Assessment of atrial septal defects using 3-dimensional transthoracic echocardiography prior to percutaneous device closure: first report from Bangladesh.

BACKGROUND: Secundum atrial septal defect (ASD) is treated following trans-catheter closure in alternative to surgical treatment. Per-intervention selection of device size with balloon occlusive diameter (BOD) often cause tearing or enlarging, causing arrhythmias and hypotension. We assessed the suitability of percutaneous device closure for ASD using 3-dimensional transthoracic echocardiography (3DTTE). OBJECTIVES: This study was conducted to investigate if 3DTTE could be an alternative of balloon sizing for selection of device size in atrial septal defect device closure. DESIGN: It was a cross-sectional comparative study. METHODS: This study was conducted at the department of Pediatric Cardiology, Bangabandhu Sheikh Mujib Medical University for a period of 2 years. Thirty-three purposively selected secundum ASD patients suitable for device closure were included in the study. Ethical permission was taken from the Institutional Review Board and written consent was taken from each patient's guardian. In this study, 3DTTE derived ASD diameter and BOD were compared with that of deployed device size using correlation analysis. RESULTS: Out of 33 patients, 63.6% were female and 36.4% were males had a mean age of 18.07 ± 14.58 years (range 2-55 years). Mean diameter of ASD measured by 2-dimensional (2D) and 3-dimensional (3D) echocardiography were 17.09 ± 6.08 mm and 21.30 ± 6.56 mm, respectively, yielding a significant difference (p < 0.001). 3D echocardiography derived ASDs diameter were highly correlated with device size than BOD and 2D echocardiography derived diameter (2D echocardiography: r = 0.796, p = <0.001, 3D echocardiography: r = 0.960, p = <0.001, BOD: r = 0.840, p = <0.001). CONCLUSION: 3DTTE can accurately measure ASD diameter and can be used as an alternate, effective, and safe method to select device size.

Assessment of subclinical left ventricular systolic dysfunction in patients with asymptomatic severe aortic stenosis with preserved left ventricular systolic function by three-dimensional speckle tracking echocardiography.

OBJECTIVES: Left ventricular dysfunction and remodeling can occur as a result of aortic valve stenosis (AS). Three-dimensional speckle tracking echocardiography (3D-STE) can detect early left ventricular myocardial dysfunction even before ejection fraction declines. The purpose of this study was to look at the relationship between various myocardial strain parameters measured by 3D-STE in asymptomatic severe AS patients from Bangladesh. METHODS: This study included 46 patients with asymptomatic severe AS but preserved LV systolic function (mean age 50.11 ± 12.66 years, LVEF 63.78 ± 3.95%, AS group) and 33 healthy subjects with no cardiovascular disease (mean age 48.21 ± 4.53 years, LVEF 65.15 ± 3.13%, control group). 3D-STE was used to measure left ventricular global myocardial strain parameters such as peak systolic longitudinal strain (PSLS), circumferential strain, radial strain, and area strain. RESULTS: The AS group had significantly thicker interventricular septum and posterior ventricular wall than the control group (1.49 ± .19 cm vs. .81 ± .09 cm, p < .001; 1.73 ± 1.71 cm vs. .81 ± .10 cm, p = .003, respectively.) In the AS group, the Indexed Aortic Valve Area (AVA) was significantly lower than in the control group. (.29 ± .10 vs. 2.03 ± .18, p < .001, respectively). In terms of LVEF (p = .102), left ventricular end diastolic volume (p = .075), or left ventricular end systolic volume (p = .092), no significant inter-group difference was found. However, global PSLS (-10.75 ± 2.27 vs. -16.42 ± 2.76, p < .001), circumferential strain (-14.26 ± 3.40 vs. -16.64 ± 2.56, p = .001), area strain (-22.70 ± 4.19 vs. -26.45 ± 9.90, p = .024) and radial strain (32.20 ± 8.77 vs. 41.00 ± 7.52, p < .001) in the AS group were significantly lower than in the control group. CONCLUSION: Our findings showed reductions in left ventricular global myocardial strains, particularly PSLS in patients suffering from asymptomatic severe AS in Bangladesh; this is consistent with other studies. Reduced area strain, detectable with 3D-STE, is also consistent with that pattern.

Enhancing the Safety and Efficacy of PSMA-Based Small-Molecule Drug Conjugates by Linker Stabilization and Conjugation to Transthyretin Binding Ligand.

This work describes the enhancement of a novel antitumor therapeutic platform that combines advantages from small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Valine-citrulline (VCit) dipeptide linkers are commonly used cathepsin B cleavable linkers for ADCs. However, the instability of these linkers in mouse serum makes translating efficacy data from mouse to human more challenging. Replacing the VCit linker with glutamic acid-valine-citrulline (EVCit) has been reported to enhance the stability of ADCs in mouse serum. However, the effect of EVCit linker on the stability of SMDCs has not been reported. Here, we report that incorporating the EVCit linker in prostate-specific membrane antigen-targeting SMDCs, equipped with the transthyretin ligand AG10, resulted in conjugates with lower toxicity, an extended half-life, and superior therapeutic efficacy to docetaxel in a xenograft mouse model of prostate cancer. This should make SMDCs' preclinical toxicity and efficacy data from mice more reliable for predicting human results.

Identification of significant coronary artery disease in patients with non-ST segment elevation acute coronary syndrome by myocardial strain analyses using three dimensional speckle tracking echocardiography.

BACKGROUND: Speckle-tracking imaging is a novel method for assessing left ventricular function and ischemic changes. This study aimed to predict the presence of significant coronary artery stenosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) by 3D strain analysis using speckle tracking echocardiography (3DSTE) at rest. METHODS: This cross-sectional study included a total 60 patients with NSTE-ACS who underwent 3DSTE immediately prior to coronary angiography. Subsequently, patients undergone coronary angiogram (CAG) and divided into two groups; group- I: significant stenosis (n = 36), group-II: non-significant stenosis (n = 24). RESULTS: Global peak systolic longitudinal strain (GPSLS), circumferential strain (CS), area strain (AS), and radial strain (RS) were obtained successfully in 60 patients. All strain parameters were significantly reduced in patient group of significant stenosis. Receiver operating characteristic (ROC) curve analysis demonstrated that GPSLS could effectively detect patients with significant stenosis (area under ROC curve = 0.840, 95% CI = 0.735-0.945). GPSLS with a cutoff value of -13.50% showed good sensitivity and specificity for predicting significant stenosis (sensitivity 88.9% and specificity 70.8%). CONCLUSION: Global peak systolic longitudinal strain using 3D speckle tracking echocardiography at rest was significantly lower in patients with significant stenosis and might be useful for identifying patients with a significant stenosis with good degree of sensitivity and specificity.

Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading TTR stabilizers in clinic and structural features important for effective TTR stabilization is lacking. Here, we found that molecular interactions reflected in better binding enthalpy may be critical for development of TTR stabilizers with improved potency and selectivity. Our studies provide mechanistic insights into the unique binding mode of the TTR stabilizer, AG10, which could be attributed to mimicking the stabilizing T119M variant. Because of the lack of animal models for ATTR-CM, we developed an in vivo system in dogs which proved appropriate for assessing the pharmacokinetics-pharmacodynamics profile of TTR stabilizers. In addition to stabilizing TTR, we hypothesize that optimizing the binding enthalpy could have implications for designing therapeutic agents for other amyloid diseases.