Intrinsic Wave Velocity Propagation: A Novel Parameter for Assessing the Effect of Anthracycline Chemotherapy Agents on Cardiac Diastolic Function in Breast Cancer Patients.

OBJECTIVE: Anthracycline chemotherapeutic agents have significant cardiotoxicity. The present study emphasized the effect of anthracycline chemotherapy drugs on left ventricular (LV) myocardial stiffness in breast cancer patients by measuring the intrinsic wave velocity propagation (IVP), and evaluating the potential clinical value of IVP in detecting early LV diastolic function impairment. METHODS: A total of 68 newly diagnosed breast cancer patients, who were treated with anthracycline-based chemotherapy, were analyzed. Transthoracic echocardiography was performed at baseline (T0), and after 1, 2, 3, 4 and 8 chemotherapeutic cycles (T1, T2, T3, T4 and T5, respectively). Then, the IVP, LV strain parameters [global longitudinal strain (GLS), longitudinal peak strain rate at systole (LSRs), longitudinal peak strain rate at early diastole (LSRe), longitudinal peak strain rate at late diastole (LSRa), and the E/LSRe ratio], and conventional echocardiographic parameters were obtained and further analyzed. A relative reduction of >15% in GLS was considered a marker of early LV subclinical dysfunction. RESULTS: Compared to the T0 stage, IVP significantly increased at the T1 stage. However, there were no significant changes in GLS, LSRs, or LSRe between the T0 and T1 stages. These parameters significantly decreased from the T2 stage. LSRa started to significantly decrease at the T5 stage, and the E/LSRe ratio started to significantly increase at the T3 stage (all P<0.05). At the T0 stage, IVP (AUC=0.752, P<0.001) had a good predictive value for LV subclinical dysfunction after chemotherapy. CONCLUSIONS: IVP is a potentially sensitive parameter for the early clinical assessment of anthracycline-related cardiac diastolic impairment.

Evaluation of left atrial and ventricular remodeling in atrial fibrillation subtype by using speckle tracking echocardiography.

Background: Atrial fibrillation (AF) is associated with cardiac structural and functional remodeling. We investigated the left atrial (LA) and left ventricular (LV) changes in AF subtypes by using two-dimensional echocardiography strain techniques. Methods: The study population consisted of 102 subjects with sinus rhythm (control group) and 463 patients with AF, among which 284 patients had paroxysmal AF (PAF) and 179 patients had persistent AF (PerAF). A speckle tracking automatic functional imaging software was used to perform the strain analysis. Results: Patients with AF had dilated LA maximum and minimum volume, decreased LA reservoir strain, lower LV ejection fraction (LVEF), and impaired global longitudinal strain (GLS) compared to those of the sinus rhythm control group. In patients with PerAF, the LA maximum and minimum volumes were larger, and the LA reservoir strain [PAF vs. PerAF, 28% (21,33) vs. 19% (14, 28), P < 0.05], LVEF, and absolute GLS value (PAF vs. PerAF, -16.9 ± 3.3 vs. -14.1 ± 3.5%) were lower than those in patients with PAF. Patients with AF regardless of LA enlargement had decreased LA reservoir strain and lower LVEF and absolute GLS value than those in the sinus rhythm control group. Conclusion: Compared with those with normal sinus rhythm, patients with AF had dilated LA volume and impaired LA function, which were further worsened in patients with PerAF than those in patients with PAF. LA functional impairment occurred before LA enlargement. Left atrioventricular remodeling happened across different stages of AF development.

Exploring the prospect of intrinsic wave propagation in evaluating myocardial stiffness among patients with type 2 diabetes.

Background: Diabetes predisposes affected individuals to impaired myocardial perfusion and ischemia, leading to cardiac dysfunction. Increased myocardial stiffness is an independent and significant risk factor in diastolic dysfunction. This study sought to estimate myocardial stiffness in Type 2 diabetes (T2DM) patients using the intrinsic wave velocity propagation (IVP) along the longitudinal wall motion during late diastole and evaluate the value of IVP in assessing cardiac function and structure. Methods: 87 and 53 participants with and without T2DM (control group) were enrolled. Of the 87 T2DM patients (DM group), 43 were complicated with hypertension (DM + H group), and 44 were not (DM-H group). Ultrasound parameters were measured and analyzed, including color M-mode flow propagation velocity, global longitudinal systolic strain (GLS), and IVP. Results: IVP was higher in the DM group than in the control group (1.62 ± 0.25 m/s and 1.40 ± 0.19 m/s, P < 0.001). After stratification for hypertension, IVP in both DM + H (1.71 ± 0.25 m/s) and DM-H (1.53 ± 0.20 m/s) groups were found to be significantly higher than that in the control group (1.40 ± 0.19 m/s); also, the difference of IVP between DM + H and DM-H group reached statistical significance. Moreover, IVP was significantly correlated with flow propagation velocity during early diastole (Pve) (r = -0.580, P < 0.001), flow propagation velocity during late diastole (Pva) (r = 0.271, P < 0.001), GLS (r = 0.330, P < 0.001), interventricular septal thickness at end-diastole (IVSd) (r = 0.321, P < 0.001), blood glucose (r = 0.246, P < 0.003), systolic blood pressure (r = 0.370, P < 0.001) and diastolic blood pressure (r = 0.389, P < 0.001). Conclusions: The results indicated the application potential of IVP in assessing the early detection of cardiac function changes noninvasively and sensitively. The correlation with myocardial stiffness warrants further studies to substantiate its potential clinical utility.

Quantitative Assessment of Right Ventricular Function in Patients With Systemic Lupus Erythematosus Using the Novel Non-invasive Pressure-Strain Loop.

OBJECTIVE: Current echocardiography evaluation of right ventricular (RV) function, which heralds the prognosis in patients with systemic lupus erythematosus (SLE), is of limited utility. The non-invasive pressure-strain loop (PSL), an emerging technique, has been found to feasible, sensitive and accurate in the diagnosis of cardiovascular diseases. The aim of this study was to quantitatively evaluate, using the non-invasive PSL, the right ventricular myocardial work (RVMW) in SLE patients. METHODS: Seventy-five SLE patients were recruited and grouped by pulmonary artery systolic pressure (PASP) into normal (group A, N = 26), mild (group B, N = 22) and moderate to severe (group C, N = 27) groups. Twenty-five healthy volunteers undergoing physical examination were recruited as the control group. Right ventricular global myocardial work index (RVGWI), global constructive work (RVGCW), global wasted work (RVGWW), global work efficiency (RVGWE), global longitudinal strain (RVGLS) and other conventional parameters were measured. DISCUSSION: There were no differences between group A and the control group with respect to RVLS, RVGLS and all RVMW parameters (all p values > 0.05). RVGWI and RVGCW significantly differed among the other groups (all p values < 0.05). RVGWE was significantly lower and RVGWW was significantly higher in group C than in the control group and groups A and B (all p values < 0.05). Compared with the control group, RVGWW was significantly increased and RVGLS was significantly decreased in group B (all p values < 0.05). All but one RVMW parameter moderately to strongly correlated with SLE disease activity index (SLEDAI) and World Health Organization Functional Class (WHO-FC). RVGWW (area under the receiver operating characteristic curve [AUC] = 0.893) and RVGWE (AUC = 0.877) were sensitive parameters in detecting earlier cardiac dysfunction in SLE patients. CONCLUSION: RVGWW and RVGWE serve as sensitive and promising parameters in the integrative analysis of early right ventricular dysfunction in SLE patients. To conclude, non-invasive PSL, the novel method, facilitates the quantitative assessment of RVMW in SLE patients.

Persistent Endothelial Dysfunction in Coronavirus Disease-2019 Survivors Late After Recovery.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can result in an endothelial dysfunction in acute phase. However, information on the late vascular consequences of COVID-19 is limited. METHODS: Brachial artery flow-mediated dilation (FMD) examination were performed, and inflammatory biomarkers were assessed in 86 survivors of COVID-19 for 327 days (IQR 318-337 days) after recovery. Comparisons were made with 28 age-matched and sex-matched healthy controls and 30 risk factor-matched patients. RESULTS: Brachial artery FMD was significantly lower in the survivors of COVID-19 than in the healthy controls and risk factor-matched controls [median (IQR) 7.7 (5.1-10.7)% for healthy controls, 6.9 (5.5-9.4)% for risk factor-matched controls, and 3.5(2.2-4.6)% for COVID-19, respectively, p < 0.001]. The FMD was lower in 25 patients with elevated tumor necrosis factor (TNF)-α [2.7(1.2-3.9)] than in 61 patients without elevated TNF-α [3.8(2.6-5.3), p = 0.012]. Furthermore, FMD was inversely correlated with serum concentration of TNF-α (r = -0.237, p = 0.007). CONCLUSION: Survivors of COVID-19 have a reduced brachial artery FMD, which is inversely correlated with increased serum concentration of TNF-α. Prospective studies on the association of endothelial dysfunction with long-term cardiovascular outcomes, especially the early onset of atherosclerosis, are warranted in survivors of COVID-19.

Normalized Cardiac Structure and Function in COVID-19 Survivors Late After Recovery.

Background: Coronavirus disease 2019 can result in myocardial injury in the acute phase. However, information on the late cardiac consequences of coronavirus disease 2019 (COVID-19) is limited. Methods: We conducted a prospective observational cohort study to investigate the late cardiac consequences of COVID-19. Standard echocardiography and myocardial strain assessment were performed, and cardiac blood biomarkers were tested in 86 COVID-19 survivors 327 days (IQR 318-337 days) after recovery. Comparisons were made with 28 age-matched and sex-matched healthy controls and 30 risk factor-matched patients. Results: There were no significant differences in all echocardiographic structural and functional parameters, including left ventricular (LV) global longitudinal strain, right ventricular (RV) longitudinal strain, LV end-diastolic volume, RV dimension, and the ratio of peak early velocity in mitral inflow to peak early diastolic velocity in the septal mitral annulus (E/e') among COVID-19 survivors, healthy controls and risk factor-matched controls. Even 26 patients with myocardial injury at admission did not have any echocardiographic structural and functional abnormalities. There were no significant differences among the three groups with respect to serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (cTnI). Conclusion: This study showed that COVID-19 survivors, including those with myocardial injury at admission and those with severe and critical types of illness, do not have any echocardiographic evidence of cardiac structural and functional abnormalities 327 days after diagnosis.

Evaluation of Myocardial Stiffness in Hypertensive Patients by Intrinsic Wave Propagation of the Myocardial Stretch.

The objective of the study was to evaluate myocardial stiffness in hypertensive patients by measuring the intrinsic velocity propagation (IVP) of the myocardial stretch and to explore the correlation between IVP and cardiac systolic and diastolic functions. Eighty-one hypertensive patients and 53 healthy patients were prospectively enrolled in this study. IVP was measured using high-frame rate tissue Doppler (350-450 frames per second). IVP was significantly higher in hypertensive patients than in the control group (1.53 ± 0.39 m/s vs. 1.40 ± 0.19 m/s, p = 0.031). In the hypertensive group, IVP was significantly higher in patients with electrocardiogram (ECG) strain than in those without ECG strain (1.63 ± 0.46 m/s vs. 1.45 ± 0.32 m/s, p = 0.047). Moreover, IVP exhibited a good correlation with interventricular septal thickness at end-diastole (r = 0.434, p < 0.001), left ventricular posterior wall thickness at end-diastole (r = 0.439, p < 0.001), E/A ratio (r = 0.245, p = 0.004) and global longitudinal systolic strain (r = 0.405, p < 0.001). IVP was significantly higher in hypertensive patients, which indicates elevated myocardial stiffness in this cohort of patients. This novel measurement exhibited great potential for use in clinical practice to assess myocardial stiffness in patients with hypertension non-invasively.

Evaluation of Long-Term Impact of Pericardiectomy on Left Atrial Functions in Patients with Constrictive Pericarditis Using Speckle Tracking Echocardiography.

The aims of this study were to explore the long-term impact of pericardiectomy on left atrial (LA) functions in patients with constrictive pericarditis (CP) using speckle tracking echocardiography (STE) and to correlate post-operative LA functions with clinical status. Echocardiographic examinations were undertaken in 29 patients with CP 1 wk before and 1, 6 and 12 mo after pericardiectomy. STE was performed to obtain LA global longitudinal strain, including strain during the conduit phase (LAScd), strain during the contraction phase (LASct) the sum of the latter and strain during the reservoir phase (LASr). Control patients consisted of 29 age- and sex-matched healthy volunteers. LASct, LAScd and LASr obtained 6 mo after pericardiectomy improved significantly compared with pre-operative values, but were still lower than the values for control patients. Further increases were observed gradually with normalization of LASct 12 mo after pericardiectomy. However, there were still significant differences between LAScd and LASr obtained in control patients and those obtained 12 mo after pericardiectomy. Moreover, the improvements in LAScd, LASct and LASr 12 mo after pericardiectomy correlated well with symptomatic clinical alleviation (p < 0.01). These results indicate that LA strains analyzed with STE might be useful in evaluating the long-term impact of pericardiectomy on LA functions.

Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling.

Epidermal growth factor receptor (EGFR) gene amplification and mutation occurs most frequently in glioblastoma (GBM). However, EGFR-tyrosine kinase inhibitors (TKIs), including gefitinib, have not yet shown clear clinical benefit and the underlying mechanisms remain largely unexplored. We previously demonstrated that LRIG2 plays a protumorigenic role and functions as a modulator of multiple oncogenic receptor tyrosine kinases (RTKs) in GBM. We therefore hypothesized that LRIG2 might mediate the resistance to EGFR inhibitor through modulating other RTK signaling. In this study, we report that LRIG2 is induced by EGFR inhibitor in gefitinib-treated GBM xenografts or cell lines and promotes resistance to EGFR inhibition by driving cell cycle progression and inhibiting apoptosis in GBM cells. Mechanistically, LRIG2 increases the secretion of growth-arrest specific 6 (GAS6) and stabilizes AXL by preventing its proteasome-mediated degradation, leading to enhancement of the gefitinib-induced activation of AXL and then reactivation of the gefitinib-inhibited SRC. Targeting LRIG2 significantly sensitizes the GBM cells to gefitinib, and inhibition of the downstream GAS6/AXL/SRC signaling abrogates LRIG2-mediated gefitinib resistance in vitro and in vivo. Collectively, our findings uncover a novel mechanism in resistance to EGFR inhibition and provide a potential therapeutic strategy to overcome resistance to EGFR inhibition in GBM.

Enlarged Size and Impaired Elastic Properties of the Ascending Aorta are Associated with Endothelial Dysfunction and Elevated Plasma Matrix Metalloproteinase-2 Level in Patients with Bicuspid Aortic Valve.

The aim of this study was to test whether enlarged size and impaired elastic properties of the ascending aorta are associated with impaired endothelial function and increases in plasma matrix metalloproteinase (MMP)-2 concentrations in patients with bicuspid aortic valve (BAV) without significant valvular dysfunction. The size and the elasticity of the ascending aorta and the flow-mediated vasodilation (FMD) in the brachial artery in response to hyperemia were evaluated with 2-D echocardiography and high-frequency linear ultrasound in 42 patients with BAV without significant valvular dysfunction and 30 age- and sex-matched healthy controls. In the BAV group, diastolic ascending aortic diameter (AoD) (32.1 ± 8.1 mm vs. 25.3 ± 3.6 mm, p <0.001) and aortic stiffness index (8.0 ± 5.3 vs. 4.0 ± 1.8, p <0.001) were significantly higher, and aortic strain (7.4 ± 3.6% vs. 11.1 ± 3.0%, p <0.001) and aortic distensibility (7.4 ± 4.1 × 10-6cm2/dyn vs. 11.1 ± 4.3 × 10-6cm2/dyn, p <0.001) were significantly lower than those in the control group. The BAV group also had lower FMD (6.5 ± 2.2% vs. 11.9 ± 2.7%, p <0.001) and higher plasma MMP-2 levels (226.7 ± 55.0 ng/mL vs. 177.0 ± 45.3 ng/mL, p <0.001) compared with the control group. In the BAV group, AoD, aortic strain, aortic stiffness index and aortic distensibility significantly correlated with FMD and MMP-2 (all p <0.05). The multivariable linear regression analysis further indicated that FMD and MMP-2 were independently associated with AoD (ß = -1.1, p = 0.005, and ß = 0.09, p <0.001, respectively). These findings suggest that enlarged size and impaired elastic properties of the ascending aorta are associated with endothelial dysfunction and elevated plasma MMP-2 level in patients with BAV without significant valvular dysfunction. FMD and plasma MMP-2 level are the significant and independent predictors of dilation of the ascending aorta in patients with BAV.

Long-Term Effects of Pericardiectomy on Left Ventricular Mechanics Evaluated by Using Speckle Tracking Echocardiography in Patients with Constrictive Pericarditis.

The aim of this study was to evaluate long-term changes in left ventricular (LV) mechanics after pericardiectomy in patients with constrictive pericarditis (CP) and to correlate post-operative LV mechanics with clinical status. A total of 24 patients with CP underwent serial speckle tracking echocardiography 1 wk before and 1, 6 and 12 mo after pericardiectomy. Global LV longitudinal, circumferential and radial strains, along with LV twist, were measured. Twenty-three healthy volunteers were served as control patients. Although global LV longitudinal, circumferential and radial strains obtained 6 mo after pericardiectomy increased compared with those for pre-pericardiectomy, they were still significantly lower than those for control patients. Further improvements occurred over time with normalization of global LV longitudinal and radial strains 12 mo after pericardiectomy, but global circumferential strain obtained 12 mo after pericardiectomy was still lower than that for control patients. LV twist remained unchanged after pericardiectomy. In addition, the improvements in global LV circumferential strain after pericardiectomy were associated with improvements in clinical symptoms (p < 0.001). These findings suggest that the global LV circumferential strain may be a promising parameter in the evaluation of the effectiveness of pericardiectomy.

Usefulness of contrast perfusion echocardiography for differential diagnosis of cardiac masses.

The aim of this study was to assess the usefulness of contrast perfusion echocardiography in the differential diagnosis of different types of cardiac masses. Conventional echocardiography and contrast perfusion echocardiography were performed in 72 patients with cardiac masses. The degree of contrast enhancement of the mass and an adjacent section of myocardium after injection of contrast agent was determined by visual inspection and quantitative time-signal intensity curve analysis. The difference in maximal steady-state pixel intensity between the mass and the adjacent myocardium (ΔAmass-myocardium) was calculated. All masses had a pathologic diagnosis or resolved after anticoagulation. All 16 cardiac masses without enhancement on visual inspection were confirmed to be cardiac thrombi. Twenty-four masses with incomplete enhancement on visual inspection were recognized as benign tumors with validation methods. Of the 32 cardiac masses with complete enhancement, 30 were confirmed as malignant tumors and two as benign tumors with validation methods. The sensitivity and specificity of ΔAmass-myocardium in differentiating thrombi from tumors were 93% and 100%, respectively, and 100% and 97% in differentiating malignant tumors from benign tumors and thrombi. Both visual and quantitative assessment of degree of enhancement of cardiac masses in relation to the adjacent myocardium during contrast perfusion echocardiography had high diagnostic accuracy for differentiation of a thrombus from a tumor or a benign tumor from a malignant tumor.

Left ventricular systolic strain of the cardiac allograft evaluated with three-dimensional speckle tracking echocardiography.

Three-dimensional speckle tracking echocardiography was employed to evaluate the changes of left ventricular systolic strain in 23 heart transplant recipients at 1st, 3rd, 6th and 12th month after heart transplantation, and 23 healthy subjects served as controls. The three-dimensional full-volume echocardiographic images of left ventricle were recorded and then were analyzed using EchoPAC software. The strain curves and peak systolic strain values for each segment and overall left ventricular wall were obtained. Left ventricular global peak longitudinal strain (GPSL), global peak radial strain (GPSR), global peak circumferential strain (GPSC) and global peak area strain (GPSA) were measured and then statistically analyzed. There were no significant differences in left ventricular ejection fraction (LVEF) and cardiac output (CO) between heart transplant recipients and controls. The GPSL in heart transplant recipients at 1st month after surgery was significantly lower than that in controls, but close to the normal value at 3rd month after surgery and later. The GPSC, GPSA and GPSR were significantly lower in heart transplant recipients at 1st, 3rd, 6th and 12th month after surgery than those in controls. It is suggested that three-dimensional speckle tracking echocardiography can be used for monitoring changes of left ventricular systolic strains and evaluating left ventricular systolic function in cardiac allograft.

Correlation between enhanced intensity of atherosclerotic plaque at contrast-enhanced ultrasonography and density of histological neovascularization.

The feasibility of contrast-enhanced ultrasonography in the assessment of atherosclerotic plaque neovascularization and its relation to histological findings were investigated. Abdominal aortic atherosclerotic plaque model was induced in 25 New Zealand white rabbits by a combination of high cholesterol-rich diet and balloon aortic denudation. Standard and contrast-enhanced ultrasonography was performed at the 16th week of the model induction period. The plaques were classified as echogenic plaques or echolucent plaques according to their echogenicity at standard ultrasonography. The maximum thickness of plaque was measured in the longitudinal section. Time intensity curve was used to quantify the enhanced intensity of the plaque. Animals were euthanized and abdominal aortas were harvested for histological staining of CD31 to evaluate the neovascularization density of atherosclerotic plaque. The results showed that the echolucent plaques had higher enhanced intensity during contrastenhanced ultrasonography and higher neovascularization density at CD31 staining than the echogenic plaques. The enhanced intensity of atherosclerotic plaque and its ratio to lumen were well correlated with histological neovascularization density (r=0.75, P<0.001; r=0.68, P<0.001, respectively). However, the maximum thickness of plaque was not correlated with neovascularization density (r=0.235, P=0.081). These findings demonstrated that the enhanced intensity in the plaque and ratio of enhanced intensity to that in the lumen of abdominal aorta may be more accurate in the evaluation of plaque neovascularization than maximum thickness. Our study indicates that contrast-enhanced ultrasonography provides us a reliable method for the evaluation of plaque neovascularization.

Use of carotid plaque neovascularization at contrast-enhanced US to predict coronary events in patients with coronary artery disease.

PURPOSE: To determine whether carotid plaque neovascularization as assessed with contrast-enhanced ultrasonography (US) can help predict future coronary events in patients with stable coronary artery disease (CAD). MATERIALS AND METHODS: The study was approved by the hospital ethics committee, and informed consent was obtained from all patients. Three hundred twelve consecutive patients (228 men; mean age, 63 years ± 9; age range, 42-88 years) with both CAD and at least one carotid plaque thicker than 2.0 mm underwent both standard and contrast-enhanced carotid US. Patients with stable CAD were followed up for 8-47 months (mean, 33 months ± 9) or until a coronary event occurred. Statistical analysis was performed with the Student t test, χ(2) analysis, Kaplan-Meier method, and Cox proportional hazards regression models. RESULTS: Contrast material enhancement of plaque was seen in 42 of 51 patients (82%) with acute coronary syndrome (ACS) and 114 of 261 patients (43.7%) with stable CAD (P < .001). Coronary events occurred during the follow-up period in 24 of 111 patients (21.6%) with contrast material enhancement of plaque and only seven of 137 patients (5.1%) without enhancement (P< .001). In 248 patients with stable CAD and follow-up, Kaplan-Meier analysis demonstrated a significantly higher probability of developing coronary events in patients with contrast material enhancement of plaque than in those without contrast material enhancement (P < .001). The presence of contrast material enhancement of plaque was a significant and independent predictor of future coronary events in patients with stable CAD (odds ratio: 3.90; 95% confidence interval: 1.60, 9.46; P = .003). CONCLUSION: Contrast material enhancement of plaque is more common in patients with ACS than in those with stable CAD and is a significant and independent predictor of future coronary events in patients with stable CAD, suggesting that noninvasive contrast-enhanced carotid US may be used as a method for risk stratification of patients with stable CAD.