A Noninvasive Assessment of Flow Based on Contrast Dispersion in Computed Tomography Angiography: A Computational and Experimental Phantom Study.

Transluminal attenuation gradient (TAG), defined as the gradient of the contrast agent attenuation drop along the vessel, is an imaging biomarker that indicates stenosis in the coronary arteries. The transluminal attenuation flow encoding (TAFE) equation is a theoretical platform that quantifies blood flow in each coronary artery based on computed tomography angiography (CTA) imaging. This formulation couples TAG (i.e., contrast dispersion along the vessel) with fluid dynamics. However, this theoretical concept has never been validated experimentally. The aim of this proof-of-principle phantom study is to validate TAFE based on CTA imaging. Dynamic CTA images were acquired every 0.5 s. The average TAFE estimated flow rates were compared against four predefined pump values in a straight (20, 25, 30, 35, and 40 ml/min) and a tapered phantom (25, 35, 45, and 55 ml/min). Using the TAFE formulation with no correction, the flow rates were underestimated by 33% and 81% in the straight and tapered phantoms, respectively. The TAFE formulation was corrected for imaging artifacts focusing on partial volume averaging and radial variation of contrast enhancement. After corrections, the flow rates estimated in the straight and tapered phantoms had an excellent Pearson correlation of r = 0.99 and 0.87 (p < 0.001), respectively, with only a 0.6%±0.2 mL/min difference in estimation of the flow rate. In this proof-of-concept phantom study, we corrected the TAFE formulation and showed a good agreement with the actual pump values. Future clinical validations are needed for feasibility of TAFE in clinical use.

Flow Dynamics in the Aortic Arch and Its Effect on the Arterial Input Function in Cardiac Computed Tomography.

The arterial input function (AIF)-time-density curve (TDC) of contrast at the coronary ostia-plays a central role in contrast enhanced computed tomography angiography (CTA). This study employs computational modeling in a patient-specific aorta to investigate mixing and dispersion of contrast in the aortic arch (AA) and to compare the TDCs in the coronary ostium and the descending aorta. Here, we examine the validity of the use of TDC in the descending aorta as a surrogate for the AIF. Computational fluid dynamics (CFD) was used to study hemodynamics and contrast dispersion in a CTA-based patient model of the aorta. Variations in TDC between the aortic root, through the AA and at the descending aorta and the effect of flow patterns on contrast dispersion was studied via postprocessing of the results. Simulations showed complex unsteady patterns of contrast mixing and dispersion in the AA that are driven by the pulsatile flow. However, despite the relatively long intra-aortic distance between the coronary ostia and the descending aorta, the TDCs at these two locations were similar in terms of rise-time and up-slope, and the time lag between the two TDCs was 0.19 s. TDC in the descending aorta is an accurate analog of the AIF. Methods that use quantitative metrics such as rise-time and slope of the AIF to estimate coronary flowrate and myocardial ischemia can continue with the current practice of using the TDC at the descending aorta as a surrogate for the AIF.

Precision of regional wall motion estimates from ultra-low-dose cardiac CT using SQUEEZ.

Resting regional wall motion abnormality (RWMA) has significant prognostic value beyond the findings of computed tomography (CT) coronary angiography. Stretch quantification of endocardial engraved zones (SQUEEZ) has been proposed as a measure of regional cardiac function. The purpose of the work reported here was to determine the effect of lowering the radiation dose on the precision of automatic SQUEEZ assessments of RWMA. Chronic myocardial infarction was created by a 2-h occlusion of the left anterior descending coronary artery in 10 swine (heart rates 80-100, ejection fraction 25-57%). CT was performed 5-11 months post infarct using first-pass contrast enhanced segmented cardiac function scans on a 320-detector row scanner at 80 kVp/500 mA. Images were reconstructed at end diastole and end systole with both filtered back projection and using the "standard" adaptive iterative dose reduction (AIDR) algorithm. For each acquisition, 9 lower dose acquisitions were created. End systolic myocardial function maps were calculated using SQUEEZ for all noise levels and contrast-to-noise ratio (CNR) between the left ventricle blood and myocardium was calculated as a measure of image quality. For acquisitions with CNR > 4, SQUEEZ could be estimated with a precision of ± 0.04 (p < 0.001) or 5.7% of its dynamic range. The difference between SQUEEZ values calculated from AIDR and FBP images was not statistically significant. Regional wall motion abnormality can be quantified with good precision from low dose acquisitions, using SQUEEZ, as long as the blood-myocardium CNR stays above 4.

Safety of Magnetic Resonance Imaging in Patients with Cardiac Devices.

BACKGROUND: Patients who have pacemakers or defibrillators are often denied the opportunity to undergo magnetic resonance imaging (MRI) because of safety concerns, unless the devices meet certain criteria specified by the Food and Drug Administration (termed "MRI-conditional" devices). METHODS: We performed a prospective, nonrandomized study to assess the safety of MRI at a magnetic field strength of 1.5 Tesla in 1509 patients who had a pacemaker (58%) or an implantable cardioverter-defibrillator (42%) that was not considered to be MRI-conditional (termed a "legacy" device). Overall, the patients underwent 2103 thoracic and nonthoracic MRI examinations that were deemed to be clinically necessary. The pacing mode was changed to asynchronous mode for pacing-dependent patients and to demand mode for other patients. Tachyarrhythmia functions were disabled. Outcome assessments included adverse events and changes in the variables that indicate lead and generator function and interaction with surrounding tissue (device parameters). RESULTS: No long-term clinically significant adverse events were reported. In nine MRI examinations (0.4%; 95% confidence interval, 0.2 to 0.7), the patient's device reset to a backup mode. The reset was transient in eight of the nine examinations. In one case, a pacemaker with less than 1 month left of battery life reset to ventricular inhibited pacing and could not be reprogrammed; the device was subsequently replaced. The most common notable change in device parameters (>50% change from baseline) immediately after MRI was a decrease in P-wave amplitude, which occurred in 1% of the patients. At long-term follow-up (results of which were available for 63% of the patients), the most common notable changes from baseline were decreases in P-wave amplitude (in 4% of the patients), increases in atrial capture threshold (4%), increases in right ventricular capture threshold (4%), and increases in left ventricular capture threshold (3%). The observed changes in lead parameters were not clinically significant and did not require device revision or reprogramming. CONCLUSIONS: We evaluated the safety of MRI, performed with the use of a prespecified safety protocol, in 1509 patients who had a legacy pacemaker or a legacy implantable cardioverter-defibrillator system. No long-term clinically significant adverse events were reported. (Funded by Johns Hopkins University and the National Institutes of Health; ClinicalTrials.gov number, NCT01130896 .).

Insights from Novel Noninvasive CT and ECG Imaging Modalities on Electromechanical Myocardial Activation in a Canine Model of Ischemic Dyssynchronous Heart Failure.

INTRODUCTION: The interplay between electrical activation and mechanical contraction patterns is hypothesized to be central to reduced effectiveness of cardiac resynchronization therapy (CRT). Furthermore, complex scar substrates render CRT less effective. We used novel cardiac computed tomography (CT) and noninvasive electrocardiographic imaging (ECGI) techniques in an ischemic dyssynchronous heart failure (DHF) animal model to evaluate electrical and mechanical coupling of cardiac function, tissue viability, and venous accessibility of target pacing regions. METHODS AND RESULTS: Ischemic DHF was induced in 6 dogs using coronary occlusion, left bundle ablation and tachy RV pacing. Full body ECG was recorded during native rhythm followed by volumetric first-pass and delayed enhancement CT. Regional electrical activation were computed and overlaid with segmented venous anatomy and scar regions. Reconstructed electrical activation maps show consistency with LBBB starting on the RV and spreading in a "U-shaped" pattern to the LV. Previously reported lines of slow conduction are seen parallel to anterior or inferior interventricular grooves. Mechanical contraction showed large septal to lateral wall delay (80 ± 38 milliseconds vs. 123 ± 31 milliseconds, P = 0.0001). All animals showed electromechanical correlation except dog 5 with largest scar burden. Electromechanical decoupling was largest in basal lateral LV segments. CONCLUSION: We demonstrated a promising application of CT in combination with ECGI to gain insight into electromechanical function in ischemic dyssynchronous heart failure that can provide useful information to study regional substrate of CRT candidates.

Non-invasive electromechanical activation imaging as a tool to study left ventricular dyssynchronous patients: Implication for CRT therapy.

AIMS: Electromechanical de-coupling is hypothesized to explain non-response of dyssynchrony patient to cardiac resynchronization therapy (CRT). In this pilot study, we investigated regional electromechanical uncoupling in 10 patients referred for CRT using two non-invasive electrical and mechanical imaging techniques (CMR tissue tracking and ECGI). METHODS AND RESULTS: Reconstructed regional electrical and mechanical activation captured delayed LBBB propagation direction from septal to anterior/inferior and finally to lateral walls as well as from LV apical to basal. All 5 responders demonstrated significantly delayed mechanical and electrical activation on the lateral LV wall at baseline compared to the non-responders (P<.05). On follow-up ECGI, baseline electrical activation patterns were preserved in native rhythm and global LV activation time was reduced with biventricular pacing. CONCLUSIONS: The combination of novel imaging techniques of ECGI and CMR tissue tracking can be used to assess spatial concordance of LV electrical and mechanical activation to gain insight into electromechanical coupling.

Effect of intravenous infusion of iodinated contrast media on the coronary blood flow in dogs.

BACKGROUND: Coronary computed tomography angiography (CCTA) is obtained using peripheral intravenous iodinated contrast agents (ICA) injection. There is continuing attempts to derive coronary physiological information like coronary blood flow (CBF) and/or fractional flow reserve from CCTA images. However, no data is available regarding the effect of peripheral intravenous injection of ICA on CBF. METHODS: A series of 4 experiments was performed using healthy mongrel dogs. All dogs underwent anesthesia and open thoracotomy with placement of ultrasound flowmeter to one of the coronary artery to provide real time absolute CBF measurements. Different infusion protocols of Isovue-370 and Visipaque-320 were injected into a peripheral vein. Similar doses of normal saline injection were performed to be used as controls. The effect of iodinated contrast media injection on absolute coronary blood flow was monitored and recorded. RESULTS: Injection of normal saline in the peripheral vein did not produce any significant increase in CBF. Peripheral intravenous injection of ICA resulted in a consistent increase of 40-73% in absolute CBF as recorded 5 minutes post-contrast administration. The contrast effect starts about 30 seconds and peaks at about 2 minutepost-contrast injection then slowly fades away in the following 10-15 min. The increase in the CBF was dose related. There was greater increase in the CBF to 50 ml infusion compared to 25 ml infusion of both Visipaque and Isovue. CONCLUSIONS: Peripheral venous administration of iodinated contrast-media in dogs results in a dose related, significant and prolonged increase in CBF.

Image-based Reconstruction of 3D Myocardial Infarct Geometry for Patient Specific Applications.

Accurate reconstruction of the three-dimensional (3D) geometry of a myocardial infarct from two-dimensional (2D) multi-slice image sequences has important applications in the clinical evaluation and treatment of patients with ischemic cardiomyopathy. However, this reconstruction is challenging because the resolution of common clinical scans used to acquire infarct structure, such as short-axis, late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) images, is low, especially in the out-of-plane direction. In this study, we propose a novel technique to reconstruct the 3D infarct geometry from low resolution clinical images. Our methodology is based on a function called logarithm of odds (LogOdds), which allows the broader class of linear combinations in the LogOdds vector space as opposed to being limited to only a convex combination in the binary label space. To assess the efficacy of the method, we used high-resolution LGE-CMR images of 36 human hearts in vivo, and 3 canine hearts ex vivo. The infarct was manually segmented in each slice of the acquired images, and the manually segmented data were downsampled to clinical resolution. The developed method was then applied to the downsampled image slices, and the resulting reconstructions were compared with the manually segmented data. Several existing reconstruction techniques were also implemented, and compared with the proposed method. The results show that the LogOdds method significantly outperforms all the other tested methods in terms of region overlap.

Estimating coronary blood flow using CT transluminal attenuation flow encoding: Formulation, preclinical validation, and clinical feasibility.

BACKGROUND: We present the formulation and testing of a new CT angiography (CTA)-based method for noninvasive measurement of absolute coronary blood flow (CBF) termed transluminal attenuation flow encoding (TAFE). CTA provides assessment of coronary plaque but does not allow for detection of vessel specific ischemia. A simple and direct method to calculate absolute CBF from a standard CTA could isolate the functional consequence of disease and aid therapy decisions. METHODS: We present the theoretical framework and initial testing of TAFE. Nine canine models of ischemic heart disease were prepared and underwent CT imaging and microsphere measurements of myocardial blood flow. Additionally, 39 acute chest pain patients with normal coronary arteries underwent coronary CTA. We applied TAFE to calculate absolute CBF in the coronary arteries using 4 vessel input parameters including transluminal attenuation gradient, cross-sectional area, length, and the contrast bolus duration derived from the arterial input function. RESULTS: In animal studies, TAFE-derived CBF in the left anterior descending, left circumflex, and right coronary artery was 20.8 ± 10.4 mL/min, 27.0 ± 13.4 mL/min, and 6.0 ± 3.7 mL/min, respectively. TAFE-derived CBF divided by myocardial mass strongly correlated with microsphere myocardial blood flow (R(2) = 0.90, P < .001). In human studies, TAFE-derived CBF in the left anterior descending, left circumflex, and right coronary artery was 26.4 ± 10.7 mL/min, 20.1 ± 13.0 mL/min, and 43.2 ± 40.9 mL/min, respectively. CBF per unit mass was 0.93 ± 0.48 mL/g/min in patients. Interobserver variability was minimal with excellent correlation (R = 0.96, P < .0001) and agreement (mean difference, 4.2 mL/min). CONCLUSION: TAFE allows for quantification of absolute CBF from a standard CTA acquisition and may provide functional significance of coronary disease without complex computational methods.

Image-based reconstruction of three-dimensional myocardial infarct geometry for patient-specific modeling of cardiac electrophysiology.

PURPOSE: Accurate three-dimensional (3D) reconstruction of myocardial infarct geometry is crucial to patient-specific modeling of the heart aimed at providing therapeutic guidance in ischemic cardiomyopathy. However, myocardial infarct imaging is clinically performed using two-dimensional (2D) late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) techniques, and a method to build accurate 3D infarct reconstructions from the 2D LGE-CMR images has been lacking. The purpose of this study was to address this need. METHODS: The authors developed a novel methodology to reconstruct 3D infarct geometry from segmented low-resolution (Lo-res) clinical LGE-CMR images. Their methodology employed the so-called logarithm of odds (LogOdds) function to implicitly represent the shape of the infarct in segmented image slices as LogOdds maps. These 2D maps were then interpolated into a 3D image, and the result transformed via the inverse of LogOdds to a binary image representing the 3D infarct geometry. To assess the efficacy of this method, the authors utilized 39 high-resolution (Hi-res) LGE-CMR images, including 36 in vivo acquisitions of human subjects with prior myocardial infarction and 3 ex vivo scans of canine hearts following coronary ligation to induce infarction. The infarct was manually segmented by trained experts in each slice of the Hi-res images, and the segmented data were downsampled to typical clinical resolution. The proposed method was then used to reconstruct 3D infarct geometry from the downsampled images, and the resulting reconstructions were compared with the manually segmented data. The method was extensively evaluated using metrics based on geometry as well as results of electrophysiological simulations of cardiac sinus rhythm and ventricular tachycardia in individual hearts. Several alternative reconstruction techniques were also implemented and compared with the proposed method. RESULTS: The accuracy of the LogOdds method in reconstructing 3D infarct geometry, as measured by the Dice similarity coefficient, was 82.10% ± 6.58%, a significantly higher value than those of the alternative reconstruction methods. Among outcomes of electrophysiological simulations with infarct reconstructions generated by various methods, the simulation results corresponding to the LogOdds method showed the smallest deviation from those corresponding to the manual reconstructions, as measured by metrics based on both activation maps and pseudo-ECGs. CONCLUSIONS: The authors have developed a novel method for reconstructing 3D infarct geometry from segmented slices of Lo-res clinical 2D LGE-CMR images. This method outperformed alternative approaches in reproducing expert manual 3D reconstructions and in electrophysiological simulations.

Computational Study of Computed Tomography Contrast Gradients in Models of Stenosed Coronary Arteries.

Recent computed tomography coronary angiography (CCTA) studies have noted higher transluminal contrast agent gradients in arteries with stenotic lesions, but the physical mechanism responsible for these gradients is not clear. We use computational fluid dynamics (CFD) modeling coupled with contrast agent dispersion to investigate the mechanism for these gradients. Simulations of blood flow and contrast agent dispersion in models of coronary artery are carried out for both steady and pulsatile flows, and axisymmetric stenoses of severities varying from 0% (unobstructed) to 80% are considered. Simulations show the presence of measurable gradients with magnitudes that increase monotonically with stenotic severity when other parameters are held fixed. The computational results enable us to examine and validate the hypothesis that transluminal contrast gradients (TCG) are generated due to the advection of the contrast bolus with time-varying contrast concentration that appears at the coronary ostium. Since the advection of the bolus is determined by the flow velocity in the artery, the magnitude of the gradient, therefore, encodes the coronary flow velocity. The correlation between the flow rate estimated from TCG and the actual flow rate in the computational model of a physiologically realistic coronary artery is 96% with a R2 value of 0.98. The mathematical formulae connecting TCG to flow velocity derived here represent a novel and potentially powerful approach for noninvasive estimation of coronary flow velocity from CT angiography.

Regional Strain Analysis with Multidetector CT in a Swine Cardiomyopathy Model: Relationship to Cardiac MR Tagging and Myocardial Fibrosis.

PURPOSE: To investigate the use of cine multidetector computed tomography (CT) to detect changes in myocardial function in a swine cardiomyopathy model. MATERIALS AND METHODS: All animal protocols were in accordance with the Principles for the Utilization and Care of Vertebrate Animals Used in Testing Research and Training and approved by the University of Missouri Animal Care and Use Committee. Strain analysis of cine multidetector CT images of the left ventricle was optimized and analyzed with feature-tracking software. The standard of reference for strain was harmonic phase analysis of tagged cardiac magnetic resonance (MR) images at 3.0 T. An animal model of cardiomyopathy was imaged with both cardiac MR and 320-section multidetector CT at a temporal resolution of less than 50 msec. Three groups were evaluated: control group (n = 5), aortic-banded myocardial hypertrophy group (n = 5), and aortic-banded and cyclosporine A- treated cardiomyopathy group (n = 5). Histologic samples of the myocardium were obtained for comparison with strain results. Dunnett test was used for comparisons of the concentric remodeling group and eccentric remodeling group against the control group. RESULTS: Collagen volume fraction ranged from 10.9% to 14.2%; lower collagen fraction values were seen in the control group than in the cardiomyopathy groups (P < .05). Ejection fraction and conventional metrics showed no significant differences between control and cardiomyopathy groups. Radial strain for both cardiac MR and multidetector CT was abnormal in both concentric (cardiac MR 25.1% ± 4.2; multidetector CT 28.4% ± 2.8) and eccentric (cardiac MR 23.2% ± 2.0; multidetector CT 24.4% ± 2.1) remodeling groups relative to control group (cardiac MR 18.9% ± 1.9, multidetector CT 22.0% ± 1.7, P < .05, all comparisons). Strain values for multidetector CT versus cardiac MR showed better agreement in the radial direction than in the circumferential direction (r = 0.55, P = .03 vs r = 0.40, P = .13, respectively). CONCLUSION: Multidetector CT strain analysis has potential to identify regional wall-motion abnormalities in cardiomyopathy that is not otherwise detected using conventional metrics of myocardial function.

Multiparametric molecular imaging provides mechanistic insights into sympathetic innervation impairment in the viable infarct border zone.

UNLABELLED: Impaired catecholamine handling in the viable infarct border zone may play an important role in ventricular remodeling and lethal arrhythmia. We sought to get further biologic insights into cardiac sympathetic neuronal pathology after myocardial infarction, using multiple tomographic imaging techniques. METHODS: In a porcine model of myocardial infarction (n = 13), PET and MR imaging were performed after 4-6 wk and integrated with electrophysiologic testing and postmortem histology. RESULTS: PET with the physiologic neurotransmitter (11)C-epinephrine, which is sensitive to metabolic degradation unless it is stored and protected in neuronal vesicles, identified a defect exceeding the perfusion defect (defined by (13)N-ammonia; defect size in all animals, 42 ± 12 vs. 35% ± 12% of left ventricle, P < 0.001). In a subgroup of 7 animals, defect of the metabolically resistant catecholamine (11)C-hydroxyephedrine was smaller than epinephrine (41 ± 8 vs. 47% ± 6% of left ventricle, P = 0.004), whereas defect of a third catecholamine, (11)C-phenylephrine, which is sensitive to metabolic degradation, was similar to epinephrine (48 ± 6 vs. 47% ± 6%, P = 0.011 vs. perfusion defect). Histology confirmed the presence of nerve fibers in the infarct border zone. Tagged MR imaging identified impaired peak circumferential wall strain and wall thickening in myocardial segments with epinephrine/perfusion mismatch (n = 6). Confirmatory of prior work, inducible ventricular tachycardia was associated with a larger epinephrine/perfusion mismatch (n = 11). CONCLUSION: In the viable infarct border zone, neuronal vesicular catecholamine storage and protection from metabolic degradation are more severely altered than catecholamine uptake. This alteration may reflect an intermediate state between normal innervation and complete denervation in advanced disease.

Accuracy of multidetector computed tomography for detection of coronary artery stenosis in acute coronary syndrome compared with stable coronary disease: a CORE64 multicenter trial substudy.

BACKGROUND: Multi-detector computed tomography angiography (MDCTA) is a promising method for risk assessment of patients with acute chest pain. However, its diagnostic performance in higher-risk patients has not been investigated in a large international multicenter trial. Therefore, in the present study we sought to estimate the diagnostic accuracy of MDCTA to detect significant coronary stenosis in patients with acute coronary syndrome (ACS). METHODS: Patients included in the CORE64 study were categorized as suspected-ACS or non-ACS based on clinical data. A 64-row coronary MDCTA was performed before invasive coronary angiography (ICA) and both exams were evaluated by blinded, independent core laboratories. RESULTS: From 371 patients included, 94 were categorized as suspected ACS and 277 as non-ACS. Patient-based analysis showed an area under the receiver-operating-characteristic curve (AUC) for detecting ≥ 50% coronary stenosis of 0.95 (95% CI: 0.88-0.98) in ACS and 0.92 (95% CI: 0.88-0.95) in non-ACS group (P=0.29). The sensitivity, specificity, positive and negative predictive values of MDCTA were 0.90(0.80-0.96), 0.88(0.70-0.98), 0.95(0.87-0.99) and 0.77(0.58-0.90) in suspected ACS patients and 0.87(0.81-0.92), 0.86(0.79-0.92), 0.91(0.85-0.95) and 0.82(0.74-0.89) in non-ACS patients (P NS for all comparisons). The mean calcium scores (CS) were 282 ± 449 in suspected ACS and 435 ± 668 in non-ACS group. The accuracy of CS to detect significant coronary stenosis was only moderate and the absence or minimal coronary artery calcification could not exclude the presence of significant coronary stenosis, particularly in ACS patients. CONCLUSIONS: The diagnostic accuracy of MDCTA to detect significant coronary stenosis is high and comparable for both ACS and non-ACS patients.

Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy.

OBJECTIVE: Duchenne and Becker muscular dystrophies (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine whether the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908). METHODS: Adults with DBMD and cardiomyopathy (ejection fraction ≤ 50%) were randomized to receive sildenafil (20mg 3× daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac magnetic resonance imaging. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed. RESULTS: An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4 of 14) of subjects had a ≥10% increase in LVESV after 6 months of sildenafil compared to 13% (1 of 8) of subjects receiving placebo. Subjects with LVESV > 120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p = 0.035). Due to the higher number of subjects worsening on sildenafil, the data and safety monitoring board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms. INTERPRETATION: Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD.

Efficacy of cardiac resynchronization in acutely infarcted canine hearts with electromechanical dyssynchrony.

BACKGROUND: Patients with acute myocardial infarction (MI), left bundle branch block (LBBB), and marked left ventricular (LV) decompensation suffer from nearly 50% early mortality. Whether cardiac resynchronization therapy (CRT) improves hemodynamic status in this condition is unknown. We tested CRT in this setting by using a canine model of delayed lateral wall (LW) activation combined with 2 hours of coronary artery occlusion-reperfusion. OBJECTIVE: This study aimed to evaluate the acute hemodynamic effects of CRT during and immediately after MI. METHODS: Adult dogs (n = 8) underwent open-chest 2-hour mid-left anterior descending artery occlusion followed by 1-hour reperfusion. Four pacing modes were compared: right atrial pacing, pseudo-left bundle block (right ventricular pacing), and CRT with the LV lead positioned at either the LW (LW-CRT) or the peri-infarct zone (peri-infarct zone-CRT). Continuous LV pressure-volume data, regional segment length, and proximal left anterior descending flow rates were recorded. RESULTS: At baseline, both right ventricular pacing and peri-infarct zone CRT reduced anterior wall regional work by ~50% (vs right atrial pacing). During coronary occlusion, this territory became dyskinetic, and dyskinesis rose further with both CRT modes as compared to pseudo-LBBB. Global cardiac output, stroke work, and ejection fraction all still improved by 11%-23%. After reperfusion, both CRT modes elevated infarct zone regional work and blood flow by ~10% as compared to pseudo-LBBB, as well as improved global function. CONCLUSION: CRT improves global chamber systolic function in left ventricles with delayed LW activation during and after sustained coronary occlusion. It does so while modestly augmenting infarct zone dyskinesis during occlusion and improving regional function and blood flow after reperfusion. These findings support CRT in the setting of early post-MI dyssynchronous heart failure.

Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial.

RATIONALE: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. OBJECTIVE: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. METHODS AND RESULTS: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 ± 1.7%, P=0.0002) and decreased scar mass (-47.5 ± 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 ± 0.07), whereas revascularized (0.5 ± 0.21) and nontreated segments (-0.07 ± 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). CONCLUSIONS: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction).

OBJECTIVES: This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial. BACKGROUND: Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown. METHODS: Autologous CDCs (12.5 to 25 × 10(6)) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients. RESULTS: In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI. CONCLUSIONS: Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction [CADUCEUS]; NCT00893360).

Mechanistic insight into prolonged electromechanical delay in dyssynchronous heart failure: a computational study.

In addition to the left bundle branch block type of electrical activation, there are further remodeling aspects associated with dyssynchronous heart failure (HF) that affect the electromechanical behavior of the heart. Among the most important are altered ventricular structure (both geometry and fiber/sheet orientation), abnormal Ca(2+) handling, slowed conduction, and reduced wall stiffness. In dyssynchronous HF, the electromechanical delay (EMD), the time interval between local myocyte depolarization and myofiber shortening onset, is prolonged. However, the contributions of the four major HF remodeling aspects in extending EMD in the dyssynchronous failing heart remain unknown. The goal of this study was to determine the individual and combined contributions of HF-induced remodeling aspects to EMD prolongation. We used MRI-based models of dyssynchronous nonfailing and HF canine electromechanics and constructed additional models in which varying combinations of the four remodeling aspects were represented. A left bundle branch block electrical activation sequence was simulated in all models. The simulation results revealed that deranged Ca(2+) handling is the primary culprit in extending EMD in dyssynchronous HF, with the other aspects of remodeling contributing insignificantly. Mechanistically, we found that abnormal Ca(2+) handling in dyssynchronous HF slows myofiber shortening velocity at the early-activated septum and depresses both myofiber shortening and stretch rate at the late-activated lateral wall. These changes in myofiber dynamics delay the onset of myofiber shortening, thus giving rise to prolonged EMD in dyssynchronous HF.

Image-guided therapies for myocardial repair: concepts and practical implementation.

Cell- and molecule-based therapeutic strategies to support wound healing and regeneration after myocardial infarction (MI) are under development. These emerging therapies aim at sustained preservation of ventricular function by enhancing tissue repair after myocardial ischaemia and reperfusion. Such therapies will benefit from guidance with regard to timing, regional targeting, suitable candidate selection, and effectiveness monitoring. Such guidance is effectively obtained by non-invasive tomographic imaging. Infarct size, tissue characteristics, muscle mass, and chamber geometry can be determined by magnetic resonance imaging and computed tomography. Radionuclide imaging can be used for the tracking of therapeutic agents and for the interrogation of molecular mechanisms such as inflammation, angiogenesis, and extracellular matrix activation. This review article portrays the hypothesis that an integrated approach with an early implementation of structural and molecular tomographic imaging in the development of novel therapies will provide a framework for achieving the goal of improved tissue repair after MI.