloidosis to be established in the absence of a tissue biopsy in a substantial proportion of patients. In the absence of a monoclonal protein (by serum and urine immunofixation as well as by serum free light chain assay), a CMR and/or echocardiogram suggesting CA with a Perugini grade 2 or 3 radionuclide scan is diagnostic of ATTR-CM . HoweverOne important role of radionuclide scintigraphy is in excluding other cardiomyopathies in patients with biventricular thickening or LV hypertrophy. In patients with diffuse cardiac uptake on radionuclide scintigraphy one can be confident that CA is the cause of the aforementioned biventricular thickening. However, the converse is not true as radionuclide scintigraphy cannot be used to exclude CA, since up to 60% of AL-CA is associated with a negative radionuclide scan. Additionally, while radionuclide scintigraphy is extremely sensitive in ATTR-CA, rare hATTR variants such as S77Y and Y114C demonstrate less than expected uptake on DPD scintigraphy. Therefore should other imaging modalities (such as echocardiography and CMR) be strongly supportive of ATTR-CA in patients with the aforementioned TTR variants, CA cannot be excluded based on bone scintigraphy and must still be considered.The multimodality imaging advances highlighted above have allowed clinicians to diagnose and exclude CA, and in some cases, definitively determine the amyloid type without recourse to invasive endomyocardial biopsies whilst also permitting cardiac amyloid burden to be carefully tracked. Diagnosis of ATTR-CM can be reliably established without recourse to histology in ~70% of patients using these newer imaging tools which are increasingly accessible in most modern healthcare systems in combination with biochemical testing. CMR has proven to be a highly sensitive imaging modality in both AL-CM and ATTR-CM allowing for earlier diagnosis and subsequent successful therapeutic intervention in these diseases; which were historically treated with considerable nihilism due to the delays in diagnosis experienced by the vast majority of patients. Whilst individual imaging modalities have their own unique advantages, they also each have disadvantages see . Therefoin vivo TTR gene editing. ATTR amyloidosis is an ideal disease for testing this new therapeutic strategy since TTR has limited normal and specific function , the clinical benefit of TTR knockdown in the disease is established, and circulating TTR is entirely liver-derived. Interim findings from a first-in-human dose escalation study of the CRISPR-Cas9 therapeutic, NTLA-2001, were extremely encouraging with patients achieving up to 96% knockdown of circulating TTR concentration following a single infusion . MF holds research grants from Pfizer and Eidos. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cardio-oncology encompasses the risk stratification, prognostication, identification and management of cancer therapeutics related cardiac dysfunction (CTRCD). Cardiovascular imaging (CVI) plays a significant role in each of these scenarios and has broadened from predominantly quantifying left ventricular function  to the identification of earlier bio-signatures of CTRCD. Recent data also demonstrate the impact of chemotherapy on the right ventricle, left atrium and pericardium and highlight a possible role for CVI in the identification of CTRCD through tissue characterization and assessment of these cardiac chambers. This review aims to provide a contemporary perspective on the role of multi-modal advanced cardiac imaging in cardio-oncology. Heart disease and cancer are the two major causes of morbidity and mortality, accounting for over 70% of medically related deaths globally . The morCardiac imaging plays an important role in the diagnosis, management, and prognostication in patients with CTRCD . LVEF haEchocardiography is the primary imaging modality of choice for baseline cardiac function assessment by American and European society consensus statements –9. The lWhile echocardiography is a good first line investigation due to its accessibility, low cost, and lack of any radiation, feasibility of high-quality echocardiographic imaging may also be limited by patient body habitus, radiation therapy, or recent surgery . In these situations, cardiac magnetic resonance imaging (CMR) or contrast echocardiography can overcome some of these imaging limitations and provide a more accurate assessment of LVEF .Widely utilized standard 2D echocardiographic methods of LVEF assessment are based on geometrical assumptions which limits accuracy and reproducibility. Three-dimensional (3D) echocardiography overcomes these limitations and is currently recommended for the assessment of LV systolic function , 11. RecSpeckle tracking echocardiography, which has been validated against sonomicrometry and tagged magnetic resonance imaging, has provided accurate angle-independent measurements of myocardial strain. Efforts to standardize myocardial deformation imaging has reduced the variability in this measure compared to other conventional echocardiographic measures of LV systolic function making it ideal for CTRCD . Global 2 or equivalent), ≥30 Gy of radiotherapy to the chest involving the heart and tyrosine kinase inhibitors following doxorubicin chemotherapy  , patients in the GLS arm had higher cardioprotective therapy rates and fewer developed CTRCD   .CTRCD recovery is dependent on early detection. Those who start treatment with a cardioprotective agent(s) within 2 months of diagnosis have a better chance of LV function recovery . AdditioBaseline LV diastolic function is not predictive of CTRCD and there is limited evidence on it predicting CTRCD . The larThough still limited by small studies, quantitative assessment of the RV size and function is recommended as RV dysfunction can occur during cancer treatment . In addiTyrosine Kinase Inhibitors (TKI)  are associated with pulmonary hypertension, though the incidence is difficult to estimate because of lack of screening data due to asymptomatic study participants and overall small study sizes. A position statement suggests 3–6 monthly ECHOs in asymptomatic patients on anticancer agents that can cause pulmonary hypertension such as TKIs . DasatinThe role of stress echocardiography is potentially useful in risk stratifying patients undergoing cancer therapies associated with ischemia. This includes antimetabolites (5-FU), VEGF inhibitors and TKIs . The advAspects of the left atrium that have been investigated include baseline left atrial volume index and left atrial longitudinal strain , 34. BerLong-term cardiac surveillance is recommended post completion of chemotherapy . In low A collection of echocardiographic parameters rather than solely LVEF maybe important in identifying at risk patients, as the prevalence of abnormal GLS and diastolic function is higher in a cancer survivor cohort . This isCMR is the gold standard for measuring left and right ventricular volume and function , 43. HowThe main indication in the current cardio-oncology guidelines for CMR is when there is suboptimal image acquisition and it is preferred over nuclear imaging , 7, 16. Using the forementioned CMR sequences, CMR has a high accuracy for discriminating between benign and malignant lesions, with a good interobserver agreement . FiguresThe role of CMRs in cardio-oncology from current patients to survivors is likely to increase given its high reproducibility and lack of ionizing radiation. This may be enhanced with the potential development of a limited 10 min CMR examination focusing on volumes and function . This woThough CMR main role in baseline assessment is limited, its versatility makes it an important imaging modality in the identification of CTRCD.The definition of CTRCD is based on a LVEF decline of >10%, reiterating the importance of accurate and reproducible imaging. CMR is superior to 2D echocardiography in identifying LV dysfunction as its volumes are not based on geometric assumptions and less prone to suboptimal imaging . FurtherCMR can also measure myocardial strain. The data on CMR myocardial strain correlates with a decline in LVEF, however its prognostic ability has not been assessed to the extent it has been in echocardiography –53.The composition of the extracellular matrix is altered in myocardial fibrosis. This structural change allow gadolinium to accumulate in areas of replacement fibrosis. On T1-weighted sequences regions of gadolinium accumulation appear hyperintense (bright) in contrast to healthy myocardium, which appear dark. The data on the utility of LGE in CRTCD is conflicting. The majority of short term (<6 months) studies have not reported any LGE , 53, 54.The utility of tissue characterization has becoming increasingly popular over the last decade with the advent of validated software enabling the quantification of T1, T2 mapping, and extracellular volume (ECV) fraction estimation. T1 mapping allows us to detect a range of diffuse pathologies including myocardial fibrosis, myocarditis, cardiac amyloidosis, key aspects of cardio-oncology as well as other pathologies such as storage disorders. T1 measures the longitudinal time to equilibrium post a radiofrequency pulse. The commonest technique to acquire a T1 map is the modified Look-Locker pulse sequence (MOLLI) or “shortened” version known as the shMOLLI . Though ECV is an additive tool in the assessment of myocardial fibrosis assessing interstitial fibrosis. ECV requires a pre- and post-contrast T1 map as well as the subject's hematocrit to calculate the ECV fraction. Normal values are between 20 and 26%, with it being slightly higher in women and similar between 1.5T and 3T scanners , 62, 63.T2 measures the transverse time to equilibrium post a radiofrequency pulse. T2 mapping is used in the identification of myocardial oedema, which can occur in myocarditis to infarction to cardiomyopathy. Its use along with T1 mapping is supported in myocardial inflammation recommendations . The datThe data on T1 time and ECV in cancer survivors are heterogenous. Increases in T1 and ECV correlated to cumulative dose, reduced exercise capacity and myocardial wall thinning in cancer survivors whom received anthracycline and were at least 7 years in remission . AdditioThough immune checkpoint inhibitor (ICI) related myocarditis is rare, its frequency will increase with increased ICI usage. CMR is a valuable non-invasive diagnostic tool in the assessment of myocarditis with the Lake Louise criteria and the addition of T1 and T2 maps  64). It. It64). The calcium artery calcium (CAC) score can be determined on non-gated non-contrast CT chest scans performed for staging and assessment of the primary malignancy, this CAC should be reported as per guidelines . The conComplications of radiotherapy include accelerated atherosclerosis . EffectsRadiotherapy can impact the valvular apparatus causing thickening, fibrosis, and significant valvular heart disease . The risAcute and chronic pericarditis are side effects often associated with mediastinal radiotherapy, though can also occur with chemotherapy . Their i18F fluorodeoxyglucose (18FDG) positron emission tomography (PET)-CT scans particularly in the diagnosis and staging of cancer patients. Inflammation is associated with both cancer and cardiovascular disease. 18FDG-PET can identify cardiac inflammation within atherosclerotic plaque as well as myocardial tissue and valves  was the first imaging modality to be used in cardio-oncology . Its prid valves , 88. Ret in LVEF . This inammation , 90.in vivo  molecular imaging could become a novel imaging modality in cardio-oncology. CEU can track temporal and spatial changes in tissues and the vasculature, which is important, as anthracyclines can damage the myocardial vascular bed by labeling molecular markers with specific antibodies (All cardiac imaging modalities have a promising role in the future of cardio-oncology. Areas of particular interest that may rise to prominence, are advanced echocardiographic assessment of cardiac structures in addition to the left ventricle in conjunction with the use of 3D volumes and myocardial deformation indices over standard 2D echocardiography as described earlier. Similarly, the utility of diffusion tensor CMR can increase due to its ability to assess myocardial microstructure, such as, cardiomyocyte and sheetlet-level in vivo . As CT tin vivo , 93. Destibodies , 95. ThoThe field of cardio-oncology has evolved rapidly over the last couple of decades. Cardiac imaging has an integral role in this specialty and advances in imaging techniques allow clinicians to identify at risk patients earlier. Each imaging modality has its pros and cons with no sole technique superior in all domains of cardiac imaging. Thus, the key to a successful cardio-oncology patient journey involves a multi-modal approach so that patients can hopefully complete their optimal cancer therapy with minimal disruption to their cardiac health.All authors have contributed to the planning, writing, and reviewing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Coronary magnetic resonance angiography (CMRA) allows non-ionizing visualization of luminal narrowing in coronary artery disease (CAD). Although a prior study showed the usefulness of CMRA for risk stratification in short-term follow-up, the long-term prognostic value of CMRA remains unclear. The purpose of this study was to evaluate the long-term prognostic value of CMRA.A total of 506 patients without history of myocardial infarction or prior coronary artery revascularization underwent free-breathing whole-heart CMRA between 2009 and 2015. Images were acquired using a 1.5 T or 3 T scanner and visually evaluated as the consensus decisions of two observers. Obstructive CAD on CMRA was defined as luminal narrowing of ≥ 50% in at least one coronary artery. Major adverse cardiac events (MACE) comprised cardiac death, nonfatal myocardial infarction, and unstable angina.Obstructive CAD on CMRA was observed in 214 patients (42%). During follow-up , 31 MACE occurred. Kaplan–Meier curve analysis revealed a significant difference in event-free survival between patients with and without obstructive CAD for MACE  and cardiac death (p = 0.012). Annualized event rates for MACE in patients with no obstructive CAD, 1-vessel disease, 2-vessel disease, and left-main or 3-vessel disease were 0.6%, 1.5%, 2.3%, and 3.6%, respectively . Cox proportional hazard regression analysis showed that, among obstructive CAD on CMRA and clinical risk factors , obstructive CAD and diabetes were significant predictors of MACE . In multivariate analysis, obstructive CAD remained an independent predictor  after adjusting for diabetes. Addition of obstructive CAD to clinical risk factors significantly increased the global chi-square result from 8.3 to 13.8 (p = 0.022).In long-term follow-up, free breathing whole heart CMRA allows non-invasive risk stratification for MACE and cardiac death and provides incremental prognostic value over conventional risk factors in patients without a history of myocardial infarction or prior coronary artery revascularization. The presence and severity of obstructive CAD detected by CMRA were associated with worse prognosis. Importantly, patients without obstructive CAD on CMRA displayed favorable prognosis.The online version contains supplementary material available at 10.1186/s12968-021-00749-w. Coronary artery disease (CAD) is a leading cause of morbidity and mortality around the world . Early dThis retrospective study included 882 patients ≥ 45 years old who were referred for whole-heart CMRA for the indications shown in Additional file All CMRA were performed using a 1.5 T (n = 205) or 3 T (n = 301) scanner . Radiofrequency reception was performed using a 32-element cardiac coil. CMRA was performed as a part of a: (1) cine CMR and CMRA protocol (n = 23); (2) cine CMR, late gadolinium-enhanced (LGE), and CMRA protocol (n = 25); or (3) cine CMR, stress perfusion, LGE, and CMRA protocol (n = 458) using a 1.5 T or 3 T scanner. The protocol (1), performed by the 1.5 T CMR scanner alone, used no contrast agent. The protocols (2) and (3) were performed with gadolinium-based contrast agent using 1.5 T or 3 T scanners. To assess left ventricular (LV) volume, function, and mass, breath-holding cine CMR was performed with a segmented balanced steady-state free precession (bSSFP) sequence in the short-axis planes covering the entire LV , 3.2 ms; echo time (TE), 1.6 ms; flip angle (FA), 55°; field-of-view (FOV), 35 × 35 cm; acquisition matrix, 192 × 192; reconstruction matrix, 256 × 256 for 1.5 T scanner; TR, 2.8 ms; TE, 1.4 ms; FA, 55°; FOV, 35 × 35 cm; acquisition matrix size, 176 × 308; reconstruction matrix, 352 × 352 for 3 T scanner). Acquisition methods for stress perfusion CMR and LGE are presented in the Additional file Sublingual isosorbide denitrate 5 mg was administered to all subjects before CMRA acquisition. Beta-blockers were not used. CMRA was acquired after cine CMR at the protocol (1) or after LGE imaging (2) and (3). To monitor motion of the right coronary artery (RCA), transaxial cine CMR was performed under free breathing for 50 cardiac phases. A patient-specific acquisition window in the cardiac cycle was set during either systole or diastole, depending on the phase of minimal motion of the RCA . Free-brCMR images were analyzed by two independent, blinded observers using cvi42 software . At end-diastole and end-systole, endocardial LV borders were manually traced in contiguous images from short-axis cine CMR covering from apex to mitral valve planes to calculate LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) and ejection fraction (LVEF). After tracing epicardial LV borders at end-diastole, LV mass was calculated as the sum of myocardial volume at end-diastole multiplied by the specific gravity (1.05 g/mL) of myocardial tissue.Two observers blinded to clinical information evaluated the coronary arteries with a diameter ≥ 2 mm on whole-heart CMRA using sliding thin-slab maximum intensity projection. All coronary arteries were included for the evaluation regardless the image quality of coronary MRA. The presence or absence of significant luminal narrowing (≥ 50% diameter narrowing) was interpreted using an intention-to-read approach , 10, 12.Follow-up information was collected through a review of hospital records or telephone interviews blindly to CMRA results. Major adverse cardiac events (MACE) comprised cardiac death, non-fatal MI, and unstable angina –15. CardContinuous variables are presented as mean ± standard deviation and categorical variables are expressed as frequency and percentage. The influence of predictors on MACE was determined using Cox proportional hazards regression analysis, with the results reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Univariate Cox proportional hazards regression analysis was performed to identify potential predictors of MACE. Multivariate Cox proportional hazards regression analysis was performed using the “enter” method for variables showing values of p < 0.05 in univariate analysis to determine independent predictors of MACE. The incremental value of obstructive CAD on CMRA over clinical risk factors was evaluated by using the global chi-square test. Kaplan–Meier curves were used to estimate event-free rates for MACE and cardiac death. Differences between time-to-event curves were compared using the log-rank test. Annualized event rates were calculated by dividing 5-year Kaplan–Meier event rates by 5. Two-sided values of p < 0.05 were considered significant. All analyses were performed using the SPSS .Of the 551 patients, 45 8.2%) were lost to follow-up. The final study population thus comprised 506 patients  Body mass index, coronary risk factors, pre-test likelihood of CAD, and the number of early revascularizations were shown in Table % were loKaplan–Meier curve analysis revealed a significant difference in event-free survival between patients with and without obstructive CAD on CMRA for MACE  significantly increased the global chi-square from 8.3 to 13.8  on whole-heart CMRA was strongly associated with future major cardiac events in patients n = 207) with suspected CAD . Patient7 with suith CCTA , 13, thiOur results implied that free breathing whole-heart CMRA allowed long-term risk stratification of patients through visualization of coronary arteries without radiation exposure. The presence and severity of obstructive CAD detected using CMRA were associated with worse prognosis. More importantly, patients without obstructive CAD on CMRA displayed an event rate < 1%, consistent with results from studies on the prognostic value of CCTA , 21, 22.Several limitations should be noted in this study. First, this was a single-center, retrospective study. A large, multi-center, prospective study is needed to confirm the present results. Second, we used both 1.5 T and 3 T CMR scanners, which differed in several respects, including diagnostic performance . HoweverIn a long-term follow-up, free breathing whole-heart CMRA allows non-invasive risk stratification for MACE and cardiac death and provides incremental prognostic value over conventional risk factors. Importantly, patients without obstructive CAD on CMRA displayed favorable prognosis.Additional file 1: Table S1. Indications for CMR.


Prosthetic valve thrombosis is a potentially life-threatening complication diagnosed by a combination of clinical features and imaging modalities, but the optimal management in high bleeding risk patients remains controversial. Current treatment options for prosthetic valve thrombosis included surgery, thrombolytic therapy, and anticoagulation. We present a very unusual case of a patient with a recent ST-elevation myocardial infarction complicated by contained left ventricle free wall rupture and mechanical mitral valve thrombosis. Deemed a high surgical risk candidate, low-dose tissue plasminogen activator was used despite significant bleeding risk from contained left ventricle free wall rupture, which resulted in resolution of the thrombus. To the best of our knowledge, this is the first report of successful thrombolytic therapy for prosthetic mechanical mitral valve thrombosis in a patient with recent postmyocardial infarction contained left ventricular free wall rupture. The most common complications after native valve replacement include prosthetic valve thrombosis (PVT), pannus formation, embolic events, bleeding, and infective endocarditis . The ratA 52-year-old woman with a history of chronic kidney disease status post kidney transplant, remote history of mitral valve endocarditis status post St Jude mechanical mitral valve replacement, and heart failure presented with an ST-elevation myocardial infarction. She underwent emergent left heart catheterization revealing a 100% occluded obtuse marginal branch for which percutaneous intervention with stent implantation was performed. Follow-up transthoracic echocardiogram (TTE) showed a low normal ejection fraction of 52% and normal mitral valve gradients. She was discharged home on guideline-directed medical therapy postacute myocardial infarction.2. PVT was diagnosed based on her acute clinical symptoms and echocardiography findings.Approximately three weeks later, she presented with acute dyspnea, orthopnea, and acute hypoxic respiratory failure. Her international normalized ratio (INR) on presentation was supratherapeutic at 8.29 with a repeat the following day of 2.02. She was initially treated for a heart failure exacerbation with bilevel positive airway pressure and aggressive intravenous diuretics. A TTE was repeated given her acute clinical change, revealing a severely reduced ejection fraction of 30-35%, abnormal prosthetic mitral valve gradients, and restricted posterior valve leaflet mobility. The mitral valve max pressure gradient was 21.1 mmHg with a mean gradient across the mitral valve of 11.0 mmHg. The TTE also revealed a tricuspid regurgitation (TR) max velocity of 343.9 cm/sec, TR max PG 47.3 mmHg, RVSP 50.3 mmHg, and pressure half-time of 2.5 cmIncidentally, contrast TTE also revealed a posterolateral pseudoaneurysm with contrast extending into the pericardial space concerning for left ventricular free wall rupture . A transDue to mechanical mitral PVT and left ventricular pseudoaneurysm, felt to be secondary to recent myocardial infarction, cardiothoracic surgery was consulted. She was considered inoperable due to multiple factors: recent myocardial infarction on dual antiplatelet therapy, heart failure with reduced ejection fraction, acute respiratory failure, worsening renal function, prior renal transplant, and prior open-heart surgery. Management options were extremely limited, but after discussion with the patient's family, low-dose tissue plasminogen activator (tPA) was administered and infused at 25 mg over six hours. The following day, patient's dyspnea improved. She underwent a TEE showing a normally functioning mechanical mitral valve with a mean gradient across the valve of 5 mmHg. There was no evidence of thrombus and the left ventricle posterior wall pseudoaneurysm was unchanged Figures  and 4.Although her initial hospital course was complicated by renal failure requiring continuous renal replacement therapy, prolonged respiratory failure requiring high doses of supplemental oxygen, and hypotension limiting guideline-directed medical therapy, she recovered gradually with conservative management of the contained posterior wall rupture. She continued to show improvement and was discharged home following a twenty-five-day hospitalization. She was seen in the ambulatory setting two months later without complaints of dyspnea or orthopnea and an echocardiogram showing a mean mitral valve gradient of 8.9 mmHg with no pericardial effusion. Since then, she has been seen multiple times in our outpatient clinic and is doing very well.The current prevalence of mitral and aortic valve disease in the United States is approximately 2.5% in the general population and up to 10% in people 75 years or older [PVT should be considered when patients present with acute symptoms, new murmur, signs of heart failure, diminished valve sounds, and thromboembolic events . The exaKapos and colleagues presented a case of a 52-year-old female presenting with signs of cardiac congestion. An urgent TTE revealed an elevated diastolic transmitral gradient of 21 mmHg with impaired movement of one of the disc. TEE confirmed the TTE findings, but no mass was seen. Given her symptoms and echocardiographic findings, she was diagnosed with a PVT and started on unfractionated heparin. Despite five days of therapy, the mitral stenosis remained unchanged, and she was started on low-dose-ultraslow fibrinolytic therapy [2. She had no contraindications to thrombolytic therapy and was started on low-dose tPA 25 mg over the course of 25 hours (low-dose and ultraslow fibrinolytic therapy). Repeat TTE showed a decreased transvalvular gradient and relaxation in the restricted leaflet. She was discharged on oral anticoagulation and did not require surgical intervention [Kalҫik and colleagues present a case of a 57-year-old female that presented with NYHA class III dyspnea. TTE revealed an increased mean mitral transvalvular gradient of 15 mmHg with a decreased mitral valve area of 0.9 cmrvention .The ultraslow PROMETEE trial evaluated the use of low-dose slow infusion of tPA (25 mg over 6 hours) in patients with mechanical PVT. Thrombolytic therapy was administered to 114 patients under TTE guidance. They found a low-dose ultraslow infusion of tPA was associated with an overall success rate of 90% and low morbidity and mortality in each NYHA class except class IV . Low-dosThe optimal management option is unclear in patients presenting with both PVT and extremely high bleeding risk. Our patient is unique in that she presented with both acute respiratory failures from mechanical mitral PVT and a left ventricular free wall contained rupture after a recent ST-elevation myocardial infarction. A successful outcome in our highly unusual case illustrates that despite the extreme bleeding risk, low-dose thrombolytics are potentially lifesaving and should always be considered, especially in inoperable patients.