CMR reveals myocardial damage from cardiotoxic oncologic therapies in breast cancer patients.

BACKGROUND: Breast cancer is a common and increasingly treatable disease. However, survivors have a significantly elevated risk of cardiac events afterwards. This study aimed to characterise cardiac changes during cardiotoxic cancer therapy using cardiovascular magnetic resonance (CMR) imaging. METHODS: This study involved 34 patients with histologically proven breast cancer and planned cardiotoxic therapy. All patients underwent CMR before starting therapy, and 6 and 12 months thereafter. The CMR protocol included volumetric and functional analyses, parametric mapping, and deformation analysis using feature tracking. As the control group, 10 healthy female volunteers were scanned using the same protocol. RESULTS: With therapy, there was a significant reduction of left ventricular and right ventricular ejection fractions (both p < 0.05) without reaching pathologic values. Left ventricular radial (p = 0.008), circumferential (p = 0.010), and longitudinal strain (p = 0.036) were also reduced at follow-up. In the parametric mapping, there was a significant increase in native T1 time (start: 1037 ± 41 ms vs. 6 months: 1068 ± 51 ms vs. 12 months: 1017 ± 57 ms, p < 0.001) and T2 time (start: 55 ± 4 ms vs. 6 months: 59 ± 3 ms vs. 12 months: 57 ± 3 ms, p = 0.001), with unchanged extracellular volume and relative late gadolinium enhancement. Twelve months after cancer diagnosis, the breast cancer patients exhibited significant impairments in left ventricular global radial (p = 0.001), circumferential (p = 0.001), and longitudinal strain (p = 0.002) and T2 time (p = 0.008) compared to the healthy controls. DISCUSSION: Breast cancer patients receiving cardiotoxic chemotherapy show persistent deterioration in left ventricular strain values. This is accompanied by inflammatory changes in non-invasive tissue characterisation. Larger studies with longer follow-up periods are needed to identify patients at risk and establish preventive and therapeutic approaches.

Longitudinal strain assessed by cardiac magnetic resonance correlates to hemodynamic findings in patients with severe aortic stenosis and predicts positive remodeling after transcatheter aortic valve replacement.

AIMS: To assess left-ventricular strain parameters before and after transcatheter aortic valve replacement (TAVR) by feature tracking cardiac magnetic resonance imaging (FT CMR) and to correlate the findings to hemodynamic state and left-ventricular remodeling. METHODS AND RESULTS: Patients with symptomatic AS underwent FT CMR before and after TAVR. Patients were carefully evaluated by a comprehensive work-up including CMR, echocardiography and left and right heart catheterization. Thirty patients formed the study population. High-flow/high-gradient (HF/HG) aortic stenosis was diagnosed in 11 patients (36.7%), 6 patients (20.0%) exhibited low-flow/low-gradient AS (LF/LG) and 13 patients (43.3%) were classified to have so-called paradoxical low-flow/low-gradient (PLF/LG) AS. The HF/HG patients had a significantly reduced longitudinal strain which recovered after TAVR (-12.67 ± 4.60 to -15.46 ± 5.61%, p = 0.048). In the LF/LG group, an even more pronounced reduction of longitudinal strain and also an impairment of longitudinal velocity could be observed. Both parameters improved after therapy (strain: -5.06 ± 4.25 to -8.02 ± 3.28%, p = 0.045; velocity: 25.33 ± 9.63 to 37.13 ± 11.64 mm/s, p = 0.042). Patients with PLF/LG showed preserved longitudinal strain but a reduction of longitudinal velocity similar to the LF/LG group. These patients did not show a significant improvement of strain parameters after TAVR. Longitudinal velocity exhibited the highest predictive power for the identification of a low-flow state (sensitivity 75%, specificity 80%). CONCLUSION: Improvement of longitudinal strain parameters after TAVR is dependent on the initial hemodynamically defined AS subgroup.

Myocardial strain characteristics and outcomes after transcatheter aortic valve replacement.

BACKGROUND: Objective of this study was to make an assessment of standard functional and defor-mation parameters (strain) in patients after transcatheter aortic valve replacement (TAVR) by cardiac magnetic resonance imaging (CMR) and the evaluation of their prognostic impact. METHODS: Patients undergoing TAVR received CMR on a 1.5 T whole-body scanner at 3 months after the procedure. Deformation parameters (strain, strain rate, velocity, displacement) were assessed in lon-gitudinal, circumferential and radial orientation using a feature tracking approach. Primary outcome measure was defined according to Valve Academic Research Consortium-2 (VARC-2) criteria. RESULTS: Eighty-three patients formed the study population. Deformation parameters were significantly reduced in all three orientations for strain (longitudinal: -12.1 ± 5.4% vs. -15.9 ± 1.96%, p < 0.0001; radial: 34.4 ± 15.3% vs. 47.2 ± 11.4%, p < 0.0001; circumferential: -16.8 ± 4.3% vs. -21.1 ± 2.5%, p < 0.0001) and strain rate (longitudinal: -0.79 ± 0.33%/s vs. -0.91 ± 0.23%/s, p = 0.043; radial: 2.5 ± 1.2%/s vs. 2.9 ± 0.9%, p = 0.067; circumferential: -1.1 ± 0.6%/s vs. -1.3 ± 0.3%/s, p = 0.006) in comparison to a healthy control population. Median follow-up was 614 days. During this period, 13 endpoints occurred (cumulative event rate of 10.7%). Patients with event by trend exhibited poorer strain and strain rate in longitudinal and radial orientation without reaching statistical significance (longitudinal strain: -11.2 ± 5.4% vs. -12.3 ± 5.4%, p = 0.52; longitudinal strain rate: -0.73 ± ± 0.23%/s vs. 0.80 ± 0.35%/s, p = 0.53; radial strain: 29.5 ± 19.6% vs. 35.2 ± 14.5%, p = 0.24; radial strain rate: 2.2 ± 1.6%/s vs. 2.6 ± 1.2%/s, p = 0.31). CONCLUSIONS: Assessment of left ventricular deformation parameters by CMR revealed functional abnormalities in comparison to healthy controls. Prognostic significance remains to be further investi-gated.

On the influence of respiratory motion in radial tissue phase mapping cardiac MRI.

PURPOSE: To investigate the impact of respiratory motion on radial tissue phase mapping (TPM) measurements, and to improve image quality and scan efficiency without compromising velocity fidelity by increasing the respiratory acceptance window with and without motion correction. MATERIALS AND METHODS: A radial golden angle TPM sequence was measured in 10 healthy volunteers in three short axis slices at 3T. Ungated ( CFREE), self-gated with a single acceptance window ( CREF), motion-corrected averaging using all ( CMCall), or selected ( CMC) data reconstructions were compared by means of various image quality measures and resulting velocities. RESULTS: Using all data ( CFREE) resulted in significantly higher perceived signal-to-noise ratio (SNR) (P < 0.001), but significantly reduced sharpness (P < 0.001) and contrast (P = 0.02), when compared to CREF. Coefficient of variation (CV) and perceived sharpness were not significantly different (P > 0.05). With motion-correction, perceived sharpness could be significantly improved ( CMC: P = 0.002; CMCall: P = 0.002) in comparison to CFREE. Velocity peaks of CFREE were significantly reduced compared to CREF (all peaks: P < 0.001; except the longitudinal "E" peak: P = 0.03). The peak velocities in CMC and CMCall were not significantly different from CREF (all peaks: P > 0.08; except longitudinal "E"/"A" peaks: P > 0.01). CONCLUSION: Free-breathing reconstruction results in good perceived image sharpness and velocity information with slightly, but significantly, reduced peak velocities. For achieving velocities and image quality comparable to data from a single acceptance window, but higher gating efficiency, selected motion-corrected TPM (CMC) can be applied. J. Magn. Reson. Imaging 2016;44:1218-1228.

Non-contrast-enhanced magnetic resonance angiography is equal to contrast-enhanced multislice computed tomography for correct aortic sizing before transcatheter aortic valve implantation.

BACKGROUND: Correct sizing of the aortic annulus in aortic valve stenosis is crucial for successful transcatheter aortic valve implantation (TAVI). Multislice computed tomography (MSCT) seems to be most promising imaging modality for this pre-interventional diagnostic work-up, but has the disadvantage of exposing mostly co-morbid patients to iodine and nephrotoxic contrast agents. To establish a useful sizing method for TAVI without the use of contrast media, we compared measurements of a non-contrast magnetic resonance imaging (MRI) technique with MSCT serving as the reference standard. METHODS: Fifty-two patients who underwent TAVI were previously examined with MSCT and MRI, respectively. MRI examination included a 3D steady-state free-precession sequence covering the entire ascending aorta. Perimeter and area of the aortic root were analyzed by two blinded readers in consensus using a dedicated software. Decisions for Sapien 3 valve size of both imaging modalities were compared using the mean derived annulus diameter. RESULTS: Mean age of the study cohort was 82.2 ± 4.9 years, log EuroScore was 25.2 ± 4.8 %. Mean aortic annulus perimeter as measured by MSCT was 76.7 ± 6.9 mm. MRI yielded a mean perimeter of 76.5 ± 6.7 mm with a good correlation coefficient (r = 0.93, p < 0.0001). Decision for valve size showed good correlation between both imaging modalities (r = 0.94, p < 0.0001). CONCLUSION: In conclusion, non-contrast MRI shows good correlation to MSCT in the assessment of the aortic annulus and valve sizing. This non-contrast technique might be a reasonable alternative for aortic root sizing before TAVI without the use of nephrotoxic contrast agents, especially in patients with severely reduced kidney function.

Improvement of regional and global left ventricular function in magnetic resonance imaging after recanalization of true coronary chronic total occlusions.

BACKGROUND: Successful recanalization of true chronic total occlusion (CTO) has been linked to a decrease in cardiac mortality. We evaluated the effect of CTO recanalization on LVEF and regional wall motion using paired cardiac magnetic resonance imaging (cMRI) studies. METHODS AND RESULTS: 43 patients underwent contrast enhanced cMRI prior to and 9 months after successful recanalization of a true CTO defined as thrombolysis in myocardial infarction flow 0 and duration of occlusion of more than 3 months. Regional wall motion was analyzed using the AHA model. For each segment the wall thickness (WT) was measured over the duration of one heart cycle and segmental wall thickening (SWT) was calculated. Left ventricular ejection fraction (LVEF) and volumes were measured. LVEF significantly increased by 2.4 ± 6.0% (p = 0.01). The increase was confined to patients with baseline LVEF below the median of 49.3% (4.1 ± 7.0%, p = 0.01) compared to 0.6 ± 4.0 (p = 0.48) in patients with baseline LVEF higher than the median. Segmental wall motion analysis was performed in 706 myocardial segments. SWT significantly increased in segments within the perfusion territory of the CTO vessel (5.1 ± 30.4%, p = 0.01), especially in dysfunctional segments at baseline with SWT(init) <45% (13.3 ± 24.3%, p < 0.001). In addition, SWT significantly increased in segments of non-CTO vessels (4.1 ± 32.1%, p < 0.01). CONCLUSIONS: In conclusion, in patients with successful recanalization of CTO left ventricular ejection fraction and regional wall motion are significantly improved, especially in patients with decreased LVEF and in dysfunctional segments.

Impact of cell number and microvascular obstruction in patients with bone-marrow derived cell therapy: final results from the randomized, double-blind, placebo controlled intracoronary Stem Cell therapy in patients with Acute Myocardial Infarction (SCAMI) trial.

BACKGROUND: In patients with acute myocardial infarction (AMI), the number of transplanted autologous bone-marrow cells (BMC) has been linked to improvement in left ventricular ejection fraction (LVEF). Complete obstruction of myocardial microvasculature is indicated by microvascular obstruction (MO) in cardiac magnetic resonance imaging (CMR). We analyzed whether the number of transplanted cells and presence of MO were associated with improved LVEF in the double-blind, placebo-controlled, randomized intracoronary Stem Cell therapy in patients with Acute Myocardial Infarction (SCAMI) trial. METHODS AND RESULTS: Patients (N = 42) received study therapy mean 7 days after AMI. Median number of transplanted BMC was 324 × 10(6). CMR was performed prior to study therapy and annually up to 3 years and revealed no difference between BMC and placebo population. Patients treated with a cell number above the median experienced a significant improvement in LVEF compared with patients with cell number below the median 3.6 ± 3.4 versus -0.5 ± 6.4 % (difference 4.1, 95 % CI 0.2 to 8.1 %, p = 0.04) at 6 months. The difference in LVEF change between the groups remained with 3.8 % (p = 0.12) at 12 months, 4.5 % (p = 0.07) at 24 months and 5.6 % (p = 0.03) at 36 months. BMC treated patients without MO experienced a better improvement in LVEF compared with patients with MO at 6, 12, 24 and 36 months with 3.5, 5.3, 6.4 and 3.2 %. CONCLUSIONS: In the randomized, placebo-controlled double-blind SCAMI trial improvement in LVEF up to 3 years was higher in BMC patients treated with a high cell number or without MO.

Myocardial perfusion reserve assessed by T2-prepared steady-state free precession blood oxygen level-dependent magnetic resonance imaging in comparison to fractional flow reserve.

BACKGROUND: Blood oxygen level-dependent (BOLD) cardiac magnetic resonance imaging (CMR) has been shown to be able to detect myocardial perfusion differences. However, validation of BOLD CMR against fractional flow reserve (FFR) is lacking. The aim of our study was to analyze the potential diagnostic accuracy of BOLD CMR in comparison to invasively measured FFR, which served as gold standard for a hemodynamic significant coronary lesion. METHODS AND RESULTS: BOLD image was performed at rest and during adenosine infusion in a 1.5-T CMR scanner. Thirty-six patients were analyzed for relative BOLD signal intensity increase according to the 16-segment model. Invasive FFR measurements were performed in the 3 major coronary arteries during adenosine infusion in all patients. An FFR≤0.8 was regarded to indicate a significant coronary lesion. Relative BOLD signal intensity increase was significantly lower in myocardial segments supplied by coronary arteries with an FFR≤0.8 compared with segments with an FFR>0.8 (1.1±0.2 versus 1.5±0.2; P<0.0001). Sensitivity and specificity yielded 88.2% and 89.5%, respectively. CONCLUSIONS: CMR BOLD imaging reliably detects hemodynamic significant coronary artery disease and is, thus, an alternative to contrast-enhanced perfusion studies.

C-peptide promotes lesion development in a mouse model of arteriosclerosis.

Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C-peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C-peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C-peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide-treated mice contained significantly more macrophages (1.6 ± 0.3% versus 0.7 ± 0.2% positive area; P < 0.01) and more vascular smooth muscle cells (4.8 ± 0.6% versus 2.4 ± 0.3% positive area; P < 0.01). Finally, lipid deposition measured by Oil-red-O staining in the aortic arch was significantly higher in the C-peptide group compared with controls. Our results demonstrate that elevated C-peptide levels promote inflammatory cell infiltration and lesion development in ApoE-deficient mice without having metabolic effects. These data obtained in a mouse model of arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance.

Direct inhibitory effects of Ganciclovir on ICAM-1 expression and proliferation in human coronary vascular cells (SI/MPL-ratio: >1).

BACKGROUND: Treatment of the human cytomegalovirus (HCMV) infection with ganciclovir has beneficial indirect effects on the complex interactions of HCMV with restenosis, atherosclerosis, and transplant vascular sclerosis. The current study reports on direct effects of ganciclovir on expression of ICAM-1 and cell proliferation, key events of coronary atherosclerosis/restenosis. A potential clinical relevance of the data will be evaluated with the help of SI/MPL-ratio's. MATERIAL/METHODS: Definition of the SI/MPL-ratio: relation between significant inhibitory effects in vitro/ex vivo and the maximal plasma level after systemic administration in vivo (ganciclovir: 9 µg/ml). Part I of the study investigated in cytoflow studies the effect of ganciclovir (0.05-5000 µg/mL) on TNF-a induced expression of intercellular adhesion molecule 1 (ICAM-1) in endothelial cells derived from umbilical veins (HUVEC), human coronary endothelial cells (HCAEC), and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of ganciclovir (0.05-5000 µg/mL) on cell proliferation (HUVEC, HCAEC, and HCMSMC). In part III cytotoxic effects of ganciclovir (0.05-5000 µg/mL) were studied (HUVEC, HCAEC, and HCMSMC). RESULTS: Ganciclovir caused slight but significant inhibitory effects on expression of ICAM-1 in HUVEC, HCAEC, and HCMSMC. In all three cell types studied strong dose depending significant antiproliferative effects of ganciclovir were detected. Partially, the antiproliferative effects of ganciclovir were caused by cytotoxic effects. CONCLUSIONS: SI/MPL-ratio's >1 in HCAEC and HCMSMC indicate that the inhibitory effects of gancliclovir on ICAM-1-expression and cell proliferation may only be expected in vivo following local high dose administration e.g. in drug eluting stents (DES).

Myocardial scar extent evaluated by cardiac magnetic resonance imaging in ICD patients: relationship to spontaneous VT during long-term follow-up.

Patients with ischemic cardiomyopathy have an increased risk for ventricular arrhythmia, since myocardial infarction can be the substrate for re-entrant arrhythmias. Contrast-enhanced cardiac magnetic resonance imaging (CMR) has proven to reliably quantify myocardial infarction. Aim of our study was to evaluate correlations between functional and contrast-enhanced CMR findings and spontaneous ventricular tachy-arrhythmias in patients with ischemic cardiomyopathy who underwent implantable cardioverter-defibrillator (ICD) therapy. Forty-one patients with ischemic cardiomyopathy and indication for ICD therapy underwent cine and late gadolinium enhancement CMR for quantification of left ventricular volumes, function and scar tissue before subsequent implantation of ICD device. During a follow-up period of 1184 ± 442 days 68 monomorphic and 14 polymorphic types of ventricular tachycardia (VT) could be observed in 12 patients. Patients with monomorphic VT had larger scar volumes (25.3 ± 11.3 vs. 11.8 ± 7.5% of myocardial mass, P < 0.05) than patients with polymorphic VT. Moreover myocardial infarction involved more segments in the LAD perfusion territory (86 vs. 20%, P < 0.05) than in patients with polymorphic VT. Patients with spontaneous monomorphic VT during the long-term follow-up period had more infarcted tissue, which was more often present in the LAD perfusion territory than patients with polymorphic events. These data strengthen the diagnostic benefit of CMR in patients with ischemic cardiomyopathy. CMR may be used for better risk stratification in patients with ischemic cardiomyopathy undergoing ICD therapy.

Blood oxygen level-dependent magnetic resonance imaging using T2-prepared steady-state free-precession imaging in comparison to contrast-enhanced myocardial perfusion imaging.

BACKGROUND: Diagnosis of inducible myocardial ischemia is important for deciding further diagnosis and therapy in coronary artery disease (CAD). Blood oxygen level-dependent (BOLD) cardiac magnetic resonance imaging (CMR) is a potential method to evaluate myocardial perfusion reserve alternatively to first-pass perfusion using contrast agents. METHODS AND RESULTS: We imaged 46 patients with suspected CAD on a 1.5 T whole-body CMR scanner using a T2-prepared steady-state free-precession (SSFP) BOLD-sensitive sequence and a SSFP-based first-pass sequence. All patients were scanned during rest and after 3 min of adenosine infusion (140 µg/kg/min). For myocardial first-pass visualization 0.1 mmol/kg Gadolinium-based contrast agent was used. In 90 myocardial segments a first-pass perfusion deficit could be seen. Relative BOLD signal increase was significantly lower in patients with perfusion deficits compared to patients without perfusion deficits (p < 0.0001). Patients with non-transmural and with transmural first-pass perfusion deficit also differed significantly for BOLD signal increase (p < 0.0001). ROC analysis showed an area under the curve of 0.83 for the T2-prepared SSFP sequence regarding detection of inducible perfusion deficit. CONCLUSIONS: T2-prepared BOLD imaging allows for visualization of myocardial perfusion reserve in a clinical setting without additional use of contrast agents.

Prognostic significance of cardiac magnetic resonance imaging: Update 2010.

Cardiac magnetic resonance imaging (CMR) has become an indispensible imaging technique for the diagnosis and treatment of patients with cardiovascular diseases. Technical advances in the past have rendered CMR unique in the evaluation of cardiovascular anatomy, physiology, and pathophysiology due to its unique ability to produce high resolution tomographic images of the human heart and vessels in any arbitrary orientation, with soft tissue contrast that is superior to competing imaging modalities without the use of ionizing radiation. CMR imaging is the gold standard for assessing left and right ventricular function and for detecting myocardial tissue abnormalities like edema, infarction, or scars. For prognostic reasons abnormal structure and dysfunction of the heart, and the detection of myocardial ischemia and/ /or myocardial scars are the main targets for CMR imaging. In this review we briefly describe the prognostic significance of several CMR imaging techniques and special CMR parameters in patients with coronary artery disease (CAD), with cardiomyopathies, and with chronic heart failure. Myocardial ischemia proved to be a strong predictor of an adverse outcome in patients with CAD. Microvascular obstruction in acute myocardial infarction is a new and independent parameter of negative left ventricular remodeling and a worse prognosis. Myocardial scars in patients with CAD and unrecognized myocardial infarction heralds a negative outcome. Scar in patients with dilated or hypertrophic cardiomyopathy are a strong predictor of both life-threatening ventricular tachyarrhythmias and prognosis. CMR imaging may improve the assessment of inter- and intraventricular dyssynchrony and provide prognostic information by detecting myocardial scars.

Pulsed perfusion in a venous human organ culture model with a Windkessel function (pulsed perfusion venous HOC-model).

BACKGROUND: The effectiveness of human saphenous vein grafting is limited by hyperplasia of the vessel wall. The current paper reports on a pulsed perfused venous human organ culture model (pp-venous HOC-model) with a Windkessel function. MATERIAL/METHODS: Saphenous vein grafts from 21 patients undergoing coronary bypass grafting were cultured either in venous or arterial hemodynamic conditions. Up to four vein segments were fixed in parallel connection and attached to a closed loop pulsed perfusion system consisting of large and small elastic tubes, mimicking the Windkessel function. RESULTS: First, after exposure to arterial blood pressure first signs of reactive cell proliferation (n.s.) were detected at day 4. Second, media thickness of the venous segments in the pulsed pressure group was decreased at day 4 (n.s.) and day 7 (n.s.). Third, staining against smooth muscle alpha actin and v. Willebrand factor was always positive at day 1, 4, and 7. CONCLUSIONS: Pulsed perfusion in a human venous organ culture model with a Windkessel function is an approach to better understand the events taking place during early arterial-vein grafting. First signs of reactive cell proliferation were detected at day four. A period of seven days as described in the current model is probably too short to detect reactive cell proliferation and medial thickening. If the device might be activated for a longer period of time, it should be a suitable model to characterize the effects of intra- and extravascular drug administration as treatment strategies of vein graft disease.

Prevalence of myocardial scar in patients with cryptogenic cerebral ischemic events and patent foramen ovale.

OBJECTIVES: This study sought to evaluate the prevalence of subclinical myocardial infarctions with cardiovascular magnetic resonance imaging (CMRI) in patients with patent foramen ovale (PFO) after cryptogenic cerebral ischemic events. BACKGROUND: A thrombotic mass passing a PFO may embolize in cerebral but also in coronary arteries, resulting in both cerebral and myocardial ischemic events. CMRI with late gadolinium enhancement (LGE) analysis is the most sensitive imaging technique to detect small myocardial infarctions. METHODS: PFO patients (n = 74) with a first cryptogenic cerebral ischemic event without a clinical history for myocardial infarction underwent CMRI and coronary angiography. Right and left ventricular volumes and ejection fractions were measured by CMRI. LGE imaging was performed after administration of gadolinium-diethylenetriaminepentaacetic acid. The presence of atrial septal aneurysm (ASA) was evaluated by transesophageal echocardiography. RESULTS: LGE was detected in 8 of 74 (10.8%) patients. LGE pattern was transmural or subendocardial. Patients with LGE and those without did not differ in cardiovascular risk factors, type of ischemic event, presence of ASA, right and left ventricular volumes, and ejection fractions. LGE volume was small and comprised only 7.9 +/- 2.4% of left ventricular muscle mass. Coronary artery disease was ruled out in 7 of 8 patients with LGE. There was a trend towards a larger PFO size in patients with LGE compared with patients without LGE (13.2 +/- 4.1 mm vs. 16.0 +/- 2.8 mm, p = 0.06). CONCLUSIONS: Subclinical myocardial infarctions determined in CMRI were observed in 10.8% of patients with PFO after a first cryptogenic cerebral ischemic event. Our results strengthen the pathophysiologic role of a PFO with paradoxical embolism in patients with cryptogenic cerebral ischemic events.

Valproic acid inhibits proliferation of human coronary vascular cells (SI/MPL-ratio: 0.5): a novel candidate for systemic and local therapy of postinterventional restenosis.

OBJECTIVES: The branched-chain fatty acid, valproic acid (VPA), is the most commonly used anti-epileptic drug for treating generalized epilepsy. Recently antiproliferative effects of VPA have been described in human cancer cells, and phase I trials for the treatment of solid tumors have been initiated. In cardiologic patients, increased cell proliferation and migration from the media into the subendothelial space are the key events causing restenosis after coronary angioplasty and stenting. This study investigates the effect of VPA on proliferation and migration in human coronary vascular cells. METHODS AND RESULTS: The theoretical clinical relevance of the data is estimated with a SI/MPL-ratio, which is defined as the relationship between a significant effect in vitro (SI) and the maximal plasma level in vivo (MPL). Dilution of VPA: Aqua dest, MPL in vivo: 100 microg/ml. Cell culture: HUVEC, human umbilical endothelial cells; HCAEC, human coronary artery endothelial cells; HCMSMC, human coronary media smooth muscle cells. Proliferation assay: HUVEC, HCAEC, and HCMSMC were seeded as described. At day 1, after seeding the cell number was calculated in a cell counter. VPA was added in six different concentrations ranging between 50 and 300 microg/ml. At day 3, the medium and agent were renewed, and after another 2 days, the cell number was calculated in relation with the cell number at day 1. Cell toxicity: Cytotoxic effects of VPA were studied in concentrations ranging from 50 to 300 microg/ml. Migration assay: migration of HCMSMC after incubation with VPA in concentrations ranging from 50 to 300 microg/ml was studied for a period of 24 h. Proliferation assay: strong dose-dependent antiproliferative effects were detected after 5 days of incubation with all the three tested cell types. In HUVEC, significant antiproliferative effects were found with VPA in concentrations of 100 microg/ml (P<0.05, SI/MPL-ratio: 1.0) and more. In HCAEC and HCMSMC, significant antiproliferative effects were detected after incubation with VPA in the concentrations of 50 microg/ml (HCAEC: P<0.01, SI/MPL ratio: 0.5; HCMSMC: P<0.001, SI/MPL-ratio: 0.5). Migration assay: no effect on cell migration was detected after incubation of HCMSMC for a period of 48 h with VPA in concentrations ranging from 50 to 300 microg/ml. Cell toxicity: in HUVEC, HCAEC, and HCMSMC significant toxic effects were detected in all the VPA concentrations studied. CONCLUSION: Significant dose-dependent antiproliferative effects of VPA with SI/MPL ratios of 0.5 identify the drug as a promising candidate for both systemic and local therapy of postinterventional restenosis. The partial cytotoxic effects, however, may restrict the use of VPA to local high-dose devices such as drug eluting stents.

Rapid effect of single-dose rosiglitazone treatment on endothelial function in healthy men with normal glucose tolerance: data from a randomised, placebo-controlled, double-blind study.

Antidiabetic thiazolidinediones (TZDs) improve endothelial function in patients with or without type 2 diabetes. The present randomised, placebo-controlled, double-blind study examined the time course of a single dose of rosiglitazone on flow-mediated endothelium-dependent vasodilation (FMD), metabolic parameters, and its effect on inflammatory markers in non-diabetic men. Forty non-obese, healthy men with normal glucose tolerance were randomised to a single dose of rosiglitazone (8 mg) or placebo, and FMD was assessed at baseline as well as after 6 h and 24 h. Rosiglitazone did not significantly affect blood glucose and insulin levels or lipid parameters after 6 and 24 h compared with placebo. Treatment with rosiglitazone significantly increased FMD after 6 h from 4.3% (3.3; 4.9) to 7.6% (5.6; 9.2) (p<0.0001 vs. baseline) resulting in a highly significant effect compared with placebo (p<0.0001 for difference between groups). After 24 h FMD was still significantly higher in the rosiglitazone group compared with baseline (p=0.001), but the effect was no longer statistically significant versus placebo (p=0.171). Our study shows a very rapid effect of single dose rosiglitazone treatment on endothelial function in non-diabetic healthy men, underscoring the hypothesis that TZDs may exhibit direct effect in the vasculature independent of their metabolic action.

Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes.

The present study examined the effect of GLP-1(1-37) on chemokine-induced CD4-positive lymphocyte migration as an early and critical step in atherogenesis. Pretreatment with GLP-1(1-37) reduced the SDF-induced migration of isolated human CD4-positive lymphocytes in a concentration-dependent manner. Similar effects were seen when RANTES was used as a chemokine. GLP-1(1-37)'s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream, GLP-1(1-37) inhibited SDF-induced phosphorylation of MLC and cofilin and limited f-actin formation as well as ICAM3 translocation. Furthermore, exendin-4 inhibited SDF-induced migration of CD4-positive lymphocytes similarly to GLP-1(1-37), and transfection of these cells with GLP-1 receptor siRNA abolished GLP-1(1-37)'s action on chemokine-induced ICAM3 translocation, suggesting an effect mediated via the GLP-1 receptor. Thus, GLP-1(1-37) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase pathway and via the GLP-1 receptor. This effect provides a potential novel mechanism for how GLP-1(1-37) may modulate vascular disease.