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Aims Acute myocardial infarction (MI) is the major cause of chronic heart failure. The activity of blood coagulation factor XIII (FXIIIa) plays an important role in rodents as a healing factor after MI, whereas its role in healing and remodelling processes in humans remains unclear. We prospectively evaluated the relevance of FXIIIa after acute MI as a potential early prognostic marker for adequate healing.
Methods and results This monocentric prospective cohort study investigated cardiac remodelling in patients with ST-elevation MI and followed them up for 1 year. Serum FXIIIa was serially assessed during the first 9 days after MI and after 2, 6, and 12 months. Cardiac magnetic resonance imaging was performed within 4 days after MI (Scan 1), after 7 to 9 days (Scan 2), and after 12 months (Scan 3). The FXIII valine-to-leucine (V34L) single-nucleotide polymorphism rs5985 was genotyped. One hundred forty-six patients were investigated (mean age 58 ± 11 years, 13% women). Median FXIIIa was 118 % (quartiles, 102–132%) and dropped to a trough on the second day after MI: 109%(98–109%; P < 0.001). FXIIIa recovered slowly over time, reaching the baseline level after 2 to 6 months and surpassed baseline levels only after 12 months: 124 % (110–142%). The development of FXIIIa after MI was independent of the genotype. FXIIIa on Day 2 was strongly and inversely associated with the relative size of MI in Scan 1 (Spearman’s ρ = –0.31; P = 0.01) and Scan 3 (ρ = –0.39; P < 0.01) and positively associated with left ventricular ejection fraction: ρ = 0.32 (P < 0.01) and ρ = 0.24 (P = 0.04), respectively.
Conclusions FXIII activity after MI is highly dynamic, exhibiting a significant decline in the early healing period, with reconstitution 6 months later. Depressed FXIIIa early after MI predicted a greater size of MI and lower left ventricular ejection fraction after 1 year. The clinical relevance of these findings awaits to be tested in a randomized trial.
Although heart failure following myocardial infarction (MI) represents a major health burden, underlying microstructural and functional changes remain incompletely understood. Here, we report on a case of unexpected MI after treatment with the catecholamine isoproterenol in an experimental imaging study in mice using different state-of-the-art imaging modalities. The decline in cardiac function was documented by ultrahigh-frequency echocardiography and speckle-tracking analyses. Myocardial microstructure was studied ex vivo at a spatial resolution of 100 × 100 × 100 μm\(^{3}\) using diffusion tensor magnetic resonance imaging (DT-MRI) and histopathologic analyses. Two weeks after ISO treatment, the animal showed an apical aneurysm accompanied by reduced radial strain in corresponding segments and impaired global systolic function. DT-MRI revealed a loss of contractile fiber tracts together with a disarray of remaining fibers as corresponding microstructural correlates. This preclinical case report provides valuable insights into pathophysiology and morphologic–functional relations of heart failure following MI using emerging imaging technologies.
Background
Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region.
Methods
The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals.
Results
Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31%), mainly in secondary stroke prevention; b) improvement over time (44%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period.
Conclusion
The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.
Purpose:
Bolus‐based dynamic contrast agent (CA) perfusion measurements of the heart are subject to systematic errors due to CA bolus dispersion in the coronary arteries. To better understand these effects on quantification of myocardial blood flow and myocardial perfusion reserve (MPR), an in‐silico model of the coronary arteries down to the pre‐arteriolar vessels has been developed.
Methods:
In this work, a computational fluid dynamics analysis is performed to investigate these errors on the basis of realistic 3D models of the left and right porcine coronary artery trees, including vessels at the pre‐arteriolar level. Using advanced boundary conditions, simulations of blood flow and CA transport are conducted at rest and under stress. These are evaluated with regard to dispersion (assessed by the width of CA concentration time curves and associated vascular transport functions) and errors of myocardial blood flow and myocardial perfusion reserve quantification.
Results:
Contrast agent dispersion increases with traveled distance as well as vessel diameter, and decreases with higher flow velocities. Overall, the average myocardial blood flow errors are −28% ± 16% and −8.5% ± 3.3% at rest and stress, respectively, and the average myocardial perfusion reserve error is 26% ± 22%. The calculated values are different in the left and right coronary tree.
Conclusion:
Contrast agent dispersion is dependent on a complex interplay of several different factors characterizing the cardiovascular bed, including vessel size and integrated vascular length. Quantification errors evoked by the observed CA dispersion show nonnegligible distortion in dynamic CA bolus‐based perfusion measurements. We expect future improvements of quantitative perfusion measurements to make the systematic errors described here more apparent.
L-type calcium channels (LTCCs) control crucial physiological processes in cardiomyocytes such as the duration and amplitude of action potentials, excitation-contraction coupling and gene expression, by regulating the entry of Ca2+ into the cells. Cardiac LTCCs consist of one pore-forming α1 subunit and the accessory subunits Cavβ, Cavα2δ and Cavγ. Of these auxiliary subunits, Cavβ is the most important regulator of the channel activity; however, it can also have LTCC-independent cellular regulatory functions. Therefore, changes in the expression of Cavβ can lead not only to a dysregulation of LTCC activity, but also to changes in other cellular functions. Cardiac hypertrophy is one of the most relevant risk factors for congestive heart failure and depends on the activation of calcium-dependent prohypertrophic signaling pathways. However, the role of LTCCs and especially Cavβ in this pathology is controversial and needs to be further elucidated.
Of the four Cavβ isoforms, Cavβ2 is the predominant one in cardiomyocytes. Moreover, there are five different splice variants of Cavβ2 (Cavβ2a-e), differing only in the N-terminal region. We reported that Cavβ2b is the predominant variant expressed in the heart. We also revealed that a pool of Cavβ2 is targeted to the nucleus in cardiomyocytes. The expression of the nuclear Cavβ2 decreases during in vitro and in vivo induction of cardiomyocyte hypertrophy and overexpression of a nucleus-targeted Cavβ2 completely abolishes the in vitro induced hypertrophy. Additionally, we demonstrated by shRNA-mediated protein knockdown that downregulation of Cavβ2 enhances the hypertrophy induced by the α1-adrenergic agonist phenylephrine (PE) without involvement of LTCC activity. These results suggest that Cavβ2 can regulate cardiac hypertrophy through LTCC-independent pathways. To further validate the role of the nuclear Cavβ2, we performed quantitative proteome analyses of Cavβ2-deficient neonatal rat cardiomyocytes (NRCs). The results show that downregulation of Cavβ2 influences the expression of various proteins, including a decrease of calpastatin, an inhibitor of the calcium-dependent cysteine protease calpain. Moreover, downregulation of Cavβ2 during cardiomyocyte hypertrophy drastically increases calpain activity as compared to controls after treatment with PE. Finally, the inhibition of calpain by calpeptin abolishes the increase in PE-induced hypertrophy in Cavβ2-deficient cells. These results suggest that nuclear Cavβ2 has Ca2+- and LTCC-independent functions during the development of hypertrophy. Overall, our results indicate a new role for Cavβ2 in antihypertrophic signaling in cardiac hypertrophy.
A novel mono-surface antisymmetric 16-element transmit/receive (Tx/Rx) coil array was designed, simulated, constructed, and tested for cardiac magnetic resonance imaging (cMRI) in pigs at 7T. The cardiac array comprised of a mono-surface 16-loops with two central elements arranged antisymmetrically and flanked by seven elements on either side. The array was configured for parallel transmit (pTx) mode to have an eight channel transmit and 16-channel receive (8Tx/16Rx) coil array. Electromagnetic (EM) simulations, bench-top measurements, phantom, and MRI experiments with two pig cadavers (68 and 46 kg) were performed. Finally, the coil was used in pilot in-vivo measurements with a 60 kg pig. Flip angle (FA), geometry factor (g-factor), signal-to-noise ratio (SNR) maps, and high-resolution cardiac images were acquired with an in-plane resolution of 0.6 mm x 0.6 mm (in-vivo) and 0.3 mm x 0.3 mm (ex-vivo). The mean g-factor over the heart was 1.26 (R = 6). Static phase B-1(+) shimming in a pig body phantom with the optimal phase vectors makes possible to improve the B-1(+) homogeneity by factor > 2 and transmit efficiency by factor > 3 compared to zero phases (before RF shimming). Parallel imaging performed in the in-vivo measurements demonstrated well preserved diagnostic quality of the resulting images at acceleration factors up to R = 6. The described hardware design can be adapted for arrays optimized for animals and humans with a larger number of elements (32-64) while maintaining good decoupling for various MRI applications at UHF (e.g., cardiac, head, and spine).
Einleitung:
TRPC-Kanäle spielen eine wichtige Rolle in der Pathologie der Herzinsuffizienz und kardialen Hypertrophie. Diese Effekte werden unter anderem über den Calcineurin-NFAT-Signalweg vermittelt. Ein wichtiger Interaktionspartner und Regulator von TRPC-Kanälen ist das Protein FKBP52. Mittels eines Yeast Two-Hybrid Systems wurde in einer kardialen cDNA library eine Interaktion zwischen einem C-terminalen Fragment von TRPC3 (AS 742-848), welches außerhalb der bekannten FKBP-Bindungsdomäne (AS 703-714) liegt, und FKBP52 beobachtet. Da dies eine weitere Bindungsstelle in FKBP52 vermuten ließ, erzeugten wir ein Fragment von FKBP52, welches FKBP52s genannt wurde und dem die funktionell relevante PPIase I-Domäne mit der bekannten Bindungsstelle fehlt. Eine erste Co-IP zwischen diesem Fragment und TRPC3 war erfolgreich.
Ziel:
Die Bestimmung, ob die Anwesenheit des verkürzten FKBP52 in vivo die Komplexbildung aus TRPC3 bzw. TRPC4 und dem Wildtyp-FKBP52 unterdrückt. Zusätzlich, ob FKBP52s die Interaktion zwischen TRPC3 bzw. TRPC4 und Calcineurin in vivo unterbricht und damit die Aktivierung des Calcineurin-NFAT-Signalweges hemmt.
Methoden:
Co-Immunopräzipitationen (Co-IP) wurden mit HEK-293-Zellen durchgeführt, die mit cDNA transfiziert wurden, welche Gene für TRPC3, TRPC4, Calcineurin A und FKBP52s enthielt. Zur Bestimmung der nukleären Translokation von NFATc1 mittels Fluoreszenzmikroskopie wurden HEK-293-Zellen mit TRPC3, TRPC4, GFP-NFATc1 ± FKBP52s transfiziert. Die statistische Analyse erfolgte mit einer One-Way ANOVA.
Ergebnisse:
In dieser Arbeit konnte gezeigt werden, dass FKBP52 sowohl mit TRPC3 als auch mit TRPC4 interagiert. Ebenso wurde festgestellt, dass FKBP52 auch ohne seine katalytische PPIase I-Domäne Bindungen mit TRPC3 bzw. TRPC4 eingeht. Dieses FKBP52-Konstrukt nimmt ebenso an der Komplexbildung mit TRPC3 bzw. TRPC4 und Calcineurin teil. Des Weiteren ließ sich für TRPC3 zeigen, dass unter Stimulation mit Carbachol (GPCR-Agonist) bei Anwesenheit dieses gekürzten FKBP52 eine signifikant geringere Aktivierung und Wanderung des Transkriptionsfaktors NFAT in den Nucleus erfolgte.
Schlussfolgerung:
FKBP52 spielt daher eine wichtige Rolle in dieser Signalkaskade, indem es entscheidend an der Aktivierung von Calcineurin und dessen Rekrutierung zum TRPC-Kanalkomplex beteiligt ist und damit auch an der Aktivierung des Calcineurin-NFAT-Signalweges.
Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.
Die nicht-invasive Gefäßdiagnostik stellt einen wichtigen Pfeiler in der Prävention von Herz-Kreislauferkrankungen dar. Während lange Zeit die sonographische Messung der cIMT, als morphologisches Korrelat der Gefäßalterung, als Goldstandard galt, ist in den letzten Jahren in Gestalt der Pulswellenanalyse/PWV-Messung eine Technik weiterentwickelt worden, die, als funktionelles Korrelat der Gefäßalterung, aufgrund der leichteren Durchführbarkeit und geringerer Untersucherabhängigkeit und Kosten vielversprechend ist. So erlaubt die Messung der Pulswelle mittels gewöhnlicher Blutdruckmanschetten, genau wie die cIMT, die Berechnung des individuellen Gefäßalters und die Diagnostik für das Vorliegen eines Endorganschadens der Blutgefäße.
Um die Messergebnisse der beiden Untersuchungen miteinander zu vergleichen, wurden beide in der EUROASPIRE-IV Studie an Patienten mit koronarer Herzkrankheit durchgeführt. Die Auswertung der Messergebnisse der mit dem Vascular Explorer durchgeführten Pulswellenanalyse/PWV-Messung ergab überraschenderweise, dass die Mehrheit der herzkranken Patienten weder eine vaskuläre Voralterung noch einen Endorganschaden der Blutgefäße aufweisen. Im Falle der cIMT-Messung war Gegenteiliges der Fall, was trotz der medikamentösen Therapie der Patienten so zu erwarten war. Weiterhin zeigte sich lediglich eine geringe Korrelation zwischen den Messergebnissen beider Untersuchungen. Die Determinanten der einzelnen Messwerte aus cIMT und Pulswellenanalyse/PWV-Messung waren deckungsgleich mit den in der Literatur beschriebenen Faktoren, wenn auch viele der sonst signifikanten Regressoren das Signifikanzniveau in unserer Auswertung nicht unterschritten.
Eine Limitation der funktionellen Gefäßdiagnostik liegt derzeit darin, dass die Messergebnisse stark von dem verwendeten Messgerät abhängen. Es liegen noch zu wenig Vergleichsstudien vor, um die Messergebnisse, speziell von neueren Geräten wie dem Vascular Explorer, auf andere zu übertragen. Bei der Berechnung des Gefäßalters sollten daher optimalerweise gerätespezifische Normwerte vorliegen, was beim Vascular Explorer nicht der Fall ist. Gleiches gilt für die Verwendung des PWVcf-Grenzwerts für die Diagnose eines Endorganschadens der Blutgefäße.
Analog hat auch die Messung der cIMT gewisse Einschränkungen. So wäre eine weitere Standardisierung der Messorte (A. carotis communis vs Bulbus vs A. carotis interna), zwischen denen sich die durchschnittliche cIMT erheblich unterscheidet, sowie der Messparameter (Minimal- vs Maximal- vs Mittelwert) wünschenswert. Die universelle Anwendung eines cIMT-Grenzwerts zur Diagnose eines Endorganschadens der Blutgefäße ist daher kritisch zu sehen. Dies zeigt sich auch darin, dass in den neuesten Leitlinien der bislang geltende Grenzwert angezweifelt und kein aktuell gültiger Grenzwert mehr genannt wird.
Wir interpretieren unsere Ergebnisse dahingehend, dass unsere Messung der cIMT die zu erwartende pathologische Gefäßalterung bei Patienten mit koronarer Herzkrankheit besser widerspiegelt als die Messung der Pulswelle mit dem Vascular Explorer. Welche der beiden Untersuchungen hinsichtlich der prognostischen Wertigkeit überlegen ist, muss im Rahmen von Längsschnittstudien geklärt werden.
Background
Small-animal single-photon emission computed tomography (SPECT) systems with multi-pinhole collimation and large stationary detectors have advantages compared to systems with moving small detectors. These systems benefit from less labour-intensive maintenance and quality control as fewer prone parts are moving, higher accuracy for focused scans and maintaining high resolution with increased sensitivity due to focused pinholes on the field of view. This study aims to investigate the performance of a novel ultra-high-resolution scanner with two-detector configuration (U-SPECT5-E) and to compare its image quality to a conventional micro-SPECT system with three stationary detectors (U-SPECT\(^+\)).
Methods
The new U-SPECT5-E with two stationary detectors was used for acquiring data with \(^{99m}\)Tc-filled point source, hot-rod and uniformity phantoms to analyse sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR). Three dedicated multi-pinhole mouse collimators with 75 pinholes each and 0.25-, 0.60- and 1.00-mm pinholes for extra ultra-high resolution (XUHR-M), general-purpose (GP-M) and ultra-high sensitivity (UHS-M) imaging were examined. For CNR analysis, four different activity ranges representing low- and high-count settings were investigated for all three collimators. The experiments for the performance assessment were repeated with the same GP-M collimator in the three-detector U-SPECT\(^+\) for comparison.
Results
Peak sensitivity was 237 cps/MBq (XUHR-M), 847 cps/MBq (GP-M), 2054 cps/MBq (UHS-M) for U-SPECT5-E and 1710 cps/MBq (GP-M) for U-SPECT\(^+\). In the visually analysed sections of the reconstructed mini Derenzo phantoms, rods as small as 0.35 mm (XUHR-M), 0.50 mm (GP-M) for the two-detector as well as the three-detector SPECT and 0.75 mm (UHS-M) were resolved. Uniformity for maximum resolution recorded 40.7% (XUHR-M), 29.1% (GP-M, U-SPECT5-E), 16.3% (GP-M, U-SPECT\(^+\)) and 23.0% (UHS-M), respectively. UHS-M reached highest CNR values for low-count images; for rods smaller than 0.45 mm, acceptable CNR was only achieved by XUHR-M. GP-M was superior for imaging rods sized from 0.60 to 1.50 mm for intermediate activity concentrations. U-SPECT5-E and U-SPECT+ both provided comparable CNR.
Conclusions
While uniformity and sensitivity are negatively affected by the absence of a third detector, the investigated U-SPECT5-E system with two stationary detectors delivers excellent spatial resolution and CNR comparable to the performance of an established three-detector-setup.