Inhibition of neointimal hyperplasia with a novel zotarolimus coated balloon catheter.

BACKGROUND: Non stent based delivery of antiproliferative agents using drug coated balloon catheters may offer additional flexibility and efficacy in a broad range of applications. The lipophilic antiproliferative drug zotarolimus makes it a potential candidate for balloon delivery. The aim of the present study was to evaluate the safety and efficacy of a prototype zotarolimus coated balloon (ZCB) catheter in comparison to a zotarolimus eluting stent (ZES) in the porcine coronary overstretch model. METHODS: Eighty-four stents (diameters 3.0 and 3.5 mm; length 15 mm) were implanted in LAD and Cx of 42 domestic pigs: control (TriMaxx, Abbott, polymer coated stent without drug, implanted with uncoated PCI catheter, n = 56); ZES (ZoMaxx, Abbott, stent coated with zotarolimus in polymer, implanted with uncoated PCI catheter, n = 14); ZCB (TriMaxx, Abbott, polymer coated stent without drug, implanted with zotarolimus coated PCI catheter, n = 14). Drug content of the vessel wall (n = 9) was measured about 10-30 min post intervention with ZCB in additional pigs. RESULTS: Immediately after ZCB treatment 101 ± 31 µg of zotarolimus was detected in the coronary arteries. After 28 days ZES led to a reduction of neointimal area from 4.32 ± 1.45 to 3.32 ± 1.11 mm2 (P = 0.019 vs. control). The effect of neointimal inhibition was more pronounced with the novel ZCB (2.79 ± 1.43 mm², P = 0.001 vs. control). Inflammation score was significantly reduced in vessels treated with the ZCB (0.75 ± 0.86 compared to control (1.45 ± 0.94, P = 0.013) and ZES (1.65 ± 0.90, P = 0.012). CONCLUSION: Zotarolimus coated balloons and stents were found to effectively reduce neointimal proliferation in the porcine coronary model. Inflammation scores were significantly reduced after treatment with the coated balloon. Zotarolimus balloon coating might be a novel option in preventing and treating restenosis.

A minimally invasive method for induction of myocardial infarction in an animal model using tungsten spirals.

Most animal models use surgical thoracotomy with ligation of a coronary artery to induce myocardial infarction. Incision of the chest wall and myocardium affect remodeling after myocardial infarction. The aim of our study was to evaluate a new minimally invasive technique for inducing acute myocardial infarction in pigs. To this end, coronary angiography using a 6-F cardiac catheter was performed in 20 pigs. The cardiac catheter was advanced into the left circumflex artery (LCX) under electrocardiographic monitoring and small tungsten spirals were deployed in the vessel. LCX occlusion was verified by coronary angiography. Two days later, magnetic resonance imaging (MRI) was performed to estimate the extent of infarction. Thereafter, all animals were euthanized and the hearts stained with 2,3,5-triphenyltetrazolium chloride for histologic measurement of infarct size. Tungsten spirals were successfully placed in the LCX in all 20 pigs. About 13 of the 20 animals survived until the end of the experiment. The mean infarct size in the area supplied by the LCX was 4.4 +/- 2.3 cm(3) at MRI and 4.3 +/- 2.2 cm(3) at histology (r = 0.99, P < 0.001). No other myocardial regions showed infarction in any of the 13 pigs. Five of nine pigs requiring defibrillation due to ventricular fibrillation died because defibrillation was unsuccessful. One animal each died from pericarditis and pneumonia. Our results show that the minimally invasive method presented here enables reliable induction of myocardial infarction in a fairly straightforward manner. The 25% mortality rate associated with induction of myocardial infarction in our study is comparable to that reported by other investigators.

Drug-eluting balloon: very short-term exposure and overlapping.

Paclitaxel balloon coating has shown promising effects in inhibiting restenosis in initial clinical trials. The aim of the present study was to evaluate the influence of two critical features of drug-eluting balloon (DEB) application - inflation time and increased dose due to overlapping balloons. Fifty-six stainless steel stents were implanted in the left anterior descending and circumflex coronary arteries of 28 domestic pigs using a 1.2:1.0 overstretch ratio. Stents were mounted on conventional uncoated and paclitaxel-coated angioplasty balloon catheters. The animals were randomized to five different treatments with a range of short (10 seconds [s] inflation using 1 DEB) to extended (2x60 s inflation using 2 DEB) intima contact time. After 28 days, quantitative angiography and histomorphometry of the stented arteries was performed on a total of 23 pigs. Paclitaxel balloon coating led to a marked reduction of parameters characterizing in-stent stenosis: Late lumen loss was 1.37 +/- 0.49 mm for uncoated balloons, 0.23 +/- 0.42 mm for one coated balloon 60 s inflation time, 0.37 +/- 0.28 mm for 10 s inflation time and 0.30 +/- 0.19 mm for the vessel segment treated by two coated balloons with 60 s inflation each. Neointimal areas were 4.26 +/- 1.18, 1.68 +/- 0.23, 1.83 +/- 0.40 and 1.67 +/- 0.46 mm(2), respectively (p = 0.001 versus control, p > 0.05 between paclitaxel-treated groups). Despite the marked reduction of neointimal proliferation, endothelialization of stent struts was present in all samples. DEB were found to effectively reduce neointimal proliferation regardless of inflation time and dose within the tested range. No adverse reactions were seen as dose was increased to more than three times the clinically tested dose.

Absolute quantification of regional renal blood flow in swine by dynamic contrast-enhanced magnetic resonance imaging using a blood pool contrast agent.

AIM: To evaluate for the first time in an animal model the possibility of absolute regional quantification of renal medullary and cortical perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using a blood pool contrast agent. MATERIAL AND METHODS: A total of 18 adult female pigs (age, 16-22 weeks; body weight, 45-65 kg; no dietary restrictions) were investigated by DCE-MRI. Absolute renal blood flow (RBF) measured by an ultrasound transit time flow probe around the renal vein was used as the standard of reference. An inflatable stainless cuff placed around the renal artery near its origin from the abdominal aorta was used to reduce RBF to 60%, 40%, and 20% of the baseline flow. The last measurement was performed with the cuff fully reopened. Absolute RBF values during these 4 perfusion states were compared with the results of DCE-MRI performed on a 1.5-T scanner with an 8-channel phased-array surface coil. All scans were acquired in breath-hold technique in the coronal plane using a field of view of 460 mm.Each dynamic scan commenced with a set of five 3D T1-weighted gradient echo sequences with different flip angles (alpha = 2 degrees, 5 degrees, 10 degrees, 20 degrees, 30 degrees): TE, 0.88 milliseconds; TR, 2.65 milliseconds; slice thickness, 8.8 mm for 4 slices; acquisition matrix, 128 x 128; and acquisitions, 4. These data served to calculate 3D intrinsic longitudinal relaxation rate maps (R10) and magnetization (M0). Immediately after these images, the dynamic 3D T1-weighted gradient echo images were acquired with the same parameters and a constant alpha = 30 degrees, half Fourier, 1 acquisition, 64 frames, a time interval of 1.65 seconds between each frame, and a total duration of 105.6. Three milliliters of an albumin-binding blood pool contrast agent (0.25 mmol/mL gadofosveset trisodium, Vasovist, Bayer Schering Pharma AG, Berlin, Germany) was injected at a rate of 3 mL/s. Perfusion was calculated using the arterial input function from the aorta, which was extracted from the dynamic relaxation rate change maps and perfusion images were calculated on a voxel-by-voxel basis using a singular value decomposition. RESULTS: In 11 pigs, 4 different perfusion states were investigated sequentially. The reduced kidney perfusion measured by ultrasound highly correlated with total renal blood flow determined by DCE-MRI, P < 0.001. The correlation coefficient between both measurements was 0.843. Regional cortical and medullary renal flow was also highly correlated (r = 0.77/0.78, P < 0.001) with the degree of flow reduction. Perfusion values smaller than 50 mL/min/100 cm were overestimated by MRI, high perfusion values slightly underestimated. CONCLUSION: DCE-MRI using a blood pool contrast agent allows absolute quantification of total kidney perfusion as well as separate determination of cortical and medullary flow. The results show that our technique has sufficient accuracy and reproducibility to be transferred to the clinical setting.

Magnetic resonance imaging of liver metastases: experimental comparison of anionic and conventional superparamagnetic iron oxide particles with a hepatobiliary contrast medium during dynamic and uptake phases.

OBJECTIVES: To assess the contrast-enhancing effects of citrate-coated superparamagnetic iron oxide particles (VSOP-C184) in a rat liver tumor model using dynamic and delayed magnetic resonance imaging in comparison to carboxydextran-coated particles (ferucarbotran) and a hepatobiliary contrast medium (gadobenate dimeglumine). MATERIALS AND METHODS: A total of 32 male rats with liver tumors (CC-531 colorectal carcinoma) were examined at 1.5 T with a T1-weighted dynamic series (3D gradient echo sequence) and T1-weighted and T2*-weighted images (2D gradient echo sequences) before and 15 and 90 minutes after injection. VSOP-C184 was investigated at doses of 0.015, 0.045, and 0.06 mmol Fe/kg, ferucarbotran at 0.015 mmol Fe/kg, and gadobenate dimeglumine at 0.025, 0.05, and 0.1 mmol Gd/kg. Liver-tumor contrast-to-noise ratio (CNR) was calculated and statistically compared. RESULTS: T1-weighted dynamic images: VSOP-C184 has significantly higher CNR values at a dose of 0,015 mmol Fe/kg than ferucarbotran at the same dose (P = 0.001). VSOP-C184 produces a significantly higher CNR at a dose of 0.045 mmol Fe/kg than gadobenate dimeglumine at a dose of 0.05 mmol Gd/kg (P = 0.019). At a dose of 0.06 mmol Fe/kg, the CNR for VSOP-C184 is significantly lower than that of gadobenate dimeglumine (0.1 mmol Gd/kg) (P = 0.005).T2-weighted delayed images: CNR values of VSOP-C184 are similar to those of ferucarbotran and are significantly higher than those of gadobenate dimeglumine (P < 0.05). CONCLUSIONS: On T1-weighted magnetic resonance imaging of liver tumors VSOP-C184 produces a high contrast comparable to that of a hepatobiliary contrast medium in addition to its contrast-enhancing effect in T2-weighted imaging.

Whole-heart coronary magnetic resonance angiography: contrast-enhanced high-resolution, time-resolved 3D imaging.

OBJECTIVES: To test the feasibility and performance of a 4D magnetic resonance coronary angiography sequence compared with conventional inversion recovery (IR) prepared gradient echo imaging. MATERIALS AND METHODS: A 4D sequence with 100 milliseconds temporal resolution was implemented on a 1.5 T system. Five minipigs were examined after administration of very small superparamagnetic iron oxide particles. Coronary angiographies with an isotropic resolution of 0.82 mm were performed in the pigs using 4D and IR sequences. RESULTS: The 4D sequence allowed visualization of the coronary arteries, the effect of their movement and that of the entire heart without prolonging scan time. The contrast-to-noise ratio of the IR images was on average 38% higher than that of the corresponding 4D phase. CONCLUSIONS: 4D magnetic resonance imaging is superior in that no trigger delay time needs to be determined and an additional whole-heart cine study can be obtained.

3D and 2D delayed-enhancement magnetic resonance imaging for detection of myocardial infarction: preclinical and clinical results.

RATIONALE AND OBJECTIVES: The purpose was to verify whether myocardial viability can be detected by a delayed enhancement magnetic resonance imaging (MRI) approach using a rapid three-dimensional inversion-recovery fast low-angle shot (3D IR-FLASH) sequence in a preclinical and clinical setting. MATERIALS AND METHODS: Nonreperfused myocardial infarctions were induced in eight minipigs. Both the pigs and 15 patients with suspected myocardial infarction underwent MRI using a rapid 3D IR-FLASH sequence and a two-dimensional IR-FLASH sequence as the reference standard. RESULTS: In the pigs, a total of 52 segments with myocardial infarction were identified with both sequences and there was good agreement in transmurality of 99.5%. The infarction volume determined with the 3D IR-FLASH in the animal study (2.4 +/- 1.5 cm(3)) showed a good correlation with the histomorphometrically determined volume using triphenyltetrazolium chloride (2.3 +/- 1.2 cm(3), r = 0.98, P < .001) and the two-dimensional IR-FLASH sequence (2.3 +/- 1.4 cm(3), r = 0.99, P < .001). Eleven of 15 patients were found to have myocardial infarction in 37 myocardial segments with both sequences and there was a good agreement in transmurality of 98.8%. There was also a good correlation in the clinical study between the 3D and 2D sequences (6.9 +/- 6.7 cm(3) vs. 6.8 +/- 6.5 cm(3), r = 0.98, P < .001). In Bland-Altman analysis there was no significant under- or overestimation of the myocardial infarction volume using the 3D IR-FLASH sequence in comparison to the two-dimensional reference standard in both the preclinical and clinical study. The contrast-to-noise ratios were not significantly different between 3D and 2D sequences in the animal (34.7 +/- 1.5 vs. 33.8 +/- 2.6; P = .51) and clinical study (31.4 +/- 12.5 vs. 36.7 +/- 11.5; P = .31). The breathhold time for the 3D IR-FLASH sequence in the clinical study (20.4 +/- 2.2 s) was significantly shorter than that of the 2D IR-FLASH sequence (190.1 +/- 20.8 s, P < .001). CONCLUSIONS: The rapid 3D IR-FLASH sequence detects myocardial infarction with high accuracy and allows a relevant reduction in acquisition time.

Improved evaluation of myocardial perfusion and viability with the magnetic resonance blood pool contrast agent p792 in a nonreperfused porcine infarction model.

OBJECTIVES: To investigate whether a magnetic resonance (MR) blood pool contrast agent enables both evaluation of myocardial perfusion and viability in nonreperfused infarction in pigs. MATERIALS AND METHODS: An optimized MR protocol using the blood pool contrast agent P792 (0.026 mmol/kg, twice the clinical dose, Guerbet, France) was investigated to evaluate nonreperfused myocardial infarction in an animal model. P792 was compared with the extracellular contrast agent Gd-DOTA (0.1 mmol/kg). The MRI findings were compared with histomorphometry performed with microspheres to evaluate perfusion and triphenyltetrazolium chloride (TTC) to evaluate viability. Contrast-enhanced MR imaging of the heart was performed on a 1.5-Tesla scanner 2 days after instrumentation in 6 minipigs. A saturation recovery steady-state free precession sequence was used for perfusion imaging and an inversion recovery fast low-angle shot sequence for evaluation of myocardial viability. RESULTS: P792 tended to depict areas of reduced perfusion more accurately than Gd-DOTA (17.2% +/- 11.1% versus 13.7% +/- 8.0%) in comparison to the gold standard of histomorphometry with microspheres (18.2% +/- 9.8%). Moreover, P792, but not Gd-DOTA, depicted ischemic areas for 30 minutes after intravenous injection. The change in myocardial signal intensity during first pass was not significantly different after P792 compared with Gd-DOTA (140.3% +/- 64.4% versus 123.3% +/- 22.5%, P = 0.56). P792 was highly accurate in depicting infarcted areas (11.1% +/- 7.1%) compared with Gd-DOTA (12.1% +/- 8.2%, r = 0.98, P < 0.001) and histomorphometry with TTC (12.2% +/- 8.0%, r = 0.99, P < 0.001). CONCLUSIONS: Unlike Gd-DOTA, the blood pool contrast agent P792 allows evaluation of myocardial perfusion for a period of 30 minutes and shows good agreement with histomorphometry. P792 must be examined in further studies to evaluate its potential in evaluating early myocardial lesions and reperfusion. In addition, P792 also allows for evaluation of myocardial viability.

Myocardial viability: assessment with three-dimensional MR imaging in pigs and patients.

PURPOSE: To prospectively evaluate the correlation between a three-dimensional (3D) delayed enhancement magnetic resonance (MR) imaging sequence and a two-dimensional (2D) delayed enhancement MR imaging sequence for noninvasive assessment of myocardial viability in pigs and patients. MATERIALS AND METHODS: The pig and patient studies were approved by the responsible authorities, and patients gave written informed consent. MR imaging was performed by using a rapid 3D inversion-recovery balanced steady-state free precession sequence and a 2D segmented inversion-recovery fast low-angle shot sequence as the reference standard. Fourteen pigs with reperfused (n=7) or nonreperfused (n=7) myocardial infarction and 17 patients (13 men, four women; mean age, 64.9 years+/-8.6 [standard deviation]) suspected of having myocardial infarction were included. Linear regression analysis and Bland-Altman analysis were used to compare the infarction volumes. RESULTS: In 10 of the 14 pigs the induction of myocardial infarction was successful. In these pigs, altogether 81 segments with myocardial infarction were demonstrated by both MR sequences, and agreement between the two sequences for classification of transmural extent of myocardial infarction was 99.7%. The infarction volume determined by using 3D MR imaging (4.64 cm3+/-2.48) in the pigs highly correlated with that of 2D MR imaging (4.65 cm3+/-2.39, r=0.989, P<.001) and that of staining by using triphenyltetrazolium chloride (4.67 cm3+/-2.44, r=0.996, P<.001). Thirteen of the 17 patients examined showed myocardial infarction in 34 myocardial segments with both sequences, and agreement between the two sequences for classification of transmural extent of myocardial infarction was 98.6%. In the patients, the infarction volume determined with both sequences highly correlated (9.71 cm3+/-7.47 for the 3D sequence vs 10.01 cm3+/-8.04 for the 2D sequence, r=0.982, P<.001). The breath-hold time necessary for the 3D MR imaging (21.0+/-2.3 seconds) was significantly shorter than that for 2D MR imaging (188.3+/-20.2 seconds, P<.001). CONCLUSION: Myocardial infarction volumes obtained with the 3D MR imaging sequence are highly correlated and in good agreement with volumes obtained with the 2D MR imaging standard approach and reduced the acquisition time by a factor of nine.

Magnetic resonance imaging of myocardial perfusion and viability using a blood pool contrast agent.

RATIONALE AND OBJECTIVES: A comprehensive cardiac magnetic resonance (MR) examination should comprise imaging of myocardial perfusion, viability, and the coronary arteries. Blood pool contrast agents (BPCAs) improve coronary MR angiography, whereas their potential for imaging of perfusion and viability is unknown. The abilities to noninvasively image myocardial perfusion and viability using the BPCA P792 (Guerbet, France) were tested in a closed-chest model of nonreperfused myocardial infarction in 5 pigs. MATERIALS AND METHODS: Two to 3 days after instrumentation, myocardial perfusion imaging with a saturation-recovery steady-state free precession technique and viability imaging with an inversion-recovery fast low-angle shot sequence were conducted on a 1.5-T MR scanner using the extracellular contrast agents (ECCA) Gd-DOTA (0.1 mmol Gd/kg) and blood pool contrast agent (BPCA) P792 (0.013 mmol Gd/kg). RESULTS: Perfusion defects were visualized in all pigs with good correlation between the ECCA and the BPCA (1.77 +/- 1.16 cm2 vs. 1.80 +/- 1.19 cm2, r = 0.959, P < 0.01). Reduced myocardial perfusion was detected using the ECCA up to 80 seconds after injection. In contrast, BPCA administration enabled visualization of perfusion defects on equilibrium perfusion imaging in all cases for 10 minutes. The size of myocardial infarction detected with viability MR imaging correlated well between the standard method (ECCA) and delayed-enhancement imaging with the BPCA (5.40 +/- 3.16 versus 5.52 +/- 3.13 cm3, r = 0.994, P < 0.002). CONCLUSIONS: The BPCA investigated in this study allows both reliable detection of perfusion defects on first pass and equilibrium perfusion imaging and characterization of viability after myocardial infarction. Thus, this contrast agent is suitable for a comprehensive cardiac MR examination.

Assessment of myocardial infarction in pigs using a rapid clearance blood pool contrast medium.

Delayed enhancement MRI using extracellular contrast media allows reliable detection of myocardial infarction. If blood pool contrast media like P792 (Vistarem, Guerbet, France), in addition to improving coronary MR angiography, can be shown to also produce delayed enhancement in myocardial infarction they could improve the prerequisites for a comprehensive cardiac MR examination. In this study reperfused myocardial infarction in five minipigs was imaged with an inversion-recovery fast low-angle shot sequence using P792 (0.013 mmol Gd/kg) and the extracellular contrast medium Gd-DOTA (Dotarem, 0.1 mmol Gd/kg, Guerbet). The infarction size determined on MRI using P792 (7.55 +/- 2.31 cm(2)) highly correlated both with histomorphometry (7.81 +/- 2.18 cm(2), r = 0.991, P < 0.002) and with MRI using Gd-DOTA (7.85 +/- 2.35 cm(2), r = 0.978, P < 0.005). Bland-Altman analysis showed that the limit of agreement of MRI using P792 compared to histomorphometry was 3.3 +/- 7.6% of the infarction size. The contrast-to-noise ratio between infarcted and remote myocardium was not significantly different between Gd-DOTA (5.9 +/- 2.4) and P792 (4.4 +/- 1.1, P = 0.5). The blood pool contrast medium P792 allows reliable assessment of viability with good contrast and accuracy.