Analgesic and Anti-Inflammatory Effects of the Novel Semicarbazide-Sensitive Amine-Oxidase Inhibitor SzV-1287 in Chronic Arthritis Models of the Mouse.

Semicarbazide-sensitive amine oxidase (SSAO) catalyses oxidative deamination of primary amines. Since there is no data about its function in pain and arthritis mechanisms, we investigated the effects of our novel SSAO inhibitor SzV-1287 in chronic mouse models of joint inflammation. Effects of SzV-1287 (20 mg/kg i.p./day) were investigated in the K/BxN serum-transfer and complete Freund's adjuvant (CFA)-evoked active immunization models compared to the reference SSAO inhibitor LJP-1207. Mechanonociception was assessed by aesthesiometry, oedema by plethysmometry, clinical severity by scoring, joint function by grid test, myeloperoxidase activity by luminescence, vascular leakage by fluorescence in vivo imaging, histopathological changes by semiquantitative evaluation, and cytokines by Luminex assay. SzV-1287 significantly inhibited hyperalgesia and oedema in both models. Plasma leakage and keratinocyte chemoattractant production in the tibiotarsal joint, but not myeloperoxidase activity was significantly reduced by SzV-1287 in K/BxN-arthritis. SzV-1287 did not influence vascular and cellular mechanisms in CFA-arthritis, but significantly decreased histopathological alterations. There was no difference in the anti-hyperalgesic and anti-inflammatory actions of SzV-1287 and LJP-1207, but only SzV-1287 decreased CFA-induced tissue damage. Unlike SzV-1287, LJP-1207 induced cartilage destruction, which was confirmed in vitro. SzV-1287 exerts potent analgesic and anti-inflammatory actions in chronic arthritis models of distinct mechanisms, without inducing cartilage damage

Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training

Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role modulating cardiac function in both health and disease. Here, we determined the effect of chronic CaMKII inhibition during an exercise training program in healthy mice. CaMKII was inhibited by KN-93 injections. Mice were randomized to the following groups: sham sedentary, sham exercise, KN-93 sedentary, and KN-93 exercise. Cardiorespiratory function was evaluated by ergospirometry during treadmill running, echocardiography, and cardiomyocyte fractional shortening and calcium handling. The results revealed that KN-93 alone had no effect on exercise capacity or fractional shortening. In sham animals, exercise training increased maximal oxygen uptake by 8% (p < 0.05) compared to a 22% (p < 0.05) increase after exercise in KN-93 treated mice (group difference p < 0.01). In contrast, in vivo fractional shortening evaluated by echocardiography improved after exercise in sham animals only: from 25 to 32% (p < 0.02). In inactive mice, KN-93 reduced rates of diastolic cardiomyocyte re-lengthening (by 25%, p < 0.05) as well as Ca2+ transient decay (by 16%, p < 0.05), whereas no such effect was observed after exercise training. KN-93 blunted exercise training response on cardiomyocyte fractional shortening (63% sham vs. 18% KN-93; p < 0.01 and p < 0.05, respectively). These effects could not be solely explained by the Ca2+ transient amplitude, as KN-93 reduced it by 20% (p < 0.05) and response to exercise training was equal (64% sham and 47% KN-93; both p < 0.01). We concluded that chronic CaMKII inhibition increased time to 50% re-lengthening which were recovered by exercise training, but paradoxically led to a greater increase in maximal oxygen uptake compared to sham mice. Thus, the effect of chronic CaMKII inhibition is multifaceted and of a complex nature

Pacing to reduce refractory angina in patients with severe coronary artery disease: A crossover pilot trial

Biventricular pacing (BiV) has been shown to reduce wall stress and workload in regions near the pacing sites. This trial investigated if BiV near the ischemic region would reduce chest pain in patients with refractory angina due to severe coronary artery disease (CAD). Eleven patients were implanted with BiV devices with leads positioned at or adjacent to their ischemic regions as detected by single-photon emission computed tomography (SPECT) and randomized to either pacing turned ON or OFF for 3 months, and then crossed over for 3 months. With pacing turned ON, a Dynamic atrioventricular (AV) delay was set for approximately 90% and 70% of the intrinsic AV delay at the resting heart rate and at the onsetof symptoms, respectively. One patient was excluded from the analysis due to a large amount of RV pacing during the OFF periods (24-64%) and due to an inability to properly deliver therapy because of an excessive number of ventricular premature complexes. Overall, with the device ON vs. OFF, the number of angina episodes (0.8±0.4 vs. 1.2±0.7 per week, P=0.03) and amount of nitroglycerin used (0.2±0.1 vs. 1.0±0.7 per week, P=0.11) was lower with BiV pacing. Furthermore, the treadmill exercise time to symptoms trended higher (427±65 vs. 408±64 s, P= 0.19), and the sum of fluorodeoxyglucose-positron emission tomography (FDG-PET) scores trended lower (7.9±3.5 vs. 12.0±4.0, P=0.11) with the device ON vs. OFF. Nevertheless, there were no significant differences in SPECT myocardial perfusion scores, left ventricle ejection fraction, wall motion score index, and quality of life scores with device programmed ON vs. OFF (all P>0.05). In conclusion, this pilot study demonstrated that BiV-P at or near the ischemic region was feasible and associated with significant reductions in angina in patients with severe CAD. Adequately powered prospective studies are needed to confirm these findings. © Springer Science+Business Media, LLC 2011.link_to_subscribed_fulltex

Review and Updates in Regenerative and Personalized Medicine, Preclinical Animal Models, and Clinical Care in Cardiovascular Medicine

The goal of this paper is to provide an updated review for scientists and clinicians on the major areas in cardiovascular medicine published in the Journal. Leading topics in regenerative and personalized medicine are presented along with a critical overview of the field. New standards in large preclinical animal models of pulmonary hypertension and left bundle branch block are highlighted. Finally, clinical care in the areas of atherosclerosis, the aortic valve, platelet biology, and myocarditis is discussed as well as autonomic modulation therapies. © 2015, Springer Science+Business Media New York