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.

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 .).

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.

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.

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.

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.

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.

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.

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.

Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.

BACKGROUND: Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. METHODS: In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360. FINDINGS: Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. INTERPRETATION: We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. FUNDING: US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.

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.

Cardiovascular magnetic resonance characterization of peri-infarct zone remodeling following myocardial infarction.

BACKGROUND: Clinical studies implementing late gadolinium-enhanced (LGE) cardiovascular magnetic resonance (CMR) studies suggest that the peri-infarct zone (PIZ) contains a mixture of viable and non-viable myocytes, and is associated with greater susceptibility to ventricular tachycardia induction and adverse cardiac outcomes. However, CMR data assessing the temporal formation and functional remodeling characteristics of this complex region are limited. We intended to characterize early temporal changes in scar morphology and regional function in the PIZ. METHODS AND RESULTS: CMR studies were performed at six time points up to 90 days after induction of myocardial infarction (MI) in eight minipigs with reperfused, anterior-septal infarcts. Custom signal density threshold algorithms, based on the remote myocardium, were applied to define the infarct core and PIZ region for each time point. After the initial post-MI edema subsided, the PIZ decreased by 54% from day 10 to day 90 (p = 0.04). The size of infarct scar expanded by 14% and thinned by 56% from day 3 to 12 weeks (p = 0.004 and p < 0.001, respectively). LVEDV increased from 34.7. ± 2.2 ml to 47.8 ± 3.0 ml (day 3 and week 12, respectively; p < 0.001). At 30 days post-MI, regional circumferential strain was increased between the infarct scar and the PIZ (-2.1 ± 0.6 and -6.8 ± 0.9, respectively;* p < 0.05). CONCLUSIONS: The PIZ is dynamic and decreases in mass following reperfused MI. Tensile forces in the PIZ undergo changes following MI. Remodeling characteristics of the PIZ may provide mechanistic insights into the development of life-threatening arrhythmias and sudden cardiac death post-MI.

A prospective evaluation of a protocol for magnetic resonance imaging of patients with implanted cardiac devices.

BACKGROUND: Magnetic resonance imaging (MRI) is avoided in most patients with implanted cardiac devices because of safety concerns. OBJECTIVE: To define the safety of a protocol for MRI at the commonly used magnetic strength of 1.5 T in patients with implanted cardiac devices. DESIGN: Prospective nonrandomized trial. (ClinicalTrials.gov registration number: NCT01130896) SETTING: One center in the United States (94% of examinations) and one in Israel. PATIENTS: 438 patients with devices (54% with pacemakers and 46% with defibrillators) who underwent 555 MRI studies. INTERVENTION: Pacing mode was changed to asynchronous for pacemaker-dependent patients and to demand for others. Tachyarrhythmia functions were disabled. Blood pressure, electrocardiography, oximetry, and symptoms were monitored by a nurse with experience in cardiac life support and device programming who had immediate backup from an electrophysiologist. MEASUREMENTS: Activation or inhibition of pacing, symptoms, and device variables. RESULTS: In 3 patients (0.7% [95% CI, 0% to 1.5%]), the device reverted to a transient back-up programming mode without long-term effects. Right ventricular (RV) sensing (median change, 0 mV [interquartile range {IQR}, -0.7 to 0 V]) and atrial and right and left ventricular lead impedances (median change, -2 Ω [IQR, -13 to 0 Ω], -4 Ω [IQR, -16 to 0 Ω], and -11 Ω [IQR, -40 to 0 Ω], respectively) were reduced immediately after MRI. At long-term follow-up (61% of patients), decreased RV sensing (median, 0 mV, [IQR, -1.1 to 0.3 mV]), decreased RV lead impedance (median, -3 Ω, [IQR, -29 to 15 Ω]), increased RV capture threshold (median, 0 V, IQR, [0 to 0.2 Ω]), and decreased battery voltage (median, -0.01 V, IQR, -0.04 to 0 V) were noted. The observed changes did not require device revision or reprogramming. LIMITATIONS: Not all available cardiac devices have been tested. Long-term in-person or telephone follow-up was unavailable in 43 patients (10%), and some data were missing. Those with missing long-term capture threshold data had higher baseline right atrial and right ventricular capture thresholds and were more likely to have undergone thoracic imaging. Defibrillation threshold testing and random assignment to a control group were not performed. CONCLUSION: With appropriate precautions, MRI can be done safely in patients with selected cardiac devices. Because changes in device variables and programming may occur, electrophysiologic monitoring during MRI is essential.

Diagnostic performance of coronary angiography by 64-row CT.

BACKGROUND: The accuracy of multidetector computed tomographic (CT) angiography involving 64 detectors has not been well established. METHODS: We conducted a multicenter study to examine the accuracy of 64-row, 0.5-mm multidetector CT angiography as compared with conventional coronary angiography in patients with suspected coronary artery disease. Nine centers enrolled patients who underwent calcium scoring and multidetector CT angiography before conventional coronary angiography. In 291 patients with calcium scores of 600 or less, segments 1.5 mm or more in diameter were analyzed by means of CT and conventional angiography at independent core laboratories. Stenoses of 50% or more were considered obstructive. The area under the receiver-operating-characteristic curve (AUC) was used to evaluate diagnostic accuracy relative to that of conventional angiography and subsequent revascularization status, whereas disease severity was assessed with the use of the modified Duke Coronary Artery Disease Index. RESULTS: A total of 56% of patients had obstructive coronary artery disease. The patient-based diagnostic accuracy of quantitative CT angiography for detecting or ruling out stenoses of 50% or more according to conventional angiography revealed an AUC of 0.93 (95% confidence interval [CI], 0.90 to 0.96), with a sensitivity of 85% (95% CI, 79 to 90), a specificity of 90% (95% CI, 83 to 94), a positive predictive value of 91% (95% CI, 86 to 95), and a negative predictive value of 83% (95% CI, 75 to 89). CT angiography was similar to conventional angiography in its ability to identify patients who subsequently underwent revascularization: the AUC was 0.84 (95% CI, 0.79 to 0.88) for multidetector CT angiography and 0.82 (95% CI, 0.77 to 0.86) for conventional angiography. A per-vessel analysis of 866 vessels yielded an AUC of 0.91 (95% CI, 0.88 to 0.93). Disease severity ascertained by CT and conventional angiography was well correlated (r=0.81; 95% CI, 0.76 to 0.84). Two patients had important reactions to contrast medium after CT angiography. CONCLUSIONS: Multidetector CT angiography accurately identifies the presence and severity of obstructive coronary artery disease and subsequent revascularization in symptomatic patients. The negative and positive predictive values indicate that multidetector CT angiography cannot replace conventional coronary angiography at present. (ClinicalTrials.gov number, NCT00738218.)

Diagnostic performance of combined noninvasive coronary angiography and myocardial perfusion imaging using 320-MDCT: the CT angiography and perfusion methods of the CORE320 multicenter multinational diagnostic study.

OBJECTIVE: Coronary MDCT angiography has been shown to be an accurate noninvasive tool for the diagnosis of obstructive coronary artery disease (CAD). Its sensitivity and negative predictive value for diagnosing percentage of stenosis are unsurpassed compared with those of other noninvasive testing methods. However, in its current form, it provides no information regarding the physiologic impact of CAD and is a poor predictor of myocardial ischemia. CORE320 is a multicenter multinational diagnostic study with the primary objective to evaluate the diagnostic accuracy of 320-MDCT for detecting coronary artery luminal stenosis and corresponding myocardial perfusion deficits in patients with suspected CAD compared with the reference standard of conventional coronary angiography and SPECT myocardial perfusion imaging. CONCLUSION: We aim to describe the CT acquisition, reconstruction, and analysis methods of the CORE320 study.

CT perfusion: ready for prime time.

Advancements in computed tomography (CT) technology have revolutionized clinical practice, particularly regarding the noninvasive assessment of coronary artery disease (CAD). The versatility of cardiac CT has rendered multiple applications including assessment of cardiac structure and function, myocardial viability, and coronary anatomy. The merits of cardiac computed tomography angiography (CTA) have been proven for the detection, and particularly the exclusion, of CAD. However, CTA becomes limited in the presence of significant CAD. Its inability to consistently identify lesion-associated ischemia may necessitate additional radionuclide myocardial perfusion imaging. Myocardial computed tomography perfusion imaging (CTP) has emerged as a useful and convenient method to immediately assess myocardial ischemia. In this review, we discuss the current state of CTP including available technology, its performance to date from current literature, and future challenges to this field.

Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy.

BACKGROUND: Cardiosphere-derived cells (CDCs) isolated from human endomyocardial biopsies reduce infarct size and improve cardiac function in mice. Safety and efficacy testing in large animals is necessary for clinical translation. METHODS AND RESULTS: Mesenchymal stem cells, which resemble CDCs in size and thrombogenicity, have been associated with infarction after intracoronary infusion. To maximize CDC engraftment while avoiding infarction, we optimized the infusion protocol in 19 healthy pigs. A modified cocktail of CDCs in calcium-free PBS, 100 U/mL of heparin, and 250 microg/mL of nitroglycerin eliminated infusion-related infarction. Subsequent infusion experiments in 17 pigs with postinfarct left ventricular dysfunction showed CDC doses > or =10(7) but <2.5 x 10(7) result in new myocardial tissue formation without infarction. In a pivotal randomized study, 7 infarcted pigs received 300,000 CDCs/kg (approximately 10(7) total) and 7 received placebo (vehicle alone). Cardiac magnetic resonance imaging 8 weeks later showed CDC treatment decreased relative infarct size (19.2% to 14.2% of left ventricle infarcted, P=0.01), whereas placebo did not (17.7% to 15.3%, P=0.22). End-diastolic volume increased in placebo, but not in CDC-treated animals. Hemodynamically, the rate of pressure change (dP/dt) maximum and dP/dt minimum were significantly better with CDC infusion. There was no difference between groups in the ability to induce ventricular tachycardia, nor was there any tumor or ectopic tissue formation. CONCLUSIONS: Intracoronary delivery of CDCs in a preclinical model of postinfarct left ventricular dysfunction results in formation of new cardiac tissue, reduces relative infarct size, attenuates adverse remodeling, and improves hemodynamics. The evidence of efficacy without obvious safety concerns at 8 weeks of follow-up motivates human studies in patients after myocardial infarction and in chronic ischemic cardiomyopathy.

Characterization and correction of beam-hardening artifacts during dynamic volume CT assessment of myocardial perfusion.

PURPOSE: To fully characterize beam-hardening effects caused by iodinated contrast medium in the left ventricular (LV) cavity and aorta in the assessment of myocardial perfusion at computed tomography (CT) and to validate a beam-hardening artifact correction algorithm that considers fluid-filled vessels and chambers important sources of beam hardening. MATERIALS AND METHODS: The Johns Hopkins University animal care and use committee approved all procedures. An anatomically correct LV and myocardial phantom to characterize beam-hardening artifacts was designed. Following validation in the phantom, the beam-hardening correction (BHC) algorithm was applied to 256-detector row dynamic volume CT images in a canine ischemia model (n = 5) during adenosine stress, and the effect of beam hardening was determined by comparing regional dynamic volume CT perfusion metrics (myocardial upslope normalized by maximum LV blood pool attenuation) with microsphere-derived myocardial blood flow (MBF). A paired Student t test was used to compare continuous variables from the same subject but under different conditions, while linear regression analysis was performed to estimate the slope and statistical significance of the relationship between CT-derived perfusion metrics and microsphere-derived MBF. RESULTS: Beam-hardening artifacts were successfully reproduced in phantom studies and were eliminated with the BHC algorithm. The correlation coefficient of CT-derived perfusion metrics and microsphere-derived MBF improved from 0.60 to 0.74 (P > .05) following correction in the animal model. CONCLUSION: Beam-hardening artifacts confound dynamic volume CT assessment of myocardial perfusion. Application of the BHC algorithm is helpful for improving accuracy of myocardial perfusion at dynamic volume CT.

A method for reconstructing the arterial input function during helical CT: implications for myocardial perfusion distribution imaging.

PURPOSE: To determine if a multidetector computed tomographic (CT) image acquisition and analysis method can enable accurate measurement of the arterial input function (AIF) during first-pass adenosine stress helical multidetector CT angiography and to test the effect of using this method on the semiquantitative assessment of myocardial perfusion distribution. MATERIALS AND METHODS: The animal care and use committee of Johns Hopkins University approved the use of all procedures. The AIF was reconstructed by using a combination of bolus-tracking and time-registered helical multidetector CT data. After the AIF reconstruction method was validated in healthy animals, coronary stenosis was induced in seven dogs and contrast material-enhanced multidetector CT was performed during adenosine infusion (0.14-0.21 mg per kilogram of body weight per minute). Myocardial attenuation density (AD) parameters normalized to portions of the AIF were compared with microsphere myocardial blood flow (MBF) measurements at linear regression analysis. RESULTS: There was no significant difference between the area under the curve (AUC) for dynamic multidetector CT-derived AIF (3108 + or - 1250 [standard deviation]) and that for combined bolus-tracking and time-registered multidetector helical CT-derived AIF (3086 + or - 941) (P = .90). When AIF analysis was applied to helical multidetector CT myocardial perfusion measurements, the correlation between MBF and mean myocardial AD normalized to the AUC for the entire AIF was significant (R(2) = 0.82, P <.001). Myocardial AD normalized to the AUC for the AIF measured during helical multidetector CT correlated best with MBF (R(2) = 0.86, P <.001). CONCLUSION: The combination of bolus tracking and time-registered helical imaging enables reconstruction of the AIF during multidetector CT perfusion imaging. The helical CT AIF can be used to improve the semiquantitative assessment of myocardial perfusion distribution.

Quantitative and qualitative analysis and interpretation of CT perfusion imaging.

Coronary artery disease (CAD) remains the leading cause of death in the United States. Rest and stress myocardial perfusion imaging has an important role in the non-invasive risk stratification of patients with CAD. However, diagnostic accuracies have been limited, which has led to the development of several myocardial perfusion imaging techniques. Among them, myocardial computed tomography perfusion imaging (CTP) is especially interesting as it has the unique capability of providing anatomic- as well as coronary stenosis-related functional data when combined with computed tomography angiography (CTA). The primary aim of this article is to review the qualitative, semi-quantitative, and quantitative analysis approaches to CTP imaging. In doing so, we will describe the image data required for each analysis and discuss the advantages and disadvantages of each approach.