Association between Impaired Renal Function and Subclinical Myocardial Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction: Assessment Using Noninvasive Pressure-Strain Loop.

INTRODUCTION: The objective of this study was to evaluate the abnormal myocardial function in HFpEF patients with renal dysfunction (RD) and investigate the relationship between renal function and myocardial mechanical characteristics in patients with HFpEF. METHODS: 134 patients with HFpEF and 32 control subjects were enrolled in our study. Clinical and echocardiography data were collected for offline analysis. Global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE) were measured after noninvasive pressure-strain loop analysis. Univariate and multivariate analyses were used to determine the correlation between renal function and myocardial function in patients with HFpEF. RESULTS: In comparison to control subjects, patients with HFpEF tend to have higher GWW (78 [50-115] vs. 108 [65-160] mm Hg%, p < 0.05) and lower GWE (96 [95-97] vs. 95 [92-96] %, p < 0.05), while left ventricular ejection fraction (65.5 ± 3.3 vs. 64.3 ± 4.6%, p < 0.05) was comparable between them. Besides, increased GWW (86 [58-152] vs. 125 [94-187] mm Hg%, p < 0.05) and decreased GWE (96 [93-97] vs. 94 [92-96] %, p < 0.05) were detected in patients with RD compared to those with normal renal function. An independent correlation was found between estimated glomerular filtration rate and GWW after multivariate analysis. DISCUSSION/CONCLUSION: More severely impaired myocardial function was detected in HFpEF patients with RD compared to those with normal renal function. Estimated glomerular filtration rate was independently correlated to GWW in patients with HFpEF.

Mapping and Screening of Candidate Gene Regulating the Biomass Yield of Sorghum (Sorghum bicolor L.).

Biomass yield is one of the important traits of sorghum, which is greatly affected by leaf morphology. In this study, a lobed-leaf mutant (sblob) was screened and identified, and its F2 inbred segregating line was constructed. Subsequently, MutMap and whole-genome sequencing were employed to identify the candidate gene (sblob1), the locus of which is Sobic.003G010300. Pfam and homologous analysis indicated that sblob1 encodes a Cytochrome P450 protein and plays a crucial role in the plant serotonin/melatonin biosynthesis pathway. Structural and functional changes in the sblob1 protein were elucidated. Hormone measurements revealed that sblob1 regulates both leaf morphology and sorghum biomass through regulation of the melatonin metabolic pathway. These findings provide valuable insights for further research and the enhancement of breeding programs, emphasizing the potential to optimize biomass yield in sorghum cultivation.

Diagnostic potential of myocardial early systolic lengthening for patients with suspected non-ST-segment elevation acute coronary syndrome.

BACKGROUND: During early systole, ischemic myocardium with reduced active force experiences early systolic lengthening (ESL). This study aimed to explore the diagnostic potential of myocardial ESL in suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with normal wall motion and left ventricular ejection fraction (LVEF). METHODS: Overall, 195 suspected NSTE-ACS patients with normal wall motion and LVEF, who underwent speckle tracking echocardiography (STE) before coronary angiography, were included in this study. Patients were stratified into the coronary artery disease (CAD) group when there was ≥ 50% stenosis in at least one major coronary artery. The CAD patients were further stratified into the significant (≥ 70% reduction of vessel diameter) stenosis group or the nonsignificant stenosis group. Myocardial strain parameters, including global longitudinal strain (GLS), duration of early systolic lengthening (DESL), early systolic index (ESI), and post-systolic index (PSI), were analyzed using STE and compared between groups. Receiver operating characteristic curve (ROC) analysis was performed to determine the diagnostic accuracy. Logistic regression analysis was conducted to establish the independent and incremental determinants for the presence of significant coronary stenosis. RESULTS: The DESL and ESI values were higher in patients with CAD than those without CAD. In addition, CAD patients with significant coronary stenosis had higher DESL and ESI than those without significant coronary stenosis. The ROC analysis revealed that ESI was superior to PSI for identifying patients with CAD, and further superior to GLS and PSI for predicting significant coronary stenosis. Moreover, ESI could independently and incrementally predict significant coronary stenosis in patients with CAD. CONCLUSIONS: The myocardial ESI is of great value for the diagnosis and risk stratification of clinically suspected NSTE-ACS patients with normal LVEF and wall motion.

Subclinical left ventricular myocardial dysfunction in patients with obstructive sleep apnea syndrome: insights from noninvasive left ventricular myocardial work analysis.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with various cardiovascular diseases and has aroused public concern. Early detection for declining myocardial function is of great significance. This study was aimed at noninvasively evaluating the subclinical left ventricular (LV) myocardial dysfunction with LV pressure-strain loop (PSL) in patients with OSAS having normal LV ejection fraction. METHODS: We enrolled 200 patients with OSAS who visited the Beijing Chaoyang Hospital between February 2021 and December 2021. According to the apnea-hypopnea index (AHI), patients were divided into mild, moderate, and severe groups. The global longitudinal strain (GLS) of the left ventricle was analyzed by two-dimensional speckle tracking echocardiography. The LV PSL was used to assess global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE), and comparisons were made among groups. RESULTS: GLS was significantly lower in the severe group than in mild and moderate group. GWI, GCW, and GWE were lower in the severe group than in mild and moderate groups. GWW was significantly higher in the severe group than in the mild group. GLS, GWI, and GWE were moderately correlated with AHI (Spearman's ρ = -0.468, -0.321, and -0.319, respectively; P < 0.001), whereas GCW and GWW showed a weak correlation with AHI (Spearman's ρ = -0.226 and 0.255 respectively; P < 0.001). Multiple regression analyses revealed AHI was independently associated with GWI after adjusting for SBP, GLS, e', etc. AHI was independently associated with GCW after adjusting for SBP, GLS, etc. CONCLUSIONS: The LV PSL is a new technique to noninvasively detect myocardial function deterioration in patients with OSAS and preserved LV ejection fraction. Increased severity of OSAS was independent associated with both decreased GWI and GCW.

Left atrial strain for predicting recurrence in patients with non-valvular atrial fibrillation after catheter ablation: a single-center two-dimensional speckle tracking retrospective study.

BACKGROUND: Although catheter ablation (CA) is an effective treatment for non-valvular atrial fibrillation (AF), a good many of patients still have a recurrence following post-operation. Prediction of AF recurrence by evaluating left atrial (LA) phase function with speckle tracking echocardiography (STE) may be helpful for risk stratification and clinical management for AF patients. Therefore, the current study aimed to assess the prognostic value of LA strains in non-valvular AF patients after CA. METHODS: A total of 95 non-valvular AF patients (70.5% paroxysmal AF, 56.8% males, mean age 63.2 ± 9.7 years) were included in this retrospective study between October 2019 and August 2020. Transthoracic echocardiography was performed in all the subjects and STE was used to analyze the LA reservoir strain (LASr), LA conduit strain (LAScd) and LA contractile strain (LASct) during different phases before CA. Patients were followed up with until January 2022. The endpoint was AF recurrence. RESULTS: Over a median follow-up period of 26.0 months (interquartile range, 24.7-26.7 months), 26 patients experienced recurrence and 69 stayed in sinus rhythm. Compared with no-recurrence group, maximum volume of LA (LAVmax), minimum volume of LA (LAVmin) and LA volume index (LAVI) were increased in the recurrence group, while LAEF, LASr and LASct were worsened (P < 0.05). Multivariable logistic regression analysis revealed that LASct was an independent predictor of AF recurrence (odds ratio, 0.89; 95% confidence interval (CI), 0.82-0.97; P = 0.007) and receiver operating characteristic (ROC) curve analysis showed an area under the curve of LASct<8% was 0.70 (95% CI, 0.59-0.79; P = 0.0008). CONCLUSIONS: LASct was of independent predictive value of AF recurrence. LA function assessed by STE may contribute to the risk stratification for AF patients and selection of suitable patients for CA.

Reduced mechanical function of the left atrial predicts adverse outcome in pregnant women with clustering of metabolic risk factors.

INTRODUCTION: The left atrial (LA) strain and strain rate are sensitive indicators of LA function. However, they are not widely used for the evaluation of pregnant women with metabolic diseases. The aim of this study was to assess the LA strain and strain rate of pregnant women with clustering of metabolic risk factors and to explore its prognostic effect on adverse pregnancy outcomes. MATERIALS AND METHODS: Sixty-three pregnant women with a clustering of metabolic risk factors (CMR group), fifty-seven women with pregnancy-induced hypertension (PIH group), fifty-seven women with gestational diabetes mellitus (GDM group), and fifty matched healthy pregnant women (control group) were retrospectively evaluated. LA function was evaluated with two-dimensional speckle-tracking imaging. Iatrogenic preterm delivery caused by severe preeclampsia, placental abruption, and fetal distress was regarded as the primary adverse outcome. RESULTS: The CMR group showed the lowest LA strain during reservoir phase (LASr), strain during contraction phase (LASct) and peak strain rate during conduit phase (pLASRcd) among the three groups (P < 0.05). LA strain during conduit phase (LAScd) and peak strain rate during reservoir phase (pLASRr) in the CMR group were lower than those in the control and GDM groups (P < 0.05). Multivariable Cox regression analysis demonstrated systolic blood pressure (HR = 1.03, 95% CI 1.01-1.05, p = 0.001) and LASr (HR = 0.86, 95% CI 0.80-0.92, p < 0.0001) to be independent predictors of iatrogenic preterm delivery. An LASr cutoff value ≤ 38.35% predicted the occurrence of iatrogenic preterm delivery. CONCLUSIONS: LA mechanical function in pregnant women with metabolic aggregation is deteriorated. An LASr value of 38.35% or less may indicate the occurrence of adverse pregnancy outcomes.

Risk assessment in interstitial lung disease: the incremental prognostic value of cardiopulmonary ultrasound.

BACKGROUND: The mortality risk of chronic interstitial lung disease (ILD) is currently assessed using the ILD-GAP score. The present study evaluates whether the addition of cardiopulmonary ultrasound parameters to the ILD-GAP score can further improve the predictive value of ILD-GAP. METHODS: Medical records from 91 patients with ILD hospitalized from June 2015 to March 2016 were retrospectively examined. The Lung ultrasound (LUS) score, right ventricular (RV) function, and mechanics were obtained from the cardiopulmonary ultrasound. The ILD-GAP score was calculated from demographic characteristics and pulmonary function parameters. Patients were followed up with until May 2020. The primary endpoint was all-cause death. RESULTS: After exclusions, 74 patients with ILD were included in the analysis. During the follow-up period, 36 patients with ILD survived (ILDs), and 38 patients died (ILDd). Compared to ILDs, the ILDd cases exhibited a higher number of B-lines, LUS score, and RV end-diastolic base dimension (RVD), but lower RV function. In multivariate analysis, the ILD-GAP score (hazard ratio, 2.88; 95% CI 1.38-5.99, P = 0.005), LUS score (hazard ratio 1.13; 95% CI 1.04-1.24, P = 0.006), and RVD (hazard ratio 1.09, 95% CI 1.03-1.16, P = 0.004) were significantly related to the risk of death. Adding the LUS score and RVD to the ILD-GAP score significantly improved the predictive value compared to the ILD-GAP score alone (C statistics 0.90 vs 0.76, P = 0.018). CONCLUSION: We investigated the utility of a new prognostic model for ILD that includes both cardiopulmonary ultrasound parameters (LUS score and RVD) and the ILD-GAP score. This model better reflects the severity of pulmonary fibrosis and cardiac involvement, and has incremental predictive value over the ILD-GAP score alone.

Influence of impaired right ventricular contractile reserve on exercise capacity in patients with precapillary pulmonary hypertension: A study with exercise stress echocardiography.

OBJECTIVES: Right ventricular (RV) contractile reserve reflects the ability of RV to accommodate the increased afterload and may play an essential role in the evaluation of precapillary pulmonary hypertension (PH). This study aimed to assess RV contractile reserve based on exercise stress echocardiography (ESE) and to determine the echocardiographic determinants of exercise capacity in patients with precapillary PH. METHODS: A total of 31 patients with precapillary PH and 15 age- and sex-matched healthy control subjects were prospectively recruited. All subjects underwent ESE to assess RV function at rest and under peak exercise. Changes in these parameters during exercise were calculated to quantify the RV contractile reserve. Patients with precapillary PH also underwent cardiopulmonary exercise test (CPET), and data pertaining to peak oxygen uptake (peak VO2 ) and minute ventilation/carbon dioxide production (VE/VCO2 ) were collected. RESULTS: Right ventricular contractile reserve including change in tricuspid annular plane systolic excursion (∆TAPSE), change in RV fractional area change (∆RVFAC), and change in Doppler-derived tricuspid lateral annular peak systolic velocity (∆S') was significantly depressed in precapillary PH patients compared with control subjects (P < 0.05). Parameters of RV function and RV contractile reserve were markedly associated with maximal exercise capacity (P < 0.05). ∆RVFAC was an independent predictor of peak VO2 (r2  = 0.601, P < 0.05). CONCLUSIONS: Assessment of RV contractile reserve facilitates identification of subclinical dysfunction and evaluation of clinical status and severity of precapillary PH. ESE as a noninvasive method may provide a comprehensive clinical assessment and facilitate therapeutic decision-making for these patients.

Impaired left ventricular mechanics and functional reserve are associated with reduced exercise capacity in patients with hypertrophic cardiomyopathy.

BACKGROUND: Reduced metabolic equivalents (METs) are an indicator of exercise intolerance, which predicts poor prognosis in hypertrophic cardiomyopathy (HCM) patients. We sought to evaluate the changes in left ventricular (LV) mechanics and functional reserves, as well as their association with functional capacity in HCM patients. METHODS: Seventy HCM patients and thirty controls were included in this study. LV mechanics were evaluated at rest and during exercise by echocardiography and two-dimensional speckle-tracking imaging to obtain parameters of functional reserve, LV global longitudinal strain (LVGLS), strain rate (SR), and circumferential strain. RESULTS: Hypertrophic cardiomyopathy (HCM) patients had lower LVGLS, systolic SR, early and late diastolic SR at rest and during exercise, and reduced absolute and relative systolic and diastolic reserve compared to controls. LV circumferential strain was significantly higher at rest but lower during exercise in HCM patients. Exercise capacity was markedly reduced in HCM patients, and peak exercise LVGLS (LVGLS-exe) significantly correlated with exercise capacity. Multivariate regression analyses showed that LVGLS-exe, LV filling pressure during exercise (E/e'-exe), and LV mass index (LVMI) were independent predictors of exercise capacity. Moreover, LVGLS-exe displayed incremental predictive value over E/e'-exe and LVMI for exercise intolerance. Receiver operating characteristic curve analysis showed LVGLS-exe had optimal accuracy for predicting exercise intolerance in HCM patients. CONCLUSIONS: Hypertrophic cardiomyopathy (HCM) patients have reduced LV mechanics at rest and during exercise and impaired mechanical reserve. LVGLS-exe is associated with exercise capacity and is an optimal predictive value for reduced exercise capacity in HCM patients.

Improved heart hemodynamics after draining large-volume pleural effusion: a prospective cohort study.

BACKGROUND: Pleural effusion (PE) drainage can relieve the symptoms of dyspnea; however, details of the resulting hemodynamic changes remain undefined. METHODS: Subjects older than 12 years with massive PE requiring pleural drainage were included in this study. Hemodynamic parameters were collected using transthoracic echocardiography at pre-drainage, immediately post-drainage, and 24 h after drainage. RESULTS: We enrolled 47subjects in this prospective study from June 9, 2015 to September 18, 2016 in Beijing Chaoyang Hospital and 28 subjects were analyzed finally. Draining large-volume PE led to a progressive increase in left ventricular end-diastolic volume index, left atrial volume index, right ventricular area, right atrial area, left ventricular ejection fraction, stroke volume, and tricuspid annular plane systolic excursion, both immediately (P < 0.05) and 24 h after drainage (P < 0.05). The cardiac diastolic measurement ratios of early-transmitral flow velocity to diastolic mitral annular velocity and myocardial performance index decreased significantly following drainage (P < 0.05). More parameters were influenced by left-sided PE drainage. The correlation between effusion volume and changes in echocardiographic measurements was not statistically significant. CONCLUSIONS: Improved preload, and systolic and diastolic function is pivotal for hemodynamic change after draining large PE volumes. Subjects experienced improved cardiac hemodynamics following PE drainage, underlining the beneficial therapeutic and subjective effects.

High-Resolution Transthoracic Ultrasonography for Assessment of Pleural Lines in Patients With Dyspnea With CT Comparison: An Observational Study.

OBJECTIVES: Detection of B-line in dyspneic patients is often accompanied by abnormal changes of pleural line on transthoracic ultrasonography (TUS). The aim of the study was to evaluate the relevance and diagnostic performance of pleural line abnormalities and B-lines detected on high-resolution TUS against the computed tomography (CT) findings. METHODS: Transthoracic ultrasonography was performed in patients admitted to the emergency department with dyspnea. The pleural line and accompanying B-line were assessed using a linear transducer. The TUS findings were assessed against the corresponding high-resolution CT findings in the same location, which were considered to be the gold standard. RESULTS: Out of a total of 116 patients, 68.1% had changes of the pleural line on TUS. The characteristic changes of the pleural line were classified into four types: slightly rough pleural line with confluent B-lines on TUS corresponded with CT findings of ground-glass opacity; irregular and interrupted pleural line with confluent B-lines corresponded with parenchymal infiltration; fringed pleural line with confluent B-lines corresponded with superimposed ground-glass and irregular reticular opacities; and fringed pleural line with scattered B-lines corresponded with irregularly thickened interlobular septa. Wavy pleural line indicated subpleural emphysema. The coexistence of more than one abnormal pleural line was also found in 31 cases (26.7%). CONCLUSIONS: High-resolution TUS may help in the initial assessment of lung pathology by its ability to identify pleural line abnormalities and B-lines that are shown to be associated with CT, which could add diagnostic value in the emergency evaluation of dyspneic patients.

Longitudinal changes of cardiac structure and function in CKD (CASCADE study).

Little is known regarding the natural longitudinal changes in cardiac structure and function in CKD. We hypothesized that baseline CKD stage is associated with progressive worsening in cardiac structure and function. We conducted a prospective longitudinal study, recruiting 300 patients with stages 3-5 CKD from a major regional tertiary center and university teaching hospital in Hong Kong. Baseline CKD stages were studied in relation to natural longitudinal changes in echocardiographic and tissue Doppler imaging-derived parameters. Over 1 year, the prevalence of left ventricular (LV) hypertrophy increased from 40.3% to 48.9%, median left atrial volume index increased 4.8 (interquartile range [IQR], 2.1, 7.7) ml/m(2) (P<0.001), peak systolic mitral annular velocity decreased 0.5 (IQR, -1.5, 0.5) cm/s (P<0.001), early diastolic mitral annular velocity decreased 0.5 (IQR, -1.5, 0.5) cm/s (P<0.001), and eGFR declined 2.0 (IQR, -5.0, 0.0) ml/min per 1.73 m(2). CKD stages 4 and 5 were associated with more baseline abnormalities in cardiac structure and function and predicted greater longitudinal progression in LV mass index (odds ratio [OR], 3.02; 95% confidence interval [95% CI], 1.39 to 6.58), volume index (OR, 2.58; 95% CI, 1.18 to 5.62), and left atrial volume index (OR, 2.61; 95% CI, 1.20 to 5.69) and worse diastolic dysfunction grade (OR, 3.17; 95% CI, 1.16 to 8.69) compared with stage 3a in the fully adjusted analysis. In conclusion, more advanced CKD at baseline may be associated with larger longitudinal increases in LV mass and volume and greater deterioration in diastolic function.

Myocardial work by pressure-strain loop is associated with molecular imaging of fibroblast activation in hypertensive hearts using 99mTc-HFAPI SPECT.

99mTc-HFAPI can visualize fibroblast activation in hypertensive hearts. Myocardial work (MW) reflects the cardiac mechanical properties after accounting for the afterload in hypertensive patients. We investigated whether MW was associated with increased uptake of 99mTc-HFAPI. A total of 97 hypertensive patients and 41 healthy volunteers were prospectively recruited. Global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE) were analyzed. According to whether myocardial uptake of FAPI was higher than the adjacent blood pool, hypertensive patients were divided into two groups, namely: FAPI + and FAPI- group, respectively. GWI, GCW and GWE of the FAPI + group were lower than the FAPI- group. The value of GWW in the FAPI + group was higher than in the FAPI- group. Multiple regression analyses revealed GWI, GWW and GWE were independently associated with early myocardial fibrosis. According to receiver operating characteristics (ROC) analysis, the best cutoff points for FAPI + of GWI, GWW and GWE were 1968.50 mmHg% (AUC: 0.687, 95% CI: 0.581-0.793, P = 0.002), 133.00 mmHg% (AUC: 0.778, 95% CI: 0.688-0.869, P < 0.001) and 95.07% (AUC: 0.813, 95% CI: 0.730-0.896, P < 0.001), respectively. GWI, GWW and GWE were impaired in hypertensive patients with cardiac 99mTc-HFAPI uptake and were associated with fibroblast activation in hypertensive hearts.

ECG and Atrial Appendage Doppler Discordance Is Common in Patients Undergoing Cardiac Surgery: Prospective Study.

Background: Patients with atrial fibrillation (AF) remain at increased risk of thromboembolism despite apparent maintenance of sinus rhythm with the cause often attributed to periods of asymptomatic AF. Atrial mechanical discordance, with the body of the left atrium (LA) in sinus rhythm and the left atrial appendage (LAA) in AF may also be a contributor. Objectives: The purpose of this study was to assess the frequency of electrocardiogram (ECG) rhythm and LAA and/right atrial appendage (RAA) Doppler ejection phenotype (transesophageal echocardiography [TEE]) discordance in patients undergoing cardiac surgery. Methods: A total of 124 patients undergoing coronary artery bypass graft (CABG), CABG and valve surgery, or isolated valve repair or replacement (valve ± CABG) were prospectively studied. Intraoperative surface ECG rhythm strip and TEE were performed before cardiopulmonary bypass. The ECG and TEE LAA/RAA Doppler spectrum were independently classified as sinus or AF. Results: Of 107 patients (age 65 ± 12 years; 31% female; 65% CABG, 31% valve ± CABG) without a history of AF, 39 (36%) had ECG and LAA and/or RAA discordance (ECG/LAA Doppler discordance, n = 12 [11%]; ECG/RAA Doppler discordance, n = 35 [33%]). There was no significant difference between concordant and discordant groups with regard to age, gender, history of hypertension, diabetes, heart failure, or stroke (all P > 0.05). Conclusions: A large minority of patients without a history of AF undergoing cardiac surgery have ECG/atrial appendage Doppler discordance, a setting that may promote thromboembolism in non-anticoagulated patients. Clinical parameters do not identify patients at increased risk for discordance.

Automated echocardiographic diastolic function grading: A hybrid multi-task deep learning and machine learning approach.

BACKGROUND: Assessing left ventricular diastolic function (LVDF) with echocardiography as per ASE guidelines is tedious and time-consuming. The study aims to develop a fully automatic approach of this procedure by a lightweight hybrid algorithm combining deep learning (DL) and machine learning (ML). METHODS: The model features multi-modality input and multi-task output, measuring LV ejection fraction (LVEF), left atrial end-systolic volume (LAESV), and Doppler parameters: mitral E wave velocity (E), A wave velocity (A), mitral annulus e' velocity (e'), and tricuspid regurgitation velocity (TRmax). The algorithm was trained and tested on two internal datasets (862 and 239 echocardiograms) and validated using three external datasets, including EchoNet-Dynamic and CAMUS. The ASE diastolic function decision tree and total probability theory were used to provide diastolic grading probabilities. RESULTS: The algorithm, named MMnet, demonstrated high accuracy in both test and validation datasets, with Dice coefficients for segmentation between 0.922 and 0.932 and classification accuracies between 0.9977 and 1.0. The mean absolute errors (MAEs) for LVEF and LAESV were 3.7 % and 5.8 ml, respectively, and for LVEF in external validation, MAEs ranged from 4.9 % to 5.6 %. The diastolic function grading accuracy was 0.88 with hard criteria and up to 0.98 with soft criteria which account for the top two probability in total probability theory. CONCLUSIONS: MMnet can automatically grade ASE diastolic function with high accuracy and efficiency by annotating 2D videos and Doppler images.

Surface Engineering of HEK293 Cell-Derived Extracellular Vesicles for Improved Pharmacokinetic Profile and Targeted Delivery of IL-12 for the Treatment of Hepatocellular Carcinoma.

Background: Extracellular vesicles (EVs) are considered a promising drug delivery platform. Naïve EVs face numerous issues that limit their applications, such as fast clearance, hepatic accumulations, and a lack of target-specific tropism. We aimed to explore a series of surface engineering approaches to: 1) reduce the non-specific adhesion of EVs, and 2) improve their enrichment in the target tissue. As a proof-of-concept, we investigated the therapeutic potentials of a multi-modal EVs system carrying a tumor-specific nanobody and the immuno-stimulant interleukin-12 (IL12) using in vivo models of hepatocellular carcinoma. Methods: The major cell adhesion molecule on the HEK293-derived EVs, integrin ß1 (ITGB1), was knocked out (KO) by CRISPR/Cas9-mediated gene editing, followed by deglycosylation to generate ITGB1-Deg EVs for the subsequent pharmacokinetic and biodistribution analyses. ITGB1-Deg EVs were further loaded with glypican-3 (GPC3)-specific nanobody (HN3) and mouse single-chain IL12 (mscIL12) to generate ITGB1-mscIL12+HN3+Deg EVs, for evaluation of tumor tropism and therapeutic potential in a mice model of hepatocellular carcinoma. Results: Removal of ITGB1 led to the broad suppression of integrins on the EVs surface, resulting in a decrease in cellular uptake. Deglycosylation of ITGB1- EVs gave rise to inhibition of the EVs uptake by activated RAW264.7 cells. ITGB1 removal did not significantly alter the pharmacokinetic behaviors of HEK293-EVs, whereas the ITGB1-Deg EVs exhibited enhanced systemic exposure with reduced hepatic accumulation. Loading of HN3 conferred the ITGB1-Deg EVs with tumor-specific tropism for both subcutaneous and metastasized tumors in mice. The ITGB1-mscIL12+HN3+Deg EVs activated mouse splenocytes with high potency. Systemic administration of the EVs with the equivalent dose of 1.5µg/kg of exosomal IL12 achieved satisfactory tumor growth inhibition and good tolerability. Conclusion: The combinatorial approach of EVs surface engineering conferred HEK293-EVs with reduced non-specific clearance and enhanced tumor targeting efficacy, which constituted an efficient delivery platform for critical cancer therapeutics like IL12.

Association between left ventricular geometry and global myocardial work in patients with heart failure with preserved ejection fraction: assessment using strain-pressure loop.

Concentric LV remodeling and hypertrophy are common structural abnormalities in patients with heart failure with preserved ejection fraction (HFpEF) and tend to be accompanied by impaired LV function. Assessment of global myocardial work (GMW) using strain-pressure loop may provide more comprehensive assessment of LV myocardial function, overcoming the limitations of the conventional parameters. We investigated the value of GMW in patients with HFpEF and assessed the relationship of GMW with concentric remodeling and hypertrophy. Consecutive patients with HFpEF (n = 107) and sex-matched healthy controls (n = 32) were prospectively enrolled. Clinical and conventional echocardiography variables were obtained. Further analyses of offline data were performed to obtain GMW indices including global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE). Association of concentric remodeling and hypertrophy with GMW was analyzed by univariate and multivariate analysis. HFpEF patients showed lower GWE (94% vs 96%, P < 0.001) and higher GWW (114 mmHg% vs 78 mmHg%, P = 0.003) than control group, while GWI (2111 mmHg% vs 2146 mmHg%, P = 0.877) and GCW (2369 mmHg% vs 2469 mmHg%, P = 0.733) were comparable in the two groups. HFpEF patients with relative wall thickness (RWT) > 0.42 had reduced GWE (94% vs 95%, P = 0.034) compared to HFpEF patients with RWT ≤ 0.42, while GWI, GCW, and GWW were comparable between these two subgroups. Multivariate analysis showed an independent association of RWT with GWI, GCW, and GWE, respectively. Impaired global myocardial work was detected in patients with HFpEF. Impaired LV GMW may be associated with increased RWT.

Effects of 3-month dapagliflozin on left atrial function in treatment-naïve patients with type 2 diabetes mellitus: Assessment using 4-dimensional echocardiography.

BACKGROUND: The sodium-glucose transporter-2 (SGLT-2) inhibitor dapagliflozin can improve left ventricular (LV) performance in patients with type 2 diabetes mellitus (T2DM). However, the effects on left atrial (LA) function in treatment-naïve T2DM patients remain unclear. The aim of our study was 1) to investigate the effects of 3-month treatment with dapagliflozin on LA function in treatment-naïve patients with T2DM using 4-dimensional automated LA quantification (4D Auto LAQ) and 2) to explore linked covariation patterns of changes in clinical and LA echocardiographic variables. METHODS: 4D Auto LAQ was used to evaluate LA volumes, longitudinal and circumferential strains in treatment-naïve T2DM patients at baseline, at follow-up, and in healthy control (HC). Sparse canonical correlation analysis (sCCA) was performed to capture the linked covariation patterns between changes in clinical and LA echocardiographic variables within the treatment-naïve T2DM patient group. RESULTS: This study finally included 61 treatment-naïve patients with T2DM without cardiovascular disease and 39 healthy controls (HC). Treatment-naïve T2DM patients showed reduced LA reservoir and conduit function at baseline compared to HC, independent of age, sex, BMI, and blood pressure (LASr: 21.11 ± 5.39 vs. 27.08 ± 5.31 %, padjusted = 0.017; LAScd: -11.51 ± 4.48 vs. -16.74 ± 4.51 %, padjusted = 0.013). After 3-month treatment with dapagliflozin, T2DM patients had significant improvements in LA reservoir and conduit function independent of BMI and blood pressure changes (LASr: 21.11 ± 5.39 vs. 23.84 ± 5.74 %, padjusted < 0.001; LAScd: -11.51 ± 4.48 vs. -12.75 ± 4.70 %, padjusted < 0.001). The clinical and LA echocardiographic parameters showed significant covariation (r = 0.562, p = 0.039). In the clinical dataset, changes in heart rate, insulin, and BMI were most associated with the LA echocardiographic variate. In the LA echocardiographic dataset, changes in LAScd, LASr, and LASr_c were most associated with the clinical variate. CONCLUSION: Compared with HC, treatment-naïve patients with T2DM had lower LA function, and these patients benefited from dapagliflozin administration, particularly in LA function.

99mTc-sestamibi and 18F-fluorodeoxyglucose imaging in patients with cardiogenic shock: A pilot study.

Background: Whether perfusion/metabolism imaging differs between matched ST-segment elevation myocardial infarction (STEMI) patients with and without cardiogenic shock (CS) remains unknown. Methods: Seventeen STEMI patients with CS (13 men, 60 ± 12 years) and 16 matched STEMI patients without CS (15 men, 54 ± 15 years) were prospectively recruited. All patients underwent baseline 99mTc-sestamibi/18F-fluorodeoxyglucose (FDG) imaging and echocardiography 6 ± 2 days post-infarction. Nine patients with CS and seven without CS had repeated imaging 98 ± 7 days post-infarction. The total perfusion deficit (TPD) and total FDG uptake deficit (TFD) were calculated to assess the percentages of impaired perfusion and metabolism over the left ventricle. Patients were followed up for 337 days (213-505 days) and the major adverse cardiac events (MACE) were recorded. Results: TPD was greater in patient with CS and was independently related to the presence of CS (OR: 4.36, p = 0.013). Both acute- and convalescent TFD were inversely related to the improvement ratio of LVEF (r-values: -0.62, -0.73; both p < 0.05). MACE occurred in 16 patients (10 CS and 6 non-CS), and acute TFD was predictive of MACE in those with CS (HR: 2.06, p = 0.038). Conclusion: In this pilot study, we demonstrated that STEMI patients with CS had a significantly increased TPD, which was relevant to the presence of CS. Acute TFD was associated with improvement in LVEF, and was predictive of MACE in patients with CS.

Fulminant cardiac sarcoidosis resembling giant cell myocarditis: a case report.

BACKGROUND: Severe cardiac sarcoidosis (CS) can share clinical and histopathologic features with giant cell myocarditis (GCM). CASE SUMMARY: A 56-year-old female presented with 1 week of exertional chest pressure and dyspnoea. Echocardiogram demonstrated extensive regional dysfunction with left ventricular ejection fraction (LVEF) 38%. Cardiac catheterization revealed no obstructive coronary artery disease and cardiac index 1.5 L/min/m2. Cardiac magnetic resonance imaging (MRI) demonstrated diffuse late gadolinium enhancement. Positron emission tomography with fluorodeoxyglucose (FDG) (FDG-PET) computed tomography showed FDG uptake in the anteroseptal and anterior wall and no extracardiac activity. Endomyocardial biopsy (EMB) demonstrated fragments of endocardial fibrosis with mixed inflammatory infiltrate including histiocytic giant cells, which could be due to CS or GCM. She was initially treated for GCM with high dose steroids, tacrolimus, and mycophenolate mofetil. Repeat EMB was pursued and demonstrated multiple granulomas with sharp demarcation from adjacent uninvolved myocardium consistent with CS. A dual-chamber implantable cardioverter-defibrillator was placed, and immunosuppression was changed to prednisone alone with plan for infliximab. DISCUSSION: This case illustrates a rare presentation of fulminant isolated CS. Endomyocardial biopsy with sufficient tissue was critical to establish a diagnosis and initiate appropriate immunosuppression.