In vivo myocardial distribution of multipotent progenitor cells following intracoronary delivery in a swine model of myocardial infarction.

AIMS: There are few data comparing the fate of multipotent progenitor cells (MPCs) used in cardiac cell therapy after myocardial infarction (MI). To document in vivo distribution of MPCs delivered by intracoronary (IC) injection. METHODS AND RESULTS: Using an anterior MI swine model, near-infrared (NIR) fluorescence was used for in vivo tracking of labelled MPCs [mesenchymal stromal (MSCs), bone marrow mononuclear (BMMNCs), and peripheral blood mononuclear (PBMNCs)] cells early after IC injection. Signal intensity ratios (SIRs) of injected over non-injected (reference) zones were used to report NIR fluorescence emission. Following IC injection, significant differences in mean SIR were documented when MSCs were compared with BMMNCs [1.28 +/- 0.10 vs. 0.77 +/- 0.11, P < 0.001; 95% CI (0.219, 0.805), respectively] or PBMNCs [1.28 +/- 0.10 vs. 0.80 +/- 0.14, P = 0.005; 95% CI (0.148, 0.813), respectively]. Differences were maintained during the 60 min tracking period, with only the MSC-injected groups continuously emitting NIR fluorescence (SIR>1). This is correlated with greater cell retention for MSCs relative to mononuclear cells. However, there was evidence of MSC-related vessel plugging in some swine. CONCLUSION: Our in vivo NIR fluorescence findings suggest that MPC distribution and retention immediately after intracoronary delivery vary depending on cell population and could potentially impact the clinical efficacy of cardiac cell therapy.

Funnel-tipped aortic cannula for reduction of atheroemboli.

BACKGROUND: Atheroemboli caused by aortic manipulation poses a risk for stroke in patients undergoing cardiopulmonary bypass (CPB) surgery. One potential cause is the high velocity jet from aortic perfusion cannulae. This study describes the flow patterns of a novel funnel-tip cannula designed to reduce emboli by decreasing fluid velocity and resultant shear force on the aortic wall. METHODS: A funnel-tip cannula was constructed and compared with standard straight-tip cannulae and the Dispersion (Research Medical Inc, Midvale, UT) and Sarns Soft Flow (Terumo Cardiovascular Systems Corp, Ann Arbor, MI) cannulae. Pressure drop measurements were collected at 1 to 6 L/minute flows. Velocity flow profiles were created using phase contrast magnetic resonance imaging. Absolute velocity was measured in a phantom aorta at 5 L/minute flow. Each cannula was further studied in a synthetic model of an atherosclerotic aorta to determine the mass of dislodged particulate matter generated at 2, 3, and 5 L/minute flows. RESULTS: The funnel-tip cannula demonstrated significantly lower values (p < 0.05) in pressure drop (55 mm Hg), exit velocity (309 cm/second, 167 cm/second for center axis and wall, respectively), and particulate dislodgement (0.15 +/- 0.05 g) than other tested cannulae. The Soft Flow cannula generated the next lowest pressure drop but exhibited twice the exit velocity and particulate dislodgement of the funnel-tip cannula. The Dispersion cannula did not demonstrate a reduction in velocity or particulate dislodgement compared with the standard straight-tip cannulae. CONCLUSIONS: The results of this study suggest that a low-angled funnel-tip cannula has favorable flow characteristics warranting further investigation. Design development may reduce the risk of atheroemboli generation during CPB surgery.

3D coronary motion tracking in swine models with MR tracking catheters.

PURPOSE: To develop MR-tracked catheters to delineate the three-dimensional motion of coronary arteries at high spatial and temporal resolution. MATERIALS AND METHODS: Catheters with three tracking microcoils were placed into nine swine. During breath-holds, electrocardiographic (ECG)-synchronized 3D motion was measured at varying vessel depths. 3D motion was measured in American Heart Association left anterior descending (LAD) segments 6-7, left circumflex (LCX) segments 11-15, and right coronary artery (RCA) segments 2-3, at 60-115 beats/min heart rates. Similar-length cardiac cycles were averaged. Intercoil cross-correlation identified early systolic phase (ES) and determined segment motion delay. RESULTS: Translational and rotational motion, as a function of cardiac phase, is shown, with directionality and amplitude varying along the vessel length. Rotation (peak-to-peak solid-angle RCA approximately 0.10, LAD approximately 0.06, LCX approximately 0.18 radian) occurs primarily during fast translational motion and increases distally. LCX displacement increases with heart rate by 18%. Phantom simulations of motion effects on high-resolution images, using RCA results, show artifacts due to translation and rotation. CONCLUSION: Magnetic resonance imaging (MRI) tracking catheters quantify motion at 20 fps and 1 mm(3) resolution at multiple vessel depths, exceeding that available with other techniques. Imaging artifacts due to rotation are demonstrated. Motion-tracking catheters may provide physiological information during interventions and improve imaging spatial resolution.

Prediction of early response to radiotherapy of uterine carcinoma with dynamic contrast-enhanced MR imaging using pixel analysis of MR perfusion imaging.

PURPOSE: To assess the predictability of the response to radiotherapy of uterine carcinoma, this study retrospectively analyzed dynamic contrast-enhanced magnetic resonance images (DCE-MRI) taken before radiotherapy. MATERIALS AND METHODS: Forty-two patients with uterine carcinoma were studied, of whom 22 had adenocarcinoma and 20 had squamous cell carcinoma (SCC). In DCE-MRI analysis, two parameters, SIe and R(down), were measured. SIe is a median value for the degree of signal intensity change in all selected pixels in the tumor at 1-2 min after contrast agent injection. R(down) is the ratio of the number of down-sloped pixels to that of all selected pixels 3-7 min after injection. The tumor volume reduction rate (TVRR) was measured by MRI-based volumetry in pre- and post-radiotherapy transverse T2-weighted images. RESULTS: Overall, TVRR was significantly correlated to both SIe (r=0.37, P=.015) and R(down) (r=0.73, P<.0001). In the separate patient groups, SIe but not R(down) was significantly different between the adenocarcinoma and SCC patients (t=3.64, P<.001). TVRR was not correlated to SIe in any group. TVRR was significantly correlated to R(down) in adenocarcinoma patients (r=0.78, P<.001) but not in SCC patients. CONCLUSION: SIe may reflect differences in histological characteristics. R(down) may be useful for predicting the response to radiotherapy of uterine carcinoma.

Progressive nature of chronic mitral regurgitation and the role of tissue Doppler-derived indexes.

The aim of this study was to determine whether severe mitral regurgitation (MR) is progressive and whether tissue-Doppler (TD)-derived indexes can detect early left ventricular (LV) dysfunction in chronic severe MR. Percutaneous rupture of mitral valve chordae was performed in pigs (n = 8). Before MR (baseline), immediately after MR (post-MR), and at 1 and 3 mo after MR, cardiac function was assessed using conventional and TD-derived indexes. The severity of MR was quantified using regurgitant fraction and effective regurgitant orifice area (EROA). In all animals, MR was severe. On follow-up, the LV dilated progressively over time, but LV ejection fraction did not decrease. With the increase in LV dimensions, the forward stroke volume remained unchanged, but the mitral annular dimensions, EROA, and regurgitant fraction increased (EROA = 41 +/- 2 and 51 +/- 2 mm(2) post-MR and at 3 mo, respectively, P < 0.01). Peak systolic myocardial velocities, strain, and strain rate increased acutely post-MR and remained elevated at 1 mo but declined by 3 mo (anterior strain rate = 2.9 +/- 0.1 and 2.4 +/- 0.2 s(-1) post-MR and at 3 mo, respectively, P < 0.001). Therefore, in a chronic model of MR, serial echocardiography demonstrated that MR begets MR and that those TD-derived indexes that initially increased post-MR decreased to baseline before any changes in LV ejection fraction.

Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure.

OBJECTIVES: The aim of this study was to examine the effects of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) gene transfer in a swine heart failure (HF) model. BACKGROUND: Reduced expression and activity of SERCA2a have been documented in HF. Prior studies have reported the beneficial effects of short-term SERCA2a overexpression in rodent models. However, the effects of long-term expression of SERCA2a in pre-clinical large animal models are not known. METHODS: Yorkshire-Landrace pigs were used (n = 16) to create volume overload by percutaneously severing chordae tendinae of the mitral apparatus with a bioptome to induce mitral regurgitation. At 2 months, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 1 (rAAV1) carrying SERCA2a under a cytomegalovirus promoter (rAAV1.SERCA2a) (n = 10; group 1) or saline (n = 6; group 2). RESULTS: At 2 months, study animals were found to be in a compensated state of volume-overload HF (increased left ventricular internal diastolic and systolic diameters [LVIDd and LVIDs]). At 4 months, gene transfer resulted in: 1) positive left ventricular (LV) inotropic effects (adjusted peak left ventricular pressure rate of rise (dP/dt)max/P, 21.2 +/- 3.2 s(-1) group 1 vs. 15.5 +/- 3.0 s(-1) group 2; p < 0.01); 2) improvement in LV remodeling (% change in LVIDs -3.0 +/- 10% vs. +15 +/- 11%, respectively; p < 0.01). At follow-up, brain natriuretic peptide levels remained stable in group 1 after gene transfer, in contrast to rising levels in group 2. Further, cardiac SERCA2a expression was significantly decreased in group 2 whereas in group 1 it was restored to normal levels. There was no histopathological evidence of acute myocardial inflammation or necrosis. CONCLUSIONS: Using a large-animal, volume-overload model of HF, we report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling.

Gene therapy in the treatment of heart failure.

Heart failure is a major cause of morbidity and mortality in contemporary societies. Although progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy.

Comparison of nonuniform rotational distortion between mechanical IVUS and OCT using a phantom model.

Optical coherence tomography (OCT) is an optical analog of mechanical intravascular ultrasound (M-IVUS) with much higher spatial resolution. However, no data exist regarding the nonuniform rotational distortion (NURD) with OCT. The aim of the study was to investigate whether OCT generates less NURD relative to M-IVUS. A coronary artery phantom model was constructed with a rubber ring (3.68 mm in diameter), located at the distal end of the phantom. This model was also composed of eight equally spaced steel wires and an additional marker-wire. Two types of vascular phantoms were used, mild curve (90 degrees ) and acute curve (near 180 degrees ). Subsequent M-IVUS (n = 6) and OCT (n = 6) imaging was performed. Eight angles between eight wires, except the marker-wire, were measured from each image. These angles, measured with M-IVUS and OCT, were compared with those of high-resolution optical photography as a gold standard. The average in angle differences was significantly smaller in OCT compared with M-IVUS in the mild curve model (3.2 +/- 1.0 degrees vs, 6.9 +/- 2.1 degrees , p < 0.01). Compared with the latter model, the average in angle differences was exaggerated in the acute curve model with M-IVUS (9.1 +/- 0.9 degrees vs. 6.9 +/- 2.1 degrees , p < 0.05) but not with OCT (3.5 +/- 0.8 degrees vs. 3.2 +/- 1.0 degrees , p= not significant). OCT generates significantly less NURD compared with M-IVUS, especially in tortuous situation.

Magnetic resonance assessment of myocardial perfusion via catheter-based ventricle-coronary vein bypass in porcine myocardial infarction model.

OBJECTIVE: The goal of this study was to investigate the efficacy of VPASS with physiological measurements, magnetic resonance imaging (MRI), and histology in a porcine model of myocardial infarction. BACKGROUND: A catheter-based ventricle-to-coronary vein bypass (VPASS) has been proposed as a potential treatment strategy for refractory coronary artery disease patients. METHODS: In an acute setting, the VPASS implant was deployed percutaneously in three swine. The partial pressure of oxygen (PO(2)) in the anterior interventricular vein (AIV) and left ventricle (LV) were measured before and after VPASS implant with various combinations of balloon occlusion in the AIV and left anterior descending artery (LAD). In a separate chronic study, the VPASS procedure was completed on three swine with a mid-LAD occlusion. Thirty days post-VPASS procedure, angiography, contrast-enhanced MRI, and histology were performed to assess myocardial viability. Perfusion was analyzed using the average percent signal intensity change (APSIC) in the anterior walls (AW) and inferior walls (IW). RESULTS: The VPASS implant was performed without complication. Post-VPASS implantation, the distal AIV PO(2) increased up to the LV PO(2) level during simultaneous AIV and LAD blockage (432 +/- 24 mmHg). At day 30, quantitative perfusion analysis demonstrated no difference in APSIC between AW and IW (125 +/- 26% vs. 137 +/- 38%, P = 0.46). Delayed enhancement and histology showed focal subendomyocardial infarction. CONCLUSIONS: VPASS implant with simultaneous AIV and LAD occlusion allows perfusion of oxygenated blood to the distal AIV, which in the setting of an acute myocardial infarction model was capable of rescuing most of the myocardium at risk.

Tracking stem cells in the cardiovascular system.

Stem cells are a promising approach to cardiovascular therapeutics. Animal experiments have assessed the fate of injected stem cells through ex vivo methods on sacrificed animals. Approaches are needed for in vivo tracking of stem cells. Various imaging techniques and contrast agents for stem cell tracking will be reviewed.

In vivo volumetric analysis of coronary stent using optical coherence tomography with a novel balloon occlusion-flushing catheter: a comparison with intravascular ultrasound.

Optical coherence tomography (OCT) is limited as an intravascular imaging tool because of interference with blood. This study tested a new balloon occlusion-flushing catheter for OCT scanning of stented coronary arteries and compared stent measurements between OCT and intravascular ultrasound (IVUS). Motorized pullback with OCT and IVUS was examined in coronary stents deployed in swine. Quantitative measurements were obtained and compared between both groups. In addition, stent strut thickness was compared among OCT, IVUS and actual measurement. The occlusion catheter successfully provided motorized pullback OCT images in the stented coronary arteries without any complications. There were no differences in calculated lumen volume. However, stent volumes were significantly smaller with OCT than with IVUS (p < 0.05). OCT significantly underestimated the stent strut thickness compared with the actual measurement. Although OCT underestimates the stent strut thickness, motorized pullback OCT imaging with the occlusion catheter can provide appropriate in-stent images in the porcine coronary arteries.

Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade.

The purpose of this study is to evaluate the feasibility of percutaneous antegrade myocardial gene transfer (PAMGT). A consistent and safe technique for in vivo gene transfer is required for clinical application of myocardial gene therapy. PAMGT with concomitant coronary venous blockade was performed in 12 swine. The myocardium was preconditioned with 1 min of occlusion of the left anterior descending and left circumflex arteries. The anterior interventricular vein was occluded during left anterior descending artery delivery, and the great cardiac vein at the entrance of the middle cardiac vein was occluded during left circumflex artery delivery. With arterial and venous balloons inflated (3 min) and after adenosine (25 mug) injection, PAMGT was performed by antegrade injection of an adenoviral solution (1 ml of 10(11) plaque-forming units in each coronary artery) carrying beta-galactosidase or saline through the center lumen of the angioplasty balloon. In one set of animals, PAMGT was performed with selective coronary vein blockade (n = 9); in another set of animals, PAMGT was performed without coronary vein blockade (n = 5). At 1 wk after gene delivery, the animals were killed. Quantitative beta-galactosidase analysis was performed in the left and right ventricular walls. PAMGT was successfully performed in all animals with and without concomitant occlusion of the coronary veins. Quantitative beta-galactosidase analysis showed that PAMGT with coronary blockade was superior to PAMGT without coronary blockade. beta-Galactosidase activity increased significantly in the beta-galactosidase group compared with the saline group: 1.34 +/- 0.18 vs. 0.81 +/- 0.1 ng (P

Catheter-based ventricle-coronary vein bypass.

The goal of this study was to investigate the feasibility of a catheter-based ventricle-to-coronary vein bypass (VPASS) in order to achieve retrograde myocardial perfusion by a conduit (VSTENT) from the left ventricle (LV) to the anterior interventricular vein (AIV). Percutaneous coronary venous arterialization has been proposed as a potential treatment strategy for otherwise untreatable coronary artery disease. In an acute setting, the VSTENT implant was deployed percutaneously using the VPASS procedure in five swine. Coronary venous flow and pressure patterns were measured before and after VSTENT implant deployment with and without AIV and left anterior descending artery (LAD) occlusion. In a separate chronic pilot study, the VPASS procedure was completed on two animals that had a mid-LAD occlusion or LAD stenosis. At day 30 post-VPASS procedure, left ventriculography and magnetic resonance imaging (MRI) were performed to assess the patency and myocardial viability of the VSTENT implants. Pre-VSTENT implantation, the mid-AIV systolic wedge pressure was significantly lower than LV systolic pressure during AIV blockage (46 +/- 19 vs. 90 +/- 16 mm Hg; P < 0.01). The VSTENT implant deployment was performed without complication and achieved equalization of the AIV and LV systolic pressures and creation of retrograde flow in the distal AIV (maximal flow velocity: 37 +/- 7 cm/sec). At day 30 post-VPASS procedure, left ventriculography showed VSTENT implant patency. MRI perfusion images demonstrated myocardial viability even with an LAD occlusion. Coronary retrograde perfusion using the VPASS procedure is feasible and may represent a potential technique for end-stage myocardial ischemia.

Introduction of autopsy imaging redefines the concept of autopsy: 37 cases of clinical experience.

A new autopsy imaging (AI) system was introduced at the Research Center Hospital for Charged Particle Therapy (RCCPT) in January 2000. Autopsy imaging is a postmortem and preautopsy diagnostic procedure using magnetic resonance imaging (MRI). Scanning is performed with a 1.5 Tesla MRI system before autopsy. The AI results are reported to the pathologist and, in light of this information, autopsy is performed with minute precision. Autopsy imaging was performed on 37 cancer cases. In seven cases, AI was less informative than the autopsy, but in 30 cases, more precise reports on the final diagnosis were available with the combined application of autopsy and AI than autopsy alone, particularly in eight limited autopsy cases. Thus, AI provides critical and supplementary information for autopsy; furthermore, AI itself is a unique imaging system of great importance.