Pericoronary adipose tissue (PCAT) reflects pericoronary inflammation and is associated with coronary artery disease. We aimed to identify the association between local PCTA thickness using cardiac magnetic resonance (CMR) and prognosis of patients with ST-elevation myocardial infarction (STEMI), and to investigate the incremental prognostic value of PCAT thickness in STEMI after reperfusion.A total of 245 patients with STEMI  who underwent CMR imaging within 1 week of percutaneous coronary intervention therapy and 35 matched controls  were enrolled. PCAT thickness indexed to body surface area at five locations, ventricular volume and function, infarct-related parameters, and global strain indices were evaluated using CMR. Associations between PCAT thickness index and 1-year major adverse cardiovascular events (MACE) after STEMI were calculated. The prognostic value of the standard model based on features of clinical and CMR and updated model including PACT thickness index were further assessed.2 was an independent predictor of MACE . The updated model significantly improved the power of prediction and had better discrimination ability than that of the standard model for predicting 1-year MACE .Patients with MACE had a more significant increase in PCAT thickness index at superior interventricular groove (SIVGi) than patients without MACE. The SIVGi was significantly associated with left ventricular ejection fraction (LVEF), infarct size, and global deformation. SIVGi > 4.98 mm/mThis study demonstrated SIVGi as an independent predictor conferred incremental value over standard model based on clinical and CMR factors in 1-year MACE predictions for STEMI. Effective stratification of residual risk during the early postoperative period is particularly important for the short-term prognosis of patients with acute myocardial infarction (MI) . PreviouInflammation has long been postulated to play an important role in the atherosclerotic progression and recurrent major adverse cardiovascular events (MACE) , 6. RepoTherefore, the purpose of this study was to evaluate the changes in PCAT thickness at different locations after STEMI, to evaluate the association of PCAT thickness indices with the occurrence MACE, and to determine the effective predictors among PCAT thickness indices to investigate the incremental prognostic value of PCAT thickness index in MACE within 1 year after STEMI.From April 2017 to December 2019, we retrospectively screened 323 patients who had STEMI for the first time and underwent percutaneous coronary intervention (PCI) therapy at Shengjing Hospital of China Medical University. STEMI was defined according to current definitions . We exclWe collected the relevant clinical history data of all patients and controls, including information on baseline clinical characteristics, cardiovascular risk factors, laboratory parameters, current medication, and angiographic information. The follow-up information was obtained from the patients' medical records and from telephone interviews. The endpoint was time to first MACE within the 12-month follow-up period post-revascularization, and included a composite of cardiovascular death, recurrent MI, clinically driven target lesion revascularization, and readmission for heart failure . Planned®, Calgary, Canada). The images were analyzed by two experienced observers blinded to all patient data. CMR data were prospectively incorporated into the database. The details of the technical aspects of CMR acquisitions, sequences, and quantification have been described previously . Anonymized CMR images were analyzed offline using customized software , left ventricular end-systolic volume (LVESV) index (ml/m2), left ventricular mass index, right ventricular ejection fraction (%), right ventricular end-diastolic volume index (ml/m2), right ventricular end-systolic volume index (ml/m2), microvascular obstruction (%), edema size (% of left ventricular mass), infarct size (% of left ventricular mass), and myocardial salvage index  were calculated. Tissue tracking-CMR strain analysis was also performed, and the global strain values  through the entire cardiac cycle were calculated semi-automatically using the software as previously described (Left ventricular ejection fraction (LVEF) (%), left ventricular end-diastolic volume (LVEDV) index (ml/mescribed .Pericoronary adipose tissue thickness was measured using the end-diastolic phase CMR cine images . PCAT tht-test. Nonparametric data were expressed as medians (interquartile ranges) and compared using the Mann–Whitney U test. Categorical variables were expressed as percentages and compared using the chi-square test or Fisher's exact test where appropriate. The correlations between PCAT thickness indices and CMR imaging parameters were evaluated using Pearson's correlation coefficient and the reproducibility was assessed using Bland–Altman analysis and intra-class correlation coefficients.Continuous data were tested for normal distribution using the Kolmogorov–Smirnov test. Normally distributed data were expressed as mean ± SD and compared using Student's CI were calculated as well. Meanwhile, the optimal cutoff for each index was determined. Kaplan–Meier curves were used to estimate MACE-free survival rates with respect to high and low level of the PCAT index with best discriminative ability. The comparison of survival rates between groups was examined using the log-rank test.The time-dependent receiver operating characteristics (ROC) curve analysis was used to assess the performance of the strain indexes and PCAT thickness indexes for the prediction of adverse cardiac events 1-year post STEMI. The areas under the ROC curve (AUCs) and the corresponding 95% HR) and 95% CIs. Two multivariable Cox regression models were then conducted. Those were the standard model and updated model. The least absolute shrinkage and selection operator (LASSO) strategy, an efficient in handling high-dimensional data . The following packages were involved: “timeROC,” “survivalROC,” “survival,” “survminer,” “glmnet,” and “survIDINRI.”A two-tailed 2, LVEF < 50%:5.34 ± 1.63 mm/m2, p = 0.001; infarction size ≤ 13.73%:4.60 ± 1.38 mm/m2, infarction size > 13.73%:5.37 ± 1.69 mm/m2, p < 0.001; GRS ≥ 22.77%:4.67 ± 1.57 mm/m2, GRS < 22.77%:5.30 ± 1.55 mm/m2, p < 0.01; GCS ≤ −14.2%:4.71 ± 1.52 mm/m2, GCS > −14.2%:5.61 ± 1.57 mm/m2, p < 0.001; GLS ≤ −8.6%:4.79 ± 1.61 mm/m2, GLS > −8.6%:5.26 ± 1.53 mm/m2, p = 0.02)  .p < 0.01, cutoff value: 4.98 mm/m2) for SIVGi was the highest among the AUCs of the PCAT thickness indices  with STEMI had their first MACE . For all indices . Moreoveth STEMI . TherefoSimilarly, the discriminative ability of different strain characteristics for predicting 1-year MACE was also identified by the time-dependent ROC curve. It was shown that the AUC for GRS was higher among the three parameters, and there was no significant difference compared with the other two AUCs .I > 31.60 ng/ml, a LVEF < 50%, and an infarct size >13.73% were associated with a two- to three-fold increased risk for adverse events, and that a LVESV index > 35.99% ml/m2, a GRS < 22.77%, a GCS > −14.2%, and a GLS > −8.6% were associated with an approximately four-fold increased risk for adverse events for all the patients with STEMI . Similar results were found when LVESV index, GRS, GCS, GLS, and SIVGi were enrolled into Cox regression model as continuous variables. There was a 1.49-fold higher risk in adverse events per mm/m2 increase in SIVGi (The standard model in in SIVGi .AUC: 0.8 vs. 0.76). The delta AUC and p-value were 0.046 and 0.047, respectively. The incremental prognostic value of SIVGi was further confirmed by reclassification analysis. As compared with the standard model, the updated model could more accurately assigned 38% of the participants into the MACE group or non-MACE group , which was consistent with the non-zero IDI value . Similar findings were depicted in the sensitivity analysis in which traditional risk factors such as age, sex, smoking, BMI, diabetes mellitus, hypertension, dyslipidemia, eGFR, LVEF, statins, ACEI/ARB, and β blocker were further adjusted  . However, we failed to detect a significant IDI value .A higher AUC was also found in the updated model than the standard model when the SIVGi was treated as a continuous variable in Cox regression models ( < 0.01) . As compBased on the updated model, a nomogram that combined all the independent predictors was constructed to predict MACE at 1 year . In thisThe main finding of the present study was that the increased PCAT thickness at the SIVG was more significant in patients with MACE after STEMI. The SIVGi was significantly associated with LVEF, infarct size and LV global deformation in STEMI. As an independent predictor for 1-year MACE, SIVGi conferred incremental value in predictions for patients with STEMI.Pericoronary adipose tissue as an organ is anatomically adjacent and functionally interrelated with the myocardium and coronary arteries. Under physiological conditions, PCAT has anti-inflammatory and protective effects and can be used as an energy reservoir to provide fatty acids to the coronary arteries and myocardium –20. Howe2 was associated with a 4.52-fold increased risk for MACE after STEMI, whereas other PCAT thickness indices were associated with about 1- to 2-fold increased risk for MACE. A previous CT study indicated that PCAT around the left anterior descending (LAD) artery and right coronary artery, but not around the left circumflex coronary artery, is an independent predictor of all-cause and cardiac mortality  and larger MI sizes in MACE-STEMI compared with no MACE-STEMI in the present study. Second, given that LAD is the main artery of the left ventricle with the most extensive blood supply range, the redistribution of coronary blood flow is most significant after MI. In addition, the damage to the endothelial cells of the LAD can induce more obvious abnormal accumulation of PCAT around the LAD. The effect of PCAT at the SIVG on blood vessels is also stronger and has greater influence on prognosis . Third, 2 had better discrimination and reclassification ability for patients with 1-year MACE after STEMI. The sensitivity analysis in which traditional risk factors were further adjusted also supported this. Interestingly, the most useful predictors  for the standard model are all CMR parameters for myocardial compliance, indicating that myocardial compliance on CMR imaging may have more direct relationship with short-term STEMI prognosis compared with clinical parameters. To our knowledge, this is the first study to show that the simple measurement of PCAT thickness index at the SIVG combined with myocardial compliance indices is a useful marker of MACE after STEMI in the CMR imaging setting. Moreover, PCAT measurement has good reliability and can be completed during routine CMR examination without the need for a special sequence and complex post-processing software. Therefore, the PCAT thickness index is an ideal prognostic indicator.The results of the present study showed that compared with standard model, the updated model including SIVGi with a cutoff value of 4.98 mm/mIn this study, the MACE was observed in 19.18% of patients. The similar result is also appeared in recent study from Zhang et al. , 1-year This study has several limitations. First, the retrospective and observational cohort design of the study makes it challenging to derive causality. Second, PCAT inflammation can be caused by percutaneous endothelium injury during endovascular angioplasty . It is dPatients with MACE have more significant increase in PCAT thickness at SIVG than without MACE after STEMI. PCAT thickness index at the SIVG could possibly be a strong independent predictor of MACE in revascularized patients with STEMI. Compared with standard model based on clinical and CMR parameters, the updated model including SIVGi has significantly improved predictive power for 1-year MACE after STEMI.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Shengjing Hospital of China Medical University Research Ethics Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.YM, YH, and QM participated in the study design. XW, TY, YD, and JS participated in data collection. GL performed the statistical analysis. YM drafted the article. All authors contributed to the article and approved the submitted version.This study has received funding by the National Natural Science Foundation of China (Grant Nos. 81901741 and 82071920), the Key Research and Development Plan of Liaoning Province (No. 2020JH2/10300037), and the Talent Project in the Shengjing Hospital of China Medical University.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.


Mitral valve prolapse (MVP) is a relatively common finding in the general population, and it is associated with ventricular tachycardia (VT) and sudden cardiac death (SCD). In this report, we present a case involving a 63-year-old male who had been previously diagnosed with MVP complicated by multiple admissions for episodes of ventricular arrhythmias. The prevention of sudden cardiac arrest (SCA) and risk stratification can be challenging. Patients with known traditional risk factors classified as high-risk constitute only 30% of the total cases of SCA . In factWe present the case of a 63-year-old man with a history of implantable cardioverter-defibrillator (ICD) insertion at the age of 42 for secondary prevention after sudden cardiac arrest (SCA) with shockable rhythm at an outside hospital; since then, he had had recurrent admissions to our facility due to episodes of ventricular tachycardia (VT) Figure  despite In cases such as ours, it can be very challenging to predict the risk of SCA prior to the initial presentation with SCA . The patImaging studies are crucial for the evaluation of structural heart disease or potential causes in patients presenting with VT for differential diagnosis. TTE is a well-established and easily accessible modality used for the evaluation of ejection fraction, wall motion abnormalities, and valvular disease. MVP is a relatively common condition affecting about 2% of the population . It has MAD has been shown to be especially proarrhythmogenic in some studies ,3,9. TheMVP can be an arrhythmogenic anomaly causing malignant ventricular arrhythmias and SCA. For patients who present with SCA, echo and possibly cardiac MRI should be performed to evaluate the mitral valve. Defibrillators should be implanted in MVP patients who have SCA for secondary prevention. To date, no guidelines or sufficient data exist regarding risk stratification in patients known to have MVP, which makes their management very difficult. Nevertheless, we believe that visualization of high-risk features related to MVP on TTE should prompt closer clinical follow-up. However, there is insufficient data to support early anti-arrhythmic medication management or ICD placement in patients with MVP for primary prevention. Therefore, we believe that further studies to develop guidelines for risk stratification of patients with evident MVP seen on TTE would be beneficial in reducing the incidence of potentially fatal incidents in this relatively benign-appearing diagnosis.


JCI, Kashihara et al. explored the role of the Yes-associated protein 1 (YAP) transcription factor in the heart, using cell culturing and mouse models. YAP activity was found to be associated with changes in genes of the glycolytic and auxiliary pathways under stress. Notably, YAP upregulated glucose transporter 1 (GLUT1), and inhibition of GLUT1 blocked YAP-induced hypertrophy but worsened heart function. These findings suggest that YAP is a regulator of metabolic reprogramming in the heart during compensatory hypertrophy. This insight may help in the development of future therapies for heart failure.Cardiomyocyte hypertrophy is an integral part of cardiac remodeling that occurs under physiological or pathological stresses. It can lead to heart failure in a pathological form or oppose functional deterioration in a compensatory one. The mechanisms underlying an adaptive outcome of hypertrophy are ill defined. In this issue of the  Cardiomyocyte hypertrophy is a well-described histological feature of cardiac remodeling in response to physiological or pathological stresses and involves complex molecular and cellular reprogramming. Over the past decade, substantial progress has been made in uncovering a fetal-like metabolic switch in hearts during hypertrophic remodeling, whereby fuel utilization shifts from fatty acid oxidation to glycolysis . HoweverJCI, Kashihara et al.  in the intact mouse heart, which blocked YAP-induced hypertrophy. Conversely, GLUT1 expression restored cardiac hypertrophy and improved function following pressure overload in the YAP-deficient mouse heart. Finally, reporter- and ChIP-based analysis revealed that YAP directly bound to the Glut1 proximal promoter in cooperation with its known cofactors TEAD1 and HIF-1α to regulate Glut1 gene transcription. These lines of evidence support the conclusion that YAP critically regulates glycolysis induction in cardiomyocytes and is necessary for compensatory hypertrophy (ref. Sadoshima’s laboratory previously reported that pressure overload induces YAP expression. Conversely, cardiomyocyte-specific genetic attenuation of YAP expression inhibits cardiac hypertrophy but promotes heart failure, thus implicating a role for YAP in compensatory hypertrophy . In the phy ref. . The demphy ref. . AlthougEarlier studies found distinct characteristics in hypertrophic hearts induced under physiological and pathological conditions, such as exercise or pressure overload. These observations led to the current concept that myocyte hypertrophy can be adaptive and beneficial or pathogenic and deleterious to the heart, depending on the nature of the triggering stresses. This study from Sadoshima’s laboratory suggests that YAP-glycolysis regulation is essential to cardiomyocyte hypertrophy but that blocking it leads to a detrimental outcome for cardiac function . AlthougBeyond myocytes, it is also important to recognize that YAP-mediated regulation may differ between cardiomyocytes and other cell types. Manvendra K. Singh’s laboratory recently reported that YAP regulates macrophage activation and phenotype switching in injured myocardium and contributes to pathological remodeling and dysfunction . They alAs revealed by Kashihara and colleagues , who per


Parameters of myocardial deformation may provide improved insights into right ventricular (RV) dysfunction. We quantified RV longitudinal myocardial function using a fast, semi-automated method and investigated its diagnostic and prognostic values in patients with repaired tetralogy of Fallot (rTOF) and pulmonary arterial hypertension (PAH), who respectively exemplify patients with RV volume and pressure overload conditions.s), early diastole (GLSRe) and late diastole (GLSRa), obtained by tracking the distance from the medial and lateral tricuspid valve insertions to the RV epicardial apex on cine cardiovascular magnetic resonance (CMR).The study enrolled 150 patients  and 75 healthy controls. RV parameters of interest were fast global longitudinal strain (GLS) and strain rates during systole (GLSRP < 0.001 in pairwise comparisons). In rTOF patients, RV fast GLS was significantly associated with metabolic equivalents, peak oxygen consumption (PVO2) and percentage of predicted PVO2 achieved during cardiopulmonary exercise testing. Lower RV fast GLS was associated with subnormal exercise capacity in rTOF (area under the curve (AUC) = 0.822, sensitivity = 72%, specificity = 91%, cut-off = 19.3%). In PAH patients, reduced RV fast GLS was associated with RV decompensated hemodynamics  and higher risk of clinical worsening .The RV fast GLS exhibited good agreement with strain values obtained by conventional feature tracking approach  ± 4.3%) with fast GLS achieving greater reproducibility and requiring reduced analysis time. Mean RV fast GLS was reduced in PAH and rTOF groups compared to healthy controls (PAH < rTOF < healthy controls: 15.1 ± 4.9 < 19.3 ± 2.4 < 24.4 ± 3.0%, all Quantitative RV fast strain and strain rate parameters assessed from CMR identify abnormalities of RV function in rTOF and PAH and are predictive of exercise capacity, RV decompensation and clinical risks in these patients.Trial registry Clinicaltrials.gov: NCT03217240The online version contains supplementary material available at 10.1186/s12968-021-00724-5. Analysis of right ventricular (RV) performance has not been studied as exhaustively as that of the left ventricle (LV). An important cause of RV dysfunction is chronic pressure overload induced by conditions like pulmonary arterial hypertension (PAH). On the other hand, RV dysfunction from chronic volume overload is a complication in residual pulmonary valve regurgitation after tetralogy of Fallot repair (rTOF) .Compared with the LV, quantitative assessment of RV function is challenging due to the latter’s more complex anatomy. Cardiovascular magnetic resonance (CMR) is the reference standard for non-invasive assessment of RV structure and function . It is aWe have developed a fast, semi-automated approach for quantifying longitudinal strain and strain rate (SR) from standard cine CMR images and demonstrated its effectiveness in assessing longitudinal function of left atrium , 8, righThe study prospectively enrolled 75 patients with rTOF, 75 patients with PAH, and 75 healthy controls to undergo CMR. Additionally, all rTOF patients underwent same-day cardiopulmonary exercise testing (CPET). Exclusion criteria for rTOF included presence of intracardiac shunt, pulmonary stenosis with peak pressure gradient > 30 mmHg, supraventricular arrhythmia, significant ventricular arrhythmia, and prior pulmonary valve replacement. The diagnosis criteria for PAH was based on right heart catheterization : (1) meaEnrolled subjects underwent CMR on a 3 T CMR scanner , or 1.5 T CMR scanner . End-expiratory breath hold balanced steady-state free precession cine images were acquired in short- and long-axis LV views. The standard 4-chamber view was prescribed from the vertical long-axis through the apex and centre of the mitral and tricuspid valves. Typical parameters for the 3T Philips scanner were as follows: repetition time (TR)/echo time (TE), 3/1 ms; matrix, 240 × 240; flip angle, 45°; field of view, 300 × 300 mm; pixel bandwidth, 1776 Hz; pixel spacing, 1.25 × 1.25 mm; slice thickness, 8 mm; number of frames, 30/40 per cardiac cycle; actual temporal resolution (TR × turbo factor), 42 ms. Parameters for the 3T Siemens scanner were: TR/TE, 3.4/1.3 ms; matrix, 162 × 192; flip angle, 50°; field of view, 270 × 320 mm; pixel bandwidth, 1532 Hz; pixel spacing, 1.67 × 1.67 mm; slice thickness, 8 mm; number of frames, 25 per cardiac cycle; actual temporal resolution, 40.6 ms. Parameters for the 1.5T Siemens scanner were: TR/TE, 3.3/1.1 ms; matrix, 156 × 192; flip angle, 80°; field of view, 276 × 340 mm; pixel bandwidth, 930 Hz; pixel spacing, 1.77 × 1.77 mm; slice thickness, 6 mm; number of frames, 25 per cardiac cycle; actual temporal resolution, 39.8 ms.Volumetric analysis was performed by the cardiologists in respective centres blinded to other CMR measurements. Endocardial surfaces were manually traced from the stack of short-axis cine images to obtain ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and to calculate stroke volume (SV) and ejection fraction (EF). Papillary muscles and trabeculae were included in the blood volume .L) from the medial and lateral tricuspid valve insertions to the RV epicardial apex was automatically tracked throughout the cardiac cycle  blinded to clinical characteristics of participants and other CMR measurements. The distance  with respect to the initial time at RV end-diastole was calculated as s), early diastole (GLSRe), and late diastole (GLSRa) were obtained from the SR curve  blinded to all participant characteristics and other CMR measurements in deriving RV GLS and global longitudinal SR (GLSR), and global circumferential strain (GCS) using dedicated QStrain software . RV GLS and GLSR were obtained by endocardial tracking of cine 4-chamber CMR images. RV GCS was derived from the mid-RV short-axis view, which was localized as the level showing the LV short-axis view with both papillary muscles in cross section .2 per kilogram body weight per minute). The primary clinical outcome from CPET was peak oxygen consumption (PVO2) expressed as an absolute value (ml/kg/min) and as a percentage of predicted PVO2 (%predicted PVO2). All CPETs are symptom-limited, with PVO2 measured by averaging data during the final 15 s of exercise. Normal exercise capacity was defined as > 84 % of predicted PVO2 [CPET was performed on a Hewlett–Packard Cosmos treadmill machine as described previously . One metted PVO2 .F-test, followed up with Tukey’s honestly significant difference or Games Howell post hoc test in the event of an overall statistically significant difference in group means. Comparisons between two groups were performed using independent t tests for normally distributed data, Mann–Whitney U tests for non-normally distributed data, and chi-square test or Fisher’s exact test for categorical data.Statistical analysis was conducted using SPSS . Continuous data were summarized as mean ± standard deviation (SD) or median (interquartile range (IQR)) and categorical data as frequencies (percentages). Data were compared among the patient and the control groups using an ANOVA r correlation, Passing–Bablok non-parametric regression, and Bland–Altman plots were used to assess the agreement of RV fast GLS data with respect to RV GLS. Receiver operator characteristic (ROC) analysis was conducted to assess the clinical discriminative utility of RV strain measurements, and the area under the ROC curve (AUC) was used as a measure of overall discriminative capability. Statistical significance was set at P < 0.05.Pearson’s Intra- and inter-observer variability were studied on a randomly selected subgroup of 30 cases  using Bland–Altman analysis and coefficient of variation (CV). The time required for assessment of RV fast GLS and GLS was recorded in the selected 30 cases.Patients with rTOF were younger than patients with PAH. The female-to-male ratio was 3.7:1 in the PAH patient group. Both rTOF and PAH patients had higher RVEDV index (RVEDVI), RVESV index (RVESVI), and lower RVEF and RV GLS compared to healthy controls. RV GCS was significantly higher in rTOF than in healthy controls. Within the patient groups, RVEF and RVEDVI were higher in rTOF than in PAH, while RVESVI was comparable between rTOF and PAH (Table P = 0.997).In rTOF, the median age at which surgical repair was performed was 4 IQR 2.2-8.0) years and the median time from surgical repair was 24 (IQR 20.0-31.3) years. 43 patients had undergone transannular patch repair. Patients with subnormal exercise capacity had lower RVEDVI, RVESVI and RV SV index (SVI) (Table .2-8.0 yeP = 0.021). PAH patients with high risk of clinical worsening had lower 6MWD, cardiac index, and RVEF compared to those with low risk  had higher diastolic blood pressure, lower 6MWD and LVEF compared to those with RV hemodynamic compensation  Table . LVEF wask Table .Table 3r = 0.92, P < 0.001) in the entire subject cohort with a bias of − 4.9 % (fast GLS < GLS), and error limits (2SD) of ± 4.3 %   Fig. . The RV e and fast GLSRa were significantly lower than in the healthy control group. In addition, the RV fast GLSRe was lower in PAH patients than those with rTOF, while fast GLSRa was significantly higher in PAH than in rTOF  and fast GLSRs  compared to those with normal exercise capacity , PVO2 , and %predicted PVO2   than RV GLS (AUC = 0.557) and RVEF (AUC = 0.440) , PVR  and mPAP  in PAH. In a sub-group analysis, PAH-D had significantly reduced RV fast GLS , fast GLSRs  and fast GLSRa  in comparison to PAH-C .The intra- and inter-observer strain and SRs derived by the fast method had lower CVs compared to those derived by CMR FT Table . Average2, and %predicted PVO2 in rTOF patients. Among PAH patients, RV fast GLS and fast GLSR were significantly reduced in patients with hemodynamically decompensated RV compared to those with compensated RV. Lower RV fast GLS and fast GLSR measurements were significantly associated with higher risk of clinical worsening in PAH patients.The current study demonstrated that RV longitudinal strain can be rapidly quantified by tracking 3 distinct anatomical points in standard CMR sequences with greater reproducibility, shorter analysis time, and comparable diagnostic and prognostic capabilities compared to conventional CMR FT. Greater RV fast GLS was found to correlate significantly with higher METs, PVO2 . Our finding agreed with an earlier study by Kempny et al. [r = 0.42, P < 0.01) with exercise capacity, and was an important predictor of clinical outcome in patients with congenital heart disease [2  [RV dilation alone reflects little, but RV function relates to exercise capacity and functional health status. The current study applied the fast strain assessment by CMR to directly measure RV longitudinal shortening, and showed significant association between RV fast GLS and exercise performance in rTOF patients. The traditional RV GLS was also shown to be related to %predicted PVOy et al.  who show disease . Similar 0.0001) .Interestingly, we found circumferential RV strain to be higher in rTOF patients compared with healthy controls. Previous research dichotomized the contribution to RV SV as 80% being generated by RV longitudinal function and the remaining 20% by “radial” function . The latThe clinical gold standard for assessing disease severity in the pressure-overloaded state remains invasive hemodynamics . PAH-D iRecent guidelines recommend a multidimensional approach in comprehensive risk assessment for PAH. Patients classified as intermediate and high risk have higher estimated 1-year mortality . We founAssessment of RV contractile function is of great clinical importance, particularly in the monitoring and management of patients with congenital heart disease. Volume calculation and estimation of RVEF may be relatively insensitive for detecting changes in RV systolic function with disease . In patiTypical RV CMR FT algorithm ignores the septum and tracks the RV free wall during a cardiac cycle, resulting in free wall longitudinal strain. In the present study, we performed RV fast GLS and traditional RV GLS measurements by tracking both RV free wall and interventricular septum. The accuracy of traditional RV GLS is degraded in subjects with vigorous tricuspid annular motion, as contour tracking of the RV free wall segment adjacent to the tricuspid valve in long-axis view is adversely affected . The RV RV geometry is complex and it is virtually impossible to capture the entirety of 3D RV strain using a single parameter. RV fast GLS is an index of global RV function in the longitudinal direction and does not provide information on circumferential and radial strains such as those integrated in area strain . HoweverRV fast GLS agrees with conventional RV CMR FT strain and appears to be more reproducible. The RV fast strain and SR parameters identified abnormalities of RV function in rTOF and PAH and were associated with exercise capacity, RV decompensation and clinical risks in these patients.Additional file 1. Fast global longitudinal strain: details about the anatomical point tracking and the methodological considerations and robustness analysis on RV apical point selectionAdditional file 2. RV FGLS cut-off values with AUC, sensitivity and specificity for discriminating RVEF impairment < 35 %, < 40 % and < 45 %


Background: Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular diseases. The aims of this study were to evaluate the changes in the left ventricular myocardial work in T2DM patients using the left ventricular pressure-strain loop (PSL) technique, and to explore the risk factors for the left ventricular myocardial work impairment.Methods: Fifty patients with T2DM and 50 normal controls (NCs) were included in the study. In addition to conventional echocardiography and two-dimensional speckle tracking echocardiography, the left ventricular myocardial work parameters were measured using PSL technology.Results: The absolute value for global longitudinal strain (GLS), global work index (GWI) and, global constructive work (GCW) were significantly decreased in the T2DM group (P < 0.05), while the left ventricular ejection fraction (LVEF) was not significantly different between the T2DM and NC groups. Multivariable linear regression analysis showed that hemoglobin A1c (HbA1c) was independently related to GWI , while HbA1c and the diabetes duration were independently related to GCW .Conclusions: Changes in the left ventricular myocardial systolic function in T2DM patients were identified using PSL technology. HbA1c was shown to be an independent risk factor affecting GWI, while HbA1c and diabetes duration were demonstrated to be independent risk factors affecting GCW. Diabetes is a common clinical metabolic disease. Type 2 diabetes mellitus (T2DM) accounts for more than 90% of diabetic patients . The inc2 > 0.88. The major reason is that the temporal integration induces a smoothing of the difference between measured and estimated works, so the deducted estimation of left ventricular work is accurate (Left ventricular ejection fraction (LVEF) and two-dimensional speckle tracking technology are commonly used to evaluate the left ventricular systolic function, but these methods are load-dependent . Recentlaccurate .A previous study showed that the level of hemoglobin A1c (HbA1c) was independently associated with decreased left ventricular strain in T2DM patients with preserved LVEF . HoweverThe aims of the present study were to evaluate the changes in the left ventricular myocardial work in T2DM patients using the left ventricular PSL technique, and to explore the clinical factors impairing the left ventricular myocardial work.A total of 100 participants were consecutively enrolled in Fuwai Central China Cardiovascular Hospital between May and December of 2020, of which 50 were in the T2DM group  and 50 age- and gender-matched healthy individuals were in the normal control (NC) group  . The incTotal cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and HbA1c levels were measured <2 weeks before the echocardiographic evaluation using standard laboratory techniques. Fasting plasma glucose (FPG) and 2-h postprandial plasma glucose (2h-PPG) levels were measured in T2DM patients.Transthoracic echocardiography was performed using a Vivid E95 system  equipped with an M5Sc-D probe (1.4-4.6 MHz). All study participants were scanned in the left lateral position with continuous electrocardiogram monitoring. Left atrial diameter (LAD), left ventricular end diastolic diameter (LVDd), left ventricular end diastolic volume (LVEDV), left ventricular end systolic diameter (LVDs), left ventricular end systolic volume (LVESV), and LVEF were measured in the parasternal long-axis view of the left ventricle. Doppler spectrum images of the aortic and mitral valves were collected from apical five- and four-chamber views. Two-dimensional images consisting of three cardiac cycles from the apical four-, three-, and two-chamber views were acquired at frame rates between 57 and 68 frames/s . All images were stored on a hard disk for offline analysis.Echopac version 203 software  was used for image analysis. Three index points were used to define the mitral annulus and left ventricular apex at the end-systolic frame in each apical view. Automated tracking of myocardial motion was performed with the region of interest adjusted by correcting the endocardial border or width if necessary. The software calculated global longitudinal strain (GLS) from the weighted average of the peak systolic longitudinal strain of the 17 segments. Peak systolic left ventricular pressure was assumed to be equal to the peak arterial pressure, which was recorded from the brachial cuff blood pressure measured immediately before the echocardiographic recordings. A non-invasive left ventricular pressure curve was constructed using the strain and blood pressure data, and a normalized reference curve adjusted according to the duration of isovolumic and ejection phases defined by the timing of aortic and mitral valve opening and closing events on Doppler spectrum images . Left veGlobal work index (GWI): total work within the area of the left ventricular PSL calculated from mitral valve closure to mitral valve opening.Global constructive work (GCW): work performed by during left ventricular shortening in systole and lengthening during the isovolumic relaxation phase.Global wasted work (GWW): the negative work performed during left ventricular lengthening in systole and shortening in isolvolumic relaxation phase.Global work efficiency (GWE): the percentage of constructive work divided by the sum of constructive and wasted work.P-value <0.05 was considered statistically significant. Continuous variables were expressed as mean ± standard deviation for normally distributed data, or as median (interquartile range) for non-normally distributed data. Categorical variables were expressed as frequencies and percentages.The statistical analyses were performed using SPSS 26.0 software . t-test, Mann-Whitney U-test, and χ2 test as appropriate to compare the T2DM and NC groups. Pearson's correlation coefficient was used for determining the correlation between GLS and myocardial work parameters. The clinical factors with P-value <0.05 in univariable linear regression outcomes were incorporated into the multivariable linear regression analysis models by means of stepwise selection to detect the independent predictors of abnormal myocardial function in T2DM patients. There was no multicollinearity between variables in these models. Ten subjects were randomly selected and re-measured the global myocardial work parameters by two observers. Intra-observer and inter-observer variability was assessed in 20 randomly selected subjects using the Bland-Altman analyses.The statistical analysis was performed using the Student's P < 0.05) (P > 0.05).Body mass index (BMI), body surface area (BSA), HbA1c, TG, and LDL-C in the T2DM group were significantly increased compared to the NC group ( < 0.05) . There wP < 0.05). No significant difference was observed in LAD, LVDd, LVEDV, LVDs, LVESV, and LVEF between the T2DM and NC groups (P > 0.05)  .P < 0.05) (P > 0.05).The GWI and GCW in the T2DM group were significantly decreased compared to the NC group ( < 0.05) . Howeverr = −0.795, P < 0.001 and r = −0.809, P < 0.001, respectively) (GLS showed a good correlation with GWI and GCW (ctively) .P < 0.05)  , 5. , 5.P < Intra-observer and inter-observer variability for global myocardial work parameters are summarized in The main findings of this study showed that GWI and GCW were significantly different between the NC and T2DM groups. PSL technology was able to assess the impairment of left ventricular systolic function in T2DM patients. Multivariable linear regression analysis confirmed that HbA1c was independently related to GWI, while HbA1c and diabetes duration were independently related to GCW.The HbA1c level in the T2DM group was higher than that in the NC group. HbA1c has been widely used as an indicator of diabetes control and it is correlated with FPG and 2h-PPG , 12. T2DThe absolute value of GLS in the T2DM group was lower compared to that in the NC group, while the LVEF was similar. Consistent with previous studies , 18, thiSeveral prior studies have shown that T2DM is closely related to vascular arteriosclerosis, which can elevate pulse pressure , 20. A wHbA1c is an independent risk factor affecting GWI, while HbA1c and the diabetes duration are the independent risk factors affecting GCW, which may be related to the long-term hyperglycaemic environment. The potentially pathogenic conditions, such as endothelial dysfunction and oxidative stress, may impair the left ventricular systolic function –27. PrevThe limitations of this study are as follows. The present investigation was a cross-sectional research study performed at a single center with a relatively small sample size. PSL technology is based on two-dimensional speckle tracking imaging, which requires a high-quality ultrasound image. The follow-up data for prognostic effects in T2DM patients are lacking, so the relationship between PSL related parameters and left ventricular systolic dysfunction needs further longitudinal study.In conclusion, combined with the cardiac afterload, PSL technology can evaluate the changes in the left ventricular myocardial systolic function in T2DM patients with normal LVEF. HbA1c is an independent risk factor affecting GWI, while HbA1c and diabetes duration are the independent risk factors affecting GCW. Therefore, T2DM patients should be treated as soon as possible and the HbA1c level should be strictly controlled.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 the Ethics Committee of Fuwai Central China Cardiovascular Hospital. The patients/participants provided their written informed consent to participate in this study.DH and CC designed the study, analyzed the data, and wrote the manuscript. CC, YLi, YLiu, YH, YW, and RL assisted recruitment and manuscript revision. LL, QZ, and CC assisted in study design, data interpretation, and manuscript revision. All authors had read and approved the final manuscript.This study was supported by National Natural Science Foundation of China (82071950), National Natural Science Foundation of Henan for Excellent Young Scientists (202300410364), Medical Science and Technology Project of Henan Province (SB201901099), and Henan Provincial Medical Science and Technology Research Project (LHGJ20190805 and LHGJ20200084).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.


Background: Anorexia nervosa (AN) and obesity (OB) lead to changes in SBP  that may affect left ventricular (LV) myocardial work (MW). The novel concept of LV pressure-strain loops allows non-invasive estimation of MW, this latter being correlated with cardiac energy metabolism. In addition, the study of regional MW can detect subtle alterations in cardiac function by highlighting an abnormal distribution of MW. Objective: The aim of this study was to assess the cardiac function of AN and OB patients by evaluating global and regional LV strains and MW. Methods: Eighty-seven female adolescents, comprising 26 with AN (14.6 ± 1.9 yrs. old), 28 with OB (13.2 ± 1.4 yrs. old), and 33 controls (14.0 ± 2.0 yrs. old) underwent speckle-tracking echography to assess global and regional LV strains and MW. Results: SBP was higher in adolescents with obesity than in AN patients or controls. Global MW was similar between groups. In AN patients and controls, longitudinal strains were higher at the apex than at the base of the LV, whereas they were similar in obesity patients, owing to a decrease in their apical longitudinal strain. Consequently, their MW was higher at the basal level than either of the other two groups (1854 ± 272 vs. 1501 ± 280 vs. 1575 ± 295 mmHg% in OB patients, AN patients, and controls, respectively. Conclusion: Despite altered SBP, the global MW of adolescents with weight disorders was unaffected. However, in adolescents with obesity, the distribution of their regional LV MW was altered, which might reflect specific regional remodeling. Adolescent weight disorders are extremely common ,2, rangiMyocardial strain analysis from speckle-tracking echocardiography (STE) has emerged in the last decade as a reliable tool for studying myocardial mechanics, adding information on cardiac performance compared with traditional variables of LV function such as EF . HoweverAnother important feature of STE analysis is that it offers a regional assessment of LV strains and MW. In the normal heart, it is well-established that LV strains are higher at the apex than in middle and basal regions ,16. In aThis study set out to describe global and regional LV strains and MW in adolescents with weight disorders. We hypothesized that: (I) GMW would be reduced in AN patients secondarily to a decrease in SBP and conversely increased in OB patients owing to an increase in SBP; and (II) differences in the distribution of regional MW would be present in adolescents with weight disorders, compared with controls, as a result of regional alteration of strains and adverse LV remodeling.n = 30), normal weight (n = 34), and obesity  aged 10–18 years. The patients had been diagnosed in a pediatric department of a university hospital in France between March 2019 and January 2020. The duration of the disease was evaluated from the study of their body mass index (BMI) curves. AN patients fulfilled the DSM V criteria for AN (American Psychiatric Association) [n = 16) or during the first months of the refeeding period (n = 10). None of the AN adolescents reported purge and/or binge behavior or had refeeding syndrome, as evidenced by their normal ionogram. The adolescents with obesity had primary obesity  and did not present diabetes or dyslipidemia (verified on the same day as echocardiography by a blood test). They were not diagnosed with arterial hypertension. The BMI z score was calculated for all participants. None had chronic disease, congenital heart defects, or positive family history of cardiac disease. Written informed consent was obtained from the study participants and their guardians. The Ile-de-France Ethics Committee approved the protocol for this study (18.12.05.66738 CAT 2).This prospective study included female adolescents with anorexia nervosa   and thosciation) . All the−2. BPand resting HR were measured using an automatic device . A fasting venous blood sample was taken for biochemical assays, with in particular NT-proBNP by automated immunoassay. Body height and body mass were measured. BMI was calculated as body mass.body heightEchocardiography was carried out with the subject in the left lateral decubitus position, with Vivid ultrasound systems  using a 3.5 MHz transducer (M4S probe). Cine loops were recorded in parasternal long axis and apical  views and saved for blinded offline analysis . Grayscale images were saved at a frame rate of 80–90 frames/sec and color tissue velocity images at a frame rate of 120–140 frames/s. 2D echocardiographic measurements were made in accordance with the American Society of Echocardiography guidelines . All ech2.7 as recommended in the pediatric population [LV diameters and myocardial thickness were measured from the parasternal long axis view. LV mass was estimated using the Devereux formula and indexed to heightpulation ,25. RelaLV diastolic function was assessed from peak early (E wave) and atrial (A wave) transmitral flow velocities. EF was assessed using Simpson’s biplane method. Global longitudinal strain (GLS) was obtained as previously detailed  and a reMW and related variables were estimated using the Automatic imaging function of the EchoPac software . MW was https://www.medcalc.org; 7 October 2021). All values were expressed as mean ± SD. One-way analysis of variance (ANOVA) was used to compare groups after checking the normality of distribution of each variable by a Shapiro–Wilk test. In the absence of normal distribution, the non-parametric Kruskal–Wallis test was used. Statistical significance for all analyses was assumed at p < 0.05. Intra-observer and inter-observer variability for 2D-strain analysis had been previously assessed in our laboratory, yielding maximal coefficient of variation values less than 8% for strains [Statistical analyses were performed using MedCalc® Statistical Software version 20.013  than in OB (34 ± 23 ng.L−1) and in normal weight (39 ± 21 ng.L−1) patients (p < 0.01).Eighty-seven female adolescents, comprising 26 with AN, 33 with normal weight, and 28 with obesity were included. SBP, GLS and GMW are presented in Regional LS and MW are presented in In adolescents with obesity, median and apical LS were lower, while basal LS was similar to controls. Their basal MW was higher than that of controls. Note that their LS and MW, unlike that of the controls, did not increase from the base and the apex.MW analysis offers the possibility of exploring LV function considering the effects of alteration in loading conditions . In thisAt variance with our hypothesis, the first main result of our study was that the GMW was similar between groups. This was an unexpected finding since differences in BP were observed between our AN patients, OB patients and controls, confirming results of previous studies ,8. MW isIn AN patients, SBP was reduced compared with controls, as previously observed . On the Although our obesity patients were not previously known to be hypertensive, 11 of them had SBP above the 95th percentile for age, the threshold for defining arterial hypertension, and on average their SBP values were significantly higher than those of controls. Moreover, eight of them had a DBP above the 95th percentile, although average values did not reach statistical significance with controls. They had a normal GLS, a result inconsistently found since other studies described a decrease in GLS in children with obesity ,33,34,35In healthy subjects, the LS increased from the base to the apex ,16, probImportantly, the normal LS of subjects with obesity associated with higher BP significantly increased their basal MW compared with controls. These findings underline the usefulness of assessing regional LS and MW to detect subtle alterations in myocardial function, especially in our obesity patients with normal EF, GLS and GMW. Our results in obesity patients raise the question of the significance of the specific increase in basal MW and its possible predictive value for an adverse remodeling of these regions, as suggested by previous studies in other pathological situations ,38. InteTo assess the impact of weight disorders on myocardial mechanics, we recruited AN and OB patients. We chose to analyze a female cohort because the prevalence of AN in male adolescents is very low . Changes in myocardial function were mainly observed in OB patients, a result potentially explained by their higher duration of illness  compared with AN patients. Further studies will be needed to assess regional LV strains and myocardial work in AN adult patients with a longer duration of illness. LV intraventricular pressures, estimated from BP measured with cuff and sphygmomanometer at the brachial artery level may represent another limitation to the study of MW . HoweverThis study is the first to describe global and regional LV strains and MW derived from LV-PLS in adolescents with weight disorders. We found that GMW was similar in AN patients, OB patients and controls. However, our data suggest a specific redistribution of regional MW in OB, with higher values at the LV base compared with controls. Taken together, our results emphasize the importance of considering a regional assessment of LV strains and MW. This approach, taking into account not only deformations but also dynamic non-invasive LV pressure, seems a promising means to detect early subtle alterations in regional myocardial function in AN and OB patients with altered afterload.


Real-time blood pressure, cardiac output, heart rate and diaphragmatic EMG were recorded in all animals. Respiratory modulated pacing was generated by a proprietary device  to pace the heart with real-time respiratory modulation. RSA pacing substantially increased cardiac output by 1.4 L/min (20%) compared to contemporary (monotonic) pacing. This increase in cardiac output led to a significant decrease in apnoeas associated with heart failure, reversed cardiomyocyte hypertrophy, and restored the T-tubule structure that is essential for force generation. Re-instating RSA in heart failure improves cardiac function through mechanisms of reverse re-modelling; the improvement observed is far greater than that seen with current contemporary therapies. These findings support the concept of re-instating RSA as a regime for patients who require a pacemaker.Heart rate variability (HRV) is a crucial indicator of cardiovascular health. Low HRV is correlated with disease severity and mortality in heart failure. Heart rate increases and decreases with each breath in normal physiology termed respiratory sinus arrhythmia (RSA). RSA is highly evolutionarily conserved, most prominent in the young and athletic and is lost in cardiovascular disease. Despite this, current pacemakers either pace the heart in a metronomic fashion or sense activity in the sinus node. If RSA has been lost in cardiovascular disease current pacemakers cannot restore it. We hypothesized that restoration of RSA in heart failure would improve cardiac function. Restoration of RSA in heart failure was assessed in an ovine model of heart failure with reduced ejection fraction. Conscious 24 h recordings were made from three groups, RSA paced ( The heart beats with a number of physiological rhythms including synchronization between the heart chambers, variations in heartbeat intervals, and altered resting heart rate across the day . Heart rHeart failure affects around 26 million people worldwide and around 50% of patients die within 5 years of diagnosis . While cAdult (3–5 year old) female Romney sheep were housed in individual crates, and acclimatized to laboratory conditions  and human contact for 1 week before any experiments. Sheep were fed 2–2.5 kg/day (Country harvest pellets) and had access to water ad libitum. All animal experiments and surgical procedures followed relevant guidelines and were approved by the Animal Ethics Committee of the University of Auckland (#2082). Experiments were carried out over a period of 6 months in each animal; a summary is schematized in Fig. 2 mixture and were intubated for mechanical ventilation. Anaesthesia depth was monitored throughout the surgery by an absence of the corneal reflex and an absence of a withdrawal response to a noxious pinch. The left or right femoral artery was accessed percutaneously using an 8F  sheath and under fluoroscopic guidance, the left main coronary artery was then cannulated, and the catheter advanced into either the proximal left main coronary artery or left descending coronary arteries as described before [Three groups of heart failure sheep were studied: RSA, monotonically paced, and a time control. In the conscious state and standing, echocardiography was performed (Phillips HD-11 Ultrasound) to measure ejection fraction in the healthy animals . Subsequently, sheep were anaesthetized which was induced with 2% Diprivan (Propofol) , maintained with a 2% isoflurane-air-Od before . To induThree days post embolization, conscious sheep underwent echocardiography; once ejection fraction dropped from 70 to 80% to ~ 45%, no more embolizations were performed. A drop in ejection fraction to ~ 45% was selected as the criteria for successful induction of heart failure. Giving all sheep the maximum three embolizations without taking into account ejection fraction resulted in unnecessary animal loss in previous studies. There was a loss of three animals during or within 48 h post the embolizations in this study. Echocardiograms were repeated 1 week, and 3 months post embolization, then once weekly during pacing and the post-pace period. In the long-axis M-mode, diastole, systole, fractional shortening, and ejection fraction were obtained and calculated for the left ventricle. There were no differences in body weight or baseline ejection fraction between groups at the start of the experiment.2 mixture. An intercostal nerve block was performed on ribs 2–6, using a 22G needle 1 mL sterile saline followed by 3 mL Bupivavaine which was injected into the intercostal space immediately cranially of each rib. Sheep were placed on their right side and instrumentation was carried out in full sterile conditions.Three months after heart failure was induced by microembolization, left ventricle ejection fraction was again checked using echocardiography. No sheep was found to significantly increase in ejection fraction over the 3 months and there was a loss of one animal during this period. Once confirmed to be ~ 45%, sheep underwent instrumentation under general anaesthesia (induced with 2% Diprivan (Propofol) 5 mg/kg i.v., AstraZeneca, AUS) and maintained with a 2% isoflurane-air-OA 10 cm incision was made on the left side of the neck. To get an index of blood pressure a single-tip pressure probe  was inserted into the left common carotid artery. Cannulae were inserted into both the jugular vein for venous infusion and the common carotid artery for arterial blood sampling. The pressure probe and catheters were secured with a purse-string suture  to maintain blood flow through the vessel. The incision in the neck was closed with 1.0 suture.To gain access to the heart a dorsal to ventral incision was made on the left side of the chest with a scalpel (size 20) and diathermy , muscle layers were separated and either the fourth or fifth rib was removed. The chest was opened with a retractor and the pericardial sack opened. To measure cardiac output the aorta was separated from the pulmonary artery, and a doppler flow probe  was placed around the ascending aorta for a direct measure of cardiac output on a beat-by-beat basis. For cardiac pacing two pacing leads  were secured externally to the left atrium with 3.0 Filasilk suture and silicone gel. The pericardial sack was closed with 3.0 Filasilk suture. To gain a real time measure of respiration electrodes were implanted into the diaphragm to give a measure of diaphragmatic EMG (‘DEMG’) as previously described . Two strThe chest was closed using sutures in each of the tissue layers including the intercostal muscles  and skin (1.0 braided silk suture). Negative pressure was re-established in the chest, flow probe, pacing and DEMG leads were tunnelled sub-cutaneously and exited percutaneously on the dorsum of the sheep for connecting to chronic recording devices after recovery.Sheep were given antibiotic injections , and analgesia  at the start of surgery, and for the first 3 days post-operatively. Animals were allowed to recover for 5–7 days.All analyses were repeated independently by two experienced members of the group. Cardiovascular and respiratory parameters were recorded from conscious sheep in heart failure on a desktop computer with a CED micro 1401 interface and a data acquisition program . A baseline recording period was acquired when heart rate and cardiac output had stabilized post-operatively (between 5 and 7 days). Continuous arterial blood pressure, cardiac output from the ascending aorta blood flow probe and heart rate were recorded 24 h per day for 5 weeks. Heart rate was calculated from the inter-pulse interval of the blood flow in the ascending aorta. DEMG signal was amplified , and filtered (band pass 0.3–3.0 kHz).Sheep were randomized into three different groups before instrumentation surgery. There was a loss of four animals in total (out of 24) during the instrumentation surgery but this was not different between the groups. The first three animals were time controls, following which animals were randomly assigned to the different groups. The sinusoidal group was conducted once the results from the RSA and monotonic groups were collected.Pacing leads were connected to a stimulator (Grass Instruments) and pacing was set at 10–15 beats per minute above the resting heart rate of each sheep . Frequency was set to produce a peak-to-tough amplitude of 12 bpm, comparable to the RSA group .To determine the percentage of the day the animals were being paced, pacing efficacy was calculated. For monotonically paced sheep the number of heartbeats with a beat interval outside the target paced range was calculated as a percentage of the total number of heart beats. For RSA paced animals, a threshold was placed on the heart rate channel at a value just below the pre-set peak heart rate change during inspiration. This value was subtracted from the total number of breaths to give RSA pacing efficacy.Breathing parameters were assessed from 24 h DEMG recordings. Breath rate was determined as average breaths per minute over 24 h. Apnoea was defined as cessation of diaphragmatic activity. Apnoea incidence was determined by calculating the total number of apnoeas of given lengths  in 24 h.Arterial blood samples (20 mL) were collected into EDTA tubes . Plasma was separated from whole blood by centrifugation , rapidly frozen and stored at − 80 °C before processing. All samples were coded and measurements were made in blinded fashion by the Christchurch Heart Institute; results were returned for decoding. The assay for brain natriuretic peptide has been described previously.An incision was made in the left flank and the left renal artery and renal nerve exposed using methods routine in the lab. Renal sympathetic nerve activity (RSNA) was differentially recorded between a pair of electrodes. The signal was amplified  and filtered (bandpass 400–1200 Hz). Mean arterial pressure was obtained by the pressure probe already implanted. Changes in blood pressure and renal sympathetic nerve active were measured in response to phenylephrine and sodium nitroprusside. For both drugs, the concentration increased at 1-min intervals and doses were 25, 50, 100, 200, and 400 mg/min. All the parameters were recorded on a desktop computer with a CED micro 1401 interface and a data acquisition program .At the end of these experiments, the sheep were euthanized with an overdose of sodium pentobarbitone  . Once death was confirmed, heart and lungs were weighed, in relation to tibia length and cardiac tissue collected for further analysis.All tissue samples were collected from the LV mid-free wall, approximately half-way between the atria and the apex. Care was taken to ensure all tissue samples collected were from the same location between animals, and, therefore, should represent a similarly ischemic area of tissue.Freshly dissected samples from the LV were cut into 0.5 cm thick 1 cm strips spanning the epi-to endocardial surfaces. Samples were collected from all sheep from the same region of the LV. Prior to fixation samples were placed in Tyrode’s solution containing BDM to prevent contraction artifacts from rapid cooling. LV samples were fixed in 1% paraformaldehyde for 1 h 4 °C, before being moved through three solutions of increasing sucrose gradient  over 48 h. Once cryoprotected with sucrose, tissue samples were frozen in liquid nitrogen chilled methylbutane (Thermofisher), and stored at -80 °C before processing.Fixed frozen samples were cut into 12 µm sections on a Leica CM 1900 cryostat and mounted on Superfrost Plus cover slips. Slides were rinsed with phosphate-buffered saline (PBS), and incubated in Fx signal enhancer (Thermofisher) for 1 h at room temperature. Slides were then washed 3 × with PBS, followed by incubating in a 1:100 concentration of wheat-germ agglutinin  for 2 h at room temp. Slides were again washed 3 × with PBS before applying VectaShield and cover slipping. All analysis of cell size and t-tubule power was conducted by experienced members blinded to the group status.2). For each region, 5–10 different cells were measured and an average cell size presented.Fluorescent images of labelled tissue sections were imaged on an Olympus FV1000 confocal microscope . 5–8 different regions from each stained LV slice were imaged at 20×. Analysis was performed using ImageJ (Fiji). A two-pixel median filter was applied to all images. Individual cardiomyocytes deemed to be lying parallel to the imaging, in full longitudinal view were traced around the circumference to measure cell area  to a pixel size of 80 nm. 10–12 areas were imaged at 60 × per LV section. Images were analyzed in ImageJ (Fiji). All images underwent a 2 pixel median filter, and 0.3 pixel background subtract. FFT was performed along a selected 20 µm line (Extended Data 3). 2–4 individual myocytes were analyzed per image. T-tubule power was determined from a power spectrum obtained from the FFT.t-test. Histology analysis was analyzed between three groups, time control, monotonic paced, and RSA paced using an ordinary one-way ANOVA. All statistical analysis was performed in SPSS (v8.1). Data were considered significant if p < 0.05.All data are expressed as mean ± SEM, except where indicated. All-time course data  were analyzed using a repeated measures 2-way ANOVA, or mixed-effects model if any missed data points were ‘missing at random’. Posthoc analysis was completed if there was an effect of time and Dunnetts two-sided post hoc tests were used to compare the time points to baseline. Renal sympathetic nerve recordings were analyzed in SigmaPlot. Heart weight, and lung weight were analyzed between monotonic and RSA paced sheep using an unpaired two-tailed students P < 0.001, interaction factor; Fig. P < 0.05; Fig. P < 0.05) and fractional shortening  and fractional shortening . In contrast, in Mono paced sheep, there was no change in arterial pressure but there was a tendency for CO to decrease which meant that calculated systemic vascular resistance actually increased .In sheep with RSA pacing, arterial pressure was unchanged Fig. . The eleP = 0.06) re-setting to operate over a lower blood pressure range, and baroreflex saturation (blood pressure level where sympathetic activity was fully inhibited) as significantly reduced . In contrast, there was no difference in cardiac baroreflex gain between groups.Under anaesthesia, baroreflex function was assessed at the end of the protocol Fig. B and artP < 0.001); this did not occur immediately but followed after the significant increase in cardiac output during the fourth week of pacing. Breath rate (breaths per min) was not different between groups, or across the different pacing protocols.Our heart failure sheep displayed apnoeas of 3–6 s in duration Fig. A, which versus 6.74 ± 2.6 pmol/L, respectively) but after 4 weeks of pacing BNP was reduced in the RSA group only . Next, we asked whether the tissue damage caused by heart failure was reversed by RSA pacing.There was no difference in BNP concentration between RSA and Mono groups pre-pacing (6.16 ± 1.3 P < 0.05) and not different to healthy controls . There was no difference in heart or lung weights between these groups  making them discontinuous and reduced their occurrence Fig. B relativols Fig. . Additiops Table .Fig. 5T-To validate whether the coupling of heart rate to breathing was critical for elevating cardiac output, we used a sinusoidal pacing regimen independent of breathing Fig. A. The peOur findings have led us to three major conclusions: (1) Reintroduction of RSA in heart failure significantly increases cardiac output, in part by reducing systemic vascular resistance. (2) RSA pacing in heart failure leads to a slow significant reduction in apnoea incidence over time. (3) Reintroduction of RSA over 4 weeks leads to a restoration of cardiomyocyte size as well as t-tubule morphology towards those of healthy controls.The true role of RSA in cardiorespiratory physiology has long been debated and remains controversial. A number of benefits of RSA have been proposed, including optimizing gas exchange, stabilizing blood pressure, and more recently, mathematical modelling has suggested increasing cardiac energy efficiency , 39. AltPlasma brain natriuretic peptide (BNP) is released from the ventricles in response to increased ventricular pressure/stretch, correlated with heart failure severity , and treAutonomic imbalance is a negative prognostic indicator in heart failure . IncreasOf interest, the beneficial changes observed with RSA pacing, occurred when the heart was paced with respiratory modulation for approximately 40% of the time. The lower pacing efficacy in the RSA pacing group occurred over extended periods of time when respiration rate increased to a level that the pacing device was unable to vary heart rate in phase with respiration. This is similar to humans where RSA is most prominent during non-REM sleep and during periods of rest, and lost during activity , 35. ThiThere is good evidence that a reduction in heart rate variability is associated with worse outcomes in patients with heart failure. We wanted to ascertain if the variability in heart rate needed to be entrained to the respiratory cycle or whether variable heart rate pacing alone would improve outcomes. We tested this by undertaking sinusoidal pacing of heart rate that was not linked to the respiratory cycle. Surprisingly, in all animals tested, sinusoidal pacing led to a dramatic decrease in cardiac output and pacing needed to be stopped within a week. These results indicate that the variable rate pacing needs to be entrained to the respiratory cycle for the improvement in cardiac output to occur.The mechanisms whereby RSA induces or inhibits transduction pathways is currently unclear. Cyclic stretch of isolated cardiomyocytes, and cardiomyocyte-derived stem cells have been shown to induce the alignment of proteins required for efficient excitation–contraction-coupling , induce We have previously shown that this model of heart failure has a higher resting heart rate than equivalent healthy controls . This isHeart failure affects more than 26 million people globally, and is a growing pandemic . Around The 20% improvement in cardiac output seen with RSA pacing represents an impressive improvement in cardiac function. It is important to note that RSA is minimal or abolished in many patients with heart failure . So evenGiven the dramatic improvements in cardiac output, we wanted to determine the effects on systemic vascular resistance. The length of this protocol meant that conscious chronic nerve recordings were not possible in this study. However, we have calculated systemic vascular resistance from direct recordings of cardiac output and mean arterial pressure and this indicates reintroduction of RSA pacing is associated with a significant reduction in systemic vascular resistance. Together with this, our direct recordings of renal sympathetic nerve activity indicate that baroreflex control of sympathetic nerve activity to the kidney is improved. Although this study was performed in a clinically relevant translational model, it must be noted that the animals in this study were not on common heart failure medication. Given that RSA is mediated by the parasympathetic nervous system which is not targeted by current medications, we anticipate that re-introducing RSA would still be beneficial in a patient population with contemporary medication on board.Our work identifies for the first time, in a large animal translational animal model that reintroducing respiratory modulated pacing in heart failure results in a dramatic improvement in directly recorded cardiac output. In addition, RSA pacing reduces apnea incidence and re-models cardiomyocyte morphology. Taken together, our data support the concept of reintroducing RSA as a pacing paradigm in pacemakers.


The present means of confirming the cure of intra-operative polymethyl methacrylate (PMMA) cement are to wait for the remainder cement to harden. To our knowledge, there is no available technique to determine the precise moment of cure for in-vivo cement beneath the tibial tray. This study uses a novel means to determine cement curing time in two environments. One environment represents the operating theater, and the other environment attempts to model cement conditions under the tibial tray during surgery.t-test.We determined the temperature-versus-time plot of cement curing using the following two temperature sensors: one in a simulated implanted tibial tray and another in the remainder cement. We performed 55 tests using dental methyl methacrylate cement mixed in the same ratio as the orthopedic cement. To simulate in vivo conditions, a simulated stainless-steel tibial tray was implanted on a cancellous bone substitute  using standard cement technique and subsequently placed in a 90°F (32.2 °C) circulating water bath. We positioned a temperature sensor in the cement mantel and positioned a second sensor in a portion of the remaining cement. The temperature from both sensors was measured simultaneously, beginning at 5 min after mixing and continuing for 20 min. The first derivative of the temperature provided the precise curing time for each condition. We analyzed the results of 55 repeated experiments with an independent samples p value < 0.001) between the two conditions.With the described technique, we were able to accurately determine the moment of cure of the cement beneath the simulated tray. There was a mean difference between cure time of 5 min and 26 s (We validated that our technique was successful in determining the precise time to cure in two different environments.This was not a clinical trial and did not involve patients as such the level of evidence was Grade A: Consistent 1 and 2. Tcure, i.e., the temperature at which the cement is considered fully cured) is halfway between the maximum temperature of the cement during curing (Tmax) and the initial ambient temperature of the cement (Tambient).Acrylic bone cement has been used in orthopedic surgery for over 50 years and is the standard of care for fixation of total joint arthroplasty. After mixing the liquid monomer with the powdered polymer, the cement is converted from liquid to solid by an exothermic reaction. The duration to full polymerization is variable and depends on multiple factors, including temperature and humidity. The American Standard for Testing Material (ASTM) Designation F452-08  specificPresently, cement curing during implant surgery is determined either by palpating the cement edge or allowing the remainder cement to harden in vitro. Both methods are imprecise and unscientific. To clinically study intraoperative questions relating to cement cure, such as cement type, viscosity, mixing means, cement temperature, antibiotic inclusion requires the ability to precisely determine the time of cure of the in vivo cement.Furthermore, the ability to intra-operatively determine cement cure has become more important with recent investigations regarding the causes of aseptic loosening of total knee tibial implants. It has been proposed that lipid infiltration between the tibial tray and the cement interface prevents the cement from interdigitating with the undersurface of the tibial tray, resulting in an area of de-bonded cement. Knee motion prior to full cure of the tibial tray cement can hydraulically wick lipids into the cement–tray interface –4. ConseThis study aims to describe a new technique which can accurately determine cement cure beneath a simulated in vivo tibial plate. To validate that technique a comparison between simulated in vivo and in vitro conditions will be performed. The difference of the time to cure for both conditions will be statistically analyzed. It is proposed that the simulated in vivo cement will cure before the in vitro cement. Confirmation of this finding would indicate that this technique is providing accurate information on the cure point of the cement under the simulated tibial plate.A 2-inch (5.08-cm) square cube of Cellular Foam, 7.5 PCF, 40 mm  was used to simulate the cut cancellous bone surface of a tibia prepared for tibial implantation  plate composed of 4-mm-thick 316 stainless steel. The bone-facing side of the tray was grit-blasted so that the roughness of the surface finish approximated a standard cemented implant. A 1-inch-long (2.54-cm), 3/8-inch-diameter (0.95-cm) tapered 316 stainless steel stem was attached to the bone-facing side of the tray.We recognize that the testing implants are significantly smaller and of a different material then standard TKA tibial tray implants. It was not feasible to use real tibial implants given the cost and availability. Our purpose was to prove the usefulness of a new technique for determining cement cure under an orthopedic plate, we believe that the size and material of the test plates would not affect the outcome if the same structure of tray was used for all the experiments.http://www.snapware.com). An outflow opening was placed on the opposite side of the container from the inflow. An outlet pump  was attached to the outlet tube (inside diameter: 3/8 inch [0.95 cm]), which fed the water back into the water tank. During the experiment, the plastic container acted as a water bath with water at a constant temperature flowing around the simulated cancellous bone 3/4 inches (1.91 cm) below the top surface of the simulated bone surface. We surmised that the cut end of an in vivo tibia would be at a lower temperature than body temperature due to the surgical exposure. To account for the lower temperature in the distal tibia, we decreased the water bath temperature from normal body temperature by 9% to 90°F (32.2 °C).The water bath consisted of a 3-gal (11.36-L) fish aquarium with a submersible 500-W temperature controller  calibrated to 0.1 °F accuracy. A submersible 2.9-W filter pump rated at 220 L/h was placed in the tank. The pump outlet was connected to plastic inflow tubing (inside diameter: 3/8 inch [0.95 cm]), with the water exiting into a three-cup (708-cc) plastic storage container  within 0.02 g of the specified weight before mixing. We mixed the cement in an open container with a spatula for two minutes, then allowed the cement to rest for one minute. We monitored the room temperature by a factory-calibrated thermohygrometer  and maintained the room within one degree of 68°F (20 °C) with room humidity between 45 and 50% during mixing as well as throughout the experiments. Experiments performed outside of these parameters were not included for analysis.It was not possible for us to obtain sufficient orthopedic bone cement to utilize in this study due to cost as well as regulations surrounding it’s use. For that reason, we utilized dental denture acrylic as a substitute for orthopedic cement. Dental cement has the same chemical formulation as the orthopedic acrylic cement and behaves in the same manner during its cure cycle. The two-part mixture consisted of a liquid monomer  and polymer powder  and was used for each of the 55 experiments. The dental cement was mixed in the same proportion by weight as the orthopedic cement (20-g polymer powder to 10-g monomer liquid). We measured the weights of the components on a digital scale , After the rest period, the cement was applied to the top of the Sawbones and undersurface of the tray. A temperature thermistor was placed on the Sawbone side cement and then a small square of thin, porous polyethylene packing material place on the sensor facing the implant to dampen the heat sink effect. The implant was then impacted onto the Sawbones utilizing a Nylon mallet. After impaction, no further pressure was applied to the plate. Temperature controlled water was allowed to circulate around the jig. Subsequently, we inserted a second thermistor into the center of a measured 5-g ball of the remaining cement and placed this cement on the workbench.We monitored the cement temperature using a thin-film negative temperature coefficient thermistor  attached to an Arduino programable controller . The reproducibility of the system was determined to be − 0.3 °C. The controller had two channels (A and B) that could monitor two TEWA sensors simultaneously. The temperatures of both simulated in vivo and in vitro cement were recorded at a rate of 1/s on an excel spreadsheet.t-test. To determine the sample size for the study, we conducted a power analysis (using G*Power version 3.1.9.5 for Mac OS X). To determine the amount of statistical power needed to find a medium effect (Cohen’s d = 0.50) for an independent samples t-test at the power of 0.80, Cohen (1998)5 recommended an overall sample size of 102. This means that 102 participants (51 participants per group) should provide sufficient power to detect an effect.Our purpose was to compare the time to cure in the two conditions, simulated in vivo and in vitro. To obtain results that were statistically significant, we conducted an independent samples The testing consisted of 55 separate experiments. Each experiment was prepared and completed in the same manner. During the experiment, recording of the two sensors was performed simultaneously and began at 5 min after the start of the cement mixing and was continued for 20 min (25 min after initiating mixing). The temperature results were captured into a custom Excel spread sheet for analysis. The raw temperature data were smoothed by using a running average of five temperature readings before and after each data point. Further data analysis was performed as discussed in the results section.Tmax). In our study, we observed consistency in the shape of the temperature plots between experiments for both simulated in vivo and in vitro conditions. Although the plots were similar in shape, the Tmax reached by the two conditions in each experiment varied considerably. The dental cement Tmax for the in vitro condition varied from 66.71°F (34.33 °C) to 109.86°F (43.26 °C) (mean: of 93.79°F [34.33 °C]), and the Tmax for the simulated in vivo cement condition varied from 36.91°F (2.73 °C) to 71.74°F (22.63 °C) (mean: of 49.52°F [9.74 °C]). In both conditions, as the temperature approached Tmax, there was a flattening of the temperature plot into an arc-type shape. Consequently, the Tmax in the results could not be precisely determined for use in calculating the cure point (Tcure). Uniformly, the time to cure for the simulated in vivo cement was noticeably shorter than the time to cure for the in vitro cement.The dental cement temperature plots closely resembled the plots used by ASTM for determining curing, with a period of minimal change proceeding to an exponential increasing temperature and then a decreasing temperature after reaching the maximum temperature . However, based on the shape of the plot, which showed a period of minimal change followed by an exponential increase in temperature and a subsequent reversal of the slope as the cement began to cool, we concluded that using a derivative of the temperature plot would allow us to determine a precise point of cement cure.The average of all 55 experiments temperature versus time cement plots is shown in Fig. Tcure).The first derivative is a line tangent to a point on the plot and indicates the instantaneous rate of change in a plot line. As the change in the cement temperature increases, the temperature plot rate of change increases correspondingly. Consequently, the faster the rate of change in the cement temperature, the greater the value of the first derivative. A positive first derivative value means that the temperature is increasing, while a negative first derivative indicates that the cement is cooling. At that inflection point between heating and cooling, the chemical reaction is complete, and the cement can be considered cured. Figure Y/dX) formula:Using the first derivative . The time difference between the maximum value of the first derivative for the simulated in vivo condition, subtracted from the in vitro condition, is the time difference between curing in each of the 55 experiments.t-test to evaluate significant differences in cement curing time between in vivo and in vitro cement. The results revealed that the curing time for in-vivo cement (Mean(M) = 7.66 [7 min(min) 39 s(sec)], SD = 1.07 [1 min 4 s]) was significantly quicker compared to the curing time for in vitro cement . We observed that the effect size for this analysis (d = 4.82) exceeded Cohen’s [t-test.We conducted an independent samples 9 13 min  s, SD = p value of < 0.001 indicates that the results are highly significant, and there is < 1 in a thousand chance of making a type 1 error (or being incorrect).The results indicate that the simulated in vivo cement cured at a significantly faster rate than the in vitro cement. The magnitude of this effect was large, suggesting that the difference is important. The significance level  is the probability of making a type 1 error . A Orthopedic surgeons performing total joint arthroplasty are aware of the thermal characteristics of acrylic bone cement –10. PrevAseptic loosening of the tibial base tray after total knee arthroplasty remains a major cause of revision surgery . Recent To our knowledge, the use of the polymerizing cement temperature to determine the curing time under an orthopedic implant has not been previously studied. Presently, determining the duration of full cure of the cement intraoperatively is, at best, imprecise. Using the remaining cement to establish the completion of curing has not changed since the early days of arthroplasty. Waiting for the extra cement to harden is a time-honored artistic ritual for surgeons and staff.Tcure). We have also shown that it is possible to use the temperature plot to determine the cure point of cement in a simulated operative condition.A technique to determine when the tibial tray cement is cured would allow for more accurate study of cement behavior in different conditions. Variables such as cement temperature, cement viscosity and antibiotic additions could be evaluated by finding the precise time of cement cure in vivo. From a clinical standpoint, knowing the time of cement cure would allow the surgeon to determine when it is safe to move the knee, potentially decreasing the risk of aseptic loosening. We have demonstrated that using the first derivative of the temperature plot of curing cement is valid in ascertaining the point of full cure  of bone cement in two conditions: simulated in vivo and in vitro. The study validated that by using the first derivative of the temperature plot, the accurate cure time of bone cement under a simulated in vivo tibial tray can be determined. Developing a clinical device using temperature sensors to determine tibial tray cement cure during surgery would allow for further investigations into cement behavior. Such a device could also be used to potentially shorten the surgical time of cemented total knee arthroplasty while decreasing the risk of lipid infiltration.In conclusion, the temperature-versus-time plot of acrylic bone cement was utilized to determine the cure point (