Accurate grading of MR severity is crucial for appropriate patient management but remains challenging. VE-CMR with 3D three-directional acquisition has been recently proposed as the reference method.

A total of 64 patients with functional MR were included. A VE-CMR acquisition was applied to quantify mitral regurgitant volume (Rvol). Color Doppler 3D echocardiography was applied for direct measurement, in "en face" view, of mitral effective regurgitant orifice area (EROA); Rvol was subsequently calculated as EROA multiplied by the velocity-time integral of the regurgitant jet on the continuous-wave Doppler. To assess the relative potential error of the conventional approach, color Doppler 2-dimensional (2D) echocardiography was performed: vena contracta width was measured in the 4-chamber view and EROA calculated as circular (EROA-4CH); EROA was also calculated as elliptical (EROA-elliptical), measuring vena contracta also in the 2-chamber view. From these 2D measurements of EROA, the Rvols were also calculated.

The EROA measured by 3D echocardiography was significantly higher than EROA-4CH (p < 0.001) and EROA-elliptical (p < 0.001), with a significant bias between these measurements (0.10 cm² and 0.06 cm², respectively). Rvol measured by 3D echocardiography showed excellent correlation with Rvol measured by CMR (r = 0.94), without a significant difference between these techniques (mean difference = –0.08 ml/beat). Conversely, 2D echocardiographic approach from the 4-chamber view significantly underestimated Rvol (p = 0.006) as compared with CMR (mean difference = 2.9 ml/beat). The 2D elliptical approach demonstrated a better agreement with CMR (mean difference = –1.6 ml/beat, p = 0.04).

Quantification of EROA and Rvol of functional MR with 3D echocardiography is feasible and accurate as compared with VE-CMR; the currently recommended 2D echocardiographic approach significantly underestimates both EROA and Rvol.

Myocardial ischemic memory imaging, denoting the visualization of abnormalities provoked by ischemia and sustained even after restoration of perfusion, is desirable and allows after-the-fact recognition of ischemic insult. PST offers a sensitive marker of myocardial ischemia, but whether this abnormal thickening remains after relief from brief ischemia is unclear.

Tissue strain echocardiographic data were acquired from 27 dogs under 2 different conditions of myocardial ischemia induced by either brief coronary occlusion (15 or 5 min) followed by reperfusion (Protocol 1) or by dobutamine stress during nonflow-limiting stenosis (Protocol 2). Peak systolic strain and post-systolic strain index (PSI), a parameter of PST, were analyzed.

In Protocol 1, peak systolic strain was significantly decreased in the risk area during occlusion. This decrease in peak systolic strain in the 15-min group did not completely recover to baseline levels even 120 min after reperfusion, whereas the decrease in the 5-min group recovered immediately after reperfusion. We found that PSI was significantly increased during occlusion, but increased PSI in the 5-min group remained until 30 min after reperfusion (–0.19 ± 0.18 [baseline] vs. 0.19 ± 0.14 [30 min], p < 0.05) despite the rapid recovery of peak systolic strain. In Protocol 2, increased PSI was sustained until 20 min after the end of dobutamine infusion (–0.26 ± 0.11 [baseline] vs. –0.16 ± 0.10 [20 min], p < 0.05), although peak systolic strain recovered by 5 min after the end of dobutamine infusion.

PST remained longer than abnormal peak systolic strain after recovery from ischemia. Assessment of PST may be valuable for detecting myocardial ischemic memory.

Data on the progression of atherosclerosis stratified by plaque composition with the use of noninvasive assessment by CT are limited and hampered by high measurement variability.

This analysis included patients who presented with acute chest pain to the emergency department but initially showed no evidence of acute coronary syndromes. All patients underwent contrast-enhanced 64-slice CT at baseline and after 2 years with the use of a similar protocol. CT datasets were coregistered and assessed for the presence of calcified and noncalcified plaque at 1 mm cross sections of the proximal 40 mm of each major coronary artery. Plaque progression over time and its association with risk factors were determined. Measurement reproducibility and correlation to plaque volume was performed in a subset of patients.

We included 69 patients (mean age 55 ± 12 years, 59% male patients) and compared 8,311 coregistered cross sections at baseline and follow-up. At baseline, any plaque, calcified plaque, and noncalcified were detected in 12.5%, 10.1%, and 2.4% of cross sections per patient, respectively. There was significant progression in the mean number of cross sections containing any plaque (16.5 ± 25.3 vs. 18.6 ± 25.5, p = 0.01) and noncalcified plaque (3.1 ± 5.8 vs. 4.4 ± 7.0, p = 0.04) but not calcified plaque (13.3 ± 23.1 vs. 14.2 ± 22.0, p = 0.2). In longitudinal regression analysis, the presence of baseline plaque, number of cardiovascular risk factors, and smoking were independently associated with plaque progression after adjustment for age, sex, and follow-up time interval. The semiquantitative score based on cross sections correlated closely with plaque volume progression (r = 0.75, p < 0.0001) and demonstrated an excellent intraobserver and interobserver agreement ( = 0.95 and = 0.93, respectively).

Coronary plaque burden of patients with acute chest pain significantly increases during the course of 2 years. Progression over time is dependent on plaque composition and cardiovascular risk profile. Larger studies are needed to confirm these results and to determine the effect of medical treatment on progression.

An integrated approach to assess ventricular pump function, myocontractility (end-systolic pressure–volume relationship [ESPVR]), and diastolic compliance (end-diastolic pressure–volume relation [EDPVR]) is of high clinical value. Cardiac magnetic resonance (CMR) is well established for measuring global pump function, and catheterization-combined CMR was previously shown to accurately measure ESPVR, but not yet the EDPVR.

In 8 pigs, the CMR technique was compared with conductance catheter methods (gold standard) for measuring the EDPVR in the left and right ventricle. Measurements were performed at rest and during dobutamine administration. For CMR, the ESPVR was estimated with a single-beat approach by synchronizing invasive ventricular pressures with cine CMR–derived ventricular volumes. The EDPVR was determined during pre-load reduction from additional volume data that were obtained from real-time velocity-encoded CMR pulmonary/aortic blood flow measurements. Pre-load reduction was achieved by transient balloon occlusion of the inferior vena cava. The stiffness coefficient β was calculated by an exponential fit from the EDPVR. After validation in the animal experiments, the EDPVR was assessed in a pilot study of 3 patients with a single ventricle using identical CMR and conductance catheter techniques.

Bland-Altman tests showed good agreement between conductance catheter–derived and CMR-derived EDPVR. In both ventricles of the pigs, dobutamine enhanced myocontractility (p < 0.01), increased stroke volume (p < 0.01), and improved diastolic function. The latter was evidenced by shorter early relaxation (p < 0.05), a downward shift of the EDPVR, and a decreased stiffness coefficient β (p < 0.05). In contrast, in the patients, early relaxation was inconspicuous but the EDPVR shifted left-upward and the stiffness constant remained unchanged. The observed changes in diastolic function were not significantly different when measured with conductance catheter and CMR.

This novel CMR method provides differential information about diastolic function in conjunction with parameters of systolic contractility and global pump function.

Patients with an unrestricted left-to-right shunt who are at risk of obstructive pulmonary vascular disease require PVR evaluation preoperatively. CMR cardiac catheter (XMR) combines noninvasive measurement of Qp by phase contrast imaging with invasive pressure measurement to accurately determine the PVR.

Patients referred for clinical assessment of the PVR were included. The XMR was used to determine the PVR. The noninvasive parameters, Qp and left-to-right shunt (Qp/Qs), were compared with the PVR using univariate regression models.

The XMR was undertaken in 26 patients (median age 0.87 years)—ventricular septal defect 46.2%, atrioventricular septal defect 42.3%. Mean aortic flow was 2.24 ± 0.59 l/min/m², and mean Qp was 6.25 ± 2.78 l/min/m². Mean Qp/Qs was 2.77 ± 1.02. Mean pulmonary artery pressure was 34.8 ± 10.9 mm Hg. Mean/median PVR was 5.5/3.0 Woods Units (WU)/m² (range 1.7 to 31.4 WU/m²). The PVR was related to both Qp and Qp/Qs in an inverse exponential fashion by the univariate regression equations PVR = exp(2.53 – 0.20[Qp]) and PVR = exp(2.75 – 0.52[Qp/Qs]). Receiver-operator characteristic (ROC) analysis was used to determine cutoff values for Qp and Qp/Qs above which the PVR could be regarded as clinically acceptable. A Qp of ≥6.05 l/min/m² predicted a PVR of ≤3.5 WU/m² with sensitivity 72%, specificity 100%, and area under the ROC curve 0.90 (p = 0.002). A Qp/Qs of ≥2.5/1 predicted a PVR of ≤3.5 WU/m² with sensitivity 83%, specificity 100%, and area under the curve ROC 0.94 (p < 0.001).

Measurement of Qp or left-to-right shunt noninvasively by CMR has potential to predict the PVR in patients with an unrestricted left-to-right shunt and could potentially determine operability without having to undertake invasive testing.

CMR is suitable for diagnosing inducible myocardial ischemia in patients with suspected CAD and has been proven to be a helpful diagnostic tool for decision of further treatment. However, little is known about its diagnostic accuracy in patients with known CAD who previously were treated by PCI or CABG.

A total of 477 patients with suspected CAD, 236 with previous PCI, and 110 after CABG referred for coronary X-ray angiography (CXA) underwent an integrated CMR examination before CXA. Myocardial ischemia was assessed using first-pass perfusion after vasodilator stress with adenosine (140 µg/kg/min for 3 min) using gadolinium-based contrast agents (0.1 mmol/kg). Late gadolinium enhancement (LGE) was assessed 10 min after a second contrast bolus.

CXA demonstrated a relevant coronary vessel stenosis (≥70% luminal reduction) in 313 (38%) patients using quantitative coronary analysis. The combination of CMR perfusion and LGE assessment for detecting a relevant coronary stenosis in patients with suspected CAD yielded sensitivity and specificity of 0.94 and 0.87, in PCI patients 0.91 and 0.90, and in CABG patients 0.79 and 0.77, respectively.

A combined CMR protocol for the assessment of myocardial perfusion and LGE is feasible for the detection of relevant coronary vessel stenosis even in patients who previously were treated by PCI or CAG in a routine clinical setting. However, diagnostic accuracy is reduced in patients with CABG. This could be due to different flow and perfusion kinetic. Further studies are needed to optimize the clinical protocols especially in post-surgical patients.

Myocardial ischemia enhances late sodium current, which then causes cellular calcium overload leading to mechanical left ventricular dysfunction and arrhythmias. Ranolazine inhibits late sodium current and improves diastolic tension and MBF in the animal model.

In this open-label, nonrandomized pilot study, we recruited 20 patients with known or a high probability of CAD and who had reversible perfusion defects on exercise treadmill gated single-photon emission computed tomography MPI while receiving conventional antianginal therapy. Ranolazine (up to 1,000 mg twice daily) was added to baseline therapy and a repeat treadmill MPI was obtained after 4 weeks. The extent and severity of total and reversible left ventricular perfusion abnormality (based on polar maps and a 17-segment model) were determined quantitatively using automated methods.

We screened 100 patients for 27 potential candidates; 5 declined and 2 did not complete the follow-up study. The mean age of the remaining 20 patients was 64 ± 9 years; 30% were women and 50% had diabetes mellitus. The exercise time increased (425 ± 105 s vs. 393 ± 116 s, p = 0.017), and angina improved in 15 (75%) patients after ranolazine treatment. In the entire cohort, summed stress scores (10 ± 7 vs. 13 ± 8, p = 0.04) and summed difference scores (4.7 ± 4 vs. 7.4 ± 5, p = 0.0037) decreased at follow-up. An improvement in perfusion pattern and severity was noted in 14 (70%) patients. In these patients, the polar maps showed a decrease in total abnormality from 26 ± 17% to 19 ± 15% and a decrease in the reversible abnormality from 16 ± 10% to 8 ± 6% (all p values <0.05).

In this preliminary hypothesis-driven study, short-term ranolazine therapy was shown to improve myocardial perfusion and decrease the ischemic burden in patients with CAD.

The ratio of the E to the e' (E/e') has been reported as a useful index even in AF patients. However, E and e' were measured during different beats in the previous studies.

Fifty-six AF patients with preserved systolic function (mean age 66 ± 11 years) underwent routine echocardiographic study. The E/e' was calculated from the E and e' simultaneously recorded by the dual Doppler echocardiography. A single-beat E/e' was calculated from simultaneously recorded E and e' when the preceding RR interval/pre-preceding RR interval = 1. Brain natriuretic peptide (BNP) levels were also examined. Twenty-one patients underwent simultaneous pulmonary artery catheterization.

The single-beat lateral E/e' correlated with pulmonary capillary wedge pressure (PCWP) (r = 0.74, p < 0.001). The single-beat lateral E/e' of ≥11 could predict elevated PCWP (≥15 mm Hg) with a sensitivity of 90% and a specificity of 90%. The single-beat lateral E/e' also correlated well with the log BNP concentration. The single-beat lateral E/e' of ≥9.2 predicted a plasma BNP level of ≥200 pg/ml with 88% sensitivity and 84% specificity.

The single-beat lateral E/e' correlated with plasma BNP level and PCWP in AF patients with preserved systolic function. In addition, the single-beat lateral E/e' (≥11) was a good predictor of elevated PCWP (≥15 mm Hg). Dual Doppler echocardiography offers an advantage of providing the single-beat lateral E/e' correctly even in AF patients, for the evaluation of left ventricular diastolic function.

Mortality and morbidity after AMI is high among patients with abnormal glucose metabolism, which may be related to abnormal microcirculation.

We studied 183 patients with a first AMI. In 161 patients with no history of diabetes mellitus (DM), an oral glucose tolerance test was performed, and patients were categorized according to World Health Organization criteria for whole blood glucose into 3 groups. After coronary angiography and revascularization, a comprehensive transthoracic echocardiogram and noninvasive assessment of CFR was performed in the distal part of left descending artery, as an indicator of microvascular function. Adenosine was administered by intravenous infusion (140 µg/kg/min) to obtain the hyperemic flow profiles. The CFR was defined as the ratio of hyperemic to baseline peak diastolic coronary flow velocities.

Median CFR was 1.9 (interquartile range [IQR] 1.4 to 2.4], and 109 (60%) patients had a CFR ≤2. The lowest CFR was seen in patients with a history of DM (1.4 [IQR 1.4 to 1.7], n = 22) and in patients with newly diagnosed DM (1.6 [IQR 1.3 to 2], n = 39), whereas CFR did not differ in patients with abnormal glucose tolerance (2.1 [IQR 1.4 to 2.6], n = 58) and in patients with normal glucose tolerance (2.2 [IQR 1.7 to 2.6], n = 62). In a stepwise logistic regression model adjusting for age, sex, site and size of AMI, heart rate, risk factors of the metabolic syndrome, degree of angiographic evidence of coronary artery disease, and medical therapy, newly diagnosed DM (odds ratio: 3.0) and a history of DM (odds ratio: 9.9) remained significant predictors of CFR <2, whereas impaired glucose tolerance was not.

CFR is decreased in patients with known or newly diagnosed DM even after adjustment of possible confounders, whereas CFR in patients with impaired glucose tolerance seems less affected. (Coronary Flow Reserve and Glucometabolic State [CFRGS]; NCT00845468)

Several studies proved the value of detecting myocardial edema from T2-weighted cardiac magnetic resonance (CMR) for differentiating acute from chronic MI. Computed tomography is suited for depicting MI, but there are no data on CT imaging of myocardial edema. We hypothesized that areas of reduced attenuation in acute MI may correspond to edema.

In 7 pigs (55.2 ± 7.3 kg), acute MI was induced using a closed chest model. Animals underwent unenhanced arterial and late-phase dual source computed tomography (DSCT) followed by T2-weighted and delayed contrast-enhanced CMR. Animals were sacrificed, and the excised hearts were stained with 2,3,5-triphenyltetrazolin chloride (TTC). Size of MI, contrast-to-noise ratio, and percent signal difference were compared among the different imaging techniques with concordance-correlation coefficients (_c), Bland-Altman plots, and analysis of variance for repeated measures.

Infarction was transmural on all slices. On unenhanced, arterial, and late-phase DSCT, mean sizes of MI were 27.2 ± 8.5%, 20.1 ± 6.9%, and 23.1 ± 8.2%, respectively. Corresponding values on T2-weighted and delayed enhanced CMR were 28.5 ± 7.8% and 22.2 ± 7.7%. Size of MI on TTC staining was 22.6 ± 7.8%. Best agreement was observed when comparing late-phase CT (_c = 0.9356) and delayed enhanced CMR (_c = 0.9248) with TTC staining. There was substantial agreement between unenhanced DSCT and T2-weighted CMR (_c = 0.8629). Unenhanced DSCT presented with the lowest percent signal difference (46.0 ± 18.3) and the lowest contrast-to-noise ratio (4.7 ± 2.0) between infarcted and healthy myocardium.

Unenhanced DSCT permits the detection of myocardial edema in large acute MI. Further studies including smaller MI in different coronary artery territories and techniques for improving the contrast-to-noise ratio are needed.

CAC is an established predictor of major cardiovascular events. Yet, the relationship between CAC and the distribution and severity of coronary artery stenoses has not been widely explored.

All MESA participants underwent noncontrast enhanced cardiac computed tomography during enrollment to determine baseline CAC. We analyzed 175 consecutive angiography reports from participants who underwent coronary catheterization for clinical indications during a median follow-up period of 18 months. The relationship between baseline CAC and the severity of coronary stenosis detected in coronary angiographies was determined.

Baseline Agatston score was 0 in only 7 of 175 (4%) MESA participants who underwent invasive angiography during follow-up. When coronary arteries were studied separately, 13% to 18% of coronary arteries with ≥75% stenosis had 0 calcium mass scores at baseline. There was close association between baseline calcium mass score and the severity of stenosis in each of the coronary arteries (test for trend, p < 0.001). For example, mean calcium mass scores for <50%, 50% to 74%, and ≥75% stenosis in the left anterior descending coronary artery were 105.1 mg, 157.2 mg, and 302.2 mg, respectively (p < 0.001). Finally, there was a direct relationship between the total Agatston Score at baseline and the number of diseased vessels (test for trend, p < 0.001).

The majority of patients with clinically indicated coronary angiography during follow-up had detectable coronary calcification at baseline. Although there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenoses had no calcification at baseline.

The electrocardiogram (ECG) is the most used and simplest clinical method to evaluate the risk for patients immediately after reperfusion therapy for acute MI. ST-segment resolution and residual ST-segment elevation have been used for prognosis in acute MI, whereas Q waves are related to outcome in chronic MI. We hypothesized that the combination of these electrocardiographic measures early after primary PCI would enhance risk stratification.

We prospectively included 180 patients with a first acute ST-segment elevation MI to assess ST-segment resolution, residual ST-segment elevation, and number of Q waves using the 12-lead ECG acquired on admission and 1 h after successful PCI. The ECG findings were related to LV function, infarction size and transmurality, and microvascular injury as assessed with cine and gadolinium-enhanced cardiac magnetic resonance 4 ± 2 days after reperfusion therapy.

Residual ST-segment elevation (β = –2.00, p = 0.004) and the number of Q waves (β = –1.66, p = 0.005) were independent ECG predictors of LV ejection fraction. Although the number of Q waves was the only independent predictor of infarct size (β = 2.01, p < 0.001) and transmural extent of infarction (β = 0.60, p < 0.001), residual ST-segment elevation was the only independent predictor of microvascular injury (odds ratio: 19.1, 95% confidence interval: 2.4 to 154, p = 0.005) in multivariable analyses. The ST-segment resolution was neither associated with LV function, infarct size, or transmurality indexes, nor with microvascular injury in multivariable analysis.

In patients after successful coronary intervention for acute MI, residual ST-segment elevation and the number of Q waves on the post-procedural ECG offer valuable complementary information on prediction of myocardial function and necrosis and its microvascular status.

The clinical application of vasodilator stress for perfusion imaging requires consideration of the effects of these vasodilating agents on systemic hemodynamics, coronary flow, and radiotracer uptake and clearance kinetics.

Sequential imaging and arterial blood sampling was performed on control, anesthetized closed-chest canines (n = 7) to evaluate radiotracer biodistribution and kinetics after either a bolus administration of regadenoson (2.5 µg/kg) or 4.5-min infusion of adenosine (280 µg/kg). The effects of regadenoson on coronary flow and myocardial radiotracer uptake were then evaluated in an open-chest canine model of a critical stenosis (n = 7). Results from ex vivo single-photon emission computed tomography were compared with tissue well-counting.

The use of regadenoson compared favorably with adenosine in regard to the duration and magnitude of the hemodynamic effects and the effect on ²⁰¹Tl and ^99mTc-sestaMIBI biodistribution and kinetics. The arterial blood clearance half-time was significantly faster for ^99mTc-sestaMIBI (regadenoson: 1.4 ± 0.03 min; adenosine: 1.5 ± 0.08 min) than for ²⁰¹Tl (regadenoson: 2.5 ± 0.16 min, p < 0.01; adenosine: 2.7 ± 0.04 min, p < 0.01) for both vasodilator stressors. The relative microsphere flow deficit (0.34 ± 0.02%) during regadenoson stress was significantly greater than the relative perfusion defect with ^99mTc-sestaMIBI (0.69 ± 0.03%, p < 0.001) or ²⁰¹Tl (0.53 ± 0.02%, p < 0.001), although ²⁰¹Tl tracked the flow deficit within the ischemic region better than ^99mTc-sestaMIBI. The perfusion defect score was larger with ²⁰¹Tl (22 ± 2.8% left ventricular) than with ^99mTc-sestaMIBI (17 ± 1.7% left ventricular, p < 0.05) on ex vivo single-photon emission computed tomography images.

The bolus administration of regadenoson produced a hyperemic response comparable to a standard infusion of adenosine. The biodistribution and clearance of both ²⁰¹Tl and ^99mTc-sestaMIBI during regadenoson were similar to adenosine vasodilation. Ex vivo perfusion images under the most ideal conditions permitted detection of a critical stenosis, although ²⁰¹Tl offered significant advantages over ^99mTc-sestaMIBI for perfusion imaging during regadenoson vasodilator stress.

Hybrid PET-CT imaging allows simultaneous assessment of atherosclerotic lesion morphology (CT) and may facilitate early risk assessment in individual patients. The early induction, confinement of expression to atherosclerotic lesions, and accessible position in proximity to the blood pool render the adhesion molecule VCAM-1 an attractive imaging biomarker for inflamed atheroma prone to complication.

A cyclic, a linear, and an oligomer affinity peptide, internalized into endothelial cells by VCAM-1–mediated binding, were initially derivatized with DOTA to determine their binding profiles and pharmacokinetics. The lead compound was then ¹⁸F-labeled and tested in atherosclerotic apoE^–/– mice receiving a high-cholesterol diet as well as wild type murine models of myocardial infarction and heart transplant rejection.

The tetrameric peptide had the highest affinity and specificity for VCAM-1 (97% inhibition with soluble VCAM-1 in vitro). In vivo PET-CT imaging using ¹⁸F-4V showed 0.31 ± 0.02 SUV in murine atheroma (ex vivo %IDGT 5.9 ± 1.5). ¹⁸F-4V uptake colocalized with atherosclerotic plaques on Oil Red O staining and correlated to mRNA levels of VCAM-1 measured by quantitative reverse transcription polymerase chain reaction (R = 0.79, p = 0.03). Atherosclerotic mice receiving an atorvastatin-enriched diet had significantly lower lesional uptake (p < 0.05). Furthermore, ¹⁸F-4V imaging in myocardial ischemia after coronary ligation and in transplanted cardiac allografts undergoing rejection showed high in vivo PET signal in inflamed myocardium and good correlation with ex vivo measurement of VCAM-1 mRNA by quantitative polymerase chain reaction.

¹⁸F-4V allows noninvasive PET-CT imaging of VCAM-1 in inflammatory atherosclerosis, has the dynamic range to quantify treatment effects, and correlates with inflammatory gene expression.

One of the causes of AF is pathological degeneration of the left atrium (LA). However, there is no appropriate method to evaluate degeneration of the LA in the clinical setting.

The IBS images were acquired with TEE with a 4- to 7-MHz transducer. The IBS values were calculated as the average power of the backscattered signal from regions of interest (ROI). In the pathological study, we measured IBS values of 21 left atrial specimens obtained from 10 autopsied hearts. Relative interstitial area in the ROI was automatically calculated by a personal computer. In the clinical study, we measured IBS values of the entire LA wall at 5-mm intervals (except the posterior wall) in 42 patients (18 non-AF patients, 14 paroxysmal AF patients, and 10 chronic AF patients). Each IBS value was color-coded to construct 3-dimensional maps.

There was a weak correlation between the relative interstitial area and IBS values (r = 0.45, p = 0.038). Average corrected IBS values of total voxels in color-coded maps in the AF group (24.4 ± 6.4 dB) and the paroxysmal AF group (23.9 ± 9.6 dB) were significantly greater than those in the non-AF group (15.6 ± 7.4 dB, p = 0.007), whereas there was no significant difference in LA diameter between the paroxysmal AF group (39.4 ± 6.5 mm) and the non-AF group (36.7 ± 5.5 mm).

With IBS-TEE, we can identify an increase in atrial degeneration that might predict the occurrence of AF before LA dilation.

Concerns about contrast agent safety led to revised recommendations for product use in the U.S.

We studied 26,774 patients who underwent SE between November 1, 2003, and December 31, 2007. The 10,792 patients who comprised the contrast cohort received second-generation perfluorocarbon-based agents for left ventricular opacification during SE. The noncontrast cohort comprised 15,982 patients who had their first SE in the same period but without contrast agents. Short-term (≤72 h and ≤30 days) and long-term (up to 4.5 years) end points were death and myocardial infarction (MI). Cox regression models were used. Immediate contrast agent-related adverse effects were also reported.

The contrast cohort had older patients (mean [SD] age, 65.8 [12.1] years vs. 62.6 [14.1] years; p < 0.001), a higher percentage of males (57.4% vs. 52.8%, p < 0.001), and higher-risk patients compared with the noncontrast cohort. In addition, dobutamine SE patients had greater cardiac risk than exercise SE patients. Abnormal SE findings in patients who received contrast agents were more frequent (32.4% vs. 27.9%, p < 0.001). The 2 cohorts had no statistical difference in the incidence of short-term events (death and MI). Within 72 h, 1 patient in the contrast cohort and 2 patients in the noncontrast cohort died (p = 0.54); 3 in the contrast cohort and 7 in the noncontrast cohort had MI (p = 0.92). Within 30 days, 37 patients (0.34%) in the contrast cohort and 57 patients (0.36%) in the noncontrast cohort died (p = 0.85); 17 patients (0.16%) in the contrast cohort and 16 patients (0.10%) in the noncontrast cohort had MI (p = 0.19). Adjusted hazard ratios were not different between cohorts for death (0.99; 95% confidence interval: 0.88 to 1.11) or MI (0.99; 95% confidence interval: 0.80 to 1.22).

The use of contrast agents during SE was not associated with an increased short-term or long-term risk of death or MI.

Patients with ischemic LV dysfunction might benefit from revascularization but not without risk. The FDG PET imaging can detect viable myocardium that recovers after revascularization. In the PARR-2 (PET and Recovery Following Revascularization-2) trial, FDG PET imaging showed a nonsignificant trend for improved outcome compared with standard care. Understanding the predictors of outcome from this prospective trial should help better identify patients at risk and which patients most benefit from revascularization.

This post hoc analysis included 182 patients with left ventricular ejection fraction (LVEF) <35% and coronary artery disease, being considered for revascularization work-up, and randomized to the PET arm of PARR-2. The primary outcome was a composite of cardiac death, myocardial infarction, or cardiac repeat hospital stay at 1 year.

There is an interaction between PET mismatch and protocol revascularization such that higher mismatch, when combined with revascularization, yields fewer primary outcome events (p = 0.02). On the basis of adjusted Cox modeling, with reduced mismatch (<7%), the risk is not significantly different with or without revascularization. As mismatch increases above this mark, risk is reduced with revascularization. Increasing creatinine (for a 10-µmol/l increase: hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.06, p = 0.010) is also associated with increased risk, whereas decreasing LVEF (for a 2% decrease: hazard ratio: 1.08, 95% confidence interval: 0.99 to 1.18, p = 0.087) trends toward an association with increased risk.

In this post hoc analysis, patients with ischemic cardiomyopathy with larger amounts of mismatch have improved outcome with revascularization. Renal function was also an independent predictor of outcome. The FDG PET seems to define high-risk patients that gain benefit from revascularization. (PET and Recovery Following Revascularization [PARR 2]; NCT00385242)

Early detection of myocardial viability should be valuable for risk stratification of patients with reperfused acute myocardial infarction (AMI).

Consecutive patients without a history of previous AMI who underwent primary PCI for an ST-segment elevation AMI were examined by DE-MDCT without an additional contrast injection immediately after completion of PCI. No medication was administrated to lower the heart rate. Dose modulation lead to an approximate mean radiation dose of 5.5 mSv.

Thirty patients constituted the study population. Mean age was 61.4 ± 15.6 years, 24 (80%) were men, and 4 (13%) were diabetic. Although post-procedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 was achieved in all patients, DE was detected in 14 (47%) patients. Age, sex, hypertension, diabetes, smoking history, serum creatinine levels, and pain duration were not associated with the presence of DE. Door-to-balloon time (DE 70.3 ± 33.6 min vs. non-DE 98.3 ± 70.7 min, p = 0.19) and lesion crossing time (DE 18.6 ± 11.4 min vs. non-DE 16.4 ± 9.6 min, p = 0.58) did not differ between groups. The TIMI myocardial perfusion grade (0 to 1 vs. 2 to 3) after stent implantation and electrocardiogram ST-segment resolution (<50% or ≥50%) were associated with the presence of DE (p = 0.001 and p = 0.02, respectively). Pre-discharge left ventricular ejection fraction was lower in DE than in non-DE patients (44.6 ± 12.4% vs. 54.1 ± 10.3%, respectively, p = 0.05). Hospitalization days (DE 5.6 ± 3.8 vs. non-DE 4.8 ± 1.0, p = 0.41) and 6-month cardiac events (DE 3 of 14 vs. non-DE 1 of 16, p = 0.22) did not differ between groups.

Early detection of myocardial viability immediately after primary PCI by the use of DE-MDCT is related to clinical and angiographic parameters of myocardial reperfusion.

MDCT angiography is a novel imaging strategy employed primarily to diagnose CAD that, in the course of these studies, can also potentially identify other important but previously unrecognized cardiovascular abnormalities.

Consecutive 64-slice MDCT angiography studies were obtained in 4,543 patients with suspected atherosclerotic CAD at the Minneapolis Heart Institute, over a 29-month period (2005 to 2007).

Nonatherosclerotic-related cardiovascular abnormalities judged to be of potential clinical relevance were identified in 201 patients (4.4%). In 50 of these patients (1.1% of 4,543) the abnormality was previously unrecognized despite other imaging studies performed in 40%. Most common among the 50 patients were: congenital coronary artery anomalies (38%; largely right coronary artery from the left aortic sinus); ascending aortic aneurysms ≥45 mm (22%); hypertrophic cardiomyopathy with apical left ventricular (LV) wall thickening (14%); valvular heart diseases (8%), congenital heart diseases, including ventricular septal defect (6%); pulmonary embolus (6%); as well as LV noncompaction, left atrial myxoma, and LV apical aneurysm (2% each). As a consequence of MDCT angiography findings, new management strategies were instituted in 15 of 50 patients (30%), including surgical correction of coronary artery anomalies of wrong sinus origin, ascending aneurysm graft repair, thrombolytic therapy for pulmonary embolism, and myxoma resection.

Approximately 1% of patients undergoing MDCT angiography for suspicion of CAD proved to have otherwise unsuspected, but clinically relevant, cardiovascular abnormalities unrelated to coronary atherosclerosis. Almost one-third of these patients had cardiovascular diseases with major clinical implications for subsequent therapy. These findings underscore the value of MDCT angiography and the importance of careful assessment of scans for the recognition of a variety of cardiovascular abnormalities.

Myeloperoxidase is a leukocyte-derived enzyme-generating reactive oxidant species that has been shown to predict risk of CVD in selected populations.

We studied 1,302 asymptomatic adults (mean age 59 years, 47% women) without known CVD who were followed for 3.8 years. We measured MPO by the use of immunoassay. Coronary artery calcium (CAC), a measure of subclinical atherosclerosis, was measured by computed tomography with the Agatston score categorized as none/minimal (0 to 9), mild (10 to 99), and moderate/significant (≥100). Cox regression, adjusted for age, sex, and other risk factors, examined the relation of CAC and/or MPO with incident CVD events.

Persons with MPO levels at or above compared with below the median (257 pM) were more likely (p < 0.05 to p < 0.001) to be women, have a higher body mass index, greater low-density lipoprotein cholesterol, greater systolic and diastolic blood pressure, and lower high-density lipoprotein cholesterol. Mean MPO levels increased according to CAC categories (p trend = 0.02). Incident CVD events were more likely in those at or above versus below the median MPO level (4.6% vs. 2.3%, p = 0.02), even after adjustment for age, sex, CAC, and risk factors (hazard ratio [HR]: 1.9, 95% confidence interval: 1.0 to 3.6, p = 0.04). Combining CAC and MPO categories, CVD incidence ranged from 0.6% in those with a CAC score of 0 to 9 to 7.1% (adjusted HR: 9.2, p < 0.001) in those with CAC scores of ≥100 and MPO below the median and 14.0% (adjusted HR: 19.5, p < 0.0001) in those with CAC scores of ≥100 and MPO at or above the median.

Our study suggests persons with both increased levels of both MPO and CAC are at an increased risk of CVD events. Imaging of subclinical atherosclerosis combined with assessment of biomarkers of plaque vulnerability may help improve CVD risk stratification.

First-pass magnetic resonance (MR) myocardial perfusion imaging can quantify MBF, but images are of low signal at conventional magnetic field strength due to the need for rapid acquisition.

A pig model was used to alter MBF in a coronary artery during FP CMR (intracoronary adenosine followed by ischemia). This produces an active zone with a range of MBF and a control zone. Microspheres were injected into the left atrium with concurrent reference sampling. FP MR perfusion imaging was performed at 1.5-T (n = 9) or 3.0-T (n = 8) with a saturation-recovery gradient echo sequence in short-axis slices during a bolus injection of 0.025 mmol/kg gadolinium–diethylenetriamine pentaacetic acid. Fermi function deconvolution was performed on active and control region of interest from short-axis slices with an arterial input function derived from the left ventricular cavity. These MR values of MBF were matched to microsphere values obtained from short-axis slices at pathology.

Occlusion MBF was 0.21 ± 0.26 ml/min/g, adenosine MBF was 2.28 ± 0.99 ml/min/g, and control zone MBF was 0.70 ± 0.22 ml/min/g. The correlation of MR FP CMR with microsphere was close for both field strengths: 3.0-T, r = 0.98, p < 0.0001 and 1.5-T, r = 0.95, p < 0.0001. The 95% confidence limits of agreement were slightly narrower at 3.0-T (3.0-T = 0.49 ml/min/g, 1.5-T = 0.68 ml/min/g, p < 0.05). The FP CMR image characteristics were better at 3.0-T (noise and contrast enhancement were both superior at 3.0-T). In myocardial zones where MBF <0.50 ml/min/g, the correlation with microspheres was closer at 3.0-T (r = 0.55 at 1.5-T, r = 0.85 at 3.0-T).

Absolute MBF by FP perfusion imaging is accurate at both 1.5- and 3.0-T. Signal quality is better at 3.0-T, which might confer a benefit for estimating MBF in ischemic zones.

Cell therapy shows great promise for the treatment of cardiovascular disease. An important limitation to previous clinical studies is the inability to accurately identify transplanted cells. GdFM-Cy3 is a lipophilic paramagnetic contrast agent that contains a perfluorinated side chain and an amphiphilic character that allows for micelle formation in an aqueous solution. Previous studies reported that it is easily taken up and stored within the cytosol of mesenchymal stem cells, thereby allowing for paramagnetic cell labeling. Investigators in our laboratory have recently developed techniques for the robust generation of ES-CPC. We reasoned that GdFM-Cy3 would be a promising agent for the in vivo detection of these cells after cardiac cell transplantation.

ES-CPC were labeled with GdFM-Cy3 by incubation. In vitro studies were performed to assess the impact of GdFM-Cy3 on cell function and survival. A total of 500,000 GdFM-Cy3–labeled ES-CPC or control ES-CPC were injected into the myocardium of mice with and without myocardial infarction. Mice were imaged (9.4-T) before and over a 2-week time interval after stem cell transplantation. Mice were then euthanized, and their hearts were sectioned for fluorescence microscopy.

In vitro studies demonstrated that GdFM-Cy3 was easily transfectable, nontoxic, stayed within cells after labeling, and could be visualized using CMR and fluorescence microscopy. In vivo studies confirmed the efficacy of the agent for the detection of cells transplanted into the hearts of mice after myocardial infarction. A correspondence between CMR and histology was observed.

The results of the current study suggest that it is possible to identify and potentially track GdFM-Cy3–labeled ES-CPC in murine infarct models via CMR.

Aortic sclerosis has been regarded predominantly as a precursor of hemodynamically significant aortic stenosis. However, ASc also represents an independent correlate of increased risk of cardiovascular morbidity and mortality; the basis of this association is incompletely understood. The assumption that the pathogenesis of aortic valve disease is similar to that of atherosclerosis has not been supported by recent studies; rather there has been increasing evidence of a pathogenetic role of inflammation and endothelial dysfunction. Furthermore, we have recently developed methodology for echocardiographic quantitation of early aortic valve disease.

Randomly selected subjects (n = 253) ages 51 to 77 years underwent transthoracic echocardiography; aortic valve ultrasonic backscatter score (AV_BS) was used to quantitate echogenicity of the aortic valve. Conventional coronary risk factors were identified. Integrity of NO generation/response was assessed via: 1) plasma asymmetric dimethylarginine concentrations, as a marker of endothelial dysfunction; 2) inhibition of platelet aggregation by the NO donor sodium nitroprusside, as a measure of tissue NO responsiveness and also a coronary prognostic marker; and 3) aortic augmentation index, as a measure of arterial stiffness/wave reflection. All putative correlations with AV_BS were examined by univariate and multiple linear regression analyses.

On the basis of AV_BS scores, ASc was present in 19.4% of subjects. The AV_BS directly correlated with patients' age but inversely correlated with high-sensitivity C-reactive protein, creatinine clearance, and platelet NO responsiveness. On multiple linear regression, ASc was associated with impaired platelet NO responsiveness (β = –0.16, p = 0.02), advancing age (β = 0.21, p = 0.003), and low body mass index (β = –0.23, p = 0.001).

Aortic sclerosis is associated with platelet NO resistance rather than conventional coronary risk factors: this might explain the increased thrombotic risk in ASc.

Surgical valve repair for AR has significant advantages over valve replacement, but little is known about the predictors and mechanisms of its failure.

We blindly reviewed all clinical, pre-operative, intraoperative, and follow-up transesophageal echocardiographic data of 186 consecutive patients who underwent valve repair for AR during a 10-year period and in whom intraoperative and follow-up echo data were available. After a median follow-up duration of 18 months, 41 patients had recurrent 3+ AR, 23 patients presented with residual 1+ to 2+ AR, and 122 had no or trivial AR. In patients with recurrent 3+ AR, the cause of recurrent AR was the rupture of a pericardial patch in 3 patients, a residual cusp prolapse in 26 patients, a restrictive cusp motion in 9 patients, an aortic dissection in 2 patients, and an infective endocarditis in 1 patient.

Pre-operatively, all 3 groups were similar for aortic root dimensions and prevalence of bicuspid valve (overall 37%). Patients with recurrent AR were more likely to display Marfan syndrome or type 3 dysfunction pre-operatively. At the opposite end, patients with continent AR repair at follow-up were more likely to have type 2 dysfunction pre-operatively. After cardiopulmonary bypass, a shorter coaptation length, the degree of cusp billowing, a lower level of coaptation (relative to the annulus), a larger diameter of the aortic annulus and the sino-tubular junction, the presence of a residual AR, and the width of its vena contracta were associated with the presence of AR at follow-up. Multivariate Cox analysis identified a shorter coaptation length (odds ratio [OR]: 0.8, p = 0.05), a coaptation occurring below the level of the aortic annulus (OR: 7.9, p < 0.01), a larger aortic annulus (OR: 1.2, p = 0.01), and residual aortic regurgitation (OR: 5.3, p = 0.01) as risk factors of repair failure.

Our results demonstrate that intraoperative transesophageal echocardiography can be used to identify patients undergoing AR repair who are at increased risk for late repair failure.

Cardiac computed tomography angiography (CCTA) has become a frequently used diagnostic tool in clinical practice. Despite continually improving CT technology, there remain concerns regarding the associated radiation exposure. A reduced tube voltage of 100 kV has been proposed as an effective means for dose reduction in nonobese patients.

The study assessed the relevant radiation dose parameters as well as quantitative and qualitative diagnostic image quality data in a subgroup of 321 patients (100 kV: 82 patients; 120 kV: 239 patients), who were scanned at study sites that applied a 100-kV tube voltage in at least 1 patient. Diagnostic image quality was assessed by an experienced CCTA investigator with a 4-point score (1: nondiagnostic to 4: excellent image quality). Effective radiation dose was estimated from the dose-length-product of each CCTA study.

The use of the 100-kV scan protocol was associated with 53% reduction in CCTA median radiation dose estimates, when compared with the conventional 120-kV scan protocol (p < 0.001). Although image noise significantly increased by 26.3% with 100 kV, signal- as well as contrast-to-noise ratios also increased by 7.9% (p = 0.254) and 10.8% (p = 0.027), respectively. Reduction of tube voltage did not impair diagnostic image quality (median diagnostic score: 3.5 [3.25 to 3.75] vs. 3.5 [3.0 to 3.75] for 100 kV vs. 120 kV; p = 0.22).

In this nonrandomized PROTECTION I dose survey, reducing the CCTA tube voltage to 100 kV in nonobese patients is associated with a significant reduction in radiation exposure while maintaining diagnostic image quality. Thus, the 100-kV scan technique should be considered for CCTA dose reduction in adequately selected patients.

Complexity of stenosis morphology affects PCI success. Whether CTA can detect the entire spectrum of recognized complex stenosis morphologies has not been investigated.

All nonbypassed, nonstented, ≥2-mm–diameter native coronary arterial segments in 85 consecutive patients who underwent ICA ≤30 days after CTA were assessed. Two blinded CTA readers qualitatively and quantitatively evaluated all lesions ≥70% stenotic by visual inspection and characterized each as type C or nontype C, according to the modified American College of Cardiology morphology criteria for estimating PCI risk. Results were compared with ICA data similarly analyzed by 2 blinded interventional cardiologists. The PCI procedure duration and contrast use were compared between type C and nontype C lesions identified on both ICA and CTA.

CTA detected 84 of 93 lesions (90%) causing ≥70% stenosis on ICA and correctly characterized 42 of 53 lesions (79%) found to concurrently show type C morphology on ICA. Type C features most frequently missed by CTA were ostial involvement (5 cases) and lesion length >20 mm (7 cases). Major branch involvement was the most frequent false-positive type C feature (12 cases). Mean PCI duration in patients with and without type C lesions on CTA were 42.4 ± 24.7 min and 21.5 ± 13.3 min (p = 0.009), respectively; mean total contrast used were 263 ± 150 ml and 140 ± 47 ml (p = 0.007), respectively.

In vessels segments ≥2 mm in diameter, CTA can predict lesions likely to reach ≥70% stenosis on ICA and provide added value in discerning complex morphologies associated with these lesions. Presence of complex, severely obstructive lesions on CTA is associated with higher contrast use and greater procedure length during PCI.

Total and ischemic left ventricular perfusion defect size predict patient outcome. Therefore, it is important to show that newer stressor agents induce similar perfusion abnormalities as observed with currently available ones.

The ADVANCE MPI 2 (Adenosine versus Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging) study was a prospective, double-blind, randomized trial comparing image results in patients undergoing standard gated adenosine single-photon emission computed tomography (SPECT) myocardial perfusion imaging who were then randomized in a 2:1 ratio to either regadenoson (N = 495) or a second adenosine SPECT (N = 260). Quantitative SPECT analysis was used to determine total left ventricular perfusion defect size and the extent of ischemia. Quantification was performed by a single observer who was blinded to randomization and image sequence.

Baseline gated perfusion results were similar in patients randomized to adenosine or regadenoson. No significant differences in total (11.5 ± 15.7 vs. 11.4 ± 15.8, p = 0.88) or ischemic (4.8 ± 9.2 vs. 4.6 ± 8.9, p = 0.43) perfusion defect sizes were observed between the regadenoson and adenosine groups, respectively. Linear regression showed a close correlation between adenosine and regadenoson for total (r = 0.97, p < 0.001) and ischemic (r = 0.95, p < 0.001) left ventricular perfusion defects. Serial differences in total (–0.03 ± 3.89 vs. –0.13 ± 4.16, p = 0.73) and ischemic (0.15 ± 4.08 vs. 0.25 ± 3.81, p = 0.74) perfusion defect size and left ventricular ejection fraction (0.12 ± 0.32 vs. 0.15 ± 0.35, p = 0.27) from study 1 to study 2 were virtually identical in patients randomized to regadenoson versus adenosine, respectively. The good correlation between serial adenosine and regadenoson studies regarding total (0.41 ± 5.43 vs. 0.21 ± 5.23, p = 0.76) and ischemic (0.17 ± 5.31 vs. 0.23 ± 6.08, p = 0.94) perfusion defects persisted in the subgroup of 308 patients with an abnormal baseline SPECT.

Applying quantitative analysis, regadenoson induces virtually identical scintigraphic results as adenosine regarding the size and severity of left ventricular perfusion defects and the extent of scintigraphic ischemia.

Contrast echocardiography (echo) detects LV thrombus based on anatomic appearance, whereas DE-CMR imaging detects thrombus based on tissue characteristics. Although DE-CMR has been validated as an accurate technique for thrombus, its utility compared with contrast echo is unknown.

Multimodality imaging was performed in 121 patients at high risk for thrombus due to myocardial infarction or heart failure. Imaging included 3 anatomic imaging techniques for thrombus detection (contrast echo, noncontrast echo, cine-CMR) and a reference of DE-CMR tissue characterization. LV structural parameters were quantified to identify markers for thrombus and predictors of additive utility of contrast-enhanced thrombus imaging.

Twenty-four patients had thrombus by DE-CMR. Patients with thrombus had larger infarcts (by DE-CMR), more aneurysms, and lower LV ejection fraction (by CMR and echo) than those without thrombus. Contrast echo nearly doubled sensitivity (61% vs. 33%, p < 0.05) and yielded improved accuracy (92% vs. 82%, p < 0.01) versus noncontrast echo. Patients who derived incremental diagnostic utility from DE-CMR had lower LV ejection fraction versus those in whom noncontrast echo alone accurately assessed thrombus (35 ± 9% vs. 42 ± 14%, p < 0.01), with a similar trend for patients who derived incremental benefit from contrast echo (p = 0.08). Contrast echo and cine-CMR closely agreed on the diagnosis of thrombus ( = 0.79, p < 0.001). Thrombus prevalence was lower by contrast echo than DE-CMR (p < 0.05). Thrombus detected by DE-CMR but not by contrast echo was more likely to be mural in shape or, when apical, small in volume (p < 0.05).

Echo contrast in high-risk patients markedly improves detection of LV thrombus, but does not detect a substantial number of thrombi identified by DE-CMR tissue characterization. Thrombi detected by DE-CMR but not by contrast echo are typically mural in shape or small in volume.

The imaging field for many CMR sequences extends outside of the heart border. As a result, noncardiac pathology may be identified. These noncardiac findings have clinical significance because they often lead to subsequent imaging/testing and intervention. The prevalence of noncardiac findings on clinical CMR studies has not been well described.

The reports of all 1,534 (62% male, age 50 ± 15 years) clinical CMR studies performed at an academic medical center during calendar years 2002 to 2006 were reviewed. All studies had been interpreted by both a staff cardiologist (level III trained in CMR) and a board-certified radiologist (with fellowship training in CMR). For each study, sex, age, indication for CMR study, and reported noncardiac pathology were extracted. Follow-up for each major noncardiac pathology was evaluated by reviewing the patient's medical center electronic medical record. These noncardiac pathologies were then categorized as significant if an intervention or change in the patient's management ensued.

A total of 116 (7.6%) studies had at least one noncardiac finding. These findings included 55 major findings (e.g., lymphadenopathy, lung abnormalities, mediastinal masses) in 48 distinct reports (prevalence of 3.1%) and 74 minor findings (e.g., small pleural effusions, liver cysts, renal cysts) in 70 distinct reports (prevalence of 4.6%). The majority (62%) of major findings were previously known, with only 8 findings in 6 (0.4%) of 1,534 reports ultimately deemed to be new and clinically important/significant. The age of those with noncardiac pathology was greater (54 ± 16 years vs. 49 ± 16 years, p < 0.001).

In this large series of consecutive clinical CMR studies interpreted by both staff cardiologists and radiologists, noncardiac pathology is uncommonly reported. When reported, the majority of major findings are previously known. New major findings were detected in <0.5% of reports.

Thrombus formation plays a central role in several vascular diseases. During the early phases of thrombus formation, activated factor XIII (FXIIIa) covalently cross-links ₂-antiplasmin to fibrin, indicating the potential of ₂-antiplasmin–based CAs in the detection of early thrombus formation.

A bimodal CA was synthesized by coupling gadolinium-diethylene triamine pentaacetic acid and rhodamine to an ₂-antiplasmin–based peptide. For the control CA, a glutamine residue essential for cross-linking was replaced by alanine. In vitro-generated thrombi were exposed to both CAs and imaged by MRI and 2-photon laser-scanning microscopy. Immunohistochemistry was performed on human pulmonary thromboemboli sections to determine the presence of ₂-antiplasmin and FXIII in different thrombus remodeling phases. In vivo feasibility of the CA in detecting early thrombus formation specifically was investigated with MRI.

In vitro–generated thrombi exposed to the ₂-antiplasmin–based CA showed hyperintense magnetic resonance signal intensities at the thrombus edge. No hyperintense signal was observed when we used the ₂-antiplasmin–based CA in the presence of FXIII inhibitor dansylcadaverine nor when we used the control CA. Two-photon laser-scanning microscopy demonstrated that the ₂-antiplasmin–based CA bound to fibrin. Immunohistochemistry demonstrated substantial ₂-antiplasmin staining in fresh compared with lytic and organized thrombi. The administration of CA in vivo within seconds after inducing thrombus formation increased contrast-to-noise ratios (CNRs 2.28 ± 0.39, n=6) at the site of thrombus formation compared with the control CA (CNRs –0.14 ± 0.55, p = 0.003, n = 6) and ₂-antiplasmin–based CA administration 24 to 48 h after thrombus formation (CNRs 0.11 ± 0.23, p = 0.006, n = 6).

A bimodal CA was developed, characterized, and validated. Our results showed that this bimodal CA enabled noninvasive in vivo magnetic resonance visualization of early thrombus formation.

Microbubbles are commonly used in clinical practice as ultrasound contrast agents. Several studies have addressed the in vivo applications of MBs for specific targeting of vascular dysfunction or sonoporation in animal models, but to date no human tissue model has been established.

Primary venular endothelial cell monolayers were targeted with MBs conjugated to an antibody against a highly expressed endothelial marker (tetraspanin CD9), and binding was assessed under increasing flow rates (0.5 to 5 dynes/cm²). Furthermore, CD9-coupled MB endothelial targeting was measured under flow conditions by contrast-enhanced ultrasound analysis in an ex vivo human macrovascular model (umbilical cord vein), and the same tissue model was used for the detection of inflamed vasculature with anti-intercellular adhesion molecule (ICAM)-1–coated MBs. Finally, plasmids encoding fluorescent proteins were sonoporated into umbilical cord vessels.

Specific endothelial targeting in the in vitro and ex vivo models described previously was achieved by the use of MBs covered with an anti-CD9. Furthermore, we managed to induce inflammation in umbilical cord veins and detect it with real-time echography imaging using anti–ICAM-1–coupled MBs. Moreover, expression and correct localization of green fluorescent protein and green fluorescent protein-tagged ICAM-1 were assessed in this human ex vivo model without causing vascular damage.

In the absence of clinical trials to test the benefits and possible applications of ultrasound contrast agents for molecular imaging and therapy, we have developed a novel ex vivo human model using umbilical cords that is valid for the detection of inflammation and for exogenous expression of proteins by sonoporation.