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A high body mass index (BMI) is often associated with metabolic syndrome, which is accompanied by systemic low-grade chronic inflammation. Here, we analyzed whether BMI, other components of metabolic syndrome, and/or inflammatory markers correlate with left ventricular geometry, function, and infarct size as assessed by serial cardiac magnetic resonance imaging (MRI) after a first (clinically evident) ST-elevation MI (STEMI).Within the Etiology, Titre-Course, and effect on Survival (ETiCS) study, cardiac MRI conducted 7-9 days and 12 months after MI enabled longitudinal characterization of patients with a first STEMI along with serial routine blood counts and multiplex cytokine measurements.Of 91 locally included STEMI patients, 47% were overweight (25 kg/mBoth BMI and HbA1c correlated negatively with LVEF only early, but not late after STEMI. Peak CRP evolved as strongest predictor of cardiac function at all time points independent of the metabolic syndrome.

Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0–4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.

Dilated cardiomyopathy (DCM) is a leading cardiomyopathy condition and is the leading reason for heart transplantation. Due to high etiologic and genetic heterogeneity of the pathologies, different therapeutic treatment strategies are available and have been successful for different treatments. Immunoadsorption (IA) therapy removes the circulating anticardiac antibodies and improves the left ventricular function in substantial proportion of DCM patients. Powerful, non-invasive analytical tools are highly desired to investigate the efficiency and success of IA therapy. In this contribution, we followed the changes of a female DCM patient undergoing IA therapy at different treatment time points in a label-free, non-invasive manner from blood samples (plasma and serum) on the basis of vibrational spectroscopy (Raman scattering and IR absorption). Chemometric methods, including dimension reduction and statistical modeling, were used to interpret spectral data. The impact of different time points of the IA treatment can be identified in both the plasma and serum, using both techniques, with high accuracy. The removal of antibodies of immunoglobulin G (IgG) group during IA therapy and their restoration was reflected in both Raman and FTIR spectra. Relative changes in the spectral bands assigned to IgG agreed well with the immunoturbidimetry measurement of total IgG. Successful clinical treatment was accompanied by spectral differences between vibrational spectra obtained at initial disease state and 11 months after the IA treatment. The long-term follow-up of the patient reveals the stabilization of the health state after therapy. It is noteworthy that the treatment time points were distinguished with a better accuracy using spectra from plasma compared to those from serum samples, which might indicate the involvement of corresponding proteins in the coagulation. Vibrational spectroscopy is a powerful tool for personalized medicine to follow-up the treatment success of IA therapy for the DCM disorder.

Peptide mimicry breaks the heart Myocarditis, a prolonged chronic inflammation of heart muscle, can eventually progress to inflammatory cardiomyopathy, a serious condition associated with heart failure. Activated T helper (T H ) cells that recognize myosin heavy chain 6–derived peptides are thought to play a central role in this pathogenesis. Using a mouse model of myocarditis, Gil-Cruz et al. found that cardiac myosin–reactive T H cells are initially primed by myosin-peptide mimics derived from commensal Bacteroides species in the gut (see the Perspective by Epelman). Unlike heathy controls, human myocarditis patients also showed detectable immune reactivity to both Bacteroides and cardiac myosin antigens. Treatment with antibiotics dampened inflammatory responses and prevented lethal heart disease. Science , this issue p. 881 ; see also p. 806

Patients suffering from chronic heart failure (CHF) caused or promoted by autoantibodies against cardiac beta1-adrenergic receptors (beta1AR) could benefit from specific therapies aimed at tolerance induction, removal or neutralisation of beta1AR autoantibodies, provided the patients can be selected for these therapies by reliable detection and quantitation of beta1AR autoantibodies in their circulation and by a valid assessment of the autoantibodies's putative cardio-pathogenic potential. Here, we discuss the current state of knowledge regarding the effects of CHF-associated (auto)antibodies on beta1AR function and beta1AR-mediated signal tranduction and discuss the presumed role of these effects in the development and progression of CHF. Identification of disease-relevant functional autoantibody effects and their specific assessment in medical diagnostic will be a prerequesite for the implementation of novel specific therapies not only for CHF caused or promoted by beta1AR autoantibodies but alos for most other diseases involving autoantibodies that target G-protein coupled receptors.

Aims Chronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β1‐adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine‐map the conformational epitope within the second extracellular loop of the human β1‐adrenoceptor (β1ECII) that is targeted by stimulating β1‐receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto‐epitope. Methods and results Non‐conserved amino acids within the β1ECII loop (compared with the amino acids constituting the ECII loop of the β2‐adrenoceptor) were one by one replaced with alanine; potential intra‐loop disulfide bridges were probed by cysteine–serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β1ECII ± the above replacements, and (ii) by (auto)antibody stimulation of human β1‐adrenoceptors bearing corresponding point mutations. With the use of stimulating β1‐receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β1ECII loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK211–214 motif and (ii) the intra‐loop disulfide bond C209↔C215. Of note, aberrant intra‐loop disulfide bond C209↔C216 almost fully disrupted the functional auto‐epitope in cyclopeptides. Conclusions The conformational auto‐epitope targeted by cardio‐pathogenic β1‐receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β1ECII loop bearing the NDPK211–214 motif and the C209↔C215 bridge while lacking cysteine C216. Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β1‐autoantibody‐positive CHF.

Rationale Despite advances in pharmacotherapy, heart failure still incurs significant morbidity and mortality. Stimulating antibodies directed against the secondextracellular loop of the human s1-adrenergic receptor (anti-s1EC2) cause myocyte damage and heart failure in rats. This receptor domain is 100% homologous between rats and humans. Objective s1EC2-mimicking cyclopeptides (25-meric) markedly improved the development and/or course of anti-s1EC2-mediated cardiomyopathy. Further developments should be investigated. Methods and results The shortened 18-meric cyclic peptide COR-1, in which one of the two disulphide bonds was removed to enable reproducible GMP production, can also be used to treat cardiomyopathic rats. Echocardiography, catheterization and histopathology of the rat hearts revealed that monthly intravenous administrations of COR-1 almost fully reversed the cardiomyopathic phenotype within 6 months at doses of 1 to 4 mg/kg body weight. Administration of COR-1 resulted in markedly reduced anti-s1EC2-expressing memory B lymphocytes in the spleen despite continued antigenic boosts, but did not significantly decrease overall peripheral anti-s1EC2 titers. COR-1 did not induce any anti-s1EC2 or other immune response in naive rats (corresponding to findings in healthy human volunteers). It did not cause any toxic side effects in GLP studies in dogs, rats or mice, and the “no observed adverse effect level” (NOAEL) exceeded the therapeutic doses by 100-fold. Conclusion The second generation immunomodulating epitope-mimicking cyclopeptide COR-1 (also termed JNJ-5442840) offers promise to treat immune-mediated cardiac diseases.

Background— Monocytes and macrophages are indispensable in the healing process after myocardial infarction (MI); however, the spatiotemporal distribution of monocyte infiltration and its correlation to prognostic indicators of reperfused MI have not been well described. Methods and Results— With combined fluorine 19/proton ( 1 H) magnetic resonance imaging, we noninvasively visualized the spatiotemporal recruitment of monocytes in vivo in a rat model of reperfused MI. Blood monocytes were labeled by intravenous injection of 19 F-perfluorocarbon emulsion 1 day after MI. The distribution patterns of monocyte infiltration were correlated to the presence of microvascular obstruction (MVO) and intramyocardial hemorrhage. In vivo, 19 F/ 1 H magnetic resonance imaging performed in series revealed that monocyte infiltration was spatially inhomogeneous in reperfused MI areas. In the absence of MVO, monocyte infiltration was more intense in MI regions with serious ischemia-reperfusion injuries, indicated by severe intramyocardial hemorrhage; however, monocyte recruitment was significantly impaired in MVO areas accompanied by severe intramyocardial hemorrhage. Compared with MI with isolated intramyocardial hemorrhage, MI with MVO resulted in significantly worse pump function of the left ventricle 28 days after MI. Conclusions— Monocyte recruitment was inhomogeneous in reperfused MI tissue. It was highly reduced in MVO areas defined by magnetic resonance imaging. The impaired monocyte infiltration in MVO regions could be related to delayed healing and worse functional outcomes in the long term. Therefore, monocyte recruitment in MI with MVO could be a potential diagnostic and therapeutic target that could be monitored noninvasively and longitudinally by 19 F/ 1 H magnetic resonance imaging in vivo.

Aims A novel concept for the treatment of heart failure is the neutralization of antibodies against the β1-adrenergic receptor (anti-β1AR-ab). In a rat model of autoimmune cardiomyopathy, the cyclic peptide COR-1 (given i.v. once monthly) neutralized anti-β1AR-abs and prevented anti-β1AR-ab-induced myocardial damage, and completely reverted cardiac dysfunction over 3–6 months. Methods and results A clinical phase I trial was designed as a single-blinded, placebo-controlled study. Fifty human volunteers received COR-1 or matching placebo as a single i.v. administration with ascending doses (10–240 mg). Primary endpoints were safety and tolerability, while the pharmacokinetic profile of COR-1 was assessed as a secondary endpoint. All five investigated dose groups were well tolerated; no drug-related side effects occurred. Pharmacokinetics revealed a favourable profile with an almost complete plasma clearance within 60 min after administration. Pharmacodynamic investigation showed dose-dependent efficacy with almost complete scavenging of pathological anti-β1AR-abs ex vivo at the two highest doses. No anti-COR-1 autoantibodies occurred. No other effects on the immune system (such as an increase of crucial cytokines) were observed up to 43 days after drug administration, nor upon incubation of anti-β1AR-ab-positive patient blood samples with COR-1 ex vivo. Conclusions COR-1 was shown to be safe after i.v. administration in vivo; no relevant side effects occurred. Efficacy was estimated from ex vivo investigation of the potency to neutralize specific anti-β1-AR-abs. Trial registration: NCT 01043146, Eudra CT 2008-07745-31.

We thank Jansen and van Royen for their interest in our publication.1 They questioned whether the widely used contrast-enhanced MRI method indeed detects microvascular obstruction (MVO), because the incidence of MRI-defined intramyocardial hemorrhage (IMH) without MVO (isolated IMH) in our rat model was higher than those reported in large animals and patients. Described for the first time by Kloner et al2 in 1974, MVO is the underlying cause of the no-reflow phenomenon in reperfused myocardial infarction (MI). It is attributable to (1) regional swelling, intraluminal protrusions, and the cytoplasm blebs of endothelium; (2) activation of blood leucocytes adhesion and subsequent plugging of erythrocytes, platelets, and neutrophils; and (3) capillary compression by surrounding edematous tissue in experimental MI. In the 1990s, the hypoenhancement of MI area on contrast-enhanced MRI was carefully examined and established for detecting MVO noninvasively. …

The cytoplasmic C terminus of the β 2 -adrenergic receptor and many other G protein-coupled receptors contains a dileucine sequence that has been implicated in endosome/lysosome targeting of diverse proteins. In the present study, we provide evidence for an essential role of this motif in the agonist-induced internalization of the β 2 -adrenergic receptor. Mutation of Leu-339 and/or Leu-340 to Ala caused little changes in surface expression, ligand binding, G protein coupling, and signaling to adenylyl cyclase, when these receptors were transiently or stably expressed in CHO or HEK-293 cells. However, agonist-induced receptor internalization was markedly impaired in the L 339,340 A double mutant and reduced in the two single mutants. This impairment in receptor internalization was seen by using various approaches to determine internalization: binding of hydrophobic vs. hydrophilic ligands, loss of surface β 2 -adrenergic receptor immunoreactivity, and immunofluorescence microscopy. The selective effects of these mutations suggest that the C-terminal dileucine motif is involved in agonist-induced internalization of the β 2 -adrenergic receptor.

Inflammation of cardiac tissue is generally associated with an activation of the host’s immune system. On the one hand, this activation is mandatory to protect the heart by fighting the invading microbial agents or toxins and by engaging myocardial reparation and healing processes. On the other hand, uncontrolled activation of the immune defense has the risk of an arousal of auto- or cross-reactive immune cells, which in some cases bring more harm than good. Dependent on the individual genetic predisposition, such heart-directed autoimmune reactions most likely occur as a result of myocyte apoptosis or necrosis and subsequent liberation of self-antigens previously hidden to the immune system. During the past two decades, evidence for a pathogenic relevance of autoimmunity in human heart disease has substantially increased. Conformational cardiac (auto)antibodies affecting cardiac function and, in particular, (auto)antibodies that target G protein-coupled cardiac membrane receptors are thought to play a key role in the development of heart failure. Clinical pilot studies even suggest that such antibodies negatively affect survival in heart failure patients. However, the true prevalence and clinical impact of many cardiac (auto)antibodies in human heart diseases are still unclear, as are the events triggering their formation, their titer course, and their patterns of clearance and/or persistence. The present article summarizes current knowledge in the field of cardiac receptor (auto)antibodies including recent efforts to address some of the aforementioned gaps of knowledge, thereby attempting to pave the way for novel, more specific therapeutic approaches.