Overexpression of VEGFα as a biomarker of endothelial dysfunction in aortic tissue of α-GAL-Tg/KO mice and its upregulation in the serum of patients with Fabry's disease.

Introduction: Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry's disease and healthy controls. Methods: Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness. Results: It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry's disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry's disease. For angiostatin, no significant difference was found between patients with Fabry's disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml). Discussion: In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry's disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.

Feature tracking cardiovascular magnetic resonance reveals recovery of atrial function after acute myocarditis.

Follow-up after acute myocarditis is important to detect persisting myocardial dysfunction. However, recovery of atrial function has not been evaluated after acute myocarditis so far. Thirty-five patients with strictly defined acute myocarditis underwent cardiovascular magnetic resonance (CMR, 1.5 T) in the acute stage at baseline (BL) and at 3 months follow-up (FU). The study population included 13 patients with biopsy-proven "cardiomyopathy-like" myocarditis (CLM) and 22 patients with "infarct-like" (ILM) clinical presentation. CMR feature tracking (FT) was performed on conventional cine SSFP sequences. Median LA-GLS increased from 33.2 (14.5; 39.2) at BL to 37.0% (25.2; 44.1, P = 0.0018) at FU in the entire study population. Median LA-GLS also increased from 36.7 (26.5; 42.3) at BL to 41.3% (34.5; 44.8, P = 0.0262) at FU in the ILM subgroup and from 11.3 (6.4; 21.1) at BL to 21.4% (14.2; 30.7, P = 0.0186) at FU in the CLM subgroup. Median RA-GLS significantly increased from BL with 30.8 (22.5; 37.0) to FU with 33.7% (26.8; 45.4, P = 0.0027) in the entire study population. Median RA-GLS also significantly increased from 32.7 (25.8; 41.0) at BL to 35.8% (27.7; 48.0, P = 0.0495) at FU in the ILM subgroup and from 22.8 (13.1; 33.9) at BL to 31.0% (26.0; 40.8, P = 0.0266) at FU in the CLM subgroup. Our findings demonstrate recovery of LA and RA function by CMR-FT strain analyses in patients after acute myocarditis independent from clinical presentation. Monitoring of atrial strain could be an important tool for an individual assessment of healing after acute myocarditis.

Accuracy of thoracic aortic measurements assessed by contrast enhanced and unenhanced magnetic resonance imaging.

AIM: To assess, whether unenhanced balanced steady-state-free precession sequences provide axial thoracic aortic measurements comparable to contrast enhanced magnetic resonance angiography with good intra- and interobserver agreement. MATERIALS AND METHODS: Enhanced and unenhanced sequences of the thoracic aorta in 23 consecutive patients were evaluated. Axial thoracic aortic diameters were measured at predefined levels by two independent readers. Pearson's correlation coefficient and Bland-Altman analysis were used to compare enhanced and unenhanced sequences. t-Test was used to determine possible significant differences between the measurements obtained by enhanced and unenhanced sequences. A p-value of less than .05 indicated statistical significance. Intraclass correlation coefficient and Bland-Altman were used for inter- and intraobserver correlation and agreement. RESULTS: There was no significant difference in diameter measurements between enhanced and unenhanced sequences (ascending aorta, p=0.98; descending aorta, p=0.52). Bland-Altman revealed good agreement between enhanced and unenhanced sequences for ascending (mean bias, -0.01cm; with 95% limits of agreement, ±0.30cm) and descending aortic diameters (mean bias, 0.05cm; with 95% limits of agreement, ±0.30cm). Inter- and intraobserver agreement (mean bias, less than ±0.15; with 95% limits of agreement, less than ±0.42cm for all measurements) as well as correlation (r>0.8 for all measurements) were excellent. CONCLUSION: Unenhanced balanced steady-state-free precession sequences enable rapid and accurate determination of axial thoracic aortic diameters with excellent inter- and intraobserver agreement, but without the risk of contrast media associated side-effects.

3D segmentation of the left ventricle combining long- and short-axis MR images.

OBJECTIVES: Segmentation of the left ventricle (LV) is required to quantify LV remodeling after myocardial infarction. Therefore spatiotemporal cine MR sequences including long-axis and short-axis images are acquired. In this paper a new segmentation method for fast and robust segmentation of the left ventricle is presented. METHODS: The new approach considers the position of the mitral valve and the apex as well as the long-axis contours to generate a 3D LV surface model. The segmentation result can be checked and adjusted in the short-axis images. Finally quantitative parameters were extracted. RESULTS: For evaluation the LV was segmented in eight datasets of the same subject by two medical experts using a contour drawing tool and the new segmentation tool. The results of both methods were compared concerning interaction time and intra- and inter-observer variance. The presented segmentation method proved to be fast. The mean difference and standard deviation of all parameters are decreased. In case of intra-observer comparison e.g. the mean ESV difference is reduced from 8.8% to 0.5%. CONCLUSION: A semi-automatic LV segmentation method has been developed that combines long- and short-axis views. Using the presented approach the intra- and interobserver difference as well as the time for the segmentation process are decreased. So the semi-automatic segmentation using long- and short-axis information proved to be fast and robust for the quantification of LV mass and volume properties.

[Surface ECG presentation and intracardiac electrogram characteristics of uncommon supraventricular tachycardia entities]. / Differenzialdiagnose ungewöhnlicher Elektrogramme - vom Oberflächen-EKG zur elektrophysiologischen Diagnose.

The vast majority of patients with supraventricular tachycardias present with specific 12-lead surface ECG characteristics allowing the diagnosis of the underlying mechanisms prior to the invasive electrophysiological study. However, an accurate diagnosis remains challenging in a subset of patients, even when using well-established stimulation maneuvers and sophisticated conventional mapping methods. Thus, the aim of the present manuscript is to describe some cases with uncommon entities of supraventricular tachycardias where the combined interpretation of 12-lead ECG presentation and invasive electrophysiological characteristics revealed the correct diagnoses.

Reproducible extraction of local and global parameters for functional analysis of the left ventricle in 4D MR image data.

OBJECTIVES: Left ventricle (LV) segmentation is required to quantify LV volume and mass parameters. Therefore, spatiotemporal Cine MR sequences in the short and long axis of the heart are acquired. Generally, LV segmentation methods consider short-axis sequences only. The reduced resolution in long-axis direction is one of the main reasons for inaccurate parameter extraction in the apical and basal area. The segmentation approach presented combines short- and long-axis information as well as motion tracking to enable the functional LV analysis in 4D MR Image Data. METHODS: First, anatomical landmarks like the mitral valve and the apex are defined in long-axis views in diastolic and systolic phase in order to specify the upper and lower boundary of the LV. Second, motion field approximation using non-linear registration enables the automatic contour propagation to all time points. Third, intersection planes are defined parallel to the mitral valve plane covering the whole ventricle. Finally, the 4D LV surface model is generated appending all in-plane contours. The segmentation results in short-axis images are checked and adjusted interactively and quantitative parameters are extracted. RESULTS: For evaluation the contours of 19 different datasets were traced by two medical experts using a contour drawing tool and the new segmentation tool. The results were compared to evaluate automatic contour propagation, robustness of the segmentation as well as interaction time. CONCLUSION: The automatic contour propagation enables the fast and reproducible generation of a 4D model for the functional analysis of the heart. The interaction time is decreased from approx. 60 minutes to 10 minutes per case. Inter- and intraobserver differences of the extracted parameters are decreased significantly.

Diastolic dysfunction in exercise and its role for exercise capacity.

Diastolic dysfunction is frequent in elderly subjects and in patients with left ventricular hypertrophy, vascular disease and diabetes mellitus. Patients with diastolic dysfunction demonstrate a reduced exercise capacity and might suffer from congestive heart failure (CHF). Presence of symptoms of CHF in the setting of a normal systolic function is referred to as heart failure with normal ejection fraction (HFNEF) or, if evidence of an impaired diastolic function is observed, as diastolic heart failure (DHF). Reduced exercise capacity in diastolic dysfunction results from a number of pathophysiological alterations such as slowed myocardial relaxation, reduced myocardial distensibility, elevated filling pressures, and reduced ventricular suction forces. These alterations limit the increase of ventricular diastolic filling and cardiac output during exercise and lead to pulmonary congestion. In healthy subjects, exercise training can enhance diastolic function and exercise capacity and prevent deterioration of diastolic function in the course of aging. In patients with diastolic dysfunction, exercise capacity can be enhanced by exercise training and pharmacological treatment, whereas improvement of diastolic function can only be observed in few patients.

Assessment of functional anatomy of the mitral valve in patients with mitral regurgitation with cine magnetic resonance imaging: comparison with transesophageal echocardiography and surgical results.

The ability of magnetic resonance imaging (MRI) to accurately define the functional anatomy of mitral regurgitation was assessed. Transesophageal echocardiography (TEE) and cine MRI were performed on 43 patients with mitral regurgitation and were compared for the jet number, location, direction and presence of a prolapse (atrial displacement, malapposition or a flail). In 36 patients, diagnostic accuracy in reference to surgery was assessed. Comparing TEE and MRI the jet number and location were judged in concordance in 86% of patients. Jet location did not show a significant difference (Wilcoxon: P = 0.66) and both modalities correlated strongly (Spearman: r = 0.68, P<0.0001). Jet direction was judged with high concordance (kappa=0.63). Additionally, prolapse evaluation showed high concordance (kappa: valve, 0.63; anterior mitral leaflet, 0.70; posterior mitral leaflet, 0.73). Compared with surgery, the sensitivity for the detection of malapposition of any leaflet or one of both leaflets ranged between 75% and 93% for TEE and 71% and 89% for MRI. Specificities ranged between 88 and 96% for TEE and 88 and 100% for MRI. TEE detected torn chordae in all ten patients, six of which were missed by MRI. MRI is comparable with TEE in prolapse and jet evaluation. MRI is inferior to TEE in depicting anatomical details such as torn chordae.

[Patterns of delayed-enhancement in MRI of ischemic and non-ischemic cardiomyopathies]. / Muster der späten Kontrastmittelanreicherung in der MRT bei ischämischen und nicht-ischämischen Kardiomyopathien.

Contrast-enhanced MRI using the delayed-enhancement technique (DE-MRI) is widely applied in the clinical work-up of myocardial diseases. Myocardial diseases of varying etiology result in myocardial changes, such as necrosis, fibrosis, edema and metabolite deposition, which can be visualized by DE-MRI. Acute and chronic ischemic diseases based on a coronary artery disease as well as non-ischemic cardiomyopathies display DE. Cardiomyopathies often show a characteristic enhancement pattern. While ischemic lesions are localized in the subendocardium, non-ischemic cardiomyopathies often display an intramyocardial or subepicardial pattern. The typical pattern for dilated cardiomyopathies is band-like and intramyocardial with septal involvement. Arrhythmogenic right-ventricular dysplasias/cardiomyopathies are frequently associated with right-ventricular DE. In the case of amyloid cardiomyopathies which are often restrictive cardiomyopathies, subendocardial and circular DE is typically observed. Hypertrophic cardiomyopathies display patchy intramyocardial DE usually in the anteroseptal region. Acute myocarditis is typically accompanied by intramyocardial or subepicardial DE affecting the lateral wall. In the case of chronic myocarditis, intramyocardial or subepicardial DE is observed most frequently. Cardiac sarcoidosis typically entails patchy subepicardial DE with right- and left-ventricular involvement. Since there is an overlap between the enhancement patterns of cardiomyopathies, the diagnostic accuracy of DE-MRI is limited and the diagnosis must be based on additional clinical and MRI findings. The amount of DE often corresponds with cardiac functional parameters as well as with the frequency of cardiac events so that DE-MRI may be useful for risk stratification. Furthermore, DE-MRI can be helpful in the planning and evaluation of myocardial biopsies and electrophysiological examinations.