Cardiovascular magnetic resonance risk stratification in patients with clinically suspected myocarditis

BACKGROUND: The diagnosis of myocarditis is challenging due to its varying clinical presentation. Since myocarditis can be associated with significant 5-year mortality, and postmortem data show myocarditis in almost 10% of all adults suffering sudden cardiac death, individual risk stratification for patients with suspected myocarditis is of great clinical interest. We sought to demonstrate that patients with clinically suspected myocarditis and a normal cardiovascular magnetic resonance (CMR) according to our definition have a good prognosis, independent of their clinical symptoms and other findings. METHODS: Prospective clinical long-term follow-up of consecutive patients undergoing CMR for work-up of clinically suspected myocarditis at our institution in 2007-2008. RESULTS: Follow-up was available for n = 405 patients (all-comers, 54.8% inpatients, 38% outpatient referrals from cardiologists). Median follow-up time was 1591 days. CMR diagnosis was “myocarditis” in 28.8%, “normal” in 55.6% and “other pathology” in 15.6%. Normal CMR was defined as normal left ventricular (LV) volumes and normal left ventricular ejection fraction (LV-EF) in the absence of late Gadolinium Enhancement (LGE). The overall mortality was 3.2%. There were seven cardiac deaths during follow-up, in addition one aborted SCD and two patients had appropriate internal cardioverter defibrillator (ICD) shocks – all of these occurred in patients with abnormal CMR. Kaplan-Meier analysis with log-rank test showed significant difference for major adverse cardiac events (cardiac death, sudden cardiac death (SCD), ICD discharge, aborted SCD) between patients with normal and abnormal CMR (p = 0.0003). CONCLUSION: In our unselected population of consecutive patients referred for CMR work-up of clinically suspected myocarditis, patients with normal CMR have a good prognosis independent of their clinical symptoms and other findings

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

PPARgamma-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARgamma-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARgamma agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na+ channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPARgamma agonists. To test this hypothesis, food containing the PPARgamma agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1-/-, n=12) and their wild-type littermates (sgk1+/+), n=12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1+/+ mice. The treatment increased body weight significantly in both, sgk1+/+ mice (+2.2+/-0.3 g) and sgk-/- mice (+1.3+/-0.2 g), and decreased hematocrit significantly in sgk1+/+ mice (-6.5+/-1.0%) and sgk1-/- mice (-3.1+/-0.6%). Both effects were significantly (p<0.05) more pronounced in sgk1+/+ mice. According to Evans Blue distribution, pioglitazone increased plasma volume only in sgk1+/+ mice (from 50.9+/-3.9 to 63.7+/-2.5 microl/g bw) but not in sgk-/- mice (from 46.8+/-3.8 to 48.3+/-5.2 microl/g bw). Pioglitazone decreased aldosterone plasma levels and blood pressure and increased leptin plasma levels in both genotypes. We conclude that SGK1 contributes to but does not fully account for the volume retention during treatment with the PPARgamma agonist pioglitazone

Prevention of cardiac dysfunction in acute coxsackievirus B3 cardiomyopathy by inducible expression of a soluble coxsackievirus-adenovirus receptor

Background— Group B coxsackieviruses (CVBs) are the prototypical agents of acute myocarditis and chronic dilated cardiomyopathy, but an effective targeted therapy is still not available. Here, we analyze the therapeutic potential of a soluble (s) virus receptor molecule against CVB3 myocarditis using a gene therapy approach. Methods and Results— We generated an inducible adenoviral vector (AdG12) for strict drug-dependent delivery of sCAR-Fc, a fusion protein composed of the coxsackievirus-adenovirus receptor (CAR) extracellular domains and the carboxyl terminus of human IgG1-Fc. Decoy receptor expression was strictly doxycycline dependent, with no expression in the absence of an inducer. CVB3 infection of HeLa cells was efficiently blocked by supernatant from AdG12-transduced cells, but only in the presence of doxycycline. After liver-specific transfer, AdG12 (plus doxycycline) significantly improved cardiac contractility and diastolic relaxation compared with a control vector in CVB3-infected mice if sCAR-Fc was induced before infection (left ventricular pressure 59±3.8 versus 45.4±2.7 mm Hg, median 59 versus 45.8 mm Hg, P<0.01; dP/dtmax 3645.1±443.6 versus 2057.9±490.2 mm Hg/s, median 3526.6 versus 2072 mm Hg/s, P<0.01; and dP/dtmin −2125.5±330.5 versus −1310.2±330.3 mm Hg/s, median −2083.7 versus −1295.9 mm Hg/s, P<0.01) and improved contractility if induced concomitantly with infection (left ventricular pressure 76.4±19.2 versus 56.8±10.3 mm Hg, median 74.8 versus 54.4 mm Hg, P<0.05; dP/dtmax 5214.2±1786.2 versus 3011.6±918.3 mm Hg/s, median 5182.1 versus 3106.6 mm Hg/s, P<0.05), respectively. Importantly, hemodynamics of animals treated with AdG12 (plus doxycycline) were similar to uninfected controls. Preinfection induction of sCAR-Fc completely blocked and concomitant induction strongly reduced cardiac CVB3 infection, myocardial injury, and inflammation. Conclusion— AdG12-mediated sCAR-Fc delivery prevents cardiac dysfunction in CVB3 myocarditis under prophylactic and therapeutic conditions

The Higgs as a Portal to Plasmon-like Unparticle Excitations

12 LaTeX pages, 2 figures.-- Published in: JHEP04(2008)028.-- Final full-text version available at: http://dx.doi.org/10.1088/1126-6708/2008/04/028.A renormalizable coupling between the Higgs and a scalar unparticle operator O_U of non-integer dimension d_U<2 triggers, after electroweak symmetry breaking, an infrared divergent vacuum expectation value for O_U. Such IR divergence should be tamed before any phenomenological implications of the Higgs-unparticle interplay can be drawn. In this paper we present a novel mechanism to cure that IR divergence through (scale-invariant) unparticle self-interactions, which has properties qualitatively different from the mechanism considered previously. Besides finding a mass gap in the unparticle continuum we also find an unparticle pole reminiscent of a plasmon resonance. Such unparticle features could be explored experimentally through their mixing with the Higgs boson.Work supported in part by the European Commission under the European Union through the Marie Curie Research and Training Networks “Quest for Unification” (MRTN-CT- 2004-503369) and “UniverseNet” (MRTN-CT-2006-035863); by the Spanish Consolider- Ingenio 2010 Programme CPAN (CSD2007-0042); by a Comunidad de Madrid project (P-ESP-00346) and by CICYT, Spain, under contracts FPA 2007-60252 and FPA 2005-02211

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica

Background: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce. Methods: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). Results: A total of 24 patients were analyzed, 23 with relapsing–remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7–10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments. Conclusions: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding