Multiparametric PET and MRI of myocardial damage after myocardial infarction: correlation of integrin αvß3 expression and myocardial blood flow.

PURPOSE: Increased angiogenesis after myocardial infarction is considered an important favorable prognostic parameter. The αvß3 integrin is a key mediator of cell-cell and cell-matrix interactions and an important molecular target for imaging of neovasculature and repair processes after MI. Thus, imaging of αvß3 expression might provide a novel biomarker for assessment of myocardial angiogenesis as a prognostic marker of left ventricular remodeling after MI. Currently, there is limited data available regarding the association of myocardial blood flow and αvß3 integrin expression after myocardial infarction in humans. METHODS: Twelve patients were examined 31 ± 14 days after MI with PET/CT using [18F]Galacto-RGD and [13N]NH3 and with cardiac MRI including late enhancement on the same day. Normal myocardium (remote) and areas of infarction (lesion) were identified on the [18F]Galacto-RGD PET/CT images by correlation with [13N]NH3 PET and cardiac MRI. Lesion/liver-, lesion/blood-, and lesion/remote ratios were calculated. Blood flow and [18F]Galacto-RGD uptake were quantified and correlated for each myocardial segment (AHA 17-segment model). RESULTS: In 5 patients, increased [18F]Galacto-RGD uptake was notable within or adjacent to the infarction areas with a lesion/remote ratio of 46% (26-83%; lesion/blood 1.15 ± 0.06; lesion/liver 0.61 ± 0.18). [18F]Galacto-RGD uptake correlated significantly with infarct size (R = 0.73; p = 0.016). Moreover, it correlated significantly with restricted blood flow for all myocardial segments (R = - 0.39; p < 0.0001) and even stronger in severely hypoperfused areas (R = - 0.75; p < 0.0001). CONCLUSION: [18F]Galacto-RGD PET/CT allows the visualization and quantification of myocardial αvß3 expression as a key player in angiogenesis in a subset of patients after MI. αvß3 expression was more pronounced in patients with larger infarcts and was generally more intense but not restricted to areas with more impaired blood flow, proving that tracer uptake was largely independent of unspecific perfusion effects. Based on these promising results, larger prospective studies are warranted to evaluate the potential of αvß3 imaging for assessment of myocardial angiogenesis and prediction of ventricular remodeling.

The role of 1.5 tesla MRI and anesthetic regimen concerning cardiac analysis in mice with cardiomyopathy.

Accurate assessment of left ventricular function in rodent models is essential for the evaluation of new therapeutic approaches for cardiac diseases. In our study, we provide new insights regarding the role of a 1.5 Tesla (T) magnetic resonance imaging (MRI) device and different anesthetic regimens on data validity. As dedicated small animal MRI and echocardiographic devices are not broadly available, we evaluated whether monitoring cardiac function in small rodents with a clinical 1.5 T MRI device is feasible. On a clinical electrocardiogram (ECG) synchronized 1.5 T MRI scanner we therefore studied cardiac function parameters of mice with chronic virus-induced cardiomyopathy. Thus, reduced left ventricular ejection fraction (LVEF) could be verified compared to healthy controls. However, our results showed a high variability. First, anesthesia with medetomidine, midazolam and fentanyl (MMF) led to depressed cardiac function parameters and more variability than isoflurane gas inhalation anesthesia, especially at high concentrations. Furthermore, calculation of an average ejection fraction value from sequenced scans significantly reduced the variance of the results. To sum up, we introduce the clinical 1.5 T MRI device as a new tool for effective analysis of left ventricular function in mice with cardiomyopathy. Besides, we suggest isoflurane gas inhalation anesthesia at high concentrations for variance reduction and recommend calculation of an average ejection fraction value from multiple sequenced MRI scans to provide valid data and a solid basis for further clinical testing.

MRI of coronary wall remodeling in a swine model of coronary injury using an elastin-binding contrast agent.

BACKGROUND: The extracellular matrix (ECM) plays an important role in the pathogenesis of atherosclerosis and in-stent restenosis. Elastin is an essential component of the ECM. ECM degradation can lead to plaque destabilization, whereas enhanced synthesis typically leads to vessel wall remodeling resulting in arterial stenosis or in-stent restenosis after stent implantation. The objective of this study was to demonstrate the feasibility of MRI of vascular remodeling using a novel elastin-binding contrast agent (BMS-753951). METHODS AND RESULTS: Coronary injury was induced in 6 pigs by endothelial denudation and stent placement. At day 28, delayed-enhancement MRI coronary vessel wall imaging was performed before and after injection of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA). Two days later, DE-MRI was repeated after administration of BMS-753951. Contrast-to-noise-ratio and areas of enhancement were determined. Delayed-enhancement MRI with BMS-753951 caused strong enhancement of the aortic, pulmonary artery, and injured coronary artery walls, whereas Gd-DTPA did not. Delayed-enhancement MRI of the stented coronary artery with BMS-753951 yielded a 3-fold higher contrast-to-noise-ratio when compared with the balloon-injured and control coronary artery (21±6 versus 7±3 versus 6±4; P<0.001). The area of enhancement correlated well with the area of remodeling obtained from histological data (R(2)=0.86, P<0.05). CONCLUSIONS: We demonstrate the noninvasive detection and quantification of vascular remodeling in an animal model of coronary vessel wall injury using an elastin-specific MR contrast agent. This novel approach may be useful for the assessment of coronary vessel wall remodeling in patients with suspected coronary artery disease. Further studies in atherosclerotic animal models and degenerative ECM disease are now warranted.

Magnetic resonance imaging of myocardial injury and ventricular torsion after marathon running.

Recent reports provide indirect evidence of myocardial injury and ventricular dysfunction after prolonged exercise. However, existing data is conflicting and lacks direct verification of functional myocardial alterations by CMR [cardiac MR (magnetic resonance)]. The present study sought to examine structural myocardial damage and modification of LV (left ventricular) wall motion by CMR imaging directly after a marathon. Analysis of cTnT (cardiac troponin T) and NT-proBNP (N-terminal pro-brain natriuretic peptide) serum levels, echocardiography [pulsed-wave and TD (tissue Doppler)] and CMR were performed before and after amateur marathon races in 28 healthy males aged 41 ± 5 years. CMR included LGE (late gadolinium enhancement) and myocardial tagging to assess myocardial injury and ventricular motion patterns. Echocardiography indicated alterations of diastolic filling [decrease in E/A (early transmitral diastolic filling velocity/late transmitral diastolic filling velocity) ratio and E' (tissue Doppler early transmitral diastolic filling velocity)] postmarathon. All participants had a significant increase in NT-proBNP and/or cTnT levels. However, we found no evidence of LV LGE. MR tagging demonstrated unaltered radial shortening, circumferential and longitudinal strain. Myocardial rotation analysis, however, revealed an increase of maximal torsion by 18.3% (13.1 ± 3.8 to 15.5 ± 3.6 °; P=0.002) and maximal torsion velocity by 35% (6.8 ± 1.6 to 9.2 ± 2.5 °·s-1; P<0.001). Apical rotation velocity during diastolic filling was increased by 1.23 ± 0.33 °·s-1 after marathon (P<0.001) in a multivariate analysis adjusted for heart rate, whereas peak untwist rate showed no relevant changes. Although marathon running leads to a transient increase of cardiac biomarkers, no detectable myocardial necrosis was observed as evidenced by LGE MRI (MR imaging). Endurance exercise induces an augmented systolic wringing motion of the myocardium and increased diastolic filling velocities. The stress of marathon running seems to be better described as a burden of myocardial overstimulation rather than cardiac injury.

Local erythropoietin and endothelial progenitor cells improve regional cardiac function in acute myocardial infarction.

BACKGROUND: Expanded endothelial progenitor cells (eEPC) improve global left ventricular function in experimental myocardial infarction (MI). Erythropoietin beta (EPO) applied together with eEPC may improve regional myocardial function even further by anti-apoptotic and cardioprotective effects. Aim of this study was to evaluate intramyocardial application of eEPCs and EPO as compared to eEPCs or EPO alone in experimental MI. METHODS AND RESULTS: In vitro experiments revealed that EPO dosed-dependently decreased eEPC and leukocyte apoptosis. Moreover, in the presence of EPO mRNA expression in eEPC of proangiogenic and proinflammatory mediators measured by TaqMan PCR was enhanced. Experimental MI was induced by ligation and reperfusion of the left anterior descending coronary artery of nude rats (n = 8-9). After myocardial transplantation of eEPC and EPO CD68+ leukocyte count and vessel density were enhanced in the border zone of the infarct area. Moreover, apoptosis of transplanted CD31 + TUNEL + eEPC was decreased as compared to transplantation of eEPCs alone. Regional wall motion of the left ventricle was measured using Magnetic Resonance Imaging. After injection of eEPC in the presence of EPO regional wall motion significantly improved as compared to injection of eEPCs or EPO alone. CONCLUSION: Intramyocardial transplantation of eEPC in the presence of EPO during experimental MI improves regional wall motion. This was associated with an increased local inflammation, vasculogenesis and survival of the transplanted cells. Local application of EPO in addition to cell therapy may prove beneficial in myocardial remodeling.

Exercise hemodynamics of bovine versus porcine bioprostheses: a prospective randomized comparison of the mosaic and perimount aortic valves.

OBJECTIVE: This prospective randomized study compares a porcine with a bovine bioprosthesis in the aortic position with regard to hemodynamic performance during exercise. METHODS: Between August of 2000 and December of 2002, 136 patients underwent aortic valve replacement with the porcine Medtronic Mosaic (n = 66) or the bovine Carpentier-Edwards Perimount (n = 70) bioprosthesis. Transthoracic echocardiography was performed to assess hemodynamic and dimensional data preoperatively and 10 months postoperatively; the latter follow-up included stress echocardiography with treadmill exercise. RESULTS: At rest and during exercise (25 and 50 W), there was a significant difference in mean pressure gradient between the bovine and the porcine valves with labeled sizes 21 and 23, with superiority of the Perimount prosthesis. There was no difference in effective orifice area and incidence of patient-prosthesis mismatch among all sizes. The left ventricular mass index decreased significantly within 10 months postoperatively in the size 23 bovine group and the size 25 porcine group. CONCLUSIONS: Our data show a significant superiority of pressure gradients for the bovine bioprosthesis, especially with small valve sizes, when compared with the porcine device, which is more distinctive during exercise.

The effective orifice area/patient aortic annulus area ratio: a better way to compare different bioprostheses? A prospective randomized comparison of the Mosaic and Perimount bioprostheses in the aortic position.

BACKGROUND AND AIM OF THE STUDY: The aim of this prospective, randomized study was to compare the hemodynamic performance of the Medtronic Mosaic and Edwards Perimount bioprostheses in the aortic position, and to evaluate prosthesis-specific differences in valve sizing and valve-size labeling. METHODS: Between August 2000 and September 2002, 139 patients underwent isolated aortic valve replacement (AVR) with the Mosaic (n = 67) or Perimount (n = 72) bioprosthesis. Intraoperatively, the internal aortic annulus diameter was measured by insertion of a gauge (Hegar dilator), while prosthesis size was determined by using the original sizers. Transthoracic echocardiography was performed to determine hemodynamic and dimensional data. As the aim of AVR is to achieve a maximal effective orifice area (EOA) within a given aortic annulus, the ratio of EOA to patient aortic annulus area was calculated, the latter being based on annulus diameter measured intraoperatively. RESULTS: Operative mortality was 2.2% (Mosaic 3.0%; Perimount 1.4%; p = NS). Upsizing (using a prosthesis larger in labeled valve size than the patient's measured internal aortic annulus diameter) was possible in 28.4% of Mosaic patients and 8.3% of Perimount patients. The postoperative mean systolic pressure gradient ranged from 10.5 to 22.2 mmHg in the Mosaic group, and from 9.4 to 12.6 mmHg in the Perimount group; it was significantly lower for 21 and 23 Perimount valves than for 21 and 23 Mosaic valves. The EOA ranged from 0.78 to 2.37 cm2 in Mosaic patients, and from 0.95 to 2.12 cm2 in Perimount patients. When indexing EOA by calculating the ratio of EOA to patient aortic annulus area to adjust for variables such as patient anatomy and valve dimensions, there was no significant difference between the two bioprostheses. CONCLUSION: Comparisons of absolute EOA values grouped by the manufacturers' valve sizes are misleading because of specific differences in geometric dimensions. The EOA:patient aortic annulus area ratio provides a new hemodynamic index which may facilitate objective comparisons between different valve types.