Publications by authors named "Wolfgang Utz"

30 Publications

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Assessment of diastolic dysfunction: comparison of different cardiovascular magnetic resonance techniques.

ESC Heart Fail 2020 10 20;7(5):2637-2649. Epub 2020 Jul 20.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Working Group on Cardiovascular Magnetic Resonance, Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrueck Center for Molecular Medicine, Lindenberger Weg 80, Berlin, 13125, Germany.

Aims: Heart failure with preserved ejection fraction is still a diagnostic and therapeutic challenge, and accurate non-invasive diagnosis of left ventricular (LV) diastolic dysfunction (DD) remains difficult. The current study aimed at identifying the most informative cardiovascular magnetic resonance (CMR) parameters for the assessment of LVDD.

Methods And Results: We prospectively included 50 patients and classified them into three groups: with DD (DD+, n = 15), without (DD-, n = 26), and uncertain (DD±, n = 9). Diagnosis of DD was based on echocardiographic E/E', invasive LV end-diastolic pressure, and N-terminal pro-brain natriuretic peptide. CMR was performed at 1.5 T to assess LV and left atrial (LA) morphology, LV diastolic strain rate (SR) by tissue tracking and tagging, myocardial peak velocities by tissue phase mapping, and transmitral inflow profile using phase contrast techniques. Statistics were performed only on definitive DD+ and DD- (total number 41). DD+ showed enlarged LA with LA end-diastolic volume/height performing best to identify DD+ with a cut-off value of ≥0.52 mL/cm (sensitivity = 0.71, specificity = 0.84, and area under the receiver operating characteristic curve = 0.75). DD+ showed significantly reduced radial (inferolateral E peak: DD-: -14.5 ± 6.5%/s vs. DD+: -10.9 ± 5.9%/s, P = 0.04; anterolateral A peak: DD-: -4.2 ± 1.6%/s vs. DD+: -3.1 ± 1.4%/s, P = 0.04) and circumferential (inferolateral A peak: DD-: 3.8 ± 1.2%/s vs. DD+: 2.8 ± 0.8%/s, P = 0.007; anterolateral A peak: DD-: 3.5 ± 1.2%/s vs. DD+: 2.5 ± 0.8%/s, P = 0.048) SR in the basal lateral wall assessed by tissue tracking. In the same segments, DD+ showed lower peak myocardial velocity by tissue phase mapping (inferolateral radial peak: DD-: -3.6 ± 0.7 ms vs. DD+: -2.8 ± 1.0 ms, P = 0.017; anterolateral longitudinal peak: DD-: -5.0 ± 1.8 ms vs. DD+: -3.4 ± 1.4 ms, P = 0.006). Tagging revealed reduced global longitudinal SR in DD+ (DD-: 45.8 ± 12.0%/s vs. DD+: 34.8 ± 9.2%/s, P = 0.022). Global circumferential and radial SR by tissue tracking and tagging, LV morphology, and transmitral flow did not differ between DD+ and DD-.

Conclusions: Left atrial size and regional quantitative myocardial deformation applying CMR identified best patients with DD.
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http://dx.doi.org/10.1002/ehf2.12846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524101PMC
October 2020

Cardiac Involvement in Myotonic Dystrophy Type 2 Patients With Preserved Ejection Fraction: Detection by Cardiovascular Magnetic Resonance.

Circ Cardiovasc Imaging 2016 07;9(7)

From the Working Group on Cardiovascular Magnetic Resonance, Experimental, and Clinical Research Center, a joint cooperation between the Charité University Medicine Berlin and the Max-Delbrueck Center for Molecular Medicine, and HELIOS Klinikum Berlin Buch, Department of Cardiology and Nephrology, Germany (L.S., J.T., W.U., M.A.D., E.B., F.v.K.-B., J.S.-M.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (L.S., F.v.K.-B, J.S.-M.); Muscle Research Unit, Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, Berlin, Germany (U.G., S.S.); and Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (P.K.).

Background: Myotonic dystrophy type 2 (DM2) is a genetic disorder characterized by skeletal muscle symptoms, metabolic changes, and cardiac involvement. Histopathologic alterations of the skeletal muscle include fibrosis and fatty infiltration. The aim of this study was to investigate whether subclinical cardiac involvement in DM2 is already detectable in preserved left ventricular function by cardiovascular magnetic resonance.

Methods And Results: Twenty-seven patients (mean age, 54±10 years; 20 females) with a genetically confirmed diagnosis of DM2 were compared with 17 healthy age- and sex-matched controls using a 1.5 T magnetic resonance imaging. For myocardial tissue differentiation, T1 and T2 mapping, fat/water-separated imaging, focal fibrosis imaging (late gadolinium enhancement [LGE]), and (1)H magnetic resonance spectroscopy were performed. Extracellular volume fraction was calculated. Conduction abnormalities were diagnosed based on Groh criteria. LGE located subepicardial basal inferolateral was detectable in 22% of the patients. Extracellular volume was increased in this region and in the adjacent medial inferolateral segment (P=0.03 compared with healthy controls). In 21% of patients with DM2, fat deposits were detectable (all women). The control group showed no abnormalities. Myocardial triglycerides were not different in LGE-positive and LGE-negative subjects (P=0.47). Six patients had indicators for conduction disease (60% of LGE-positive patients and 12.5% of LGE-negative patients).

Conclusions: In DM2, subclinical myocardial injury was already detectable in preserved left ventricular ejection fraction. Extracellular volume was also increased in regions with no focal fibrosis. Myocardial fibrosis was related to conduction abnormalities.
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http://dx.doi.org/10.1161/CIRCIMAGING.115.004615DOI Listing
July 2016

Current T₁ and T₂ mapping techniques applied with simple thresholds cannot discriminate acute from chronic myocadial infarction on an individual patient basis: a pilot study.

BMC Med Imaging 2016 Apr 29;16:35. Epub 2016 Apr 29.

Working Group Cardiovascular Magnetic Resonance, Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine and HELIOS Klinikum Berlin Buch, Department of Cardiology and Nephrology, Lindenberger Weg 80, Berlin, 13125, Germany.

Background: Studying T1- and T2-mapping for discrimination of acute from chronic myocardial infarction (AMI, CMI).

Methods: Eight patients with AMI underwent CMR at 3 T acutely and after >3 months. Imaging techniques included: T2-weighted imaging, late enhancement (LGE), T2-mapping, native and post-contrast T1-mapping. Myocardial T2- and T1-relaxation times were determined for every voxel. Abnormal voxels as defined by having T2- and T1-values beyond a predefined threshold (T2 > 50 ms, native T1 > 1250 ms and post-contrast T1 < 350 ms) were highlighted and compared with LGE as the reference.

Results: Abnormal T2-relaxation times were present in the voxels with AMI (=> delete acute infarction; unfortunately this is not possible in your web interface) acute infarction only in half of the subjects. Abnormal T2-values were also present in subjects with CMI, thereby matching the chronically infarcted territory in some. Abnormal native T1 times were present in voxels with AMI in 5/8 subjects, but also remote from the infarcted territory in four. In CMI, abnormal native T1 values corresponded with infarcted voxels, but were also abnormal remote from the infarcted territory. Voxels with abnormal post-contrast T1-relaxation times agreed well with LGE in AMI and CMI.

Conclusions: In this pilot-study, T2- and T1-mapping with simple thresholds did not facilitate the discrimination of AMI and CMI.
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http://dx.doi.org/10.1186/s12880-016-0135-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850633PMC
April 2016

Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

Hypertension 2015 Oct 17;66(4):800-8. Epub 2015 Aug 17.

From the Children's' Hospital, Department of Pediatric Cardiology, Friedrich-Alexander University Erlangen, Erlangen, Germany (O.T.); Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (J.T., J.J.); Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany (C.S., A.A., P.G.M., E.B.-K., I.H., A.M., Y.W.-N., J.S.-M., E.K., S.B., F.C.L.); Experimental and Clinical Research Center (ECRC), a joint co-operation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (A.A., P.G.M., E.B.-K., I.H., C.L., K.M., M.B., G.R., A.M., Y.W.-N., W.U., A.T., J.S.-M., S.B., F.C.L.); Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (P.G.M.); Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA (P.G.M.); Department of Cardiology/Nephrology, Helios-Klinikum Berlin, Berlin, Germany (S.E., W.U., A.T., J.S.-M.); Department of Nephrology, Hannover University Medical School, Hannover, Germany (C.L.); Staatliche Technikerschule Berlin, Berlin, Germany (C.L.); Cardiology Section, VA Salt Lake City Health Care System, UT (M.A.M.); Departments of Internal Medicine and Pharmacology and Toxicology, University of Utah, Salt Lake City (M.A.M.); Blood Transfusion Center, Deutsches Rotes Kreuz, Oldenburg, Germany (T.M., A.D., S.G.); Division of Nephrology and Hypertension, Department of Medicine, Eastern Virginia Medical School, Norfolk, VA (H.R.T.); Hampton Veterans Affairs Medical Center, Hampton, VA (H.R.T); German Centre for Cardiovascular Research (DZHK), Berlin, Germany (E.K.); and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.C.L.).

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06000DOI Listing
October 2015

Real-time phase contrast magnetic resonance imaging for assessment of haemodynamics: from phantom to patients.

Eur Radiol 2016 Apr 19;26(4):986-96. Epub 2015 Jul 19.

Department of Cardiology and Nephrology, Working Group on Cardiovascular Magnetic Resonance Imaging, Experimental and Clinical Research Center, Max-Delbrück-Centrum and Charité -Medical University Berlin and HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125, Berlin, Germany.

Objectives: Assessment of haemodynamics is crucial in many cardiac diseases. Phase contrast MRI (PC-MRI) can accurately access it. Arrhythmia is a major limitation in conventional segmented PC-MRI (SEG). A real-time PC-MRI sequence (RT) could overcome this. We validated RT by comparing to SEG.

Methods: A prototype RT using shared velocity encoding was tested against SEG at 1.5 T in a flow phantom and consecutively included patients with (n = 55) or without (n = 59) aortic valve disease. In patients with atrial fibrillation (Afib, n = 15), only RT was applied. Phantom: PC images were acquired in front of and behind an interchangeable aortic-stenosis-like inlay. Mean velocity and flow were quantified.

Patients: PC images were acquired in the ascending aorta, pulmonary trunk and superior caval vein. Peak velocity, stroke volume and regurgitant fraction were quantified.

Results: Phantom: Mean velocities (11 ± 1 to 207 ± 10 cm/s) and flow correlated closely between SEG and RT (r ≥ 0.99, ICC ≥ 0.98, p < 0.0005). Patients without AVD or with aortic regurgitation: Concordance of SEG and RT was excellent regarding peak velocities, stroke volumes (r ≥ 0.91, ICC ≥ 0.94, p < 0.0005) and regurgitant fractions (r = 0.95, ICC = 0.95, p < 0.0005). RT was feasible in all patients with Afib.

Conclusions: The real-time sequence is accurate compared to conventional segmented PC-MRI. Its applicability in Afib was shown. Real-time PC-MRI might become a valuable tool in arrhythmia.

Key Points: • Assessment of haemodynamics is crucial in many cardiac diseases. • Arrhythmias are a major limitation of conventional techniques in cardiac magnetic resonance. • A real-time technique, which allows application in arrhythmia, was validated. • This real-time technique might become a valuable tool in arrhythmic patients.
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http://dx.doi.org/10.1007/s00330-015-3897-7DOI Listing
April 2016

Differential response of the natriuretic peptide system to weight loss and exercise in overweight or obese patients.

J Hypertens 2015 Jul;33(7):1458-64

aInstitute of Clinical Pharmacology, Hannover Medical School, Hannover bDepartment of Psychology, University of Potsdam, Potsdam cWorking Group Cardiac MRI, Clinic for Cardiology and Nephrology, HELIOS Klinikum Berlin-Buch, and University Medicine Berlin, Charité Campus Buch, and Experimental and Clinical Research Centre dFranz Volhard Clinical Research Center at the Experimental and Clinical Research Center, University Medicine Berlin, Charité Campus Buch, and Max Delbrück Center for Molecular Medicine eDepartment of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, University Medicine Berlin, Charité, Berlin fInstitute for Clinical Chemistry, Hannover Medical School, Hannover, Germany.

Objective: Relative atrial natriuretic peptide (ANP) deficiency has been implicated in the pathogenesis of obesity-associated cardiovascular and metabolic disease. We tested the hypothesis that more than 5% body weight reduction through 6 months hypocaloric dieting alters ANP release at rest and more so during exercise in overweight or obese patients.

Methods: Venous mid-regional pro-ANP concentration was assessed at rest and after incremental exhaustive exercise testing before and after weight reduction. We also measured natriuretic peptide receptor A and C mRNA expression in subcutaneous adipose tissue to gauge both ANP responsiveness and clearance mechanisms.

Results: The average weight reduction of 9.1 ± 3.8  kg was associated with reductions in visceral and subcutaneous abdominal fat mass, liver fat content, insulin resistance, and ambulatory blood pressure. However, mid-regional pro-ANP plasma concentrations were unchanged with weight loss (51 ± 24 vs. 53 ± 24  pmol/l). Exercise elicited similar acute mid-regional pro-ANP increases before and after weight loss. Adipose tissue natriuretic peptide receptor type A mRNA expression remained unchanged, whereas natriuretic peptide receptor type C mRNA decreased with weight loss.

Conclusions: We conclude that physical exercise acutely increases ANP release in obese patients, whereas modest diet-induced weight loss primarily affects ANP clearance mechanisms. Interventions combining weight loss and regular physical exercise may be particularly efficacious in reversing obesity-associated relative natriuretic peptide deficiency.
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http://dx.doi.org/10.1097/HJH.0000000000000573DOI Listing
July 2015

Influence of nonenzymatic posttranslational modifications on constitution, oligomerization and receptor binding of S100A12.

PLoS One 2014 26;9(11):e113418. Epub 2014 Nov 26.

Department of Chemistry and Pharmacy, Food Chemistry Division, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

This study examined the effect of methylglyoxal (MGO)-derived nonenzymatic posttranslational modifications (nePTMs) on the binding affinity of S100A12 to its natural receptor for advanced glycation end-products (RAGE). Binding of MGO-modified S100A12 to RAGE decreased significantly with increasing MGO concentration and incubation time. Ca(2+)-induced S100A12 hexamerization was impaired only at higher MGO concentrations indicating that the loss of affinity is not predominantly caused by disturbance of ligand oligomerization. nePTM mapping showed carboxyethylation of lysine (CEL) and the N-terminus without preferential modification sites. Besides, hydroimidazolone, hemiaminals, argpyrimidine, and tetrahydropyrimidine rapidly formed at R21. Even at the highest modification rate, hexamerization of synthesized CEL-S100A12 was unaffected and RAGE-binding only slightly impaired. Thus, nePTMs at R21 seem to be the major cause of MGO-induced impairment of S100A12 oligomerization and RAGE binding.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113418PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245128PMC
July 2015

Cardiac magnetic resonance imaging of congenital bicuspid aortic valves and associated aortic pathologies in adults.

Eur Heart J Cardiovasc Imaging 2014 Jun 21;15(6):673-9. Epub 2014 Jan 21.

Working Group Cardiac MRI, Humboldt University Berlin, Charite Campus Buch, Experimental and Clinical Research Center, Berlin, Germany Cardiology and Nephrology Department, HELIOS Klinikum Berlin Buch, 13125, Berlin, Germany.

Aims: Bicuspid aortic valve (BAV) represents the most frequent congenital cardiac abnormality resulting in premature valvular degeneration and aortic dilatation. In a large series of consecutive patients, we evaluated the distribution of BAV types and the associated valvular and aortic abnormalities.

Methods And Results: We investigated 266 patients (58 ± 14 years) with BAV using a 1.5 T cardiac magnetic resonance (CMR) scanner. Valve morphology was described according to the Sievers classification. The aortic valve orifice area, aortic regurgitation (AR) fraction, and aortic dilation were quantified. Two hundred and forty-two data sets were available for analysis; 24% had BAV without a valvular lesion. The predominant valvular lesion was aortic stenosis (AS) with 51%. Lone AR was found in 17%. A combined lesion of AS and AR was found in 9%. Those with AS were older than the overall average (64 ± 12 vs. 57 ± 15 years, P < 0.001). The patients with AR and those without valvular abnormality were younger than average (49 ± 13 and 50 ± 12 years vs. 57 ± 15 years, P < 0.01 respectively). Comparing two observers Kappa coefficient was 0.77 for differentiation of six valve morphologies and 0.80 for the differentiation of bicuspid and tricuspid valve. Aortic dilatation was found in 39% of cases with no discernible preference for any specific BAV-type and mainly affecting the ascending aorta.

Conclusion: CMR can non-invasively differentiate various morphologies in BAV with low inter-observer variability. Valvular pathologies vary across age. Aortic dilatation is frequent in BAV independent from valvular morphology or lesion. In future CMR might help to guide management in patients with BAV.
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http://dx.doi.org/10.1093/ehjci/jet275DOI Listing
June 2014

Assessment of nonischemic fibrosis in hypertrophic cardiomyopathy: comparison of gadopentetate dimeglumine and gadobenate dimeglumine for enhanced cardiovascular magnetic resonance imaging.

J Magn Reson Imaging 2014 May 22;39(5):1153-60. Epub 2013 Oct 22.

Working Group on Cardiovascular Magnetic Resonance, Experimental Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany; HELIOS Klinikum Berlin-Buch, Department of Cardiology and Nephrology, Berlin, Germany.

Purpose: To compare whether the higher relaxivity contrast agent gadobenate is superior for the identification of nonischemic late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM) compared to standard relaxivity agents such as gadopentetate.

Materials And Methods: Fifteen patients with HCM and positive LGE based on routine cardiac magnetic resonance (CMR) with 0.2 mmol/kg gadopentetate were enrolled. Each patient thereafter underwent a second enhanced CMR exam with 0.2 mmol/kg gadobenate using the same CMR protocol. LGE was assessed in a short axis stack acquired after contrast administration using an inversion recovery gradient echo sequence. Two independent blinded readers quantified LGE by manual planimetry. The signal intensities of injured myocardium, remote myocardium, left ventricular cavity, and air were measured in identical locations using anatomical landmarks and dedicated software. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated.

Results: No adverse events related to contrast administration occurred. Gadobenate dimeglumine showed a higher SNR of injured myocardium (45.4 ± 24.0 vs. 31.1 ± 16.6, P = 0.002) and a higher CNR between remote and injured myocardium (37.6 ± 25.0 vs. 26.5 ± 17.6, P = 0.006) compared to gadopentetate dimeglumine. The amount of LGE (based on the same postprocessing criteria and definitions) was higher with gadobenate dimeglumine (12.7 ± 8.5 g vs. 9.4 ± 5.6 g, P = 0.005). There was no difference in intra- and interobserver variability between gadopentetate dimeglumine and gadobenate dimeglumine.

Conclusion: CMR with the high relaxivity contrast agent gadobenate dimeglumine reveals significantly more tissue with LGE in patients with HCM.
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http://dx.doi.org/10.1002/jmri.24264DOI Listing
May 2014

Long-lasting improvements in liver fat and metabolism despite body weight regain after dietary weight loss.

Diabetes Care 2013 Nov 20;36(11):3786-92. Epub 2013 Aug 20.

Corresponding author: Stefan Engeli,

Objective: Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known.

Research Design And Methods: We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m2; women, 77%) who had participated in a 6-month hypocaloric diet and were randomized to either reduced carbohydrates or reduced fat content. Before, directly after diet, and at an average of 24 (range, 17-36) months follow-up, we assessed body fat distribution by magnetic resonance imaging and markers of liver function and insulin resistance.

Results: Body weight decreased with diet but had increased again at follow-up. Subjects also partially regained abdominal subcutaneous and visceral adipose tissue. In contrast, intrahepatic fat decreased with diet and remained reduced at follow-up (7.8 ± 9.8% [baseline], 4.5 ± 5.9% [6 months], and 4.7 ± 5.9% [follow-up]). Similar patterns were observed for markers of liver function, whole-body insulin sensitivity, and hepatic insulin resistance. Changes in intrahepatic fat und intrahepatic function were independent of macronutrient composition during intervention and were most effective in subjects with nonalcoholic fatty liver disease at baseline.

Conclusions: A 6-month hypocaloric diet induced improvements in hepatic fat, liver test results, and insulin resistance despite regaining of weight up to 2 years after the active intervention. Body weight and adiposity measurements may underestimate beneficial long-term effects of dietary interventions.
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http://dx.doi.org/10.2337/dc13-0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816862PMC
November 2013

Fatty acid binding protein 4 predicts left ventricular mass and longitudinal function in overweight and obese women.

Heart 2013 Jul 18;99(13):944-8. Epub 2013 Apr 18.

Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.

Objective: To explore whether increased adipocyte-derived serum fatty acid binding protein 4 (FABP4) predisposes to cardiac remodelling and left ventricular dysfunction in human obesity.

Design: Cross-sectional investigation.

Setting: Academic clinical research centre.

Patients: 108 overweight and obese non-diabetic women (body-mass index 33 ± 5 kg/m2).

Interventions: None.

Main Outcome Measures: Relationship between serum FABP4 and abdominal adipose tissue quantified by MRI. Relationship between serum FABP4 and left ventricular morphology and function assessed by cardiac MRI.

Results: FABP4 was independently associated with visceral abdominal adipose tissue (β=0.34, p<0.01) and subcutaneous abdominal adipose tissue (β=0.22, p<0.05). After stratification into serum FABP4 tertiles, left ventricular masses were 92 ± 16 g, 86 ± 13 g and 81 ± 12 g in women with high, intermediate and low FABP4 concentrations (p<0.01), respectively. Longitudinal systolic function was reduced by 8% in women with intermediate and high versus low FABP4 concentrations (p<0.01), whereas ejection fraction did not differ among tertiles (p=0.5). In multivariate linear analysis FABP4 remained an independent predictor of left ventricular mass (β=0.17, p<0.05) and reduced longitudinal fractional shortening (β=0.21, p<0.05).

Conclusions: In overweight and obese women, FABP4 showed an independent association with parameters of left ventricular remodelling.
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http://dx.doi.org/10.1136/heartjnl-2013-303735DOI Listing
July 2013

Variability and homogeneity of cardiovascular magnetic resonance myocardial T2-mapping in volunteers compared to patients with edema.

J Cardiovasc Magn Reson 2013 Mar 27;15:27. Epub 2013 Mar 27.

Department of Cardiology and Nephrology, Working Group Cardiac MRI, Humboldt University Berlin, Charite Campus Buch Experimental and Clinical Research Center and HELIOS Klinikum Berlin Buch, Berlin, Germany.

Background: The aim of the study was to test the reproducibility and variability of myocardial T2 mapping in relation to sequence type and spatial orientation in a large group of healthy volunteers. For control T2 mapping was also applied in patients with true edema. Cardiovascular magnetic resonance (CMR) T2-mapping has potential for the detection and quantification of myocardial edema. Clinical experience is limited so far. The variability and potential pitfalls in broad application are unknown.

Methods: Healthy volunteers (n = 73, 35 ± 13 years) and patients with edema (n = 28, 55 ± 17 years) underwent CMR at 1.5 T. Steady state free precession (SSFP) cine loops and T2-weighted spin echo images were obtained. In patients, additionally late gadolinium enhancement images were acquired. We obtained T2 maps in midventricular short axis (SAX) and four-chamber view (4CV) based on images with T2 preparation times of 0, 24, 55 ms and compared fast low angle shot (FLASH) and SSFP readout. 10 volunteers were scanned twice on separate days. Two observers analysed segmental and global T2 per slice.

Results: In volunteers global myocardial T2 systematically differed depending on image orientation and sequence (FLASH 52 ± 5 vs. SSFP 55 ± 5 ms in SAX and 57 ± 6 vs. 59 ± 6 ms in 4CV; p < 0.0001 for both). Anteroseptal and apical segments had higher T2 than inferior and basal segments (SAX: 59 ± 6 vs. 48 ± 5 ms for FLASH and 59 ± 7 vs. 52 ± 4 ms for SSFP; p < 0.0001 for both). 14 volunteers had segments with T2 ≥ 70 ms. Mean intraobserver variability was 1.07 ± 1.03 ms (r = 0.94); interobserver variability was 1.6 ± 1.5 ms (r = 0.87). The coefficient of variation for repeated scans was 7.6% for SAX and 6.6% for 4CV. Mapping revealed focally increased T2 (73 ± 9 vs. 51 ± 3 ms in remote myocardium; p < 0.0001) in all patients with edema.

Conclusions: Myocardial T2 mapping is technically feasible and highly reproducible. It can detect focal edema and differentiate it from normal myocardium. Increased T2 was found in some volunteers most likely due to partial volume and residual motion.
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http://dx.doi.org/10.1186/1532-429X-15-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627620PMC
March 2013

Moderate dietary weight loss reduces myocardial steatosis in obese and overweight women.

Int J Cardiol 2013 Aug 10;167(3):905-9. Epub 2012 Apr 10.

Working Group Cardiac MR, Medical Faculty of the Charité Campus Buch and HELIOS Klinikum Berlin Buch, Berlin, Germany.

Background: Excessive myocardial triglyceride (MTG) content in obesity and type 2 diabetes is associated with impaired cardiac function. Previous studies suggest that MTG could be mobilized through lifestyle interventions. We assessed influences of moderate dietary weight loss in non diabetic obese and overweight women on MTG content and cardiac function.

Methods: We selected a subgroup of 38 women from the B-SMART study population. The B-SMART study compared weight loss and associated metabolic and cardiovascular markers with reduced-carbohydrate and reduced-fat hypocaloric diets. Selected subjects had completed a cardiac magnetic resonance (MR) scan including imaging and proton spectroscopy to assess cardiac structure and function as well as MTG content.

Results: An average weight reduction of 5.4 ± 4.3 kg at six months was associated with a relative decrease of MTG of 25% (from 0.72 ± 0.29% at baseline to 0.54 ± 0.23% at follow-up, p<0.001). The response was similar with carbohydrate and fat restriction. Diastolic function expressed as ratio of peak filling rate in E- and A-Phase (PFRE/PFRA) was unchanged. Reductions of left atrial size (from 21.9 ± 4.0 cm(2) to 20.0 ± 3.7 cm(2), p=0.002), the normalized ratio of PFRE and early diastolic lengthening velocity PLV (from 8.2 ± 2.6 to 7.5 ± 2.5, p<0.001) and fat free mass (from 55.1 ± 6.9 kg to 52.7 ± 6.5 kg, p=0.007) reflected altered cardiac volume loading after diet, but did not correlate to MTG content.

Conclusions: Moderate dietary weight loss significantly reduced MTG content in women with uncomplicated overweight or obesity. Macronutrient composition of the diet did not significantly affect the extent of MTG reduction.
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http://dx.doi.org/10.1016/j.ijcard.2012.03.104DOI Listing
August 2013

Left ventricular mass and function with reduced-fat or reduced-carbohydrate hypocaloric diets in overweight and obese subjects.

Hypertension 2012 Jan 7;59(1):70-5. Epub 2011 Nov 7.

Franz Volhard Clinical Research Center at the Experimental and Clinical Research Center, Charité University Medical Faculty and Max-Delbrück Center for Molecular Medicine, Berlin, Germany.

In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.9±4.4; range, 26.5-45.4 kg/m(2)) to 6-month hypocaloric diets with either reduced carbohydrate intake or reduced fat intake. We obtained cardiac MRI and ambulatory blood pressure recordings over 24 hours before and after 6 months. Ninety subjects completing the intervention period had a full cardiac MRI data set. Subjects lost 7.3±4.0 kg (7.9±3.8%) with reduced-carbohydrate diet and 6.2±4.2 kg (6.7±4.4%) with reduced-fat diet (P<0.001 within each group; P=not significant between interventions). Caloric restriction led to similar significant decreases in left ventricular mass with low-carbohydrate diets (5.4±5.4 g) or low-fat diets (5.2±4.8 g; P<0.001 within each group; P=not significant between interventions). Systolic and diastolic left ventricular function did not change with either diet. The 24-hour systolic blood pressure decreased similarly with both interventions. Body weight change (β=0.33; P=0.02) and percentage of ingested n-3 polyunsaturated fatty acids (β=-0.27; P=0.03) predicted changes in left ventricular mass. In conclusion, weight loss induced by reduced-fat diets or reduced-carbohydrate diets similarly improved left ventricular mass in overweight and obese subjects over a 6-month period. However, n-3 polyunsaturated fatty acid ingestion may have an independent beneficial effect on left ventricular mass.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.178616DOI Listing
January 2012

Myocardial steatosis, cardiac remodelling and fitness in insulin-sensitive and insulin-resistant obese women.

Heart 2011 Oct 20;97(19):1585-9. Epub 2011 Jul 20.

Working Group Cardiac MR Medical Faculty of the Charité Campus Buch and HELIOS Klinikum Berlin Buch, Berlin, Germany.

Background: Obesity predisposes to heart failure and premature cardiovascular death, particularly in sedentary women. In animal models and in men with type 2 diabetes mellitus, impaired cardiac function is associated with myocardial triglyceride (MTG) accumulation. Lipotoxic injury from altered myocardial metabolism may be causative. Whether such association also exists in obese, non-diabetic women is unknown.

Objective: To explore the relation between MTG content, cardiac remodelling and cardiorespiratory fitness in obese, insulin-sensitive and insulin-resistant non-diabetic women.

Design: Cross-sectional investigation.

Setting: Academic clinical research centre.

Patients: 65 Overweight/obese and sedentary, but otherwise healthy women (body mass index 33±4 kg/m(2); age 45±10 years).

Interventions: None.

Main Outcome Measures: Cardiac structure and function measured by cardiovascular magnetic resonance imaging and MTG content of the interventricular septum by (1)H MR spectroscopy. Additional outcomes were cardiopulmonary fitness and insulin sensitivity during oral glucose tolerance testing.

Results: Insulin resistance (composite insulin sensitivity index (C-ISI) <4.6) was present in 29 women. MTG content was higher (0.83±0.30 vs 0.61±0.23, p=0.002) and left ventricular diastolic (p<0.01), but not systolic function was reduced in women with insulin resistance compared with insulin-sensitive women. The remodelling index defined as left ventricular mass divided by end-diastolic volume was increased in women with impaired glucose tolerance (p=0.006). Furthermore, cardiopulmonary fitness was equal in both groups, but was inversely correlated with MTG (r=-0.28, p=0.02).

Conclusions: In overweight and obese women, insulin resistance is associated with increased MTG content, cardiac remodelling and reduced diastolic function.

Clinical Trial Registration: ClinicalTrials.gov NCT00956566.
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http://dx.doi.org/10.1136/hrt.2011.224451DOI Listing
October 2011

Cardiac magnetic resonance imaging during pulmonary hyperinflation in apnea divers.

Med Sci Sports Exerc 2011 Nov;43(11):2095-101

Department of Radiology, University Hospital Split, Croatia.

Purpose: Apnea divers hyperinflate the lung by taking a deep breath followed by glossopharyngeal insufflation. The maneuver can lead to symptomatic arterial hypotension. We tested the hypotheses that glossopharyngeal insufflation interferes with cardiac function further reducing cardiac output (CO) using cardiac magnetic resonance imaging (MRI) to fully sample both cardiac chambers.

Methods: Eleven dive athletes (10 men, 1 woman; age = 26 ± 5 yr, body mass index = 23.5 ± 1.7 kg·m(-2)) underwent cardiac MRI during breath holding at functional residual capacity (baseline), at total lung capacity (apnea), and with submaximal glossopharyngeal insufflation. Lung volumes were estimated from anatomic images. Short-axis cine MR images were acquired to study biventricular function. Dynamic changes were followed by long-axis cine MRI.

Results: Left and right ventricular end-diastolic volumes (LVEDV, RVEDV) decreased during apnea with and without glossopharyngeal insufflation (baseline: LVEDV = 198 ± 19 mL, RVEDV = 225 ± 30 mL; apnea: LVEDV = 125 ± 38 mL, RVEDV = 148 ± 37 mL, P < 0.001; glossopharyngeal insufflation: LVEDV = 108 ± 26 mL, RVEDV = 136 ± 29 mL, P < 0.001 vs baseline). CO decreased during apnea (left = -29 ± 4 %, right = -29 ± 4 %) decreasing further with glossopharyngeal insufflation (left = -38% ± 4%, right = -39% ± 4%, P < 0.05). HR increased 16 ± 4 bpm with apnea and 17 ± 5 bpm with glossopharyngeal insufflation (P < 0.01). Ejection fraction moderately decreased (apnea: left = -5% ± 2%, right = -7% ± 2%, glossopharyngeal insufflation: left = -6% ± 2%, right = -10% ± 2%, P < 0.01). With continued apnea with and without glossopharyngeal insufflation, LVEDV and CO increased over time by a similar but small amount (P < 0.01).

Conclusions: The major finding of our study was that submaximal glossopharyngeal insufflation decreased CO further albeit by a small amount compared to maximal inspiratory apnea. The response was not associated with severe biventricular dysfunction.
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http://dx.doi.org/10.1249/MSS.0b013e31821ff294DOI Listing
November 2011

Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects.

Hepatology 2011 May 11;53(5):1504-14. Epub 2011 Mar 11.

Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Unlabelled: Obesity-related hepatic steatosis is a major risk factor for metabolic and cardiovascular disease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lipids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects were randomized to either reduced carbohydrate (n = 84) or reduced fat (n = 86), total energy restricted diet (-30% of energy intake before diet) for 6 months. Body composition was estimated by bioimpedance analyses and abdominal fat distribution by magnetic resonance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glucose tolerance testing. In all, 102 subjects completed the diet intervention with measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight, total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intrahepatic lipids (>5.56%) lost ≈7-fold more intrahepatic lipids compared with those with low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in visceral fat mass and insulin sensitivity were similar between subgroups, with low and high baseline intrahepatic lipids.

Conclusion: A prolonged hypocaloric diet low in carbohydrates and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the traditional low-fat hypocaloric diet. The decrease in intrahepatic lipids appears to be independent of visceral fat loss and is not tightly coupled with changes in whole body insulin sensitivity during 6 months of an energy restricted diet.
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http://dx.doi.org/10.1002/hep.24242DOI Listing
May 2011

A series of 18F-labelled pyridinylphenyl amides as subtype-selective radioligands for the dopamine D3 receptor.

ChemMedChem 2010 Jun;5(6):941-8

Friedrich Alexander University Erlangen-Nürnberg, Clinic of Nuclear Medicine, Friedrich Alexander University, Krankenhausstrasse 12, 91054 Erlangen, Germany.

Synthesis, biological activity, and structure-selectivity relationship (SSR) studies of a novel series of potential dopamine D3 receptor radioligands as imaging agents for positron emission tomography (PET) are reported. Considering a structurally diverse library of D3 ligands, SSR studies were performed for a new series of fluorinated pyridinylphenyl amides using CoMFA and CoMSIA methods. The in vitro D3 affinities of the predicted series of biphenyl amide ligands 9 a-d revealed single-digit to sub-nanomolar potencies (K(i)=0.52-1.6 nM), displaying excellent D3 selectivity over the D2 subtype of 110- to 210-fold for the test compounds 9 a-c. Radiofluorination by nucleophilic substitution of Br or NO(2) by (18)F led to radiochemical yields of 66-92 % for [(18)F]9 a-d. However, the specific activities of [(18)F]9 b and [(18)F]9 d were insufficient, rendering their use for in vivo studies impossible. Biodistribution studies of [(18)F]9 a and [(18)F]9 c using rat brain autoradiography revealed accumulation in the ventricles, thus indicating insufficient biokinetic properties of [(18)F]9 a and [(18)F]9 c for D3 receptor imaging in vivo.
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http://dx.doi.org/10.1002/cmdc.201000067DOI Listing
June 2010

Cardiorespiratory fitness and insulin sensitivity in overweight or obese subjects may be linked through intrahepatic lipid content.

Diabetes 2010 Jul 31;59(7):1640-7. Epub 2010 Mar 31.

Franz Volhard Clinical Research Center at Experimental and Clinical Research Center, Charité University Medical School and Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Objective: Low cardiorespiratory fitness (CRF) predisposes one to cardiovascular disease and type 2 diabetes in part independently of body weight. Given the close relationship between intrahepatic lipid content (IHL) and insulin sensitivity, we hypothesized that the direct relationship between fitness and insulin sensitivity may be explained by IHL.

Research Design And Methods: We included 138 overweight to obese, otherwise healthy subjects (aged 43.6 +/- 8.9 years, BMI 33.8 +/- 4 kg/m(2)). Body composition was estimated by bioimpedance analyses. Abdominal fat distribution, intramyocellular, and IHL were assessed by magnetic resonance spectroscopy and tomography. Incremental exercise testing was performed to estimate an individual's CRF. Insulin sensitivity was determined during an oral glucose tolerance test.

Results: For all subjects, CRF was related to insulin sensitivity (r = 0.32, P < 0.05), IHL (r = -0.27, P < 0.05), and visceral (r = -0.25, P < 0.05) and total fat mass (r = -0.32, P < 0.05), but not to intramyocellular lipids (r = -0.08, NS). Insulin sensitivity correlated significantly with all fat depots. In multivariate regression analyses, independent predictors of insulin sensitivity were IHL, visceral fat, and fitness (r(2) = -0.43, P < 0.01, r(2) = -0.34, and r(2) = 0.29, P < 0.05, respectively). However, the positive correlation between fitness and insulin sensitivity was abolished after adjustment for IHL (r = 0.16, NS), whereas it remained significant when adjusted for visceral or total body fat. Further, when subjects were grouped into high versus low IHL, insulin sensitivity was higher in those subjects with low IHL, irrespective of fitness levels.

Conclusions: Our study suggests that the positive effect of increased CRF on insulin sensitivity in overweight to obese subjects may be mediated indirectly through IHL reduction.
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http://dx.doi.org/10.2337/db09-1200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889763PMC
July 2010

Cardiac involvement in sporadic inclusion-body myositis.

Circulation 2010 Feb;121(5):706-8

Franz Volhard Klinik, Helios Klinikum Berlin-Buch, Germany.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.109.866178DOI Listing
February 2010

Assessment of the effect of external counterpulsation on myocardial adaptive arteriogenesis by invasive functional measurements--design of the arteriogenesis network trial 2.

Int J Cardiol 2010 Dec 17;145(3):432-7. Epub 2009 Jun 17.

Franz-Volhard-Klinik, Helios Klinikum Buch, Schwanebecker Chaussee 50, 3125 Berlin, Germany.

Background: Stimulation of collateral artery growth is a promising therapeutic option for patients with coronary artery disease. External counterpulsation is a non-invasive technique suggested to promote the growth of myocardial collateral arteries via increase of shear stress. The Art.Net.2 Trial tests invasively and functionally for the first time the hypothesis whether a treatment course with external counterpulsation (over 7 weeks) can induce the growth of myocardial collateral arteries.

Methods: This study is designed as a prospective, controlled, proof-of-concept study. Inclusion criteria are (1) age 40 to 80 years, (2) stable coronary disease, (3) a residual significant stenosis of at least one epicardial artery and (4) a positive ischemic stress-test for the region of interest. As primary endpoint serves the pressure-derived collateral flow index (CFIp), the invasive gold-standard to assess myocardial collateral pathways. CFIp is determined by simultaneous measurement of mean aortic pressure (Pa, mm Hg), distal coronary occlusive (wedge) pressure (Pw, mm Hg) and central venous pressure (Pv, mm Hg). The index is calculated as CFIp=(Pw-Pv)/(Pa-Pv). The pressure derived fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) are assessed as secondary invasive endpoints to investigate the effect of ECP on the myocardial vasculature. The non-invasive secondary endpoints include symptoms (CCS and NYHA classification), treadmill-testing and analysis of shear-stress related soluble proteins.

Conclusions: The Art.Net.-2 Trial will report within the next months whether direct evidence can be brought that ECP promotes coronary collateral growth in patients with stable angina pectoris.
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http://dx.doi.org/10.1016/j.ijcard.2009.05.050DOI Listing
December 2010

Single lipoprotein apheresis session improves cardiac microvascular function in patients with elevated lipoprotein(a): detection by stress/rest perfusion magnetic resonance imaging.

Ther Apher Dial 2009 Apr;13(2):129-37

Department of Cardiology, HELIOS-Clinic Berlin Buch Charité University Medical School, Berlin, Germany.

The aim of this study was to explore the effects of a single lipoprotein apheresis session on myocardial stress/rest (S/R) perfusion in patients with elevated lipoprotein(a) (Lp(a)) and coronary artery disease using cardiac magnetic resonance imaging. Twenty patients with Lp(a) > 60 mg/dL and coronary artery disease were randomized into a control or a treatment group. Both groups underwent cardiac magnetic resonance imaging with assessment of left ventricular function, perfusion and viability, and the treatment group underwent lipoprotein apheresis immediately afterwards. Repeat magnetic resonance imaging was performed at 24 h for both groups and at 96 h for just the treatment group. The transmyocardial perfusion gradient (i.e. endo-epi ratio [EER]) was determined and a comprehensive parameter of resting and adenosine-induced stress perfusion was derived (EER-S/R). While the hematocrit remained unchanged, apheresis reduced lipoproteins and rheological parameters: Lp(a) - 55.1%, total cholesterol - 34.5%, low density lipoprotein (LDL) - 54.6%, Lp(a)-corrected LDL - 54.3%, high density lipoprotein - 17.4%, apolipoprotein B - 39.2%, plasma viscosity - 10.7%, and fibrinogen - 30.6% at 24 h (P < 0.05 for all). At 96 h these parameters, except for plasma viscosity, apolipoprotein B and Lp(a)-corrected LDL, recovered but did not reach baseline values (P < 0.05 for all). The EER-S/R at 24 h was lowered by therapy (DeltaEER-S/R 5%; P < 0.03), whereas this effect disappeared at 96 h. The ejection fraction (EF) was slightly improved at 24 h (67.07 +/- 6.28% vs. 64.89 +/- 6.39%; DeltaEF 2.2%, P < 0.05) and returned to baseline at 96 h. In the control group no corresponding changes were detected. In conclusion, cardiac magnetic resonance imaging detects subtle treatment-related changes in regional myocardial perfusion in patients with elevated Lp(a) and coronary artery disease undergoing lipoprotein apheresis.
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http://dx.doi.org/10.1111/j.1744-9987.2009.00667.xDOI Listing
April 2009

Cardiac magnetic resonance monitors reversible and irreversible myocardial injury in myocarditis.

JACC Cardiovasc Imaging 2009 Feb;2(2):131-8

Franz-Volhard-Klinik, Kardiologie, Charité Campus Buch, HELIOS-Klinikum Berlin, Universitätsmedizin Berlin, Berlin, Germany.

Objectives: We sought to assess the value of cardiac magnetic resonance (CMR) to monitor the spectrum of myocarditis-related injuries over the course of the disease.

Background: Myocarditis is associated with a wide range of myocardial tissue injuries, both reversible and irreversible. Differentiating these types of injuries is a clinical demand.

Methods: We studied 36 patients (31 males, age 33 +/- 14 years) hospitalized with myocarditis during the acute phase and 18 +/- 10 months thereafter. CMR was performed on 2 1.5T scanners and included the following techniques: steady-state free precession (to assess left ventricular function and volumes), T2-weighted (myocardial edema), early (global relative enhancement [gRE], reflecting increased capillary leakage) and late T1-weighted after gadolinium-DTPA injection (late gadolinium enhancement [LGE], reflecting irreversible injury).

Results: In the acute phase, T2 ratio was elevated in 86%, gRE in 80%, and LGE was present in 63%. At follow-up, ejection fraction increased from 56 +/- 8% to 62 +/- 7% (p < 0.0001) while both T2 ratio (2.4 +/- 0.5 to 1.9 +/- 0.2; p < 0.0001) and gRE (7.6 +/- 8 to 4.4 +/- 4; p = 0.018) significantly decreased. LGE persisted in all but 1 patient in whom LGE completely resolved. No patient had simultaneous elevation of T2 and gRE during the convalescent phase, resulting in a negative predictive value of 100% to differentiate the 2 phases of the disease. The acute phase T2 ratio correlated significantly with the change of end-diastolic volume over time (beta = 0.47; p = 0.008). This relation remained significant in a stepwise regression analysis model including T2 ratio, gRE, LGE extent, baseline ejection fraction, age, and creatine kinase, in which only T2 emerged as an independent predictor of the change in end-diastolic volume.

Conclusions: A comprehensive CMR approach is a useful tool to monitor the reversible and irreversible myocardial tissue injuries over the course of myocarditis and to differentiate acute from healed myocarditis in patients with still-preserved ejection fraction.
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http://dx.doi.org/10.1016/j.jcmg.2008.09.014DOI Listing
February 2009

Gender-specific differences in left ventricular remodelling and fibrosis in hypertrophic cardiomyopathy: insights from cardiovascular magnetic resonance.

Eur J Heart Fail 2008 Sep 9;10(9):850-4. Epub 2008 Aug 9.

Franz-Volhard-Klinik, Kardiologie, Charité Campus Buch, HELIOS-Klinikum Berlin, Universitätsmedizin Berlin, Germany.

Background: Gender is an independent risk factor for heart failure mortality in hypertrophic cardiomyopathy (HCM).

Aims: To explore the interaction between gender, myocardial fibrosis and remodelling in HCM.

Methods: We studied 64 HCM patients (28 females, aged 51+/-16 years) categorized as non-obstructive (HNCM, n=31) or obstructive (HOCM, n=33) and 60 healthy subjects (31 females, aged 43+/-14 years). Cine imaging was performed to assess left ventricular volumes and mass. LV remodelling index (LVRI) was calculated. Extension of late gadolinium enhancement (LGE) was quantified.

Results: Females in the control group and in the HNCM group had a lower LVRI than males (control: 0.7+/-0.1 vs. 0.9+/-0.2 g/ml, p<0.002; HNCM: 1.1+/-0.2 vs. 1.5+/-0.5 g/ml, p<0.001). In contrast, HOCM females had a similar LVRI compared to males (1.8+/-0.5 vs. 1.7+/-0.4 g/ml, p=ns). Thus the increase in LVRI was more pronounced in females compared to males. LGE was noted in 70% of the patients. No relation was found between the presence or the quantity of myocardial fibrosis and gender in any of the patient subgroups.

Conclusion: Our data suggest a disproportionate degree of remodelling in different forms of HCM depending on gender. Gender does not appear to influence the quantity of fibrosis as defined by LGE.
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http://dx.doi.org/10.1016/j.ejheart.2008.06.021DOI Listing
September 2008

Single- or dual-bolus approach for the assessment of myocardial perfusion reserve in quantitative MR perfusion imaging.

Magn Reson Med 2008 Jun;59(6):1373-7

Franz Volhard Klinik, Charite Campus Buch, HELIOS Klinikum-Berlin at the Max Delbrück Center for Molecular Medicine, Berlin, Germany.

A dual-bolus protocol can overcome limitations due to T1-induced MR signal attenuation and hence enables more accurate quantification of myocardial blood flow (MBF) by contrast enhanced MR perfusion imaging. The study explores potential benefits of the dual-bolus technique for the assessment of myocardial perfusion reserve (MPR) over a standard single-bolus protocol. Nineteen patients without obstructive coronary artery disease as assessed by cardiac catheterization underwent a stress-rest MR perfusion study using a dual-bolus protocol. Gd-DTPA dosages of 0.005 and 0.05 mmol/kg of bodyweight were delivered as pre- and main-bolus. For comparison arterial input curves where extracted from left ventricular cavity passage including both, pre-bolus and main-bolus data. Global and segmental MPR were determined from semiquantitative and from full quantitative measures of MBF. As a result good agreement between dual- and single-bolus technique was found with relative differences of maximally 10% in global MPR estimates. For the dual bolus approach a significant relative decrease of 30% (P<0.001) was found for the coefficient of segmental MPR variation, which may allow a more reliable detection of hypoperfused segments in clinical studies.
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http://dx.doi.org/10.1002/mrm.21611DOI Listing
June 2008

Contrast-dose relation in first-pass myocardial MR perfusion imaging.

J Magn Reson Imaging 2007 Jun;25(6):1131-5

Franz Volhard Klinik, Charite Campus Buch, Helios Klinikum-Berlin at the Max Delbrück Center for Molecular Medicine, Wiltbergstrasse 50, 13125 Berlin, Germany.

Purpose: To determine the regime of linear contrast enhancement in human first-pass perfusion cardiovascular magnetic resonance (CMR) imaging to improve accuracy in myocardial perfusion quantification.

Materials And Methods: A total of 10 healthy subjects were studied on a clinical 1.5T MR scanner. Seven doses of Gd-DTPA ranging from 0.00125 to 0.1 mmol/kg of body weight (b.w.) were administered as equal volumes by rapid bolus injection (6 mL/second). Resting periods of 15 minutes were introduced after delivery of Gd doses >0.01 mmol/kg b.w. For each subject, two series of rest perfusion scans were performed using two different multislice saturation-recovery perfusion sequences. Maximum contrast enhancement and maximum upslope were obtained in the blood pool of the left ventricular (LV) cavity and in the myocardium. The range of linear contrast-dose relation was determined by linear regression analysis.

Results: MR signal intensity increased linearly for contrast agent concentrations up to 0.01 mmol/kg b.w. in the LV blood pool and up to 0.05 mmol/kg b.w. in the myocardium. For Gd concentrations exceeding these thresholds the signal intensity response was not linear with respect to the contrast agent dose.

Conclusion: Quantitative evaluation of cardiac MR perfusion data needs to account for signal saturation in both the LV blood pool and the myocardium.
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http://dx.doi.org/10.1002/jmri.20910DOI Listing
June 2007

Structure-selectivity investigations of D2-like receptor ligands by CoMFA and CoMSIA guiding the discovery of D3 selective PET radioligands.

J Med Chem 2007 Feb;50(3):489-500

Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.

Elucidation of the physiological role of the D3 receptor and its distribution in the brain using positron emission tomography (PET) is hampered by the lack of bioavailable subtype selective tracer ligands. To develop appropriate D3 radioligands, we designed an integrative procedure involving the elucidation of structural features determining D3 selectivity over both congeners D2 and D4 by comparative molecular analysis. Thus, we have successfully generated CoMFA and CoMSIA models based on the affinitiy differences of a series of 79 ligands representing a broad range of selectivities. These models yielded highly significant cross-validations (q2cv(D3/D2) = 0.86; q2cv(D3/D4) = 0.92) and excellent predictions of a 16-ligand test set (r2pred = 0.79-0.93). Exploiting this information, synthesis and receptor binding studies directed us to the fluorinated lead compounds 78 and 79, featuring subnanomolar D3 affinities and considerable selectivities over D2 and D4 and, subsequently, to the subtype selective PET tracers [18F]78 and [18F]79.
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http://dx.doi.org/10.1021/jm0611152DOI Listing
February 2007

CoMFA and CoMSIA investigations of dopamine D3 receptor ligands leading to the prediction, synthesis, and evaluation of rigidized FAUC 365 analogues.

Bioorg Med Chem 2006 Sep 5;14(17):5898-912. Epub 2006 Jun 5.

Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.

Taking advantage of our in-house experimental data on dopamine D3 receptor modulators, we have successfully established highly significant CoMFA and CoMSIA models (q(cv)2 = 0.82/0.76). These models were carefully investigated to assure their stability and predictivity (r(pred)2 = 0.65/0.61) and subsequently applied to guide experimental investigations on the synthesis and receptor binding of three conformationally restricted D3 ligands. Besides the high D3 affinity, the test compound 45, incorporating a trans-1,4-cyclohexylene partial structure, exhibited improved (approximately 3200-fold) selectivity over the D4 subtype.
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http://dx.doi.org/10.1016/j.bmc.2006.05.025DOI Listing
September 2006

Blood oxygen level-dependent MRI of tissue oxygenation: relation to endothelium-dependent and endothelium-independent blood flow changes.

Arterioscler Thromb Vasc Biol 2005 Jul 12;25(7):1408-13. Epub 2005 May 12.

Medical Faculty of the Charité, Franz Volhard Klinik HELIOS Klinikum-Berlin at the Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Objectives: The contribution of endothelial function to tissue oxygenation is not well understood. Muscle blood oxygen level-dependent MRI (BOLD MRI) provides data largely dependent on hemoglobin (Hb) oxygenation. We used BOLD MRI to assess endothelium-dependent signal intensity (SI) changes.

Methods And Results: We investigated mean BOLD SI changes in the forearm musculature using a gradient-echo technique at 1.5 T in 9 healthy subjects who underwent a protocol of repeated acetylcholine infusions at 2 different doses (16 and 64 microg/min) and N(G)-monomethyl-L-arginine (L-NMMA; 5 mg/min) into the brachial artery. Sodium nitroprusside was used as a control substance. For additional correlation with standard methods, the same protocol was repeated, and forearm blood flow was measured by strain gauge plethysmography. We obtained a significant increase in BOLD SI during acetylcholine infusion (64 microg/min) and a significant decrease for L-NMMA infusion (P<0.005 for both). BOLD SI showed a different kinetic signal than did blood flow, particularly after intermittent ischemia and at high flow rates.

Conclusions: In standard endothelial function tests, BOLD MRI detects a dissociation of tissue Hb oxygenation from blood flow. BOLD MRI may be a useful adjunct in assessing endothelial function.
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http://dx.doi.org/10.1161/01.ATV.0000170131.13683.d7DOI Listing
July 2005

CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.

J Med Chem 2005 Apr;48(7):2493-508

Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.

As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
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http://dx.doi.org/10.1021/jm049269+DOI Listing
April 2005
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