Use of Contrast-Enhanced Ultrasound Sonography in Giant Cell Arteritis: A Proof-of-Concept Study.

C-Reactive protein and erythrocyte sedimentation rate are crucial parameters used to monitor giant cell arteritis (GCA). Given that tocilizumab is approved for the treatment of GCA, these parameters are less sensitive because of the effects of interleukin-6 receptor blockade. Thus, the optimal method for monitoring GCA patients undergoing tocilizumab therapy, especially patients exhibiting a persistent thickened vessel wall in large vessels, remains unclear. Contrast-enhanced ultrasonography (CEUS) can increase the visibility of tissue perfusion by slow blood flow, which cannot be detected by power color doppler. We used CEUS to investigate patients with active and inactive GCA of the large vessels (active large vessel arteritis [aLVV]/inactive large vessel arteritis [iLVV]) who were not administered tocilizumab in this proof-of-concept study. After injection of the ultrasound contrast agent, the contrasted area (CA) of large vessels in a transverse section was calculated twice: first when the lumen was contrasted completely and once again 4-8 s later. We investigated the value of increase in CA that exhibited the best sensitivity and specificity for aLVV. Twenty-four patients were included in this study: 15 with aLVV and 9 with iLVV. The CA increased from 32.2 ± 16.8 to 52.5 ± 21.3 mm2 (p < 0.0001) in aLVV. The mean CA remained unchanged in iLVV. The best cutoff value to differentiate between aLVV and iLVV was a ≥25% increase in CA with a sensitivity and specificity of 91.7% and 100%, respectively. Our study indicates that CEUS can detect aLVV with high sensitivity and specificity. Incorporation of CEUS into routine clinical practice might result in a good method for monitoring disease activity in LVV in GCA patients. The limitation of our study was the small number of patients and the lack of investigator blinding to clinical data.

Recurrent tendosynovitis as a rare manifestation of a lipid disorder.

A 33-year-old female had suffered from spontaneously recurrent bursitis and tendosynovitis/enthesitis of the patellar and Achilles tendons for about 10 years. The episodes of immobilization increased. Ultrasound imaging of the swollen and painful tendons showed chronic inflammation with neoangiogenesis within the tendons and hypoechoic lesions. Clinical and laboratory tests did not provide evidence for a rheumatic disease. Low density lipoprotein cholesterol was elevated. Biopsies of skin lesions did not confirm the suspicion of cutaneous xanthomas. Genetic testing for familial hypercholesterolemia was negative. Campesterol and sitosterol were elevated 7- to 12-fold and 20- to 38-fold over the upper limit of normal on two occasions. There was no relevant mutation in ABCG5. In ABCG8, we identified a missense mutation c.1267G>A in exon 9 changing glutamic acid 423 into lysine within the transmembrane domain, and an insertion of adenine (c.1487insA) leading to a frameshift and a premature stop codon (Ile497Aspfs*105). The patient had no clinical evidence of premature atherosclerosis. Therapeutic approaches with nonsteroidal antirheumatic drugs, prednisone, statins, and ezetimibe accompanied by a diet poor in plant sterols led to a relief of symptoms. This case report shows that tendon xanthoma along with tendosynovitis, especially on extensor areas, is suspicious for hypercholesterolemia as the underlying cause. The absence of atherosclerotic plaques in the abdominal aorta and in the carotid arteries on ultrasound may suggest that phytosterolemia is not necessarily accompanied by premature vascular disease.

In arthritis the Doppler based degree of hypervascularisation shows a positive correlation with synovial leukocyte count and distinguishes joints with leukocytes greater and less than 5/nL.

OBJECTIVES: Power Doppler ultrasound is used to assess joint vascularity in acute arthritis. PDUS signals have been correlated with synovial histology and bone deterioration. Little is known about the correlation between power Doppler signals and synovial white blood count. In our study, we analyzed power Doppler signals in inflammatory joint diseases including gout, calcium pyrophosphate deposition disease, rheumatoid arthritis, spondyloarthritis and others and correlated power Doppler signals with synovial white blood count and with serologic markers of inflammation. METHODS: We retrospectively evaluated 194 patients with arthritis. All patients underwent joint sonography, power Doppler ultrasound, synovial fluid analysis and blood examination of C-reactive protein and erythrocyte sedimentation rate. Correlation analyses (Spearman and Pearson), Chi(2) test, t-tests, a unifactorial ANOVA and regression analyses were applied. RESULTS AND CONCLUSIONS: Hypervascularisation in power Doppler was most prominent in gout and calcium pyrophosphate deposition disease. Spondyloarthritis and non-inflammatory joint diseases presented with low degrees of hypervascularisation. Mean synovial white blood count did not differ significantly between crystal-related arthritides, rheumatoid arthritis, spondyloarthritis or other inflammatory joint diseases. There was a positive but weak correlation between power Doppler signals and synovial white blood count (P<0.001, rs=0.283), erythrocyte sedimentation rate (P<0.001, rs=0.387) and C-reactive protein (P<0.001, rs=0.373) over all diagnoses. This was especially relevant in rheumatoid arthritis (P<0.01, rs=0.479). Power Doppler degrees 0 and 1 were able to predict synovial leukocytes<5/nL, degrees 2 and 3 predict leukocytes≥5/nL (P<0.001).

Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure.

BACKGROUND: Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo. METHODS AND RESULTS: Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10(-8) M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca](i) rose clearly on ISO in TG but not in wild-type cells (+20+/-5% versus +3+/-4% at 10(-6) M ISO, P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9+/-0.5 versus 2.0+/-0.4 sparks per 100 microm(-1).s(-1), P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIdelta-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P<0.05) and late (86% versus 43%, P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05). CONCLUSIONS: We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIdelta(C) mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.