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Background: While speckle tracking echocardiography (2DSTE) can be used to study longitudinal, circumferential, and radial function, real time 3D echocardiography (3DE) generates dynamic time–volume curves, offering a wide array of new parameters for characterizing mechanical and volumetric properties of the left ventricle (LV). Our aim was to investigate the merit of these new techniques to separate normal from abnormal echocardiograms as well as to identify subclinical disease in reportedly normal subjects. Methods: Eighty-one patients (mean age 61 ± 16 years) underwent standard 2D echocardiography (2DE) enhanced by 2DSTE and 3DE. The data included LV volumes and ejection fraction (EF), velocities, strain/strain rate, and peak ejection/filling rates. The patients were divided into Group 1: normal (n = 42) and Group 2: abnormal (n = 39) on the basis of an expert interpretation of the resting 2DE. Results: Global longitudinal strain (%) was 17 ± 4 in Group1 and 14 ± 4 in Group2 (P < 0.002). Strain rates (SR, 1/sec) at peak systole (1.1 ± 0.2 vs 0.9 ± 0.3, P < 0.001) and early diastole (1.3 ± 0.3 vs 0.9 ± 0.3, P < 0.001) were also higher in Group1. Three-dimensional peak ejection and filling rates (EDV/sec) were significantly higher in Group1 (−2.5 ± 0.4 vs −2.1 ± 0.7, and 1.8 ± 0.2 vs 1.5 ± 0.5, P < 0.002, P < 0.001, respectively). The best discriminatory power for predicting a normal 2DE was systolic SR with a sensitivity of 82% and a specificity of 54% using a cutoff value of 1.09. Interestingly, 19/41 (46%) of Group1 patients had systolic SR < 1.09, suggesting subclinical disease. Conclusions: 2DSTE and 3DE can discriminate between normal and abnormal echocardiograms and have the potential to detect subclinical LV dysfunction. (Echocardiography 2012;29:588-597)

Hypotheses Degree of mitral annular remodeling is directly associated with severity of chronic mitral regurgitation (MR). Mitral annular remodeling occurs in a symmetric fashion, regardless of MR severity. In addition to MR severity, MR mechanism plays a significant role in mitral annular remodeling. Background Limited data exists on mitral annular remodeling in patients with MR. Identification of annular changes may be important in aiding surgical repair. Methods Mitral annular dimensions (anteroposterior, intercommissural, surface area, and circumference) were measured in end systole and diastole using 3-dimensional reconstructive software in 83 patients: trace to no MR (23), mild MR (15), moderate MR (26), and severe MR (19). Annular sphericity indices were determined by dividing intercommissural by anteroposterior dimensions. Patients were further subgrouped by mechanism of MR. Results With increasing MR severity, there was a corresponding increase in all annular measurements, most pronounced in the anteroposterior dimension, circumference, and area. Larger increases were seen in patients with prolapse/flail and dilated mechanisms. Furthermore, the mitral annulus became more circular (sphericity index approached 1.0) with increasing MR severity. Patients with prolapse/flail mechanisms exhibited normal left ventricular volumes despite significant annular enlargement. Conclusions Mitral annular remodeling is directly associated with MR severity and occurs in an asymmetric fashion, yet is not limited to one region of the annulus. Mechanism of MR plays a significant role in annular remodeling. Annular remodeling can occur independently of left ventricular remodeling.

We defined the effects of the operative (OP) state and phenylephrine challenge on the assessment of mitral regurgitation (MR) severity.In all, 57 patients underwent transesophageal echocardiographic assessment of MR severity pre-OP (PREOP) and intra-OP. MR severity was assessed PREOP under conscious sedation and intra-OP with general anesthesia, before and after hemodynamic manipulation with vasoactive agents, to match intra-OP and PREOP transesophageal echocardiographic mean arterial blood pressures.Intra-OP MR and mean arterial pressure were less than PREOP in 27 patients (both P.001). When PREOP and OP blood pressures were matched using phenylephrine, there was no significant difference in MR severity between the two states (P = 1.0). Nonetheless, MR severity was still underestimated in 6 patients and overestimated in 7 patients intra-OP.Intra-OP transesophageal echocardiography underestimates MR severity. Phenylephrine reduces, yet does not eliminate, intra-OP underestimation of MR severity.

e21600 Background: Cardiotoxicity has been reported in cancer patients treated with anthracycline- and non-anthracycline-based chemotherapy. Myocardial strain assessed by speckle-tracking echocardiography enables early detection of subclinical chemotherapy-induced cardiotoxicity. However, comparisons of strain indices in patients undergoing chemotherapy with and without anthracyclines have not been reported. The prupose of this study was to compare myocardial strain in patients treated with these two chemotherapy regimens. Methods: This study was approved by the institutional review board at Saint Francis Hospital. 43 adult cancer patients (30 with solid tumors, 6 with lymphomas, 6 with leukemias and 1 with multiple myeloma) treated with anthracyline-based or non-anthracycline-based chemotherapy, were studied with conventional 2D and 3D echocardiography, 2D speckle-tracking imaging, and cardiac biomarkers. Results: Of the 43 patients, 22 received anthracycline-based chemotherapy, with an average cumulative anthracycline dose of 235 mg/m2. The other 21 patients received non-anthracycline-based chemotherapy including VEGF inhibitors and HER-2 receptor antagonists. There was no difference in 2D or 3D left ventricular ejection fraction (LVEF) (60.9 ± 4.5% vs 62.0 ± 4.9% by 2D; 60.5 ± 5.4 % vs 62.1± 5.2% by 3D, p = 0.35 for both 2D and 3D), troponin or NT-proBNP between anthracyline-treated patients and non-anthracycline treated patients. However, global longitudinal strain (GLS) and global circumferential strain (GCS) were decreased in patients treated with anthracycline-based chemotherapy compared with patients treated with non-anthracycline-based chemotherapy (-17.8 ± 2.8 vs 19.9 ± 2.9, p = 0.018 for GLS; -21.6 ± 4.8 vs 24.8 ± 4.8, p = 0.041 for GCS). Conclusions: In contrast with patients treated with non-anthracyline-based chemotherapy, patients treated with anthracyclines had reduced myocardial systolic strain even at low cumulative doses. This occurred in the absence of detectable reductions in LVEF. Thus early assessement of myocardial strain abnormality and early intervention with cardioprotective agents may be considered for these patients.

Introduction: Echo and cardiac magnetic resonance imaging (CMR) are often used in evaluation of patients with heart failure (HF) whether associated with systolic dysfunction or preserved ejection fraction (EF). We evaluated the relative merits of EF (by CMR and 2D echo) versus echo strain (by 2D and 3D speckle tracking echo STE) for imaged-based recognition of patients with HF. Methods: 117 subjects (81 normals and 36 HF) were evaluated. There were no significant differences in age or gender between normals (59+/-14 yrs, 39 M) and HF (54+/-14 yrs, 29 M). 2D biplane echo and CMR provided EF while 2D and 3DSTE yielded global longitudinal (GLS %) and circumferential (GCS%) strains. Since 3DSTE was optimized for strain rather than EF, 3DEF was not evaluated. HF diagnosis was based on dyspnea, plasma N-terminal pro-B type brain natriuretic peptide and EF. Results: As expected, mean EF and strains differed between normals and HF (table). Using a backward elimination regression model, only 2DEF, CMREF, 2DGCS% and 3DGLS% were retained for further analysis. ROC-guided criterion values (for HF recognition) for 2DEF, CMREF, 2DGCS% and 3DGLS% were >52%, >50%, >-22% and >-16%, respectively. Using these values, the sensitivity, specificity, and odd-ratios for HF recognition with each parameter were computed (table). Conclusions: CMREF provided the highest sensitivity and specificity for HF recognition. The most sensitive echo measure was 3DGLS% while the most specific echo measure was 2DEF. However, in a mixed population of normals and HF, whether associated with systolic dysfunction or preserved EF, 2DGCS% and 3DGLS% had the highest odds ratios.

While speckle tracking echocardiography (2DSTE) can be used to study longitudinal, circumferential, and radial function, real time 3D echocardiography (3DE) generates dynamic time-volume curves, offering a wide array of new parameters for characterizing mechanical and volumetric properties of the left ventricle (LV). Our aim was to investigate the merit of these new techniques to separate normal from abnormal echocardiograms as well as to identify subclinical disease in reportedly normal subjects.Eighty-one patients (mean age 61 ± 16 years) underwent standard 2D echocardiography (2DE) enhanced by 2DSTE and 3DE. The data included LV volumes and ejection fraction (EF), velocities, strain/strain rate, and peak ejection/filling rates. The patients were divided into Group 1: normal (n = 42) and Group 2: abnormal (n = 39) on the basis of an expert interpretation of the resting 2DE.Global longitudinal strain (%) was 17 ± 4 in Group1 and 14 ± 4 in Group2 (P0.002). Strain rates (SR, 1/sec) at peak systole (1.1 ± 0.2 vs 0.9 ± 0.3, P0.001) and early diastole (1.3 ± 0.3 vs 0.9 ± 0.3, P0.001) were also higher in Group1. Three-dimensional peak ejection and filling rates (EDV/sec) were significantly higher in Group1 (-2.5 ± 0.4 vs -2.1 ± 0.7, and 1.8 ± 0.2 vs 1.5 ± 0.5, P0.002, P0.001, respectively). The best discriminatory power for predicting a normal 2DE was systolic SR with a sensitivity of 82% and a specificity of 54% using a cutoff value of 1.09. Interestingly, 19/41 (46%) of Group1 patients had systolic SR1.09, suggesting subclinical disease.2DSTE and 3DE can discriminate between normal and abnormal echocardiograms and have the potential to detect subclinical LV dysfunction.

Assessment of regional and global left ventricular (LV) function and strain are important in the setting of prior myocardial infarction (MI). Feature tracking (FT-MRI) is a novel cardiac MRI method for assessment of myocardial strain, similar to speckle tracking in 2-D echocardiography, which provides multi-planar strain data without the need for tagged images.

Left atrial (LA) size and function are often regarded as a reflection of left ventricular (LV) hemodynamics. Purpose:In this study we investigated the hemodynamic correlates of contrast transit time within the left atrium (LA) in patients with LV systolic dysfunction by cardiac magnetic resonance imaging (CMR).

Background— Left atrial (LA) size and function reflect left ventricular (LV) hemodynamics. In the present study, we developed a novel method to determine LA circulation transit time (LATT) by MRI and demonstrated its close association with LV filling pressure. Methods and Results— All subjects were prospectively recruited and underwent contrast-enhanced MR dynamic imaging. Mean LATT was determined as the time for contrast to transit through the LA during the first pass. In an invasive study group undergoing clinically indicated cardiac catheterization (n=25), LATT normalized by R-R interval (nLATT) was closely associated with LV early diastolic pressure ( r =0.850, P =0.001), LV end-diastolic pressure ( r =0.910, P r =0.912, P P P =0.023); in B-type natriuretic peptide (interquartile range): 44 (60) pg/mL, 87 (359) pg/mL, and 371 (926) pg/mL ( P =0.002); and in N-terminal pro–B-type natriuretic peptide: 57 (163) pg/mL, 208 (990) pg/mL, and 931 (1726) pg/mL ( P =0.002), demonstrating the ability of nLATT to assess hemodynamic status. Conclusions— nLATT by cardiac MR is a promising new parameter of LV filling pressure that may provide graded noninvasive hemodynamic assessment.

Methods Subjects were prospectively enrolled and brain natriuretic peptide (BNP) and N-terminal proBNP (NT proBNP) obtained prior to CMR examination. First-pass perfusion was performed in sagital and coronal planes covering the main pulmonary artery and left atrium using a saturation recovery SSFP sequence with 0.005 to 0.01 mmol/kg gadopentetate. PTT was measured as the time interval between peak signal intensity in the main pulmonary artery and peak signal intensity in the left atrium and normalized to heart rate. SSFP cine imaging was performed for ventricular structure and function evaluation. All participants also underwent echocardiography within 2 hours of CMR. Right ventricular (RV) systolic pressure was estimated using Doppler tricuspid regurgitant velocity. Tissue Doppler was used to determine the mitral E/e' ratio. Results Of 31 subjects enrolled, 12 were normal controls and 19 CHF patients. Most with CHF (n = 17) were stable outpatients with class I to III NYHA functional class. Compared to controls, CHF patients had lower LVEF (37% vs 56%, p < 0.001), and stroke volume (74 ml vs 96 ml, p = 0.005). There was no significant difference in cardiac output (5.8 L/min vs 5.0 L/min, p = 0.077). However, PTT was significantly prolonged in CHF patients: 9.0 ± 2.9 s vs 5.7 ± 0.9 s in controls (p < 0.001). Prolonged PTT was closely associated with BNP and NT proBNP(r = 0.746 (p < 0.001), r = 0.789 (p < 0.001), respectively). PTT was also associated with low LVEF (r = -0.653, p < 0.001), low RVEF (r = 0.605, p < 0.001), reduced cardiac output (r = -0.533, p = 0.002), RV systolic pressure (r = 0.459, p = 0.032) and mitral E/e' (r = 0.615, p = 0.002). In multivariate models including PTT, cardiac output and LVEF, prolonged PTT was the only predictor of increased BNP (p = 0.003) and NT proBNP (p = 0.001), suggesting an independent relationship between PTT and BNP.

Background: Left ventricular (LV) mass is an important prognostic factor for predicting cardiac morbidity and mortality. LV mass to volume ratio (M/V) by CMR has been shown to relate to adverse outcomes in several settings. However, the relevance of this M/V has not been established for post-MI arrhythmias. We evaluated the use of 3D echo (3D) LV M/V in predicting event free survival in post-MI patients meeting the MADIT II criteria, and compared it to EDV and ESV indexed to the body surface area (EDVi, ESVi). Methods: Forty patients (35 males, mean age 69.6y) meeting the MADIT II criteria for implantable defibrillator (ICD) placement with an EF of ≤30% were imaged and followed up for a mean of 472 days for adverse events (ventricular fibrillation or sustained ventricular tachycardia, and appropriate ICD discharges). Patients had 3D within 24 hours of ICD implantation. EDVi, ESVi and LV mass were determined and M/V calculated. Receiver operator curves (ROC) were used to determine the associations between M/V, EDVi, ESVi and adverse events. Results : Mean indexed LV mass was 109.7 g. Mean EDVi, ESVi were 123.3 ml/m 2 and 93.4ml/m 2 . The adverse event rate was 25% (10/40 patients). ROC curve analysis showed that M/V was significantly associated with adverse events(p = 0.002) while EDVi (p=0.12) and ESVi (p=0.08) were not. Patients with higher M/V were more likely to have events than those with smaller M/V (area under the curve = 0.74, sensitivity 80%, specificity 67%). Conclusion: 3D derived LV M/V is useful for determining risk of adverse events in high-risk post-MI patients who meet the MADIT II criteria. M/V is superior to 3D EDV, ESV for prediction of arrhythmic events this high risk population.

Background Assessment of right ventricular function by 2-dimensional echocardiography (2DECHO) is difficult because of its complex shape. Real-time 3-dimensional echocardiography (RT3DECHO) may be superior. Methods End-diastolic volume, end-systolic volume, stroke volume, and ejection fraction obtained by 2DECHO, RT3DECHO short-axis disk summation (DS), and RT3DECHO apical rotation were compared with cardiac magnetic resonance imaging in 71 healthy individuals. Results RT3DECHO DS showed less volume underestimation compared with 2DECHO and RT3DECHO apical rotation. Test-retest variability for RT3DECHO DS end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction were 3.3%, 8.7%, 10%, and 10.3%, respectively. Normal reference ranges of indexed volumes (mean ± 2SD) for right ventricular end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction were 38.6 to 92.2 mL/m 2 , 7.8 to 50.6 mL/m 2 , 22.5 to 42.9 mL/m 2 , and 38.0% to 65.3%, respectively, for women and 47.0 to 100 mL/m 2 , 23.0 to 52.6 mL/m 2 , 14.2 to 48.4 mL/m 2 , and 29.9% to 58.4%, respectively, for men. Conclusions RT3DECHO DS is superior to RT3DECHO apical rotation and 2DECHO for right ventricular quantification, and performs acceptably when compared with cardiac magnetic resonance imaging in healthy individuals.

Cardiac Magnetic Resonance (CMR) Imaging is an important modality in the evaluation of patients with cardiomyopathy, in whom regurgitant valvular disease is highly prevalent. However, there is a lack of prospective studies to ascertain the accuracy of CMR in the assessment of regurgitant valvular

Background: Feature tracking (FT-MRI) is a novel method for assessment of myocardial strain that provides multi-planar strain data without the need for tagged images. The goal of our study was to characterize left ventricular (LV) global and regional strains in patients with prior myocardial infarction (MI) using FT-MRI. Methods: Eighty patients with prior MI were grouped by infarct location {left anterior descending (LAD), left circumlex (LCx), right coronary (RCA)}. Scar quantiication was done by computer-assisted planimetry (Medis Qmass v7.2) of gadolinium enhanced delayed images and scar percentage was determined. Global and regional circumferential endocardial (Ecc endo) and epicardial (Ecc epi) and longitudinal (Ell) strains were derived from long and short axis planes. Semi-automated tracing of endocardial and epicardial borders using FT-MRI (Diogenes MRI, Tomtec Systems) was performed and strains were mapped to a 17 segment AHA model. Repeated measures ANOVA was used to compare normal strain values from 60 healthy subjects to MI patients controlling for scar percentage. Results: The mean age was 64.4(12) years, mean ejection fraction (EF) 42(11)% and mean scar percentage 17(9)%. Peak global Ecc strains were decreased in LAD (endo: -13.7 (5)%, epi: -8.4 (3)%) and RCA infarcts (endo: -16.1(6)%, epi: -9.6%) compared to normals (Ecc endo= -24 (4)%, Ecc epi= -16.1 (3)%, all with p

CRISPR/Cas9 can be used for precise genetic knock-in of epitope tags into endogenous genes, simplifying experimental analysis of protein function. However, Cas9-assisted epitope tagging in primary mammalian cell cultures is often inefficient and reliant on plasmid-based selection strategies. Here we demonstrate improved knock-in efficiencies of diverse tags (V5, 3XFLAG, Myc, HA) using co-delivery of Cas9 protein pre-complexed with two-part synthetic modified RNAs (annealed crRNA:tracrRNA) and single-stranded oligodeoxynucleotide (ssODN) repair templates. Knock-in efficiencies of ~5-30%, were achieved without selection in embryonic stem (ES) cells, neural stem (NS) cells, and brain tumour-derived stem cells. Biallelic-tagged clonal lines were readily derived and used to define Olig2 chromatin-bound interacting partners. Using our novel web-based design tool, we established a 96-well format pipeline that enabled V5-tagging of sixty different transcription factors. This efficient, selection-free and scalable epitope tagging pipeline enables systematic surveys of protein expression levels, subcellular localization, and interactors across diverse mammalian stem cells.