There was a significant correlation between GCS (increased)  and LV longitudinal HDFs (reduced)  with age. In a multivariable analysis age, BSA, pulse pressure, heart rate and GCS were the only independent variables associated with LV HDFs . Conclusion: We report on the physiologic range of LV HDFs. Knowledge of reference values of HDFs may prompt their implementation into clinical routine and allow a more comprehensive assessment of the LV function.Background: The normal limits of left ventricular (LV) hemodynamic forces (HDFs) are not exactly known. The aim of this study was to explore the full spectrum of HDF parameters in healthy subjects and determine their physiologic correlates. Methods: 269 healthy subjects were enrolled  men). All participants underwent an echo-Doppler examination. Tri-plane tissue tracking from apical views was used to measure 2D global endocardial longitudinal strain (GLS), circumferential strain (GCS), and LV HDFs. HDFs were normalized with LV volume and divided by specific weight. Results: LV systolic longitudinal HDFs (%) were higher in men (20.8 ± 6.5 vs. 18.9 ± 5.6,  Left ventricular (LV) function is a major diagnostic and prognostic determinant of a wide range of cardiac diseases ,2,3. TheThe study population consisted of 269 healthy subjects  men) . They unTransthoracic echocardiography (TTE) examinations were performed with commercially available equipment on all subjects . Two independent experienced operators , blinded to the clinical data, performed offline left and right heart measurements and speckle-tracking (ST) analysis according to the current recommendations of the American Society of Echocardiography/European Association of Cardiovascular Imaging ,26,27. SWe included healthy subjects with frame rate acquisition of at least 50 Hz and with optimal images of all 18 segments in order to conduct strain-based HDFs analysis. In this regard, 37 subjects were excluded due to poor imaging quality . 2D images from apical views  were re-analyzed offline using a commercially available software . The cardiac cycle was selected where the endocardial borders were better visible both in diastole and in systole. The LV end-systolic endocardial borders in each apical view were drawn and the software tracked the endocardial borders over the entire heartbeat. When necessary, the end-diastolic borders were corrected manually with consequent automatic propagation of the border correction over the entire cycle to match the original end-systolic borders. The LV end-systolic and end-diastolic volumes were calculated according to the modified Simpson rule ,28. SpecHDFs were originally computed from the blood velocity in the LV volume ,16,17. AL) and transversal  components of HDFs. To improve comparability between different subjects, forces were expressed in dimensionless form after normalization with the LV volume and specific weight, and expressed as a percentage of gravity acceleration. A typical time evolution of the HDF components over the cardiac cycle is illustrated in From the three endocardial borders estimated by speckle-tracking during the cardiac cycle, and from the knowledge of the aortic root and mitral inflow dimensions, the strain software also computed the time profile of the longitudinal  the systolic impulse, computed as the area under the curve of the longitudinal force during the positive interval of the systolic phase , this vat-test. p-values less than 0.05 were considered as statistically significant. As lower and upper limits for normal HDFs, we used 95% confidence intervals (CI) and/or ± 2 SD. The Pearson’s correlation analysis was used to determine correlations between continuous variables. The variables were selected according to their clinical relevance and potential impact on LV HDFs. Multivariable linear regression analysis, including all significant clinical and echocardiographic parameters from the univariate analysis was constructed to assess the independent associations of these variables with LV HDFs. We reported the standardized beta coefficients in regression analysis. The inter- and intra-observer variabilities were examined using both paired t-tests and intraclass correlation coefficient (ICC) in 30 randomly selected cases. An ICC of >0.8 indicated good agreement. Data were processed using MATLAB® .Continuous variables were expressed as means ± standard deviation (SD). Normal distribution of the continuous values was assessed by the Kolmogorov–Smirnov test. Differences between groups were analyzed by unpaired Student The demographic data of the study population are reported in p < 0.001). On the other hand, compared to women, men had slightly higher LV ejection fraction (p = 0.049). No significant sex-related differences in mitral peak E/e’ ratio were noted (p = 0.319). However, men demonstrated higher SV (p < 0.001) and CO (p = 0.005)  .p < 0.001). No significant sex-related differences in tricuspid annular plane systolic excursion (TAPSE) (p = 0.916), S’ (p = 0.251) and pulmonary artery systolic pressure (p = 0.170) were found. Compared to women, men had slightly shorter right ventricular outflow tract (RVOT) acceleration time (Act) (p = 0.049)  .p = not significant (ns)) ) .p = 0.009; 22.0 ± 6.7 vs. 19.8 ± 5.6, p = 0.004, respectively). The lower limits of normal of the longitudinal force in the whole cycle were 6.3% in men and 6.5% in women. Systolic longitudinal force was 8.8% in both sexes. The amplitude values were lower for the transversal component. LV transversal force (%) during the whole cycle and systole was higher in men . The lower limits of normal of the transversal HDFs in the whole cycle and during systole were 0.6% and 0.7% in both sexes, respectively. No significant sex-related differences during diastole for longitudinal and transversal components were noted . On average, the force showed a good alignment of 14° ± 3.6 with the LV axis, slightly greater in women  systolic impulse = 19.8% ± 6.1, with (b) average amplitude of the longitudinal component in the entire heartbeat = 15.0% ± 4.4, that was higher during systole = 20.8% ± 6.2 and lower during diastole = 8.1% ± 2.7. LV systolic impulse (%) and LV systolic longitudinal force (%) were higher in men . GCS showed a statistically significant correlation with age  (No significant correlation between left ventricular ejection fraction (LVEF) and GLS with age was found  . p = 0.01), BSA , pulse pressure  and heart rate . Furthermore, LV longitudinal force was weakly correlated with GLS  and more significantly with GCS . On the opposite, no significant correlation between LV longitudinal HDFs and LV mass, LA volume, LVEF (%), stroke volume and E/e’ was found   . p < 0.001; 0.149, p = 0.003; 0.186, p < 0.001; 0.396, p < 0.001; −0.328, p < 0.001, respectively)  . p < 0.01) , who volunteered to repeat the measurement session of images in 20 randomly selected cases on two separate days. The intra-observer quality control analysis revealed an excellent ICC of 0.98 for GLS and GCS (95% CI: 0.95 to 0.99) and ICC of 0.97 for HDF (95% CI: 0.95−0.99)  .p < 0.01) . Reproducibility analyses was performed on the same set of images in 30 randomly selected cases. Inter-observer analysis showed excellent repeatability and reproducibility. ICC varies between 0.94 and 0.99 for both strain components (GCS and GLS), and 0.93−0.98 for HDF  . HDFs introduce novel information about cardiac mechanics. In this regard, looking at the dynamics of blood flow provides an alternative viewpoint to cardiac function. Here, HDFs correspond to the ultimate result of LV contraction–relaxation rhythm and play an important role in the description of cardiac function .IVPGs play an important physiological role  as descrp < 0.0001, respectively). A weak but statistically significant decline with advancing age was also found for HDFs parameters, following the trend of GLS . On the other hand, GCS and LVEF showed an increase with older age . Recently, Faganello et al.  have appTo the best of our knowledge, this is the largest study that: (a) comprehensively assessed the full range of HDFs parameters  in a large cohort of healthy individuals stratified by age and sex; (b) demonstrated systolic HDFs parameters were higher in men than women, except for diastolic HDFs parameters; (c) showed HDFs longitudinal parameters were reduced in older age ; (d) revealed age, BSA, pulse pressure, heart rate and GCS were the only independent variables associated with LV longitudinal HDFs. In this regard the interesting paper by Faganello et al.  on a heaOur findings suggest a physiological impact of the aging process more evident on the systolic HDFs parameters (reduced) and GCS (increased) than on GLS and LVEF. The compensatory (to preserve cardiac output) progressive increase of GCS with aging was already described in previous studies ,40,41. On = 23, amplitude = 15.0 ± 5.0; Arvidsson et al. 2017 [n = 39, amplitude = 13.5 ± 6.8) and substantially similar values in diastole , although details of normalization were not identical. This difference may be partly imputable to imaging technology: 4D flow MRI has a lower temporal resolution that smooths out the sharp systolic acceleration especially during systole, and presents a smoother flow averaged over numerous heartbeats that cancels the sharper local flow peaks. Third, values of GLS and GCS between the different ultrasound vendors were not compared. Inter-vendor variability exists even in full-thickness strain due to the differences in the analytical algorithm. Forth, the apical approach to GCS could be less accurate because the entire circumference was not visible from the apical views. These potential pitfalls were minimized by using a triplane evaluation, commonly used in the evaluation of LV volumes.Few study limitations need to be discussed. First, our study was limited to Caucasian healthy subjects. For this reason, the clinical relevance in different races and pathologic states was not assessed. Second, the present study did not validate the accuracy of strain measurements against reference standards such as MRI. The quantitative comparison with previous evaluations with 4D Flow MRI in a relatively smaller number of patients showed larger systolic values (present study: amplitude = 20.8 ± 6.2; Töger et al. 2018 : n = 23,al. 2018 : n = 23,We reported the physiologic range of LV strain and LV-HDFs parameters measured by TTE. Knowledge of age- and gender-specific reference values, for a combination of standard, mechanical and hemodynamic indices may improve the global assessment of the LV function and help to detect sub-clinical stages of LV dysfunction.


Cancer therapeutics-related cardiac dysfunction is currently of great concern as one of the pivotal therapeutic targets of onco-cardiology. Only a few studies have reported the occurrence of heart failure following the administration of osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor for EGFR mutation-positive advanced non-small cell lung cancer. We report on a 74-year-old woman with osimertinib-induced advanced heart failure with reduced ejection fraction, which was treated by the temporal termination of osimertinib and neurohormonal blocker therapy, as well as heart rate modulation therapy using ivabradine. Despite osimertinib-induced heart failure being relatively rare, aggressive neurohormonal blocker therapy using ivabradine if applicable, as well as the temporal termination of osimertinib, might be a promising therapeutic strategy. At present, cancer therapeutics-related cardiac dysfunction is a major concern as one of the pivotal therapeutic targets of onco-cardiology . Some ofHowever, the cardiotoxicity of osimertinib, a newly introduced third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) , remainsA 74-year-old woman received post-surgical first and second-line chemotherapy following a thoracoscopic left lower lobectomy to treat non-small cell lung cancer seven years ago (EGFR gene-positive and T790 mutation-negative). Two years ago, she was referred to our clinic prior to the administration of the third-line chemotherapy osimertinib to treat recurrent lung cancer (T790 mutation-positive conversion).Chest X-ray displayed right lung consolidation but no lung congestion A. ElectrFrom one month, bilateral leg edema and dyspnea on exertion had emerged. She was admitted to our institute complaining of worsening dyspnea. Her body height was 157 cm and body weight was 48 kg. Blood pressure was 124/97 mmHg and pulse rate was 132 bpm. Chest X-ray presented a cardiothoracic ratio of 0.59 and bilateral lung congestion without interstitial consolidation A. There 2. Percutaneous end-myocardial biopsy revealed slight myocardial fibrosis and atrophy without infiltration of inflammatory cells (Coronary angiogram proved no coronary artery stenosis. Right heart catheterization revealed a mean right atrial pressure of 9 mmHg, pulmonary artery wedge pressure of 22 mmHg, and a cardiac index of 2.15 L/min/mry cells A,B. The ry cells C accompary cells D. This cOsimertinib was terminated . PulmonaIvabradine 5.0 mg was initiated to modulate her heart rate. Two left ventricular inflow waves in the trans-mitral Doppler echocardiography obviously overlapped at baseline A. We up-Her systolic blood pressure increased to around 100 mmHg, which let us up-titrate bisoprolol to 5.0 mg. On in-hospital day 32, transthoracic echocardiography revealed left ventricular end-diastolic diameter of 52 mm, left ventricular ejection fraction of 42%, and plasma B-type natriuretic peptide level of 435 pg/mL. Before discharge, she received implantation of cardiac resynchronization therapy without complications. She was discharged on foot on in-hospital day 33. Chest X-ray at discharge indicated no pulmonary congestion or recurrent right lung consolidation A.One month later, transthoracic echocardiography indicated left ventricular end-diastolic diameter of 43 mm and left ventricular ejection fraction of 62%. Plasma B-type natriuretic peptide was 167 pg/mL. Given the worsening of the malignant tumor and relatively controlled heart failure B, osimerSeveral studies report the cardiotoxicity of osimertinib, although the detailed clinical course of osimertinib-related heart failure remains uncertain ,6. A retThe detailed mechanism remains unclarified. Unlike direct myocardial injury by anthracycline , osimertThe reason why only a few patients, including our patient, develop heart failure during osimertinib remains unknown. Given that a previous study reported a decline in mean LVEF in 36 patients receiving osimertinib [2, and baseline low LVEF, except for age over 65 years old and a history of hypertension [Our patient did not have most of the known risk factors, including concomitant use of anthracycline, history of thoracic radiation, body mass index above 30 g/mrtension .Several therapeutic strategies have been proposed for the general management of cancer therapeutics-related cardiac dysfunction, but the osimertinib-specific strategy remains unestablished.Screening of potential high-risk patients and careful monitoring using newly proposed echocardiography strain patterns and troponin levels are suggested for early diagnosis and prompt therapeutic intervention . Other iGiven its dose-independency, the termination of osimertinib might be helpful for the recovery of cardiac function. Kunimasa and colleagues reported three patients whose LVEF recovered at least partially by 1–3 months following the termination of osimertinib . OsimertThe implication of neurohormonal blockers remains unknown. A systemic review including 14 published articles reported that prophylactic treatment, including neurohormonal blockers, was efficacious for reducing cardiotoxicity in patients receiving chemotherapeutic agents, predominantly anthracyclines . It was In our patient, we believe that the termination of osimertinib alone was insufficient to manage her advanced heart failure. Furthermore, optimal medical therapy was essential to re-start osimertinib for recurrent malignant tumors. Further studies are warranted to validate our proposed strategy.


The combination of hypertension and obesity is a major cause of cardiovascular risk, and microvascular changes and subclinical dysfunction should be considered to illustrate the underlying mechanisms and early identification, thereby developing targeted therapies. This study aims to explore the effect of obesity on myocardial microcirculation and left ventricular (LV) deformation in hypertensive patients by cardiac magnetic resonance (CMR).2 and 47 subjects with a BMI ≥25 kg/m2, as well as 55 age- and sex-matched controls with a BMI of 18.5–24.9 kg/m2. Myocardial perfusion indicators  and LV strains  were measured.This study comprised 101 hypertensive patients, including 54 subjects with a body mass index (BMI) of 18.5–24.9 kg/mP < 0.001), Max SI , longitudinal PSSR , and PDSR . Myocardial perfusion was independently associated with longitudinal PSSR  and longitudinal PDSR  in hypertension.Upslope was numerically increased in obese patients but statistically decreased in non-obese patients compared with controls. Longitudinal PS deteriorated significantly and gradually from controls to non-obese and obese hypertensive patients. Longitudinal PSSR and PDSR were significantly decreased in obese hypertensive patients compared with the other two groups. BMI was associated with upslope (β = −0.136, Obesity had adverse effects on microvascular changes and subclinical LV dysfunction in hypertension, and BMI was independently associated with both myocardial perfusion and LV deformation. Impaired myocardial perfusion was independently associated with subclinical LV dysfunction in hypertension. Hypertension and obesity are well-recognized global health concerns, and the two conditions often coexist –3. Both Cardiac magnetic resonance (CMR) imaging has been increasingly used to evaluate myocardial microcirculation and cardiac function with high reproducibility. First-pass CMR imaging allows non-invasive assessment of myocardial perfusion during the transit of contrast agent and has been increasingly used in recent years to detect microvascular dysfunction , 14. In Therefore, we aimed to evaluate myocardial microcirculation and LV function by CMR first-pass perfusion and CMR-FT imaging in hypertensive patients without or with obesity, as well as to explore the relationship between myocardial perfusion, LV strains and BMI.This study was approved by the Biomedical Research Ethics Committee of the West China hospital of Sichuan University  and was conducted in accordance with institutional guidelines. All patients gave their informed consent for contrast-enhanced CMR examination. All patient information was used only for research purposes.2), and poor image quality. Ultimately, 101 hypertensive patients  were included in the final analysis. Then, the hypertensive patients were categorized into two groups (without and with obesity) according to World Health Organization (WHO) BMI standards (2–24.9 kg/m2 (n = 54), and the hypertensive patients with obesity group comprised those with a BMI ≥25.0 kg/m2 (n = 47). For comparison, 55 age- and sex- matched controls  were identified though subjects who underwent contrast-enhanced CMR during the study period. All these individuals had BMIs of 18.5 kg/m2–24.9 kg/m2 and no evidence of hypertension. Moreover, the aforementioned exclusion criteria for the hypertensive group also applied to the control group. Demographic and clinical data within 1 month of the CMR examination were collected through a review of electronic medical charts.We retrospectively identified patients with essential hypertension from consecutive hospitalized subjects who underwent contrast-enhanced CMR for suspected cardiomyopathy at our hospital from January 2016 to May 2021. Hypertension was defined as clinical systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg or a previous diagnosis of essential hypertension or usage of antihypertensive medication. The exclusion criteria included coronary artery disease, myocardial infarction, severe arrhythmias, symptoms of heart failure or LVEF <50%, cardiomyopathy, severe valvular disease, congenital heart disease, diabetes diseases, estimated glomerular filtration rate (e-GFR) <30 ml/min, severe hepatopulmonary dysfunction, underweight BMI <18.5 kg/m.5 kg/m2,Cardiac magnetic resonance scans were performed on a 3.0 T whole-body scanner MAGNETOM Trio Tim . Patients were placed in the supine position with a dedicated two-element cardiac-phased array coil attached.A standard ECG-triggering device was simultaneously used. Localizers were used to determine the cardiac axes. To achieve complete and high-quality LV coverage, CMR images were acquired from the base to the apex during multiple breath-holding periods. To analyze cardiac function and myocardial strain, a balanced steady-state free-precession (bSSFP) sequence  was used to obtain 8–12 continuous cine images of the long-axis, short-axis, 2-chamber, and 4-chamber views. For perfusion imaging, a contrast dose of 0.2 ml/kg gadobenate dimeglumine  was injected into the right antecubital vein using an automated injector  at a flow rate of 2.5–3.0 ml/s, followed by a 20 ml saline flush at a rate of 3.0 ml/s. Resting perfusion images were acquired concurrently with intravenous contrast agents in three stand- and short-axis slices  and in one 4-chamber view slice by inversion-recovery echo-planar sequence . Each set of first-pass perfusion images was acquired in 80 cardiac cycles. To exclude myocardial infarction, late gadolinium enhancement (LGE) imaging was obtained at an average of 10–15 min after contrast injection by segmented-turbo-FLASH–phase-sensitive inversion recovery (PSIR) sequence .All CMR data were transferred to a dedicated software program  and measured by two experienced (at least 2 years of CMR experience) investigators blinded to the clinical profiles of the subjects. For measurement of left ventricular (LV) function parameters, we manually delineated the endocardial and epicardial contours in serial short-axis slices at the end-diastolic and end-systolic, and then left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular stroke volume (LVSV), LVEF and left ventricular mass (LVM) were calculated automatically. LVEDV, LVESV and LVM were indexed to body surface area . The LV remodeling index was calculated as LVM divided by LVEDV.For semiquantitative analysis of LV myocardial perfusion, we manually delineated the endocardial contours, epicardial contours, and a region of interest drawn in the LV blood pool in all of the first-pass perfusion images of the basal, mid and apical short-axis slices. A 16-segment mode (Bull’s eye plot) was constructed based on AHA standard segmentation recommendations, including six basal segments, six middle segments, and four apical segments . SubsequCardiac magnetic resonance feature tracking (CMR-FT) was used for the analysis of LV myocardial strain. We manually delineated the endocardial and epicardial contours in long-axis 2-chamber, 4-chamber, and serial short-axis slices at the end-diastole phase, which was the reference phase, in a 3-dimensional (3D) tissue tracking module. Then, the LV global myocardial strain parameters , peak systolic strain rate (PSSR), and peak diastolic strain rate (PDSR)) were acquired automatically.After 1 month, 30 patients  were randomly selected and LV strain and first-pass myocardial perfusion parameters were measured again by the same radiologist to evaluate the intraobserver variability. The parameters were measured again as above by a second blinded investigator to determine the interobserver variability.P-value <0.1 in the univariable analyses were entered into a stepwise multivariable linear regression analysis. The inter- and intraobserver variabilities for reproducibility were evaluated using the intraclass correlation coefficient (ICC). For all statistical analyses, a P-value <0.05 was considered statistically significant.All statistical analyses were performed with R version 3.6.3 . Continuous variables are presented as the mean ± standard deviation and categorical variables are presented as frequencies (%). The Kolmogorov–Smirnov test was used to assess the normality of the distribution of continuous variables. Normally distributed continuous variables among groups were compared by one-way analysis of variance (ANOVA) followed by the least-significant difference (LSD) test. Comparisons of non-normally distributed continuous variables among groups were performed by the Kruskal-Wallis rank test. Categorical variables were compared by the Chi-square test. Correlations between myocardial perfusion and LV strain parameters were analyzed by Pearson correlation analysis. Univariable linear regression analyses were performed to demonstrate the relationship between candidate factors and myocardial perfusion/LV strain parameters. Age, sex and variables with a P < 0.05). Office SBP and DBP were significantly higher in hypertensive patients with or without obesity than in controls ; office DBP was significantly higher in hypertensive patients with obesity than in those without obesity (P = 0.003). High-density lipoprotein (HDL) was significantly increased in hypertensive patients without obesity compared with the other two groups. Calcium channel blocker use was more common in obese patients than in non-obese patients (P = 0.014). No significant differences were found in in sex, age, heart rate or other laboratory data among the three groups. There were no significant differences in other medication usage or duration of hypertension between hypertensive patients with and without obesity.P < 0.05). LVMI was significantly higher in hypertensive patients than in controls (both P < 0.05). The LV remodeling index was gradually increased in non-obese and obese hypertensive patients compared with controls .As shown in P = 0.084; Max SI: 26.24 ± 7.96 vs. 23.26 ± 6.32, P = 0.073). Hypertensive patients with obesity had a significantly reduced upslope compared with the other two groups, and a significantly decreased Max SI compared with patients without obesity   , 2.P < 0.05). Longitudinal PSSR and PDSR were significantly decreased in hypertensive patients with obesity compared with the other two groups . In addition, circumferential PDSR was significantly decreased in hypertensive patients with obesity compared with controls (P = 0.005). No significant differences were seen in other parameters among the three groups.Longitudinal PS significantly and gradually deteriorated from controls to patients without obesity to patients with obesity  (P < 0.05). Univariable linear regression analyses between potential influencing factors and perfusion/strain parameters are shown in Among hypertensive patients, TTM was correlated with all strain parameters  . In addiP < 0.001, model R2 = 0.214; Max SI: β = −0.922, P < 0.001, model R2 = 0.172) and LV strains  in hypertensive patients . The association between BMI and longitudinal PSSR remained significant , while the association between BMI and PDSR was absent . In addition, multivariable linear regression analyses including both BMI and all perfusion parameters revealed that myocardial perfusion was significantly associated with longitudinal PSSR  and longitudinal PSDR  in hypertension  and LV deformation indicators (ICC = 0.850–0.977) .In this work, we used contrast-enhanced CMR and found that (1) myocardial perfusion was slightly increased in hypertensive patients without obesity but significantly decreased in hypertensive patients with obesity; (2) subclinical LV function gradually decreased from controls to hypertensive patients without and with coexisting obesity; and (3) myocardial microcirculatory damage was independently associated with subclinical LV dysfunction in hypertensive patients.The pathophysiology of cardiomyopathy related to obesity and hypertension is complex and multifactorial. Among these, microvascular abnormalities are an important disorder in both conditions with certain common pathological changes: endothelial dysfunction, microvascular remodeling and rarefaction . Some prAlthough a combined effect of obesity and diabetes on damage to myocardial microcirculation has been reported , whetherThe results of our study showed that hypertensive patients without obesity had significantly decreased strain values but preserved LVEF compared with control subjects, which confirmed the value of CMR-FT based myocardial deformation analysis in the detection of early and subtle LV dysfunction with previous studies , 27. A pPrevious epidemiologic studies have provided substantial evidence that obesity could worsen cardiac function , 32. If In addition, the occurrence of longitudinal and circumferential PDSR impairment in obese patients indicated an adverse effect of hypertension and combined obesity on subclinical diastolic dysfunction. Consistently, Kim et al.  demonstrMultivariable stepwise regression analysis revealed that BMI exerted negative impacts on both myocardial perfusion and LV function. The negative effect of BMI on longitudinal PSSR and PDSR indicated that BMI was an important factor influencing LV systolic and diastolic function. In addition, we found that BMI was significantly associated with longitudinal PS in model adjustment with perfusion with improved model fit. With the increase in BMI, LV hypertrophic remodeling was noticeably intensified in hypertensive patients. Although the association between BMI and longitudinal PDSR lost significance after correction for myocardial perfusion, we assume that BMI is more likely to be higher in patients with lower perfusion, which also shows more severe diastolic dysfunction. Considering that microcirculation damage and subclinical LV systolic and diastolic dysfunction are predecessors of poor outcomes, these results emphasize the clinical implications of the adverse effects of obesity and the importance of weight management for hypertensive patients.The present study found an independent association between TTM and longitudinal PSSR in hypertension, which is in accordance with previous evidence regarding diabetes by Liu et al. . ConsistThere are several limitations of this study. First, this is a retrospective single-center study with inherent limitations. Therefore, further large-scale, multicenter, prospective research is needed to validate our results. Second, patient BMI was measured before CMR, and the predisease BMI and dynamic changes in BMI were not recorded and discussed in this study. Further studies are warranted to investigate the impact of dynamic changes in BMI on myocardial microcirculation and cardiac function. Third, the present study assessed only myocardial perfusion at rest, since stress perfusion has contraindications and potential risks. However, even in the resting state, the additive effect of hypertension and obesity on myocardial microcirculation has been proven.Obesity had an additive deleterious effect on myocardial microcirculation and LV function in patients with hypertension, and BMI was associated with myocardial microcirculation and LV function. Impaired myocardial perfusion was associated with subclinical LV dysfunction in hypertensive patients. These results emphasize the adverse effects of obesity and the importance of weight management for hypertensive patients and may imply mechanistic perspectives that could help in early diagnosis and the development of therapeutic strategies, thus improving prognosis for hypertensive patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee on Biomedical Research, West China Hospital of Sichuan University. The patients/participants provided their written informed consent to participate in this study.P-LH: conceptualization, and writing—original draft. P-LH, X-ML, and W-FY: data curation. LJ, Y-KG, and YL: writing—review and editing. Z-GY and KL: supervision and writing—review and editing. Z-GY: funding acquisition. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pseudoaneurysm of inferior wall of the left ventricle is an uncommon complication of myocardial infarction with high mortality.We report the case of a 63-year-old Tunisian man, diagnosed with a thrombosed left ventricular pseudoaneurysm and a pericardial effusion after 1 week of angina.Left ventricular pseudoaneurysm is a serious complication of myocardial infarction that has atypical presentations. Diagnosis is generally established by transthoracic echocardiography but confirmed by magnetic resonance imaging. Urgent surgery is the treatment choice given the risk of embolization and rupture.The online version contains supplementary material available at 10.1186/s13256-021-02709-5. In ST-segment elevation myocardial infarction, time is muscle. Despite awareness campaigns and the introduction of primary percutaneous coronary intervention as the principal reperfusion strategy following acute ST-elevation myocardial infarction, patients are still presenting late, when complications are more frequent and prognosis is poorer.The mechanical complications of myocardial infarction are the most formidable and are accompanied by high mortality. Left ventricular pseudoaneurysm is a serious complication that can lead to heart failure, arrhythmia, distal embolization, and rupture of the left ventricular free wall. It is often associated with a significant mitral regurgitation and/or interventricular communication. Cardiac ultrasonography is a simple and reproducible tool that allows early detection of these abnormalities.We report the case of a smoking, diabetic, hypertensive 63-year-old Tunisian man, who consulted the emergency department for pericardial syndrome. During the investigation, we learned that angina had been present since one week, associated with nausea, but ignored by the patient. On admission, his blood pressure was 110/74 mmHg. Physical examinations revealed mesocardiac systolic murmurs. Electrocardiography showed a regular sinus rhythm at 75 beats per minute and Q wave necrosis in the inferobasal derivations Fig. a, b Adda, b (Addet al. [Rupture of the left ventricle wall is a fatal complication of myocardial infarction, with a significant hospital mortality of up to 80% . This coet al.  had theret al. . The Euret al. . In our et al. . It conset al. . There aet al. .LV pseudoaneurysm is a rare and serious complication of myocardial infarction. It should be suspected in post-infarction patients who have unexplained clinical signs, especially dyspnea or angina, regardless of the time of onset after the infarction. Transthoracic ultrasound is an easy and accessible test to confirm the diagnosis. Surgery is the mainstay of treatment but has high mortality. Long-term survival is also low.Additional file 1: Video 1a. Transthoracic echocardiography from apical two-chamber view showing a large pseudoaneurysm from the inferior and inferolateral wall of the left ventricle.Additional file 2: Video 1b. Transthoracic echocardiography from parasternal short axis view showing a large pseudoaneurysm from the inferior and inferolateral wall of the left ventricle and pericardial effusion.Additional file 3: Video 2a. Postoperative transthoracic echocardiography from apical two-chamber view showing left ventricular remodeling.Additional file 4: Video 2b. Postoperative transthoracic echocardiography from parasternal short axis view showing left ventricular remodeling.Additional file 5: Video 3a. 18-month follow-up transthoracic echocardiography from apical two-chamber view.Additional file 6: Video 3b. 18-month follow up transthoracic echocardiography from apical four-chamber view.


Arrhythmia device developments in 2021 provided long-awaited alternatives for stroke prevention in atrial fibrillation (AF) and both non-invasive and transcatheter enhancements to cardiac pacing. In brief, the Amulet™ device  was shown to be effective in preventing thromboembolism for patients in AF. Implantable loop recorders (ILRs) have shown that AF is highly prevalent even in the non-embolic stroke population. The Micra™ leadless pacemaker  was upgraded to enhance atrioventricular (AV) synchrony. Finally, cardiac resynchronization therapy (CRT) is being enhanced by the addition of pacing sites in multi-site pacing or altering the lead placement to activate the native conduction system in left bundle branch area pacing (LBBAP).We will review these developments, comment on future directions, and consider where these trials may have impacted current arrhythmia management in 2021.1 Carrying substantial morbidity and mortality from cardioembolic stroke, advances have allowed for durable rhythm control with catheter-based ablation, improved detection with expanding options for ILR monitoring, and non-pharmacologic alternatives to anticoagulation.3 The potential impact on reducing the overall health care burden of disabling or fatal AF-related stroke cannot be overlooked.AF is the most common arrhythmia, and its true prevalence remains underestimated due to the large number of asymptomatic patients.2DS2-VASc score, which informs consideration of risk-modifying therapy.4 Previously, only vitamin K antagonists (VKAs) were available to reduce the risk of embolic events; however, the more recently developed novel or more appropriately named direct oral anticoagulants beginning with dabigatran in 2010 have been shown to be non-inferior to VKAs and are indicated for the prevention of embolic events.5 Given the risks of long-term systemic anticoagulation, non-pharmacologic management of AF’s embolic risk has been investigated by the closure of the left atrial appendage (LAA). The first percutaneously inserted intracardiac LAA occlusion (LAAO) device brought to market was the Percutaneous Left Atrial Appendage Transcatheter Occlusion device in 2001; however, it was subsequently withdrawn in 2006.6 The Lariat® device  for epicardial closure of the LAA was approved in 2009 as a soft-tissue closure device but has not seen significant use in the United States (US).7AF confers an increased risk of embolic events stratified by the CHA9 The Watchman™ device is currently in its second-generation iteration as the Watchman™ FLX was shown to be safer to implant and provide higher complete seal rates with lower device-related thrombus (DRT) than its predecessor.10 Surgical closure of the LAA was long thought to be protective against embolic events, and the landmark trial Left Atrial Appendage Occlusion Study III (LAAOS III) confirmed this, though 75% of patients were continued on oral anticoagulation.11 Other minimally invasive LAAO devices are under investigation in the US to enhance patient–device match .The Watchman™ LAAO device  was shown to be non-inferior to VKAs in the Watchman™ Left Atrial Appendage Closure Technology for Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) and Evaluation of the Watchman™ Left Atrial Appendage Closure Device in Patients with Atrial Fibrillation vs. Long-term Warfarin Therapy (PREVAIL) trials, the US Food and Drug Administration subsequently approved it in 2015 as an alternative for oral anticoagulation.Circulation. The Amulet™ device is a self-expanding nitinol mesh lobe that is inserted into the LAA using 6–10 stabilizing wires and is connected to a polyester-covered disk that seals the LAA ostium. It is available in 8 different sizes with a minimum LAA depth of 12 mm.12 In comparison, the Watchman™ device is a self-expanding nitinol frame semi-covered by a polyethylene terephthalate membrane fabric held in by 10 anchors, while the Watchman™ FLX is fully covered by the membrane fabric with 12 anchors.12 The Amulet IDE trial randomized 1,878 patients in an intention-to-treat analysis to either the Watchman™ 2.5 device or Amulet™ device. The Amulet™ device was shown to be as effective as Watchman™ in the composite outcome of stroke, systemic embolism, or cardiovascular/unexplained death . The procedural complications were higher in the Amulet™ group (4.5% vs. 2.5%) and more frequent with early case numbers consistent with an operator learning curve. The overall safety of the 2 devices was otherwise similar.12This year, the results of the Amplatzer™ Amulet™ Left Atrial Appendage Occluder IDE Trial  against the first-generation Watchman™ 2.5 device were published in 9 The Amulet IDE trial defined technical device success as a peri-device jet of less than 5 mm, which occurred in 96% of Amulet™ cases and 94.5% of Watchman™ cases, with a complete occlusion rate of 63% for the Amulet™ occluder and 46.1% for the Watchman™ device.12 The Protection Against Embolism for Nonvalvular Atrial Fibrillation Patients: Investigational Device Evaluation of the Watchman™ FLX Left Atrial Appendage Closure Technology (PINNACLE-FLX) trial of the Watchman™ FLX device similarly showed a peri-device leak of less than 5 mm in 100% of patients, with 7.4% having a residual leak between 0 and 5 mm.10 It has, however, been shown that a residual leak of even 3 mm or beyond confers an increased risk of embolic events, and more study is needed to determine if the Amulet™ does provide a better seal.13With its 2-part construction and dual-seal mechanism, the Amulet™ device hopes to produce a better seal and therefore total LAAO. A well-seated device with the absence of an LAAO flow leak of 5 mm or greater has been shown in the long-term follow-up of the PROTECT-AF participants to be as protective as VKAs for stroke, embolism, and death.12 While no differences in non–procedure-related major bleeding were reported, the higher rate of complete immediate closure might be of clinical importance in patients who require rapid de-escalation from full anticoagulation. The novel design of the Amulet™ device also allows clinicians to better select a device to meet the anatomic needs of their patient’s LAA. It can accommodate shallower LAAs that would otherwise have deferred Watchman™ style devices and placed the patient on anticoagulation. Additionally, coverage of the large proximal posterior lobes and pits on the pulmonary vein–LAA ridge is more likely with Amulet™. Pericardial effusion rates in the first 30 days post-LAAO with Amulet™ were balanced by lower DRT rates despite a dual antiplatelet therapy-only post-implant regimen in the majority of subjects. Direct comparisons of Watchman™ FLX to Amulet™ as regards complete LAA closure by computed tomography angiography versus transesophageal echocardiography support a comparable occlusion rate. Real-world evidence of Amulet™ use in the US following commercial launch is needed as operator experience ramps up .The increased rate of complete occlusion at the time of the procedure allowed more patients who received the Amulet™ occluder to be discharged off anticoagulation; however, at 9 months of follow-up, most patients from both groups were off anticoagulation.14 The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) also included a cohort of patients with atrial chamber leads and detected atrial tachyarrhythmias of more than 6 minutes in 10.1% of patients over a 3-month monitoring period. When followed for a mean of 2.5 years, those patients with a subclinical atrial tachyarrhythmia that was detected in the monitoring period were found to have an increased rate of ischemic strokes and systemic embolisms.15 Screening and Optimising Stroke Prevention in Atrial Fibrillation (SOS-AF) study of implanted devices identified 43% of patients with at least five minutes of AF over a mean follow-up of 2 years and correlated even five minutes of AF with an increased stroke risk.16 The Registry of Atrial Tachycardia and Atrial Fibrillation Episodes (RATE) prospective cohort of St. Jude devices found a 50% incidence of AF defined as ≥3 ectopic atrial beats, with an episode length of 20 seconds or more being associated with an increased risk of stroke.17 All of these studies are potentially confounded by the highly selected study populations that at baseline had elevated CHADS2 scores .17The incidence and duration of AF and its role in cardioembolic strokes have been one of intense investigation. The TRENDS study, which was an observational study of patients receiving a pacemaker or defibrillator device with an atrial lead, found an incidence of any atrial arrhythmia of 47% over a mean follow-up of 1.4 years, with an increased risk of thromboembolic events with increased duration (>5.5 hours) of atrial arrhythmia.18 Both cohorts also had elevated mean CHADS2 scores of 3 points in the ILR arm and 2.9 points in the usual care arm.18 The Post-embolic Rhythm Detection with Implantable Versus External Monitoring (PER DIEM) trial also randomized patients with a median CHA2DS2-VASc score of 4 points to ILR or 4 weeks of external cardiac monitoring and found more than 2 minutes of AF in 15.3% of the ILR arm and 4.7% of the external monitor arm.19 This led to guidelines recommending long-term cardiac monitoring following a cryptogenic stroke.4Recent studies have taken advantage of the improvements in safety, longevity, and clinical use of ILRs to better clarify the relationship of AF and stroke. The Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL-AF) trial randomized patients with cryptogenic strokes to ILR versus usual care and reported an AF incidence of 8.9% in patients with ILRs versus 1.4% found by usual care.2DS2-VASc score of five points were randomized in the acute post-stroke period to an ILR or usual care. AF of longer than 30 seconds was detected in 12.1% of patients with an ILR over the course of 12 months compared to 1.8% of patients receiving usual care, with most events occurring beyond 30 days post-stroke. Post-hoc analysis showed that 67% of patients with detected AF were started on anticoagulation and that placement of an implantable cardiac monitor was associated with a non-significant reduction in recurrent ischemic or hemorrhagic stroke.20The STROKE-AF trial published this year looked to determine if the incidence of AF was different in patients with small and large vessel strokes. A total of 492 patients with a mean CHA2DS2-VASc score that predispose to both stroke and AF. The CRYSTAL-AF and PER DIEM trials sought to establish the role of extended cardiac monitoring for AF in the setting of cryptogenic stroke; however, STROKE-AF showed that, even in non-embolic small vessel strokes, the incidence of AF was elevated. ILRs are effective at detecting AF; the question remains as to who needs to have AF detected.Further work is still needed to elucidate the pathophysiologic role of AF and stroke. AF is clearly associated with an increased risk of stroke; however, every study has been confounded by the shared risk factors of the CHA2DS2-VASc scores but without the clinical events of AF or stroke to see if early detection and treatment modify outcomes. The present evidence, and especially the similarity of AF detection rates between CRYSTAL-AF and STROKE-AF, remains confounded by the similarity of stroke and AF risk factors and calls into question the limited use of ILRs in the stroke population.Future studies need to look at the prospective use of ILRs to detect AF in populations with elevated CHA21Since the implantation of the first myocardial electrodes connected to a pulse generator in 1958, implantable cardiac pacemakers have undergone numerous innovations culminating in the multifunctional devices in use today.22 It has continued to function well and has been shown to have reduced rates of complications compared to transvenous pacemakers.24 However, its use is limited as a single-chamber pacing system as it lost the benefits of AV synchrony. A downloadable algorithm was designed and implemented in a prospective cohort with complete AV block to assess if AV synchrony could be added to device functionality in the Micra™ Atrial Tracking Using a Ventricular Accelerometer (MARVEL)-2 trial this year. The algorithm made use of the Micra™ device’s accelerometer to detect atrial filling and atrial kick to better time the ventricular stimulus. Following the download, the percentage of patients with synchronous AV pacing measured by surface Holter monitors increased from 26.8% to 89.2%. This translated to an increase in left ventricular (LV) stroke volume measured on echo.25 This represents an important proof of principle that a leadless ventricular pacemaker can achieve significant AV synchrony. While persistent AV dyssynchrony is a clear alteration of normal cardiac hemodynamics, trials are mixed as to whether there is a difference in outcomes apart from pacemaker syndrome with single-lead pacing versus dual-chamber pacemakers.26 To date, there is no clear minimum threshold of AV pacing to avoid the development of pacemaker syndrome; however, it is possible that some minimum amount of synchrony might avoid it even if not 100% synchronous. The development of Micra™ AV devices that restore a high percentage of AV synchrony might prevent the development of pacemaker syndrome, adding another advantage to the Micra™ or Micra™ AV system over traditional single-lead pacemakers. See Figure 2.The Micra™ single-chamber pacemaker  was introduced in 2016 as an alternative to single-lead pacemakers for VVI pacing.29 The current recommendations suggest the use of BiV CRT if the QRS duration is more than 150 ms with a left bundle branch block morphology.30 However, some patients will not respond to CRT even in normal sinus rhythm with more than 95% paced beats, which has posed a clinical dilemma. To address this issue, 2 novel pacing schemes have been published this year: MSP and LBBAP.CRT uses an atrial lead and 2 ventricular leads (right ventricle [RV] and coronary sinus [CS]) to recreate the normal cardiac cycle by stimulating atrial and then biventricular (BiV) contraction. The Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial, Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT), and Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) all showed benefit with CRT pacing in patients with reduced ejection fractions, symptoms of heart failure, and wide QRS complexes.33 Small trials showed mixed results of TriV pacing on symptoms but did consistently lead to improved echocardiographic function.36 Although promising, CRT using TriV pacing was limited by the era of devices it was investigated in, as devices only had 2 ventricular ports necessitating the use of a Y connector, which resulted in large current draws due to a drop in impedance.37 Quadripolar leads, first introduced in 2010 under the IS-4 connection standard to increase pacing configurations via “electronic repositioning,” allow for single-lead MSP. MSP via quadripolar leads has been shown to be safe and effective in improving LV function, but comparative effectiveness data have been lacking.41 The MultiPoint Pacing trial, a 6-month randomized trial of MSP via a quadripolar lead versus traditional BiV pacing, showed improved cardiac function and clinical outcomes with MSP.42 This year, the SMART-MSP trial randomized CRT non-responders to MSP or traditional BiV pacing and showed that 51% of non-responders had an improvement in a clinical composite score of mortality, heart failure events, New York Heart Association assessment, and a global symptom assessment with a minimal reduction in battery life.43 MSP via quadripolar leads is an exciting development in the use of CRT because it requires no change in technique for existing operators, the leads are already in use, and patients can realize an upgrade without any change in hardware.The concept of MSP first began with the use of triple ventricular (TriV) site pacing, utilizing either 2 RV leads and 1 CS lead or 1 RV lead and 2 CS leads.45 The Left Bundle Branch–Optimized Cardiac Resynchronization Therapy (LOT-CRT) trial was a feasibility study using a lead setup with a pacing CS lead, a defibrillation coil-only RV lead, and a pacing left bundle branch area (LBBA) lead in patients with a CRT indication. The LBBA lead was screwed across the septum approximately 1.5 to 2 cm distal to the His bundle to stimulate the left bundle branch. CRT utilizing the CS and LBBA leads in 91 patients resulted in a significantly narrower QRS complex compared to traditional BiV CRT pacing and LBBAP alone . This corresponded to an increase in mean the LV ejection fraction from 28.5% to 37.2%, with additional improvements in the LV end-diastolic and end-systolic parameters.46 LBBAP holds several advantages over HBP, including indifference for the development of AF, which might be oversensed by HBP; preservation of lead ports for future implantable cardiac defibrillator upgrade; and early LV septal endocardial activation to bypass any potential disease of the conduction system.LBBAP seeks to utilize the native conduction system to achieve more efficient ventricular stimulation. Prior work has shown that His-bundle pacing (HBP) was an effective strategy to achieve more efficient and synchronous ventricular capture.CRT targeting more coordinated ventricular resynchronization using MSP and LBBAP seeks to improve outcomes for patients with heart failure. However, though it mechanistically fits that improvements in cardiac conduction will translate to better outcomes, further work is needed. Trials involving frontline use of MSP and LBBAP for CRT are needed to determine if the improvements in coordinated ventricular stimulation using these novel pacing techniques give an additional advantage over CRT or if simply achieving CRT is the deterministic outcome.This year has been another one marked by landmark developments in cardiac devices. The Amulet™ device offers immediate LAAO and is as effective as the Watchman™ device. ILRs are being increasingly deployed to unravel the link between AF and stroke. The Micra™ single-chamber leadless pacemaker was upgraded to have increased AV synchrony (Micra™ AV). Finally, CRT is being enhanced by adding additional pacing sites in MSP or altering the lead placement to activate the native conduction system in LBBAP. While further work is needed, these devices are already changing practice and will be coming increasingly into use as those additional trials are completed.


Allograft failure secondary to rejection commonly requires a multimodal treatment, ultimately including mechanical circulatory support. A few case reports have demonstrated the use of Impella-devices due to its assumed favorable safety profile in this fragile cohort. However, this treatment option does not play a role in choice of anti-rejective therapy in clinical routine up to date. We summarize our institutional experiences and literature mini-review on Impella-based treatment strategies in allograft rejection after heart transplantation. In all seven cases, three from our institution and four reported in the literature, Impella-based therapies led to hemodynamic stabilization in allograft failure secondary to rejection. Adverse events included hemolysis, non-fatal bleeding and in one patient a relevant aortic valve insufficiency occurred. All patients showed an improvement of allograft function. Two patients died in context of severe immunosuppression or late secondary organ failure. Based on the limited available data, we propose that Impella-mediated mechanical unloading represents a valuable option for hemodynamic stabilization in severe allograft failure due to rejection, enabling an initiation of causal therapy and thereby potentially representing an opportunity to prevent mortality. Furthermore, we hypothesize it might add to the traditional therapeutic approaches by facilitating recovery by decompressing the myocardium in allograft rejection. Allograft failure (AF) due to rejection is one of the leading causes of mortality after orthotopic heart transplantation (OHT) . TemporaWe report three cases of late AF due to acute rejection (AR) in which we applied mechanical unloading in a bridge-to-recovery strategy and present a mini-review of the literature. The data were analyzed retrospectively according to the approval by the local ethics committee.All patients presented with cardiogenic shock in the context of late AF due to AR differing in acuity of onset. Patient 1 was previously treated with immunosuppressant therapy including tocilizumab, which has been described once by January et al. , and was® pumps  were inserted via 10 mm Gore-Tex-vascular-grafts anastomosed to the axillary artery. The longest duration of Impella support provided was 44 days. In this patient, myocardial recovery enabled a MitraClip procedure, which was performed under Impella support.Impella5.5Our weaning considerations were based on echocardiographic investigations with a stepwise, temporary reduction of the support by decreasing the pump flow. Left and right ventricular ejection fractions, dimensions, heart valve regurgitations and hemodynamics were carefully assessed.Ultimately, LV functions partially recovered from 0–15 to 30–40% in all patients and we observed no severe complications. In one patient dislocation of the Impella into the aortic-root and hemolysis occurred, prompting device exchange. Eventually, two patients died after partial myocardial recovery. Patient 2 was discharge home after 44 days of PROPELLA-therapy; the left ventricular ejection fraction was 41% in a routine follow-up visit 9 months after discharge.In the described life-threatening constellations of all three patients, rapid installation of cardiopulmonary support was crucial for hemodynamic stabilization and enabled an initiation of anti-rejective therapies with a consecutive partial recovery of LV function.We observed no severe complications, which was in line with the current body of the literature: a most recent clinical trial comparing ECMO and Impella in non-transplanted patients showed significantly less complications and better mid-term outcomes in the Impella-cohort. Additionally, these patients required less transfusion, a noteworthy aspect for transplanted patients reducing the risk of an induction or an increase in humoral sensitization .® or Impella5.0® pumps have been described in four single case reports in adults after OHT with early or late AF secondary to humoral or cellular rejection in a bridge-to-recovery strategy [® for RV support for 2–14 days. The hemodynamic stabilization allowed an initiation of intense antirejection medication including methylprednisolone combined with antithymocyte globulin (in case of cellular rejections) or plasmapheresis, intravenous immunoglobulin and rituximab   were recently described in two case series of pediatric transplanted patients with a comparable profile of adverse events, including bleeding, hemolysis and femoral arterial dissection , 10.Our experiences and the mini-review of literature lead us to assume that an Impella-mediated circulatory support represents a valuable treatment option for hemodynamic stabilization, enabling an initiation of causal therapy, which leads to an allograft recovery and possibly prevents mortality. In the future, a preventive approach with lowering the threshold for the decision of initiating LV decompression and opening up for a shift in concept of early mechanical circulatory support, for example, before onset of secondary organ failure, is potentially conceivable in allograft rejection. However, large-scale clinical research and evidence is needed to confirm these hypotheses.


Objective: This study aimed to: (1) evaluate the association between myocardial fibrosis (MF) quantified by extracellular volume fraction (ECV) and myocardial strain measured by two-dimensional (2D)- and three-dimensional speckle-tracking echocardiography (3D-STE) and (2) further investigate which strain parameter measured by 2D- and 3D-STE is the more robust predictor of MF in heart transplant (HT) recipients.Methods: A total of 40 patients with HT and 20 healthy controls were prospectively enrolled. Left ventricular (LV)-global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were measured by 2D- and 3D-STE. LV diffuse MF was defined by cardiovascular magnetic resonance (CMR)-ECV.Results: The HT recipients had a significantly higher native T1 and ECV than healthy controls . The 3D- and 2D-STE-LVGLS and LVGCS were lower (p < 0.005) in the HT recipients than in healthy controls. ECV showed a moderate correlation with 2D-LVGLS  and 3D-LVGLS , but it was not correlated with 2D or 3D-LVGCS, or LVGRS. Furthermore, 3D-LVGLS and 2D-LVGLS had a similar correlation with CMR-ECV . A separate stepwise multivariate linear analysis showed that both the 2D-LVGLS  and 3D-LVGLS  were independently associated with CMR-ECV.Conclusion: CMR marker of diffuse MF was present in asymptomatic patients with HT and appeared to be associated with decreased myocardial strain by echocardiography. Both the 2D- and 3D-LVGLS were independently correlated with diffuse LVMF, which may provide an alternative non-invasive tool for monitoring the development of adverse fibrotic remodeling during the follow-up of HT recipients. Heart transplant (HT) is the most effective treatment for patients with end-stage heart failure . The outHistological biopsy is the gold standard for the assessment of MF, but it is invasive and not practical for serial follow-up after HT. Besides, the biopsied region only reflects the local pathological information and cannot quantify diffuse MF. However, numerous studies have validated that diffuse MF can be measured non-invasively by extracellular volume fraction (ECV) that was derived from cardiovascular magnetic resonance (CMR) in various cardiovascular diseases –13. FurtTherefore, this study aimed to: (1) evaluate the association between MF and myocardial strain measured by 2D- and 3D-STE and (2) further investigate which strain parameter measured by 2D- and 3D-STE is the more robust predictor of MF defined by CMR-ECV in HT recipients.n = 6) and arrhythmia (n = 4). The remaining 40 patients were included in the final analysis. Demographic data including sex, age, height, and weight at the time of echocardiographic examination were obtained. Clinical data including recipient age, weight at HT, bypass time, ischemia time, donor age, weight, and history of AR and CAV were collected from a medical record review. Additionally, 20 healthy volunteers with a similar distribution of sex and age to the HT group were recruited as the control group. They had no history of hypertension, diabetes mellitus, renal failure, or other organic diseases based on physical examinations, biochemical tests, ECG, and echocardiography that were enrolled as a control group.A total of 50 asymptomatic patients with HT who were scheduled for echocardiogram at their routine follow-up examinations were prospectively enrolled in this study. As myocardial edema due to inflammation can expand the extracellular volume and increase native T1 times, patients with acute rejection (AR) at the time of recruitment were excluded. Patients with the following conditions were also excluded: time after HT <6 months, left ventricular ejection fraction (LVEF) <50%, significant coronary allograft vasculopathy (CAV), uncontrolled hypertension, uncontrolled blood glucose, renal failure, arrhythmia, and poor image quality. There were 10 patients excluded due to poor echocardiographic image quality  with S5-1 and X5-1 transthoracic echocardiography transducers. Four heartbeat images were collected and stored in digital format. All the echocardiographic parameters were acquired according to the published guidelines . LV diamThe 2D myocardial strain was performed on the 2D cardiac performance analysis 1.2 software  in the 2D echocardiographic images with a frame rate of 50–70 MHz. LV longitudinal strain was determined by endocardial tracing in the apical four-, three-, and two-chamber views. LV circumferential and radial strain were measured by endocardial tracing in the basal, middle, and apical level of LV short-axis views on a frame-by-frame basis during one cardiac cycle. If the tracking was suboptimal, manual adjustment was performed. The LV global longitudinal strain (LVGLS), LV global circumferential strain (LVGCS), and LV global radial strain (LVGRS) were defined as the average peak strain values automatically generated from the 16 segmental strain curves by the software .The 3D-STE was performed on the four-dimensional (4D) LV-Analysis 3.1 Software  in the 3D LV full-volume images with frame rate of 19–23 MHz. After selecting the center of the mitral annulus line and the apex of the left ventricle at end-diastole, the workstation would track the LV endocardium automatically and the manual adjustment was performed in case of unsatisfactory tracking. The same procedure was performed at the end-systolic frame. Subsequently, the software would perform the 3D-STE throughout the cardiac cycle. Ultimately, the 3D-LV-end-diastolic volume (EDV), end-systolic volume (ESV), LVEF, and the myocardial strain would be generated automatically. LVGLS, LVGCS, and LVGRS, respectively, were calculated as the average peak systolic longitudinal, circumferential, and radial strain of all the 16 LV segments . Subject2; matrix, 256 pixels × 205 pixels; and flip angle, 80°. T1 mapping was performed on three standard LV short-axis slices before and 15 min after the administration of a bolus of gadopentetate dimeglumine contrast agent  by using a modified Look-Locker inversion recovery (MOLLI) sequence with a 5- and 3-sampling scheme. The typical MOLLI sequence parameters were: TR/TE, 255.76/1.01 ms; slice thickness, 8 mm; matrix, 144 × 256 pixels; flip angle, 35°; and scan time, 11 s. The parameters of postcontrast T1 were similar to those of the native T1, except for a TE of 1.12 ms and a TR of 359.76 ms. Image acquisitions at LV basal, middle, and apical short-axis slices in diastole were performed before and 15 min after the injection of gadolinium, respectively.Cardiovascular magnetic resonance imaging was performed with a 1.5-Tesla system . CMR examination was performed within 24 h of the echocardiography examination. Three long axes and a set of contiguous short-axis cine images of LV were acquired with a steady-state free precession sequence during breath-hold of 10–15 s. The cine image parameters were as follows: repetition time (TR)/echo time (TE), 38.09/1.21 ms; slice thickness, 8 mm; field of view, 340 × 255 mmCardiovascular magnetic resonance data were analyzed with a commercial software  by an experienced reader blinded to the echocardiographic results. Regions of interest were drawn in the blood and a midwall region of the myocardium and copied between the pre- and postcontrast T1 and ECV maps. To measure the T1 value of blood, a circular region of interest was positioned in the LV cavity, avoiding papillary muscle . Then, tTo evaluate the reproducibility of 2D-STE and 3D-STE measurements, a total of 20 subjects  were selected randomly. For intraobserver variability, analysis of the first 2D-STE and 3D-STE data set of the 20 subjects  was repeated 2–4 weeks later by the same primary investigator. For interobserver variability, the data set was analyzed by two blinded investigators.t-test or the Mann–Whitney U-test was used to compare continuous variables and the chi-squared test or the Fisher's exact test was used to compare categorical variables between the HT and control group. Correlations between continuous variables were evaluated with the Pearson's correlation coefficients. Potential predictors  of ECV in HT recipients were identified by the univariate linear regression analysis. The variables with univariate p < 0.10 were included in the multivariate linear regression analysis. To avoid collinearity issues, the multivariate stepwise linear regression analysis for 2D-LVGLS and 3D-LVGLS (model 1 for 2D-LVGLS and model 2 for 3D-LVGLS) was performed separately, along with those echocardiographic and clinical variables that demonstrated a univariate p < 0.10. The interobserver and intraobserver variability of the 10 HT recipients and 10 healthy volunteers were assessed by the intraclass correlation coefficients (ICCs) and the Bland–Altman analyses. Comparison of correlation coefficients was performed with the MedCalc version 19.0.4 . All the statistical analyses, except for the comparison of correlation coefficients, were performed with SPSS Statistics version 23.0 . p < 0.05 was considered as statistically significant.Continuous variables are presented as mean ± SD or median [interquartile range (IQR)] and categorical variables are presented as absolute numbers (percentages). The unpaired two-sample The baseline clinical characteristics of the 40 patients with HT are given in p = 0.008), but remained within the normal range. However, HT group showed impaired 2D-LVGLS, 2D-LVGCS, 3D-LVGLS, and 3D-LVGCS. In contrast, the two groups did not differ in 2D- and 3D-LVGRS. Moreover, a weak to moderate but significant correlation of global strain values between the 2D- and 3D-STE was noted in the entire study population  (p < 0.001) and greater ECV .Comparisons of echocardiographic and CMR parameters in the 40 patients with HT and 20 healthy controls are shown in < 0.001) . There wr = 0.53, p = 0.002), whereas LVGCS and LVGRS showed no correlation with ECV. r = 0.60, p < 0.001) and not had correlation with 3D-LVGCS or 3D-LVGRS. Moreover, 3D-LVEF did not correlate with CMR-ECV. Furthermore, there was no significant difference between the correlation of 2D-LVGLS with CMR-ECV and the correlation of 3D-LVGLS with CMR-ECV .The diffuse LVMF was defined by CMR-ECV in this study. The correlations between LV myocardial strain and CMR-ECV are shown in r = 0.57, p < 0.001) (p = 0.019) and 3D-LVGLS  both were independently associated with CMR-ECV.< 0.001) . TherefoThe measurements obtained by 2D-STE and 3D-STE showed excellent reproducibility. The complete data of interobserver variability and intraobserver variability were shown in To the best of our knowledge, this is the first study to evaluate the level of diffuse LVMF with non-invasive CMR-ECV, further investigating the predictive value of 3D-STE-derived LV strain for diffuse LVMF in patients with post-HT, and directly compares its utility with that of 2D-STE-derived strains. The main findings of this study were: (1) the level of diffuse MF defined by CMR-ECV was higher even in asymptomatic patients with HT than in healthy controls; (2) the increased LVMF measured by CMR-ECV was correlated with 2D- and 3D-LVGLS, not correlated with LV-GCS, GRS, or ejection fraction (EF); and (3) both the 2D- and 3D-LVGLS were independently correlated with the extent of diffuse LVMF in HT recipients.The MF is a commonly demonstrated histopathologic feature in patients with HT and its correlation with a higher risk of adverse clinical outcome has been validated by the previous studies –5. AdverHistological biopsy is the gold standard for assessing MF, but it is invasive. The myocardial samples by the biopsy cannot accurately assess the diffuse MF. Furthermore, the endomyocardial biopsy is usually performed from the right ventricular side in the transplanted hearts and, thus, can not necessarily reflect LV information . RecentlThe echocardiographic myocardial strain can accurately quantify ventricular mechanical function and it has emerged as a promising modality for predicting MF non-invasively and conveniently , 15. HowThis study showed that CMR-ECV both correlated with the 2D- and the 3D-LVGLS. A possible mechanism linking ECV to reduced systolic strain may be that the increased fibrosis leading to increased LV stiffness, which resulted in reduced end-diastolic muscle fiber length and, by the Frank–Starling law, reduced cardiac muscle contraction and systolic strain. The significant correlation between MF and GLS in the HT recipients in this study is in agreement with previous studies for other cardiovascular diseases , 16, 28.Theoretically, compared with 2D-STE, 3D-STE is not affected by geometric modeling and out-of-plane motion, and it can evaluate the myocardial deformation in all the three spatial dimensions , 31. HowThis study proved that the level of diffuse MF defined by CMR-ECV was higher even in asymptomatic patients with HT than in healthy controls. Since MF is an adverse pathologic remodeling and can result in poor clinical outcomes, a reliable non-invasive method to monitor graft fibrosis would be clinically effective for the early identification of higher risk of patients with HT. This study showed that both 2D- and 3D-LVGLS were independently correlated with diffuse MF in HT recipients. Considering the correlation between 2D-STE or 3D-STE derived strain and MF is not robust and only presents up to 36% variations of MF. Therefore, CMR and cardiac biopsy cannot be replaced by these echocardiography modalities. Still this study suggested that measurements of 2D- and 3D-LVGLS may provide a valuable preliminary alternative non-invasive assessment of MF in the transplanted hearts, which may facilitate early risk stratification of HT recipients during follow-up examinations.This study is a single-center study and is limited by a relatively small sample size. The HT recipients with AR and CAV at the time of CMR were not included in this study. So, the range of diffuse MF in this study was relatively narrow. In addition, there were no results of the histological biopsy in this study. . Moreover, 3D-STE is highly independent of image quality and its frame rate was lower. Last, as the strain parameters are vendor dependent and not interchangeable, our results may not apply to other software algorithms.This study showed that CMR marker of diffuse MF was present in asymptomatic patients with HT and it was correlated with the 2D- and the 3D-LVGLS, not with LVGCS and LVGRS by echocardiography. The findings highlight the clinical superiority of the 2D- and the 3D-LVGLS over LVGCS, LVGRS, and other conventional parameters in predicting diffuse MF in HT recipients. 2D- and 3D-LVFLS may provide noninvasive tools for monitoring the development of adverse fibrotic remodeling during the serial follow-up of HT recipients.The raw data supporting the conclusions of this article will be made available by the corresponding authors, without undue reservation.This study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.WS, BL, LZ, and MX: conception and design of study. WS, XS, JW, SZ, YZ, CW, YX, and YY: acquisition of data. WS, XS, JW, ND, GW, YL, and QL: analysis and/or interpretation of data. JW, BL, LZ, and MX: revised the manuscript. WS, XS, and JW: drafting the manuscript. QL, BL, LZ, and MX: revising the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version.This study was supported by the National Natural Science Foundation of China  and the Key Research and Development Program of Hubei (Grant Number: 2020DCD015).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.


Cardiovascular magnetic resonance (CMR) cine imaging by compressed sensing (CS) is promising for patients unable to tolerate long breath-holding. However, the need for a steady-state free-precession (SSFP) preparation cardiac cycle for each slice extends the breath-hold duration  to an impractical length. We investigated a method reducing breath-hold duration by half and assessed its reliability for biventricular volume analysis in a pediatric population.Fifty-five consecutive pediatric patients  referred for assessment of congenital heart disease or cardiomyopathy were included. Conventional multiple breath-hold SSFP short-axis (SAX) stack cines served as the reference. Real-time CS SSFP cines were applied without the steady-state preparation cycle preceding each SAX cine slice, accepting the limitation of omitting late diastole. The total acquisition time was 1 RR interval/slice. Volumetric analysis was performed for conventional and “single-cycle-stack-advance” (SCSA) cine stacks.p = 0.37).Bland–Altman analyses [bias (limits of agreement)] showed good agreement in left ventricular (LV) end-diastolic volume (EDV) [3.6 mL ], LV end-systolic volume (ESV) [1.3 mL ], LV ejection fraction (EF) [0.1% ], right ventricular (RV) EDV [3.5 mL ], RV ESV [− 0.23 mL ], and RV EF  with a trend toward underestimating LV and RV EDVs with the SCSA method. Image quality was comparable for both methods (LV and RV volumetric parameters agreed well between the SCSA and the conventional sequences. The SCSA method halves the breath-hold duration of the commercially available CS sequence and is a reliable alternative for volumetric analysis in a pediatric population.• Compressed sensing is a promising accelerated cardiovascular magnetic resonance imaging technique.• We omitted the steady-state preparation cardiac cycle preceding each cine slice in compressed sensing and achieved an acquisition speed of 1 RR interval/slice.• This modification called “single-cycle-stack-advance” enabled the acquisition of an entire short-axis cine stack in a single short breath hold.• When tested in a pediatric patient group, the left and right ventricular volumetric parameters agreed well between the “single-cycle-stack-advance” and the conventional sequences. Left ventricular (LV) volumes and ejection fraction (EF) are the most widely used markers of cardiovascular outcome , 2. TheyThe standard volumetric assessment by CMR requires acquisition of 10–12 short-axis (SAX) steady-state free-precession (SSFP) cines with retrospective triggering and separate breath holds (BHs) . ConventWhen multiple cine SSFP slices are obtained in one breath hold, SSFP “stabilization” for the next slice lasting a whole cardiac cycle is generally applied –25. For We applied a minor modification to the commercial multi-slice real-time CS sequence by omitting each SSFP stabilization cardiac cycle before acquiring each SAX cine slice. This modification named “single-cycle-stack-advance” (SCSA) reduced the total time required for the SAX cine stack to 1 RR interval per slice. End-diastolic measurement of each slice was obtained at the R-wave, circumventing the shortcoming that prospective cine acquisition omits late diastole. An important difference of this modification is that slice stabilization for the next slice occupies the late diastole of the previous cycle, so the real-time cine frame obtained at the R-wave has already experienced at least partial SSFP stabilization. This work aimed to investigate the feasibility of the SCSA method in a clinical setting and assessed its reliability for biventricular volume analysis in a pediatric patient population.We enrolled 55 consecutive pediatric patients referred for CMR from July 2018 to March 2019. Clinical CMR protocols included both standard and SCSA SAX cine stacks. This work was prospectively registered as an audit in the Royal Brompton Hospital clinical audit register , and parents provided written informed consent for teaching and research use of anonymized images. The exclusion criteria were general MRI contraindications including claustrophobia and invasively ventilated patients.fit Siemens Healthineers), the conventional SSFP SAX cine stack was acquired as for standard clinical CMR as widely described in the literature and using GRAPPA with 46 reference lines acquired during each BH [With conventional ECG gating and array coils at 1.5 T  by a single CMR experienced cardiologist . Papillary muscles and LV/RV trabeculations were included in the myocardial mass calculation and excluded from the blood volume [LV and RV volumetric analysis and LV mass measurements were performed for conventional and SCSA SAX cine stacks using cvid volume . Volumesd volume . Accordith–75th percentile) values were reported for variables which were not distributed normally. Categorical data are shown in frequencies and percentages. The standard multiple-BH and the single-BH real-time SCSA techniques were compared using Bland–Altman and linear regression analyses. Variability % was calculated as the absolute difference between the two measurements divided by the mean of the two measurements. Spearman rank correlation was also applied, and the Wilcoxon signed-rank test was used to compare differences between volumetric analysis parameters obtained by two methods. Intra- and interobserver reproducibility was assessed by the interclass correlation (ICC) method. Differences in image quality scores between the standard multiple-BH and single-BH real-time SCSA technique were explored using the Wilcoxon rank-sum test. Values of p < 0.05 were considered statistically significant. Stata software  was used for statistical analysis.Continuous variables were tested by the Kolmogorov–Smirnov test for normality of distribution. Variables meeting normality were reported as mean ± SD. Median (25The demographic characteristics of the study population are presented in Table p = 0.37), while, interestingly, the standard SAX cine stack had more patients with score 1 than SCSA . Sample images for conventional and SCSA cine stacks are shown in Fig. For the image quality scoring of the 55 patients included in the analysis, no image was given the score 2 or 3. The non-parametric paired samples Wilcoxon signed-rank-sum test showed that there was no significant difference in image quality scores (p = 0.010), the RV ESV had a trend to be overestimated . When the RV and LV volumes were indexed to the BSA, closer agreement was achieved between SCSA and conventional methods , LV end-systolic volume (ESV), LV EF, LV mass, RV EDV, RV ESV, and RV EF. LV EDV and RV EDV had good agreement but were systematically underestimated by the SCSA method Figures  and 4. Ts Figure –b.Fig. 3The LV EF and RV EF by SCSA showed close agreement with the gold standard Figure . The difThe LV mass and BSA-indexed LV mass calculated with the two image acquisition methods had moderate agreement Figures  and 5A. In the current study, we describe the clinical evaluation of a minor modification to the real-time (“single-shot”) CS SSFP multi-slice cine sequence (SCSA), which accelerates the SAX stack acquisition speed to one R–R interval for each required slice, thus halving the breath-hold time compared to the use of steady-state preparation cardiac cycles incorporated in most of the previous real-time CS cine methods. The SCSA modification was tested during clinical pediatric CMR scans and proved to be reliable in terms of RV/LV volumetric analysis compared to the gold standard of multiple-BH SSFP SAX cine stack. It was also proved practical to apply this method in a busy clinical setting, because no pre-scans or sequence adjustments were necessary, except the usual good practice of minimizing the phase-encode FOV along the shortest available direction across the patient. To the best of our knowledge, this is the first clinical report describing/assessing the clinical applicability and reliability of a real-time CS cine SAX stack sequence with an overall acquisition speed of a single RR interval per slice.The agreement for the LV EF values was good with no significant difference between the two acquisition methods, whereas LV EDV, LV ESV, RV EDV, and RV EF were systematically underestimated by the SCSA method, but the differences for all the parameters Table  were comThe omission of late-diastolic imaging by the SCSA acquisitions could cause such an underestimation of the EDVs if, for example, the increase in LV volume during atrial contraction were missed , 21, 24.Interestingly, the standard multiple-BH SAX cine stack had more patients with score 1 than SCSA. This may have resulted from the innate robustness of real-time imaging to poor breath-holding. Also, the criteria used by the image quality scoring were based on the images’ usability for volumetry analysis and do not reflect their utility for more subtle aspects.There are previous reports on CS applications assessing ventricular function. Although the image quality of each real-time image at short frame times is considered robust to respiratory motion , for cliPersistent underestimation of LV EDV in previous CS volumetry reports listed is consistent with our findings. Vermersch et al employed multi-slice 2D CS real-time SSFP SAX stack cines in comparison to the conventional method, in 100 consecutive patients over a wide range of cardiac function, requiring two cardiac cycles  per cine slice. The diagnostic performance compared well against conventional BH cines, including for the detection of wall-motion disorders and regurgitant valve flow, finding only a small but statistically significant underestimation of LV EDV (− 1.8%) and overestimation of LV mass (+ 1.9%) by the real-time cine CS. There was also an underestimation trend for RVEDV similar to our work . The undReal-time CS imaging may be adequate for biventricular EF and volume measurements, whereas the evaluation of small pathological structures as present in cardiomyopathies or congenital heart diseases is generally considered to be more reliable when performed on conventional cine images, if supported by breath-holding and reasonably normal cardiac rhythm. As with any CS or accelerated method, coarser spatial and temporal resolution than the stated nominal resolution may occur. Also, the sequence was prospectively triggered and although we believe that it captured the maximal ventricular volume at the R-wave as explained above, it did not capture other cardiac motions during the late-diastolic phases of the cardiac cycle which may be important in certain other clinical questions. The time constraints of a busy clinical service prevented adding another scan to test the free-breathing versions of CS. Another limitation potentially occurs if the preceding cycle is short, so that the time for SSFP stabilization in the next slice is short (in the region of 50 ms) before the R-wave occurs and data acquisition is enabled. In this situation, the image contrast between the blood and myocardium will not have developed fully, because this arises from the myocardial T2 and may require in the region of 80–100 ms to fully darken the myocardium in the SSFP sequence. However, this effect was not observed, nor were any SSFP stabilization artifacts, because the SCSA acquisition window was set to ensure that stabilization took place for long enough before data acquisition began. The reconstruction times on two unmodified clinical CMR systems (with GPU upgrades as sold by the manufacturer) were unobtrusive and did not prevent the following scan from proceeding.SCSA yielded comparable quantitative volumetric results as conventional SAX cine stack with several BHs in a pediatric cohort referred for assessment of congenital heart disease or cardiomyopathy.


High sensitivity cardiac troponin T (hs-cTnT) and NT-pro-brain natriuretic peptide (NT-pro BNP) are often elevated in chronic kidney disease (CKD) and associated with both cardiovascular remodeling and outcome. Relationship between these biomarkers and quantitative imaging measures of myocardial fibrosis and edema by T1 and T2 mapping remains unknown.2 (n = 276) were compared to age/sex matched patients with eGFR ≥ 60 ml/min/1.73 m2 (n = 242) and healthy controls (n = 38). Comprehensive cardiovascular magnetic resonance (CMR) with native T1 and T2 mapping, myocardial ischemia and scar imaging was performed with venous sampling immediately prior to CMR.Consecutive patients with established CKD and estimated glomerular filtration rate (eGFR) < 59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2 groups, with associations being stronger at lower eGFR : native T1 r = 0.43 and r = 0.57, native T2 r = 0.39 and r = 0.48 respectively; log-transformed hs-cTnT(lg10): native T1 r = 0.23 and r = 0.43, native T2 r = 0.38 and r = 0.58 respectively, p < 0.001 for all, p < 0.05 for interaction). On multivariable analyses, we found independent associations of native T1 with NT-pro BNP  and of T2 with hs-cTnT .Patients with CKD showed significant cardiac remodeling in comparison with both healthy individuals and non-CKD patients, including a stepwise increase of native T1 and T2 . Native T1 and T2 were the sole imaging markers independently associated with worsening CKD in patients [B = 0.125 (95% CI 0.022–0.235) and B = 0.272 (95% CI 0.164–0.374) with p = 0.019 and < 0.001 respectively]. At univariable analysis, both hs-cTnT and NT-pro BNP significantly correlated with native T1 and T2 in groups with eGFR 30–59 ml/min/1.73 mWe demonstrate independent associations between cardiac biomarkers with imaging markers of interstitial expansion, which are CKD-group specific. Our findings indicate the role of diffuse non-ischemic tissue processes, including excess of myocardial fluid in addition to diffuse fibrosis in CKD-related adverse remodeling.The online version contains supplementary material available at 10.1186/s12968-021-00762-z. Chronic kidney disease (CKD) and heart failure (HF) often coexist and worsening renal function is a strong predictor of poor cardiovascular outcome . PatientMyocardial T1 and T2 mapping with cardiovascular magnetic resonance (CMR) allows quantifiable tissue characterization and provide direct measures of the pathological myocardial processes non-invasively . Native 2 using the Modification of Diet in Renal Disease (MDRD) formula  ongoing recruitment since March 2018) were enrolled. The CKD diagnosis was established independently by nephrologists and defined as abnormalities of kidney function or structure present for more than 3 months and eGFR < 59 ml/min/1.73 m2 on at least two occasions separated by a period of at least 90 days (with or without markers of kidney damage)  and of hs-cTnT with native T2 in eGFR < 29 ml/min/1.73 m2 only   and B = 0.272 (95% CI 0.164–0.374), respectively]  ± SD − 0.2 ± 5.3 ms; interobserver: r = 0.96, p < 0.01, MD ± SD − 2.4 ± 10.3 ms. T2 mapping: intraobserver: r = 0.98; MD ± SD = − 1.2 ± 1.5; interobserver r = 0.96, p < 0.001 MD ± SD = 1.8 ± 3.3). GLS and GCS strain analysis, intra- and inter-observer agreements were moderate: GLS: intra-observer: r = 0.78, p < 0.001, MD ± SD of 0.1 ± 3.1, interobserver: r = 0.72, 1.0 ± 4.3.In this prospective study, we demonstrate independent associations between cardiac biomarkers with imaging marker of myocardial edema and diffuse fibrosis, which are CKD-group specific. Native T1 and T2 were the only imaging markers to be independently associated with worsening CKD. Serological marker of increased LV wall stress, NT-pro BNP, and of myocardial injury, hs-cTnT, were independently associated with native T1 and T2 respectively, albeit only in patients with reduced renal function. Also, there was a significant reduction of native T2 when measured immediately post-hemodialysis with the change in T2 proportional to the removed ultrafiltration volume. Together, these results indicate a link between myocardial injury and LV wall stress with an increase of myocardial fluid, in addition to myocardial fibrosis, which is inherent to the presence of CKD.2, but similar CVD risk factors by PSM of the two cohorts, we report elevated native T1 and T2, but not more prevalent LGE, reiterating that markedly raised troponin levels are unlikely fully explained by the consequences of atherosclerotic CAD [Our observations expand the current knowledge about the pathophysiology of CVD and adverse myocardial remodeling in CKD. We employed two independent approaches of detecting myocardial abnormalities, by serology and imaging, which are both well established in terms of accuracy and prognostic significance , 8, 10. otic CAD .2) is a central new finding, reiterating the role of increased myocardial fluid, in addition to myocardial fibrosis, as an integral part of structural LV remodeling in CKD [2) and CKD (eGFR < 59 ml/min/1.73 m2) patients, which could reduce the added value of mapping assessment in this context, T2 exhibited significant correlation with cardiac injury in patients with severe renal insufficiency (eGFR < 29 ml/min/1.73 m2) only. Further studies are required to explore whether focused myocardial water-shifts might translate into a modifiable intervention conferring cardio-protection in some patients with advanced CKD, hypothetically those with higher T2 and hs-cTnT. We also observed an interrelatedness between T1 and T2, which becomes much stronger as renal function declines, indirectly supporting that both measures are much more influenced by excess myocardial fluid in CKD [The independent association between native T2 and hs-cTnT in patients with severe CKD , however, histological correlations with myocardial fibrosis in CKD may differ and require verification in future studies. Myocardial edema cannot be validated by classical histology, as it is complicated by dehydration through tissue fixation with formaldehyde. However, a previous experimental study used a tissue desiccation method to provide validation of T2 mapping measurements against myocardial water content [A few limitations of our study apply. We strived to control for inclusion bias in several ways. Respiratory variation of IVC was used as a proxy-measure of the total body fluid status, because it was obtainable in all subjects across the eGFR spectrum. Participants with reduced kidney function were recruited from tertiary centers as well as peripheral nephrology practices, thus reducing the potential referral bias. The clinical indications for CMR were uniform for both groups and approved by an independent cardiologist in line with cardiological practice guidelines. Native T1 moderately correlates with collagen volume fraction in model diseases of pressure overload . NA (not applicable), eGFR—estimated glomerular filtration rate , CRP—C-reactive protein, EDV—end-diastolic volume, ESV—end-systolic volume, EF—ejection fraction, GLS—global longitudinal strain, LV—left ventricular, LGE—late gadolinium enhancement, IVC—inferior vena cava.Additional file 2: Figure S2: Heat map for correlations between cardiac biomarkers and CMR imaging markers of adverse cardiac remodeling at different CKD stages. A more intense color indicates closer association . eGFR—estimated glomerular filtration rate , EV—end-diastolic volume, ESV—end-systolic volume, EF—ejection fraction, GLS—global longitudinal strain, LV—left ventricular, LGE—late gadolinium enhancement, IVC—inferior vena cava.Additional file 3: Supplementary methods.