Regional analysis of inflammation and contractile function in reperfused acute myocardial infarction by in vivo 19F cardiovascular magnetic resonance in pigs.

Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and regional and global LV function is not clear. Here we noninvasively characterized regional inflammation and contractile function in reperfused AMI in pigs using fluorine (19F) cardiovascular magnetic resonance (CMR). Adult anesthetized pigs underwent left anterior descending coronary artery instrumentation with either 90 min occlusion (n = 17) or without occlusion (sham, n = 5). After 3 days, in surviving animals a perfluorooctyl bromide nanoemulsion was infused intravenously to label monocytes/macrophages. At day 6, in vivo 1H-CMR was performed with cine, T2 and T2* weighted imaging, T2 and T1 mapping, perfusion and late gadolinium enhancement followed by 19F-CMR. Pigs were sacrificed for subsequent ex vivo scans and histology. Edema extent was 35 ± 8% and IS was 22 ± 6% of LV mass. Six of ten surviving AMI animals displayed both MVO and IMH (3.3 ± 1.6% and 1.9 ± 0.8% of LV mass). The 19F signal, reflecting the presence and density of monocytes/macrophages, was consistently smaller than edema volume or IS and not apparent in remote areas. The 19F signal-to-noise ratio (SNR) > 8 in the infarct border zone was associated with impaired remote systolic wall thickening. A whole heart value of 19F integral (19F SNR × milliliter) > 200 was related to initial LV remodeling independently of edema, IS, MVO, and IMH. Thus, 19F-CMR quantitatively characterizes regional inflammation after AMI and its relation to edema, IS, MVO, IMH and regional and global LV function and remodeling.

Quantifying the Dzyaloshinskii-Moriya Interaction Induced by the Bulk Magnetic Asymmetry.

A broken interfacial inversion symmetry in ultrathin ferromagnet/heavy metal (FM/HM) bilayers is generally believed to be a prerequisite for accommodating the Dzyaloshinskii-Moriya interaction (DMI) and for stabilizing chiral spin textures. In these bilayers, the strength of the DMI decays as the thickness of the FM layer increases and vanishes around a few nanometers. In the present study, through synthesizing relatively thick films of compositions CoPt or FePt, CoCu or FeCu, FeGd and FeNi, contributions to DMI from the composition gradient-induced bulk magnetic asymmetry (BMA) and spin-orbit coupling (SOC) are systematically examined. Using Brillouin light scattering spectroscopy, both the sign and amplitude of DMI in films with controllable direction and strength of BMA, in the presence and absence of SOC, are experimentally studied. In particular, we show that a sizable amplitude of DMI (±0.15 mJ/m^{2}) can be realized in CoPt or FePt films with BMA and strong SOC, whereas negligible DMI strengths are observed in other thick films with BMA but without significant SOC. The pivotal roles of BMA and SOC are further examined based on the three-site Fert-Lévy model and first-principles calculations. It is expected that our findings may help to further understand the origin of chiral magnetism and to design novel noncollinear spin textures.

Time Refraction of Spin Waves.

We present an experimental study of time refraction of spin waves (SWs) propagating in microscopic waveguides under the influence of time-varying magnetic fields. Using space- and time-resolved Brillouin light scattering microscopy, we demonstrate that the broken translational symmetry along the time coordinate results in a loss of energy conservation for SWs and thus allows for a broadband and controllable shift of the SW frequency. With an integrated design of SW waveguide and microscopic current line for the generation of strong, nanosecond-long, magnetic field pulses, a conversion efficiency up to 39% of the carrier SW frequency is achieved, significantly larger compared to photonic systems. Given the strength of the magnetic field pulses and its strong impact on the SW dispersion relation, the effect of time refraction can be quantified on a length scale comparable to the SW wavelength. Furthermore, we utilize time refraction to excite SW bursts with pulse durations in the nanosecond range and a frequency shift depending on the pulse polarity.

Nonlocal Stimulation of Three-Magnon Splitting in a Magnetic Vortex.

We present a combined numerical, theoretical, and experimental study on stimulated three-magnon splitting in a magnetic disk in the vortex state. Our micromagnetic simulations and Brillouin-light-scattering results confirm that three-magnon splitting can be triggered even below threshold by exciting one of the secondary modes by magnons propagating in a waveguide next to the disk. The experiments show that stimulation is possible over an extended range of excitation powers and a wide range of frequencies around the eigenfrequencies of the secondary modes. Rate-equation calculations predict an instantaneous response to stimulation and the possibility to prematurely trigger three-magnon splitting even above threshold in a sustainable manner. These predictions are confirmed experimentally using time-resolved Brillouin-light-scattering measurements and are in a good qualitative agreement with the theoretical results. We believe that the controllable mechanism of stimulated three-magnon splitting could provide a possibility to utilize magnon-based nonlinear networks as hardware for neuromorphic computing.

Domain Wall Based Spin-Hall Nano-Oscillators.

In the last decade, two revolutionary concepts in nanomagnetism emerged from research for storage technologies and advanced information processing. The first suggests the use of magnetic domain walls in ferromagnetic nanowires to permanently store information in domain-wall racetrack memories. The second proposes a hardware realization of neuromorphic computing in nanomagnets using nonlinear magnetic oscillations in the gigahertz range. Both ideas originate from the transfer of angular momentum from conduction electrons to localized spins in ferromagnets, either to push data encoded in domain walls along nanowires or to sustain magnetic oscillations in artificial neurones. Even though both concepts share a common ground, they live on very different timescales which rendered them incompatible so far. Here, we bridge both ideas by demonstrating the excitation of magnetic auto-oscillations inside nanoscale domain walls using pure spin currents. This Letter will shed light on the current characteristic and spatial distribution of the excited auto-oscillations.

Excitation of Whispering Gallery Magnons in a Magnetic Vortex.

We present the generation of whispering gallery magnons with unprecedented high wave vectors via nonlinear 3-magnon scattering in a µm-sized magnetic Ni_{81}Fe_{19} disc which is in the vortex state. These modes exhibit a strong localization at the perimeter of the disc and practically zero amplitude in an extended area around the vortex core. They originate from the splitting of the fundamental radial magnon modes, which can be resonantly excited in a vortex texture by an out-of-plane microwave field. We shed light on the basics of this nonlinear scattering mechanism from an experimental and theoretical point of view. Using Brillouin light scattering microscopy, we investigated the frequency and power dependence of the 3-magnon splitting. The spatially resolved mode profiles give evidence for the localization at the boundaries of the disc and allow for a direct determination of the modes wave number.

Improved diagnosis of idiopathic giant cell myocarditis and cardiac sarcoidosis by myocardial gene expression profiling.

AIMS: Improvement of clinical diagnostics of idiopathic giant cell myocarditis (IGCM) and cardiac sarcoidosis (CS), two frequently fatal human myocardial diseases. Currently, IGCM and CS are diagnosed based on differential patterns of inflammatory cell infiltration and non-caseating granulomas in histological sections of endomyocardial biopsies (EMBs), after heart explantation or postmortem. We report on a method for improved differential diagnosis by myocardial gene expression profiling in EMBs. METHODS AND RESULTS: We examined gene expression profiles in EMBs from 10 patients with histopathologically proven IGCM, 10 with CS, 18 with active myocarditis (MCA), and 80 inflammation-free control subjects by quantitative RT-QPCR. We identified distinct differential profiles that allowed a clear discrimination of tissues harbouring giant cells (IGCS, CS) from those with MCA or inflammation-free controls. The expression levels of genes coding for cytokines or chemokines (CCL20, IFNB1, IL6, IL17D; P < 0.05), cellular receptors (ADIPOR2, CCR5, CCR6, TLR4, TLR8; P < 0.05), and proteins involved in the mitochondrial energy metabolism (CPT1, CYB, DHODH; P < 0.05) were deregulated in 2- to 300-fold, respectively. Bioinformatic analyses and correlation of the gene expression data with immunohistochemical findings provided novel information regarding the differential cellular and molecular pathomechanisms in IGCM, CS, and MCA. CONCLUSION: Myocardial gene expression profiling is a reliable method to predict the presence of multinuclear giant cells in the myocardium, even without a direct histological proof, in single small EMB sections, and thus to reduce the risk of sampling errors. This profiling also facilitates the discrimination between IGCM and CS, as two different clinical entities that require immediate and tailored differential therapy.

Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses.

Adiponectin (APN) is an immunomodulatory adipocytokine that improves outcome in patients with virus-negative inflammatory cardiomyopathy and mice with autoimmune myocarditis. Here, we investigated whether APN modulates cardiac inflammation and injury in coxsackievirus B3 (CVB3) myocarditis. Myocarditis was induced by CVB3 infection of APN-KO and WT mice. APN reconstitution was performed by adenoviral gene transfer. Expression analyses were performed by qRT-PCR and immunoblot. Cardiac histology was analyzed by H&E-stain and immunohistochemistry. APN-KO mice exhibited diminished subacute myocarditis with reduced viral load, attenuated inflammatory infiltrates determined by NKp46, F4/80 and CD3/CD4/CD8 expression and reduced IFNß, IFNγ, TNFα, IL-1ß and IL-12 levels. Moreover, myocardial injury assessed by necrotic lesions and troponin I release was attenuated resulting in preserved left ventricular function. Those changes were reversed by APN reconstitution. APN had no influence on adhesion, uptake or replication of CVB3 in cardiac myocytes. In acute CVB3 myocarditis, cardiac viral load did not differ between APN-KO and WT mice. However, APN-KO mice displayed an enhanced acute immune response, i.e. increased expression of myocardial CD14, IFNß, IFNγ, IL-12, and TNFα resulting in increased cardiac infiltration with pro-inflammatory M1 macrophages and activated NK cells. Up-regulation of cardiac CD14 expression, type I and II IFNs and inflammatory cell accumulation in APN-KO mice was inhibited by APN reconstitution. Our observations indicate that APN promotes CVB3 myocarditis by suppression of toll-like receptor-dependent innate immune responses, polarization of anti-inflammatory M2 macrophages and reduction of number and activation of NK cells resulting in attenuated acute anti-viral immune responses.

Etiologies and predictors of mortality in an all-comer population of patients with non-ischemic heart failure.

BACKGROUND: Despite progress in diagnosis and therapy of heart failure (HF), etiology and risk stratification remain elusive in many patients. METHODS: The My Biopsy HF Study (German clinical trials register number: DRKS22178) is a retrospective monocentric study investigating an all-comer population of patients with unexplained HF based on a thorough workup including endomyocardial biopsy (EMB). RESULTS: 655 patients (70.9% men, median age 55 [45/66] years) with non-ischemic, non-valvular HF were included in the analyses. 489 patients were diagnosed with HF with reduced ejection fraction (HFrEF), 52 patients with HF with mildly reduced ejection fraction (HFmrEF) and 114 patients with HF with preserved ejection fraction (HFpEF). After a median follow-up of 4.6 (2.5/6.6) years, 94 deaths were enumerated (HFrEF: 68; HFmrEF: 8; HFpEF: 18), equating to mortality rates of 3.3% and 11.6% for patients with HFrEF, 7.7% and 15.4% for patients with HFmrEF and 5.3% and 11.4% for patients with HFpEF after 1 and 5 years, respectively. In EMB, we detected a variety of putative etiologies of HF, including incidental cardiac amyloidosis (CA, 5.8%). In multivariate logistic regression analysis adjusting for age, sex and comorbidities only CA, age and NYHA functional class III + IV remained independently associated with all-cause mortality (CA: HRperui 3.13, 95% CI 1.5-6.51; p = 0.002). CONCLUSIONS: In an all-comer population of patients presenting with HF of unknown etiology, incidental finding of CA stands out to be independently associated with all-cause mortality. Our findings suggest that prospective trials would be helpful to test the added value of a systematic and holistic work-up of HF of unknown etiology.

A distinct subgroup of cardiomyopathy patients characterized by transcriptionally active cardiotropic erythrovirus and altered cardiac gene expression.

Recent studies have detected erythrovirus genomes in the hearts of cardiomyopathy and cardiac transplant patients. Assessment of the functional status of viruses may provide clinically important information beyond detection of the viral genomes. Here, we report transcriptional activation of cardiotropic erythrovirus to be associated with strongly altered myocardial gene expression in a distinct subgroup of cardiomyopathy patients. Endomyocardial biopsies (EMBs) from 415 consecutive cardiac erythrovirus (B19V)-positive patients with clinically suspected cardiomyopathy were screened for virus-encoded VP1/VP2 mRNA indicating transcriptional activation of the virus, and correlated with cardiac host gene expression patterns in transcriptionally active versus latent infections, and in virus-free control hearts. Transcriptional activity was detected in baseline biopsies of only 66/415 patients (15.9 %) harbouring erythrovirus. At the molecular level, significant differences between cardiac B19V-positive patients with transcriptionally active versus latent virus were revealed by expression profiling of EMBs. Importantly, latent B19V infection was indistinguishable from controls. Genes involved encode proteins of antiviral immune response, B19V receptor complex, and mitochondrial energy metabolism. Thus, functional mapping of erythrovirus allows definition of a subgroup of B19V-infected cardiomyopathy patients characterized by virus-encoded VP1/VP2 transcripts and anomalous host myocardial transcriptomes. Cardiac B19V reactivation from latency, as reported here for the first time, is a key factor required for erythrovirus to induce altered cardiac gene expression in a subgroup of cardiomyopathy patients. Virus genome detection is insufficient to assess pathogenic potential, but additional transcriptional mapping should be incorporated into future pathogenetic and therapeutic studies both in cardiology and transplantation medicine.

Alternatively spliced tissue factor and full-length tissue factor protect cardiomyocytes against TNF-α-induced apoptosis.

Tissue Factor (TF) is expressed in various cell types of the heart, such as cardiomyocytes. In addition to its role in the initiation of blood coagulation, the TF:FVIIa complex protects cells from apoptosis. There are two isoforms of Tissue Factor (TF): "full length" (fl)TF--an integral membrane protein, and alternatively spliced (as)TF--a protein that lacks a transmembrane domain and can thus be secreted in a soluble form. Whether asTF or flTF affects apoptosis of cardiomyocytes is unknown. In this study, we examined whether asTF or flTF protects murine cardiomyocytes from TNF-α-induced apoptosis. We used murine cardiomyocytic HL-1 cells and primary murine embryonic cardiomyocytes that overexpressed either murine asTF or murine flTF, and stimulated them with TNF-α to initiate cell death. Apoptosis was assessed by annexin-V assay, propidium iodide assay, as well as activation of caspase-3 and -9. In addition, signaling via integrins, Akt, NFκB and Erk1/2, and gene-expression of Bcl-2 family members were analyzed. We here report that overexpression of asTF reduced phosphatidylserine exposure upon TNF-α-stimulation. asTF overexpression led to an increased expression and phosphorylation of Akt, as well as up-regulation of the anti-apoptotic protein Bcl-x(L). The anti-apoptotic effects of asTF overexpression were mediated via α(V)ß(3)/Akt/NFκB signaling and were dependent on Bcl-x(L) expression in HL-1 cells. The anti-apoptotic activity of asTF was also observed using primary cardiomyocytes. Analogous yet less pronounced anti-apoptotic sequelae were observed due to overexpression of flTF. Importantly, cardiomyocytes deficient in TF exhibited increased apoptosis compared to wild type cells. We propose that asTF and flTF protect cardiomyocytes against TNF-α-induced apoptosis via activation of specific signaling pathways, and up-regulation of anti-apoptotic members of the Bcl-2 protein family.

Transgenic overexpression of the adenine nucleotide translocase 1 protects cardiomyocytes against TGFß1-induced apoptosis by stabilization of the mitochondrial permeability transition pore.

AIMS: Since adenine nucleotide translocase 1 (ANT1) overexpression improved cardiac function in rats with activated renin-angiotensin system (RAS) and angiotensin II is known to enhance transforming growth factor ß (TGFß) signaling in cardiomyocytes, we assumed that ANT1 might modulate the classical TGFß/SMAD pathway. We therefore investigated whether the cardioprotective effect of ANT1 overexpression suppresses TGFß(1)-induced apoptosis, whether mitochondrial permeability transition pore (MPTP) regulation is involved, and SMAD signaling pathway is affected. METHODS AND RESULTS: Ventricular cardiomyocytes isolated from wild-type (WT) and ANT1 transgenic rats were treated with the apoptosis-inducing agent TGFß(1) (1 ng/ml). TGFß(1) treatment of WT cells enhanced the number of apoptotic cells by 31.8 ± 11.7% (p<0.01 vs. WT) measured by chromatin condensation. Apoptosis was blocked by 1µM cyclosporine A and by ANT1 overexpression. The protecting effect of ANT1 overexpression on TGFß(1)-induced apoptosis was verified by reduced caspase 3/7 activity and increased Bcl-2 expression. In addition, TGFß(1) decreased mitochondrial membrane potential as measured by JC-1 staining by 18.0 ± 3.7% in WT cardiomyocytes, but only by 7.2 ± 2.8% (p<0.05 vs. WT) in ANT1 cardiomyocytes. Cyclosporine A also attenuated the decline in mitochondrial membrane potential under TGFß(1) in WT cardiomyocytes. Determination of MPTP opening by Calcein assay in isolated cardiomyocytes and calcium retention assay in isolated mitochondria revealed a reduced open probability of MPTP after ANT1 overexpression. In addition to the effects of ANT1 on MPTP opening we investigated if ANT1 may interfere with the classical TGFß signaling pathway. Interestingly, ANT1-transgenic cardiomyocytes expressed less TGFß receptor II than WT cells. However, SMAD2 phosphorylation was already enhanced without TGFß(1) stimulation in these cells. Although no additional increase in SMAD2 phosphorylation was detectable after TGFß(1) treatment, SMAD signaling was still responsive to TGFß(1) indicated by an upregulation of SMAD7, a TGFß(1) target protein. CONCLUSION: Heart-specific overexpression of ANT1 leads to a reduced apoptotic response to TGFß(1) by preservation of the mitochondrial membrane potential, resistance to MPTP opening and altered TGFß signaling.

Thermoelectric detection of spin waves.

We report on the thermoelectric detection of spin waves in Permalloy stripes via the anomalous Nernst effect. Spin waves are locally excited by a dynamic magnetic field generated from a microwave current flowing in a coplanar waveguide placed on top of a Permalloy stripe, which acts as a waveguide for spin waves. Electric contacts at the ends of the Permalloy stripe measure a dc voltage generated along the stripe. Magnetic field sweeps for different applied microwave frequencies reveal, with a remarkable signal-to-noise ratio, an electric voltage signature characteristic of spin-wave excitations. The symmetry of the signal with respect to the applied magnetic field direction indicates that the anomalous Nernst effect is responsible; Seebeck effects, anisotropic magnetoresistance, and voltages due to spin-motive forces are excluded. The dissipation of spin waves causes local heating that drains into the substrate, giving rise to a temperature gradient perpendicular to the sample plane, resulting in the anomalous Nernst voltage.

miRNA as activity markers in Parvo B19 associated heart disease.

Parvovirus B19 is a frequent virus detected in endomyocardial biopsies of patients with clinically suspected myocarditis or dilated cardiomyopathy (DCM). Viruses often cause a more symptomatic disease with increased tissue injury if they become reactivated. A disease-specific differential expression of microRNAs (miRNAs) has been described in the regulation of replicating viruses. Analyzing patients with latent and reactivated B19V infection, we found 29 differentially regulated miRNAs and, in order to test whether predicted genes are differentially expressed, selected mRNAs were tested by TaqMan-QPCR.

Mesenchymal stem cells improve murine acute coxsackievirus B3-induced myocarditis.

AIMS: Coxsackievirus B3 (CVB3)-induced myocarditis, initially considered a sole immune-mediated disease, also results from a direct CVB3-mediated injury of the cardiomyocytes. Mesenchymal stem cells (MSCs) have, besides immunomodulatory, also anti-apoptotic features. In view of clinical translation, we first analysed whether MSCs can be infected by CVB3. Next, we explored whether and how MSCs could reduce the direct CVB3-mediated cardiomyocyte injury and viral progeny release, in vitro, in the absence of immune cells. Finally, we investigated whether MSC application could improve murine acute CVB3-induced myocarditis. METHODS AND RESULTS: Phase contrast pictures and MTS viability assay demonstrated that MSCs did not suffer from CVB3 infection 4-12-24-48 h after CVB3 infection. Coxsackievirus B3 RNA copy number decreased in this time frame, suggesting that no CVB3 replication took place. Co-culture of MSCs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis, oxidative stress, intracellular viral particle production, and viral progeny release in a nitric oxide (NO)-dependent manner. Moreover, MSCs required priming via interferon-γ (IFN-γ) to exert their protective effects. In vivo, MSC application improved the contractility and relaxation parameters in CVB3-induced myocarditis, which was paralleled with a reduction in cardiac apoptosis, cardiomyocyte damage, left ventricular tumour necrosis factor-α mRNA expression, and cardiac mononuclear cell activation. Mesenchymal stem cells reduced the CVB3-induced CD4- and CD8- T cell activation in an NO-dependent way and required IFN-γ priming. CONCLUSION: We conclude that MSCs improve murine acute CVB3-induced myocarditis via their anti-apoptotic and immunomodulatory properties, which occur in an NO-dependent manner and require priming via IFN-γ.

Optical detection of spin transport in nonmagnetic metals.

We determine the dynamic magnetization induced in nonmagnetic metal wedges composed of silver, copper, and platinum by means of Brillouin light scattering microscopy. The magnetization is transferred from a ferromagnetic Ni80Fe20 layer to the metal wedge via the spin pumping effect. The spin pumping efficiency can be controlled by adding an insulating interlayer between the magnetic and nonmagnetic layer. By comparing the experimental results to a dynamical macroscopic spin-transport model we determine the transverse relaxation time of the pumped spin current which is much smaller than the longitudinal relaxation time.

Increased C reactive protein, cardiac troponin I and GLS are associated with myocardial inflammation in patients with non-ischemic heart failure.

Inflammatory cardiomyopathy diagnosed by endomyocardial biopsy (EMB) is common in non-ischemic heart failure (HF) and might be associated with adverse outcome. We aimed to identify markers predicting myocardial inflammation in HF. We screened 517 patients with symptomatic non-ischemic HF who underwent EMB; 397 patients (median age 54 [IQR 43/64], 28.7% females) were included in this study. 230 patients were diagnosed with myocardial inflammation, defined as ≥ 7.0 CD3+ lymphocytes/mm2 and/or ≥ 35.0 Mac1 macrophages/mm2 and were compared to 167 inflammation negative patients. Patients with myocardial inflammation were more often smokers (52.4% vs. 39.8%, p = 0.013) and had higher C-reactive protein (CRP) levels (5.4 mg/dl vs. 3.7 mg/dl, p = 0.003). In logistic regression models CRP ≥ 8.15 mg/dl (OR 1.985 [95%CI 1.160-3.397]; p = 0.012) and Troponin I (TnI) ≥ 136.5 pg/ml (OR 3.011 [1.215-7.464]; p = 0.017) were independently associated with myocardial inflammation, whereas no association was found for elevated brain natriuretic peptide (OR 1.811 [0.873-3.757]; p = 0.111). In prognostic performance calculation the highest positive predictive value (90%) was detected for the combination of Global longitudinal strain (GLS) ≥ -13.95% and TnI ≥ 136.5 pg/ml (0.90 (0.74-0.96)). Elevated CRP, TnI and GLS in combination with TnI can be useful to detect myocardial inflammation. Smoking seems to predispose for myocardial inflammation.

The 2021 Magnonics Roadmap.

Magnonics is a budding research field in nanomagnetism and nanoscience that addresses the use of spin waves (magnons) to transmit, store, and process information. The rapid advancements of this field during last one decade in terms of upsurge in research papers, review articles, citations, proposals of devices as well as introduction of new sub-topics prompted us to present the first roadmap on magnonics. This is a collection of 22 sections written by leading experts in this field who review and discuss the current status besides presenting their vision of future perspectives. Today, the principal challenges in applied magnonics are the excitation of sub-100 nm wavelength magnons, their manipulation on the nanoscale and the creation of sub-micrometre devices using low-Gilbert damping magnetic materials and its interconnections to standard electronics. To this end, magnonics offers lower energy consumption, easier integrability and compatibility with CMOS structure, reprogrammability, shorter wavelength, smaller device features, anisotropic properties, negative group velocity, non-reciprocity and efficient tunability by various external stimuli to name a few. Hence, despite being a young research field, magnonics has come a long way since its early inception. This roadmap asserts a milestone for future emerging research directions in magnonics, and hopefully, it will inspire a series of exciting new articles on the same topic in the coming years.

Antibody-mediated enhancement of calcium permeability in cardiac myocytes.

Our study shows that antibodies, specific to the ADP/ATP carrier of the inner mitochondrial membrane, crossreact with the cell surface of cardiac myocytes, where the calcium channel seems to be the antigenic determinant. The antibodies enhanced the calcium current and suppressed its inactivation. Affinity-purified antibodies (IgG) exhibit an acute cytotoxic effect, which required extracellular calcium and was prevented by calcium channel blockers. Our findings suggest that antibody-mediated cytotoxicity results secondary to calcium overload caused by enhanced cellular calcium permeability, requiring no complement-dependent process.

Biglycan is required for adaptive remodeling after myocardial infarction.

BACKGROUND: After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI. METHODS AND RESULTS: Experimental MI was induced in wild-type (WT) and bgn(-/0) mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn(-/0) mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn(-/0) mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn(-/0) mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn(-/0) mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn(-/0), 111+/-4.2 microL versus WT, 96+/-4.4 microL; P<0.05) and LV end-diastolic pressure (bgn(-/0), 24+/-2.7 versus WT, 18+/-1.8 mm Hg; P<0.05) and severely impaired LV function (EF, bgn(-/0), 12+/-2% versus WT, 21+/-4%; P<0.05) 21 days after MI. CONCLUSIONS: Biglycan is required for stable collagen matrix formation of infarct scars and for preservation of cardiac hemodynamic function.