PATIENT-SPECIFIC SIMULATION OF RIGHT VENTRICLE OUTFLOW TRACT CONDUIT BALLOON ANGIOPLASTY USING CARDIAC MRI-DERIVED 3D VIRTUAL MODELS TO ASSESS THE RISK OF CORONARY ARTERY COMPRESSION DURING TRANSCATHETER PULMONARY VALVE REPLACEMENT [Meeting Abstract]
Bhatla, Puneet; Chakravarti, Sujata; Ludomirsky, Achiau; Argilla, Michael; Berman, Phillip; McElhinney, Doff; Flamini, Vittoria
A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies
Briassouli, Paraskevi; Halushka, Marc K; Reed, Joanne H; Molad, Yair; Fox-Talbot, Karen; Buyon, Lucas; Guzman, Edwin; Ludomirsky, Achiau; Clancy, Robert M; Buyon, Jill P
Objective. Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating beta2-glycoprotein I (beta2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined. Methods. Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies. Results. uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 +/- 0.1 vs 1.9 +/- 0.05 ng/ml (P < 0.0001), 6.6 +/- 0.3 vs 2.1 +/- 0.2 ng/ml (P < 0.0001) and 435 +/- 34 vs 220 +/- 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 +/- 0.1 vs 1.9 +/- 0.05 ng/ml; P = 0.0086, 6.2 +/- 1.4 vs 2.2 +/- 0.7 ng/ml; P = 0.147 and 412 +/- 61 vs 260 +/- 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region. Conclusion. Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.
Therapeutic ultrasound to noninvasively create intracardiac communications in an intact animal model
Owens, Gabe E; Miller, Ryan M; Ensing, Greg; Ives, Kimberly; Gordon, David; Ludomirsky, Achi; Xu, Zhen
OBJECTIVE: To determine if pulsed cavitational ultrasound therapy (histotripsy) can accurately and safely generate ventricular septal defects (VSDs) through the intact chest of a neonatal animal, with the eventual goal of developing a noninvasive technique of creating intra-cardiac communications in patients with congenital heart disease. BACKGROUND: Histotripsy is an innovative ultrasonic technique that generates demarcated, mechanical tissue fractionation utilizing high intensity ultrasound pulses. Previous work has shown that histotripsy can create atrial septal defects in a beating heart in an open-chest canine model. METHODS: Nine neonatal pigs were treated with transcutaneous histotripsy targeting the ventricular septum. Ultrasound pulses of 5-musec duration at a peak negative pressure of 13 MPa and a pulse repetition frequency of 1 kHz were generated by a 1 MHz focused transducer. The procedure was guided by real-time ultrasound imaging. RESULTS: VSDs were created in all pigs with diameters ranging from 2 to 6.5 mm. Six pigs were euthanized within 2 hrs of treatment, while three were recovered and maintained for 2-3 days to evaluate lesion maturation and clinical side effects. There were only transient clinical effects and pathology revealed mild collateral damage around the VSD with no significant damage to other cardiac or extra-cardiac structures. CONCLUSIONS: Histotripsy can accurately and safely generate VSDs through the intact chest in a neonatal animal model. These results suggest that with further advances, histotripsy can be a useful, noninvasive technique to create intracardiac communications, which currently require invasive catheter-based or surgical procedures, to clinically stabilize newborn infants with complex congenital heart disease.
Accuracy and reproducibility of strain by speckle tracking in pediatric subjects with normal heart and single ventricular physiology: a two-dimensional speckle-tracking echocardiography and magnetic resonance imaging correlative study
Singh, Gautam K; Cupps, Brian; Pasque, Michael; Woodard, Pamela K; Holland, Mark R; Ludomirsky, Achiau
BACKGROUND: Myocardial strain is a sensitive measure of ventricular systolic function. Two-dimensional speckle-tracking echocardiography (2DSE) is an angle-independent method for strain measurement but has not been validated in pediatric subjects. The aim of this study was to evaluate the accuracy and reproducibility of 2DSE-measured strain against reference tagged magnetic resonance imaging-measured strain in pediatric subjects with normal hearts and those with single ventricles (SVs) of left ventricular morphology after the Fontan procedure. METHODS: Peak systolic circumferential strain and longitudinal strain (LS) in segments (n = 16) of left ventricles in age-matched and body surface area-matched 20 healthy and 12 pediatric subjects with tricuspid atresia after the Fontan procedure were measured by 2DSE and tagged magnetic resonance imaging. Average (global) and regional segmental strains measured by the two methods were compared using Spearman's and Bland-Altman analyses. RESULTS: Global strains measured by 2DSE and tagged magnetic resonance imaging demonstrated close agreements, which were better for LS than circumferential strain and in normal left ventricles than in SVs (95% limits of agreement, +0.0% to +3.12%, -2.48% to +1.08%, -4.6% to +1.8%, and -3.6% to +1.8%, respectively). There was variability in agreement between regional strains, with wider limits in apical than in basal regions in normal left ventricles and heterogeneity in SVs. Strain values were significantly (P < .05) higher in normal left ventricles than in SVs except for basal LS, which were similar in both cohorts. The regional strains in normal left ventricles demonstrated an apicobasal magnitude gradient, whereas SVs showed heterogeneity. Reproducibility was the most robust for images obtained with frame rates between 60 and 90 frames/sec, global LS in both cohorts, and basal strains in normal left ventricles. CONCLUSIONS: Strains measured by 2DSE agree with strain measured by magnetic resonance imaging globally but vary regionally, particularly in SVs. Global strain may be a more robust tool for cardiac functional evaluation than regional strain in SV physiology. The reliability of 2DSE-measured strain is affected by the frame rate, the nature of strain, and ventricular geometry.
Noninvasive creation of an atrial septal defect by histotripsy in a canine model
Xu, Zhen; Owens, Gabe; Gordon, David; Cain, Charles; Ludomirsky, Achi
BACKGROUND: The primary objective of this study was to develop an image-guided, noninvasive procedure to create or enlarge an atrial septal defect for the treatment of neonates with hypoplastic left heart syndrome and an intact or restrictive atrial septum. Histotripsy is an innovative ultrasonic technique that produces nonthermal, mechanical tissue fractionation through the use of high-intensity ultrasound pulses. This article reports the pilot in vivo study to create an atrial septal defect through the use of extracardiac application of histotripsy in an open-chest canine model. METHODS AND RESULTS: In 10 canines, the atrial septum was exposed to histotripsy by an ultrasound transducer positioned outside the heart. Ultrasound pulses of 6-microsecond duration at a peak negative pressure of 15 MPa and a pulse repetition frequency of 3.3 kHz were generated by a 1-MHz focused transducer. The procedure was guided and monitored by real-time ultrasound imaging. In 9 of 10 canines, an atrial septal defect was produced, and shunting across the atrial septum was visualized. Pathology of the hearts showed atrial septal defects with minimal damage to surrounding tissue. No damage was found on the epicardial surface of the heart or other structures. CONCLUSIONS: Under real-time ultrasound guidance, atrial septal defects were successfully created with extracardiac histotripsy in a live canine model. Although further studies in an intact animal model are needed, these results provide promise of histotripsy becoming a valuable clinical tool.
Transcutaneous Creation of Ventricular Septal Defects Using Histotripsy in a Neonatal Animal Model [Meeting Abstract]
Owens, G; Ensing, G; Miller, R; Ludomirsky, A; Charles, C; Xu, Z
Intrinsic myoarchitectural differences between the left and right ventricles of fetal human hearts: an ultrasonic backscatter feasibility study
Holland, Mark R; Gibson, Allyson A; Kirschner, Carol A; Hicks, Deborah; Ludomirsky, Achiau; Singh, Gautam K
OBJECTIVE: Embryologically, cardiac chambers differ in their morphologic and contractile properties from the beginning. We hypothesized that a noninvasive ultrasonic backscatter investigation might illustrate the fundamental differences in myocardial morphologic properties of the 2 ventricles during heart development. The goals of this investigation were to 1) explore the feasibility of measuring the magnitude of cyclic variation of ultrasonic backscatter from the left and right ventricular free walls of fetal hearts; 2) compare measurements of the magnitude of cyclic variation from the left and right sides of the heart; and 3) determine if the observed results are consistent with predictions relating the overall backscatter level and the magnitude of cyclic variation. METHODS: Cyclic variation data from the left and right ventricular free walls were generated from analyses of the backscatter from echocardiographic images of 16 structurally normal fetal hearts at mid-gestation. RESULTS: The magnitude of cyclic variation was found to be greater for the left ventricular free wall than for the right ventricular free wall (4.5 +/- 1.1 dB vs 2.3 +/- 0.9 dB, respectively; mean +/- standard deviation; P < .0001, paired t test). CONCLUSION: Measurements of the cyclic variation of backscatter can be obtained from both the left and right sides of fetal hearts demonstrating a significant difference between the measured magnitude of cyclic variation in the left and right ventricular myocardium. This observation is consistent with predictions relating the overall backscatter level and the magnitude of cyclic variation. The results of this study suggest cyclic variation measurements may offer a useful approach for characterizing intrinsic differences in myocardial properties of the 2 ventricles in assessing fetal heart development
Measurements of ultrasonic attenuation properties of midgestational fetal pig hearts
Gibson, Allyson A; Singh, Gautam K; Hoffman, Joseph J; Ludomirsky, Achiau; Holland, Mark R
The objectives of this study were to measure the relative attenuation properties of the left and right ventricles in fetal pig hearts and to compare the spatial variation in attenuation measurements with those observed in previously published backscatter measurements. Approximately 1.0-mm-thick, short-axis slices of excised, formalin-fixed heart were examined from 15 midgestational fetal pigs using a 50-MHz single-element transducer. Measurements of the attenuation properties demonstrate regional differences in the left and right ventricular myocardium that appear consistent with the previously reported regional differences in apparent integrated backscatter measurements of the same fetal pig hearts. For regions of perpendicular insonification relative to the myofiber orientation, the right ventricular free wall showed larger values for the slope of the attenuation coefficient from 30-60 MHz (1.48 +/- 0.22 dB/(cm x MHz) (mean +/- SD) and attenuation coefficient at 45 MHz (46.3 +/- 7.3 dB/cm [mean +/- SD]) than the left ventricular free wall (1.18 +/- 0.24 dB/(cm x MHz) and 37.0 +/- 7.9 dB/cm (mean +/- SD) for slope of attenuation coefficient and attenuation coefficient at 45 MHz, respectively). This attenuation study supports the hypothesis that intrinsic differences in the myocardium of the left and right ventricles exist in fetal pig hearts at midgestation
Maturational and growth-related changes in left ventricular longitudinal strain and strain rate measured by two-dimensional speckle tracking echocardiography in healthy pediatric population
Lorch, Steven M; Ludomirsky, Achiau; Singh, Gautam K
OBJECTIVE: We aimed to evaluate myocardial strain and strain rate (SR) by novel 2-dimensional speckle tracking echocardiography in a large pediatric cohort (1) to establish their normal values and (2) to discern the influence of maturation and cardiac growth on them. METHODS: Echocardiograms of 284 consecutive subjects of a healthy pediatric cohort aged between birth and 18 years were analyzed by vector velocity imaging software to measure longitudinal systolic strain (epsilon) and systolic and diastolic SR in left ventricular septal and lateral segments. Regression analysis was performed to determine the effect of aging and cardiac growth on epsilon and SR. RESULTS: Longitudinal epsilon (septal -18.30% +/- 6.67% and lateral -20.68% +/- 8.08%) did not change significantly with maturation and declining heart rate from birth to 18 years. Systolic and early diastolic SR declined until age 5 to 10 years. Longitudinal epsilon significantly (P < .05) correlated with left ventricular growth. CONCLUSION: This study establishes reference values for longitudinal epsilon and SR and reveals that epsilon is relatively independent of maturational changes, lending it as a tool for cardiac evaluation across differing ages in pediatric subjects
Regional variation in the measured apparent ultrasonic backscatter of mid-gestational fetal pig hearts
Gibson, Allyson A; Singh, Gautam K; Kulikowska, Agnieszka; Wallace, Kirk D; Hoffman, Joseph J; Ludomirsky, Achiau; Holland, Mark R
The goal of this study was to characterize and compare regional backscatter properties of fetal hearts through measurements of the apparent integrated backscatter. Sixteen excised, formalin-fixed fetal pig hearts, representing an estimated 53 to 63 days of gestation, were investigated. Spatially localized measurements of integrated backscatter from these specimens were acquired using a 50 MHz single-element transducer. The apparent integrated backscatter measurements demonstrate different patterns of backscatter from the myocardium of the right ventricle compared with that of the left ventricle. These backscatter measurements appear to be consistent with the anisotropy of the fiber orientation observed in histologic assessment of the same specimens. For each of the 16 hearts, the apparent integrated backscatter from the right ventricular myocardium was larger than that from the left ventricular myocardium, exhibiting mean apparent backscatter values of -35.9 +/- 2.0 dB and -40.1 +/- 1.9 dB (mean +/- standard deviation; n = 16; p < 0.001), respectively. This study suggests that the intrinsic ultrasonic properties of the left and right ventricular myocardium are distinct in fetal pig hearts at mid-gestation