| 1.1Evaluation of Subclinical Anthracycline-induced Cardiotoxicity in the Long-term Follow-up Survivors by Speckle Tracking ImagingObjective:To detect the subclinical myocardial injury after epirubicin exposure in the long-term follow-up asymptomatic survivors with large B-cell non-Hodgkin lymphoma using two-dimensional speckle tracking imaging.Methods:Twenty patients (chemotherapy group) aged48.7±15.7years with large B-cell non-Hodgkin lymphoma who had treated with anthracycline-based chemotherapy20±9months previously, and20controls were studied. Left ventricular ejection fraction (LVEF) and diastolic function, including mitral valve early diastolic E velocity, late diastolic A velocity, E/A, deceleration time (DT) and isovolumic relaxation time (IVRT) were analyzed. Global and regional longitudinal (LS), circumferential (CS) and radial strain (RS), standard deviation of time to peak LS (TLS-SD), CS (TCS-SD), RS (TRS-SD) were calculated using two-dimensional speckle tracking imaging.Results:The chemotherapy group had longer DT and IVRT in comparison with the controls (201.5±48.4ms vs172.9±34.4ms,92.8±1.1ms vs80.9±7.4ms, p<0.05)。 Despite of normal LVEF, global, basal, mid and apical LS, global, basal and mid CS were markedly reduced in the chemotherapy group compared with those of the control group (-15.80±1.79%vs-18.15±1.90%,-15.45±2.99%vs-18.83±2.67%,-14.82±2.35%vs-16.78±2.19%,-16.27±1.68%vs-18.51±3.33%,-17.14±2.17%vs-19.67±2.42%,-17.65±2.46%vs19.59±2.83%,-17.49±2.62%vs-19.43±3.07%, respectively, p all<0.05). However, global and segmental RS, TLS-SD, TCS-SD and TRS-SD showed no significant difference between the two groups. Among age, hypertension, smoking, cumulative doses of anthracycline, anthracycline dose of each session and follow-up time from last dose, no statistic significant correlation was found between these clinical risk factors and strain values.Conclusions:Subtle abnormalities in myocardial systolic function were present in asymptomatic long-term follow-up patients after anthracycline exposure, which could be detected by two-dimensional-speckle tracking imaging. 1.2Speckle Tracking Imaging Combined with High Sensitive Cardiac Troponin T in Early Detection and Prediction of Cardiotoxicity during Anthracycline-based ChemotherapyObjective:To detect the early subclinical myocardial injury during and shortly after epirubicin exposure in asymptomatic patients with large B-cell non-Hodgkin lymphoma by two-dimensional speckle tracking imaging and high sensitive cardiac troponin T (hs-cTnT) and to investigate whether alterations of myocardial strains and high sensitive cardiac troponin T could predict future cardiac dysfunction in patients after epirubicin exposure.Methods:Seventy-five patients aged53.9±13.8years with newly-diagnosed large B-cell non-Hodgkin lymphoma treated with anthracycline were studied. Blood collection and echocardiography were performed at baseline,1day after the third cycle, and1day after chemotherapy completion. After4-6months of chemotherapy, echocardiography was followed up. Levels of cTnT were detected with a highly sensitive assay. Longitudinal (LS), circumferential (CS) and radial strain (RS) were calculated using two-dimensional speckle tracking echocardiography. Left ventricular ejection fraction (LVEF) was analyzed by real-time3D echocardiography. Cardiotoxicity was defined according to the guidelines (Cardiac Review and Evaluation Committee of Trastuzumab-associated cardiotoxicity, CREC) as a reduction of the left ventricular ejection fraction (LVEF) of≥5%to <55%with symptoms of heart failure or an asymptomatic reduction of the LVEF of≥10%to <55%.Results:LVEF remained stable and within normal limits in the whole course of chemotherapy. However it was decreased from65.0±3.8%at baseline to60.8±4.9%during follow-up (p=0.000). Fourteen patients (18.67%) developed cardiotoxicity4-6months after treatment. Global LS (-18.5±1.7%vs-16.5±1.9%), CS (-20.9±2.9%vs-19.3±3.5%), RS (39.2±6.4%vs35.3±5.2%) were markedly reduced and cTnT was elevated from0.0010±0.0020ng/ml to0.0063±0.0089ng/ml (p all<0.01) at the completion of the third cycle of chemotherapy compared with baseline values. The correlation between the increment of cTnT levels and percentage of global LS deduction was good (rho=0.60, p<0.01), and percentage of CS and RS decrease was modest (rho=0.31,-0.29, respectively, p all<0.01). A>15.9%decrease in longitudinal strain (sensitivity:86%, specificity:75%, AUC=0.815, P=0.001) and a>0.004ng/ml elevation in cTnT levels (sensitivity:79%, specificity:64%, AUC=0.757, P=0.005) from baseline to the third cycle of chemotherapy predicted later cardiotoxicity. The decrease of longitudinal strain between baseline and the third cycle of chemotherapy remained the only independent predictor of cardiotoxicity (p=0.000).Conclusions:Two-dimensional speckle tracking imaging combined with high sensitive cTnT may provide a reliable and accurate non-invasive method to detect subtle myocardial injury during anthracycline-based chemotherapy. Longitudinal strain combined with high sensitive cTnT may provide a reliable and non-invasive method to predict cardiac dysfunction in patients receiving anthracycline-based chemotherapy. The decrease of longitudinal strain is the only independent predictor of cardiotoxicity. Part TwoAssessment of Subclinical doxorubicin-induced Cardiotoxicity in a Rat Model by Speckle Tracking ImagingObjective:To investigate, by means of an experimental rat model using doxorubicin, whether speckle tracking imaging based strain and strain rate analysis could provide a more sensitive and accurate measurement in detecting left ventricular injury.Methods:Thirty-seven adult male Wistar rats, weighing250.4±4.3g, were divided into4groups of8rats each, given doxorubicin intraperitoneally at weekly intervals for up to4weeks. Group1:2.5mg/kg/week, total dose10mg/kg; group2:3mg/kg/week, total dose12mg/kg; group3:3.5mg/kg/week, total dose14mg/kg; group4:4mg/kg/week, total dose16mg/kg. An additional5rats were used as controls in which1ml0.9%saline solution was administered intraperitoneally at weekly intervals for4weeks. Echocardiographic images were obtained at baseline and1week after the last dose of anthracycline treatment. Left ventricular dimensions were measured using M-mode echocardiography at the short-axis view of the mid-papillary level and left ventricular ejection fraction (LVEF) was calculated using the Teicholz method. Peak systolic radial strain (RS), circumferential strain (CS), radial strain rate (RSr) and circumferential strain rate (CSr) was obtained from6segments of the papillary muscle levels by speckle tracking imaging. One week after the end of doxorubicin administration, blood samples were collected for cardiac troponin I (cTnI) analysis and portions of the heart were fixed and stained for histological evaluation.Results:There was no significant difference of LVEF, strain and strain rate values at baseline among the four groups. After doxorubicin exposure, LVEF was reduced from85.5±1.2%to82.5±1.8%(p=0.006) in animals given16mg/kg doxorubicin. However, LVEF in other animals receiving less doxorubicin showed no statistical difference before and after treatment. After doxorubicin exposure, radial strains was reduced in animals of group2, group3and group4(from52.1±5.6%to43.2±5.7%,52.5±5.1to38.6±4.8%and52.3±7.3%to34.6±7.4%respectively, p all<0.05). Circumferential strain was reduced from-17.4±2.1%to-14.1±1.8%in those given16mg/kg doxorubicin after treatment (p=0.004). The reduction of radial strains induced by doxorubicin was dose-related (p=0.000). Radial strain rate and circumferential strain rate remained unchanged after exposure, independent of doxorubicin doses. The severity of myocardial lesions in histological analysis was significantly more severe in group3and4than those given less doxorubicin (p<0.05). The serum cTnI levels (except for that of group1) were significantly elevated with the increase of total cumulative doses of doxorubicin in comparison with those of control group (p<0.05). The decrease of radial strains exhibited a significant correlation with the cTnI concentration (spearman correlation rho=-0.736, p=0.000) and with cardiomyopathy scores (spearman correlation rho=-0.797, p=0.000).Conclusion:Radial strain based on speckle tracking imaging can provide a sensitive and noninvasive index in early detection of doxorubicin-induced myocardial injury. The changes of radial strain had a significant correlation with myocardial lesions and serum cardiac troponin I levels, indicating that this parameter could accurately evaluate the severity of cardiotoxicity Part Three Clinical studies of predicting response to cardiac resynchronization therapyObjective:To establish a score system derived from clinical, echocardiographic and electrocardiographic factors and evaluate its clinical value for cardiac resynchronization therapy (CRT) patient selection.Methods:A total of90patients receiving CRT (60.8±12.9years) were enrolled. All patients underwent standard EKG and echocardiography evaluation before implantation and during follow-up. The parameters measured by EKG were:duration of QRS, morphology of QRS. Left ventricular end-systolic and end-diastolic dimensions (LVESD, LVEDD), end-systolic and end-diastolic volumes (LVESV, LVEDV), left ventricular ejection fraction (LVEF), interventricular mechanical delay (IVMD), tricuspid annular plane systolic excursion (TAPSE), degree of mitral and tricuspid regurgitation and pulmonary artery pressure (PAH) were calculated by echocardiography. Global longitudinal (LS), circumferential (CS) and radial strain (RS) values were analyzed based on speckle tracking imaging. We measured standard deviation of time to reach minimum regional volume of16segments (systolic dyssynchrony index, SDI) related to the heart cycle from real-time three-dimensional echocardiography. A patient selection score system was generated by the clinical, echocardiographic and electrocardiographic parameters achieving a significance level by univariate and multivariate regression model. The Wald test was used to evaluate the weight of the variables to predict CRT response. A positive response to CRT was a LVESV decrease of≥15%and not reaching primary clinical endpoint (death or rehospitalization for heart failure) at the end of follow-up.Results:Thirty-seven patients were CRT non-responders (41.11%) and53were responders(58.89%). After CRT implantation, in all patients, LVEDV, LVESV, LVEF, IVMD and SDI were marked improved from230.05±96.10ml to199.59±82.53ml, from163.88±78.75ml to129.51±67.93ml, from31.06±8.66%to38.52±10.20%, from41.21±30.34ms to25.54±18.02ms and from23.56±18.30%to10.87±11.91%, respectively (p all<0.01). PAH was also decreased from42.25±16.54mmHg to35.92±11.67mmHg,(p=0.000). However, in non-responders, all the parameters above showed no significant change after CRT. A4-point score system was generated based on TAPSE, SDI, LS and QRSd. The sensitivity and specificity for prediction a positive response to CRT at a score≥3were0.792and0.946, respectively (AUC:0.945,95%CI:0.902-0.988, p<0.001)。Conclusion:A patient selection score system based on the integration of TAPSE, SDI, LS and QRSd can help to predict positive response to CRT effectively and reliably. Part FourThree-Dimensional Speckle Tracking Imaging for Assessment of Left Ventricular Function and Mechanical DyssynchronyObjective:Evaluation of left ventricular (LV) function and dyssynchrony is of vital importance. A newly-developed three-dimensional (3D) speckle tracking imaging (STI) has the potential to circumvent limitations of two-dimensional STI. Our study was to evaluate LV function and dyssynchrony and acute effect of cardiac resynchronization therapy (CRT) in dilated cardiomyopathy patients (DCM) with complete left bundle branch block (CLBBB) by3D-STI.Methods:Fifty-two nonischemic DCM with CLBBB and55healthy subjects were enrolled in. In these patients,24underwent cardiac resynchronization therapy. DCM patients were divied into3groups according to left ventricular ejection fraction (LVEF).3D-STI was performed before and1month after CRT. We measured3D (3DS), longitudinal (LS), circumferential (CS) and radial (RS) strain of LV. The LV dyssynchrony was evaluated by the standard deviation of time to peak negative value of3D strain (3DS-SD) and time to reach minimum regional volume of16segments (SDI) related to the heart cycle.Results:In healthy volunteers, LS, CS, RS and3DS values were largest in the apical region and decreased significantly from apical to basal level. DCM patients had significantly lower global3DS (-17.12±6.70%vs-38.38±4.28%, P<0.01), LS (-9.46±4.07%vs-21.09±2.45%), CS (-10.28±5.21%vs-27.60±4.35%) and RS (32.23±26.94%vs97.08±16.08%), P all<0.01and significantly greater3DS-SD (11.11±5.14%vs4.04±1.43%, P<0.01) and SDI (9.69±4.82%vs4.23±1.33%, P<0.01) than normal volunteers.3DS, LS, CS, RS had an excellent correlation with LVEF (spearman rho=-0.94,-0.91,-0.93,0.89respectively, P<0.01for all).3DS-SD correlated well with SDI (ICC=0.85). For mild, moderate and severe systolic dysfunction,3DS-SDs were4.56±1.53%,9.87±2.58%, and14.54±4.71%, respectively (P<0.01) and SDIs were4.46±1.27%,8.19±2.35%, and12.83±4.87%, respectively (P<0.01) but independently of QRS width. After CRT therapy, global3DS (-13.12±2.63%to-14.06±2.53%, P=0.025),3DS-SDs (12.99±3.92%to11.53±4.53%, P=0.015) and SDIs (10.85±3.74%to9.50±4.63%, P=0.013) were markedly improved.Conclusion:When image quality is optimal,3D STI seems to be a promising approach assessing LV function and dyssynchrony. |
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