Objective: The goal of this paper was to present the effects of the vagus nerve stimulation (VNS) on a blood pressure (BP) and heart rate (HR) in arterial hypertension patient. Design and Method: The pilot study (SPM-005) was designed to evaluate the eficiancy and safety profile of the neurostimulation of the cholinergic anti-inflammatory pathways using the active implantable device for the vagus nerve stimulation in rheumatoid arthritis patient. We investigated the VNS on the BP and HR in 68 years old female patient with a long-standing arterial hypertension and the lisinopril and hydrochlorothiazide in a therapy. Her BMI was 25.4 This device that is surgically implantated under the skin provides the electrical impulses to the vagus nerve of the left side of the body. Results: The basic value of arterial hypertension under medication was within normal range. BP was 120/80 mmHg before implantation and HR was 72/min. Following immediate VNS, the BP raised to 140/90 mmHg and HR was 70/min. The 4 hours after VNS, BP was 130/70 mmHg and HR was 86/min. After 24 hours, BP was 160/100 mmHg and HR 80/min. On a day 7, BP was 130/80 mmHg and HR 74/min. Day 21, BP was 135/84 mmHg, and HR 83/min. Day 28, BP was 135/85 mmHg, and HR was 87/min. After 3 months, BP was 160/100 mmHg and HR 82/min. The Amlodipine 5 mg and Doxazosin 2 mg was added to ACE inhibitor and diuretics. After 6 months, BP was still high with a values of 170/95 mmHg and HR of 70/min. Doxazosin dosage was increased to 4 mm daily. One year after, BP was 130/80 mmHg and HR 72/min. Conclusions: There was a slight increase in a blood pressure following the first VNS, but not in a heart rate. No significant correlation betwen BP and HR was observed.

Significance Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed “the inflammatory reflex,” action potentials transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studied in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients. Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Introduction: The commonest mitral regurgitation etiologies are degenerative (60%), rheumatic post-inflammatory, 12%) and functional (25%). Due to the large number of patients with acute MI, the incidence of ischaemic MR is also high. Ischaemic mitral regurgitation is a complex multifactorial disease that involves left ventricular geometry, the mitral annulus, and the valvular/subvalvular apparatus. Ischaemic mitral regurgitation is an important consequence of LV remodeling after myocardial infarction. Research Objectives: The objective of this study is to determine the role of echocardiography in detecting and assessment of mitral regurgitation mechanism, severity, impact on treatment strategy and long term outcome in patients with myocardial infarction during the follow up period of 5 years. Also one of objectives to determine if the absence or presence of ischaemic MR is associated with increased morbidity and mortality in patients with myocardial infarction. Patients and methods: The study covered 138 adult patients. All patients were subjected to echocardiography evaluation after acute myocardial infarction during the period of follow up for 5 years. The patients were examined on an ultrasound machine Philips iE 33 xMatrix, Philips HD 11 XE, and GE Vivid 7 equipped with all cardiologic probes for adults and multi-plan TEE probes. We evaluated mechanisms and severity of mitral regurgitation which includes the regurgitant volume (RV), effective regurgitant orifice area (EROA), the regurgitant fraction (RF), Jet/LA area, also we measured the of vena contracta width (VC width cm) for assessment of IMR severity, papillary muscles anatomy and displacement, LV systolic function ± dilation, LV regional wall motion abnormality WMA, LV WMI, Left ventricle LV remodeling, impact on treatment strategy and long term mortality. Results: We analyzed and follow up 138 patients with previous (>16 days) Q-wave myocardial infarction by ECG who underwent TTE and TEE echocardiography for detection and assessment of ischaemic mitral regurgitation (IMR) with baseline age (62 ± 9), ejection fraction (EF 41±12%), the regurgitant volume (RV) were 42±21 mL/beat, and effective regurgitant orifice area (EROA) 20±16 mm2, the regurgitant fraction (RF) were 48±10%, Jet/LA area 47±12%. Also we measured the of vena contracta width (VC width cm) 0,4±0,6 for assessment of IMR severity. During 5 years follow up, total mortality for patients with moderate/severe IMR–grade II-IV (54.2±1.8%) were higher than for those with mild IMR–grade I (30.4±2.9%) (P<0.05), the total mortality for patients with EROA ≥20 mm2(54±1.9%) were higher than for those with EROA <20 mm2(27.2±2.7%) (P<0.05), and the total mortality for patients with RVol ≥30 mL (56.8±1.7%) were higher than for those with RVol<30ml (29.4±2.9%) (P<0.05). After assessment of IMR and during follow up period 64 patients (46%) underwent CABG alone or combined CABG with mitral valve repair or replacement. In this study, the procedure of concomitant down-sized ring annuloplasty at the time if CABG surgery has a failure rate around 24% in terms of high late recurrence rate of IMR during the follow period especially after 18–42 months. Conclusion: The presence of ischaemic MR is associated with increased morbidity and mortality. Chronic IMR, an independent predictor of mortality with a reported survival of 40–60% at 5 years. Ischaemic mitral regurgitation has important prognosis implications in patients with coronary heart disease. Recognizing the mechanism of valve incompetence is an essential point for the surgical planning and for a good result of the mitral repair. It is important that echocardiographers understand the complex nature of the condition. Despite remarkable progress in reparative surgery, further investigation is still necessary to find the best approach to treat ischaemic mitral regurgitation.

OBJECTIVE The goal of this paper was to present the effects of the vagus nerve stimulation (VNS) on a blood pressure (BP) and heart rate (HR) in arterial hypertension patient. DESIGN AND METHOD The pilot study (SPM-005) was designed to evaluate the eficiancy and safety profile of the neurostimulation of the cholinergic anti-inflammatory pathways using the active implantable device for the vagus nerve stimulation in rheumatoid arthritis patient. We investigated the VNS on the BP and HR in 68 years old female patient with a long-standing arterial hypertension and the lisinopril and hydrochlorothiazide in a therapy. Her BMI was 25.4 This device that is surgically implantated under the skin provides the electrical impulses to the vagus nerve of the left side of the body. RESULTS The basic value of arterial hypertension under medication was within normal range. BP was 120/80 mmHg before implantation and HR was 72/min. Following immediate VNS, the BP raised to 140/90 mmHg and HR was 70/min. The 4 hours after VNS, BP was 130/70 mmHg and HR was 86/min. After 24 hours, BP was 160/100 mmHg and HR 80/min. On a day 7, BP was 130/80 mmHg and HR 74/min. Day 21, BP was 135/84 mmHg, and HR 83/min. Day 28, BP was 135/85 mmHg, and HR was 87/min. After 3 months, BP was 160/100 mmHg and HR 82/min. The Amlodipine 5 mg and Doxazosin 2 mg was added to ACE inhibitor and diuretics. After 6 months, BP was still high with a values of 170/95 mmHg and HR of 70/min. Doxazosin dosage was increased to 4 mm daily. One year after, BP was 130/80 mmHg and HR 72/min. CONCLUSIONS There was a slight increase in a blood pressure following the first VNS, but not in a heart rate. No significant correlation betwen BP and HR was observed.

Objective: The purpose of our study was to investigate the possible association between atheroslerosis and osteoporosis and ti evaluate the common risk profile for both disorders. Design and method: A clinical prospective open label study has been designed. Total of 36 patients with a severe osteoporosis were screened for atherosclerotic changes in aorta and heart valves. The 2D and 3D transthoracic echocardiography including the color doppler was performed in all subjects. The morphology of build-up calcium and functional assessment of the blood flow either as regurgitation or stenosis through the valves was estimated. The transoesophageal echocardiography was performed in a selective cases where indicated.The analysis of severety of osteoporosis and atherosclerosis was done. The cardiovascular risk profile for both disease including arterial hypertension, smoking, lipid profile, diabetes, comorbidities etc was notified. Results: All 36 patients with established severe osteoporosis had a significant atherosclerosis manifested by high calcification of mitral anulus, mitral valves and aortic valves. The severe atherosclerosis was manifested also functionally with a mitral and aortic regurgitation and stenosis. The average T-score in osteoporotic patients was -3,1 proving severe osteoporosis with a high risk for the bone fractured. The cardiovacular risk factors were the the significantly similar in atherosclerosis and osteoporosis. The arterial hypertension, smoking, high cholesterol and diabetes were the mostly presented. Conclusions: Our results indicate the common risk factor profile for both degenerative disorders, atherosclerosis and osteoporosis. The severe osteoporosis, the more severe atherosclerosis. The loss of calcium from the bones has to be stored in other tissue like aortic, coronary arteries and heart valves. The hypothesis raise from this study is whether atherosclerosis and osteoporosis is a single disease?!

OBJECTIVE A significant number of patients with rheumatoid arthritis (RA) link the start of illness with psychological trauma or severe stress. Impaired mental health (IMH), defined as depression and anxiety with psychoneuroimmunological factors, can play a significant role in RA. The main objective of this research was to investigate the mutual correlation of IMH and RA activity, estimated by the laboratory and clinical parameters in RA patients. MATERIAL AND METHODS An open clinical prospective study that lasted for 6 months was designed. There were 72 patients included, 58 women and 14 men, aged 34 to 80 years and screened for mental health status. The study population was randomized following the Brief Symptoms Inventory (BSI) scale, comprised of 53 questions with a range from 0 (no symptoms) to 4 (severe). This mental test was done only once during the study. Following the results from the BSI scale, RA patients were divided into mentally stable and mentally unstable patients to investigate the influence of RA activity on mental health. The following laboratory and clinical parameters were analyzed: sex, age, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), C-reactive protein (CRP), anti-cyclic citrullinated peptide (anti-CCP) antibody, and disease activity score (DAS28). All RA patients did not express extra-articular manifestations or Sjögren's syndrome. The chi-square test, ANOVA, Pearson's coefficient, and IBM Statistics - SPSS v19 were used. RESULTS From a total of 72 RA patients, there were 44 mentally stable and 28 mentally unstable patients. All patients had either moderate or severe active disease. The only significant correlation of IMH and activity of RA was found in CRP and DAS28, but no significance was observed in ESR, RF, and anti-CCP. The DAS28 showed high disease activity with an average of 5.3 and CRP of 20.9 mg/L in patients with unstable mental health compared to stable mental health patients, where RA was associated with a moderate DAS average value of 4.35 and CRP of 14.1 mg/L. Depression and anxiety were found in all 28 (39%) RA patients. CONCLUSION Mentally unstable RA patients correlate more with severe disease activity, while mentally stable patients express moderate disease activity.

Introduction : The Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic disease that is usually the most evident and commonly manifested on diarthrosis joints. The initial etiological factors that trigger the immune-inflammatory response still remains unknown. RA is result of the simultaneous influence of genetic risk factors, external factors and changes in immune system. Objective : The goal of this study was to determine the mutual correlation between smoking and RA activities expressed by the quantitative values of laboratory and disease activity parameters. Material and Method : The open clinical retrospective study included 100 RA patients stages from I to IV aged from 21 to 77 ys. There were 85 (85%) females and 15 (15%) males selected by randomization. The study analysed: age, gender, smoking, duration of smoking, sedimentation rate (ESR), rheumatoid factor (RF), C-Reactive Protein (CRP) anti-cyclic citrullinated peptide (anti-CCP) antibodies and X-ray. Statistical analyses was done with SPSS software, Student's t-test and chi-square test. Results : The quantitative values of laboratory parameters are directly related with the smoking period. All inflammatory markers were increased in both groups, but more elevated in smoker's group. The only statistical significance was found in anti-CCP where this test was significantly higher compared to non-smokers. There was no statistical significance in the onset of disease, gender, ESR, CRP, RF, and radiological changes between two groups, although smokers had some more higher values. Conclusion : Smoking plays significant role in RA activity and leads to longer duration of symptoms and increased disability. All inflammatory markers were increased in both groups, but more elevated in smoker's group, with the only significancy in anti-CCP level. The cessation of smoking should be part of disease management proccess.

Background The inflammatory reflex regulates innate and adaptive immunity. Activation of its efferent arm (the Cholinergic Anti-inflammatory Pathway (CAP)), by electrical vagus nerve stimulation (VNS) reduces systemic inflammation and ameliorates disease in many acute and chronic animal models1. Objectives We determined whether VNS could improve clinical manifestations and biomarkers of inflammation in rheumatoid arthritis (RA). Methods This is an open label study of patients with active RA (>/= 4 tender and 4 swollen joints, and CRP at least 7 mg/L) despite stable methotrexate for 3 months. After a pre-implantation baseline visit, patients were surgically implanted with a Cyberonics VNS system. The device delivered the first VNS during its standard intraoperative diagnostic check sequence. Two weeks after implantation, patients returned for initial in-clinic VNS. Treatment continued through the primary endpoint at Day 42, was withdrawn for a 14-day hiatus, reinitiated at day 56, and then maintained through the final day 84 visit. Biomarker assessments including serum cytokine levels, FACS of circulating cell markers, and whole blood in vitro LPS-stimulated TNF release were performed. Results 8 patients (7/8 RF+, 6/8 ACPA+) were enrolled. Implantation and stimulation were generally well tolerated. Moderate postoperative hoarseness occurred in one patient. ACR 20/50/70 responses at the day 42 primary endpoint were 75, 50, and 25%, respectively. During the 14-day treatment withdrawal period after day 42, the mean DAS28 worsened significantly (+0.95, 95% CI 0.15-1.75). After treatment re-initiation at day 56, the ACR 20/50/70 responses at the day 84 final visit were 62.5, 25, and 12.5%, respectively. Circulating CD25+FoxP3+Tregs were increased by 31%, and whole blood in vitro LPS-stimulated TNF release was reduced by 59% at day 42 compared with pre-implantation baseline values. In patients with a day 42 EULAR response, serum IL-6 was reduced by 56%. Conclusions VNS was generally well tolerated and improved signs and symptoms of RA. Treatment withdrawal was associated with worsening, and re-initiation with improvement in disease activity. Clinical improvement was associated with reduction in important mediators of systemic inflammation, increases in circulating T regulatory cells and decrease in the ability of circulating leukocytes to release TNF in response to endotoxin. These improvements in objective biomarkers were consistent with effects observed in preclinical inflammation models using VNS. This is the first demonstration in humans that stimulation of the CAP can favorably impact clinical manifestations of systemic inflammation. If efficacy and safety are confirmed in larger controlled studies, implantable medical devices may offer a feasible alternative approach to the treatment of RA and other chronic inflammatory diseases. References Andersson U, Tracey K, Annu. Rev. Immunol. 2012; 30:313 Disclosure of Interest F. Koopman: None Declared, S. Miljko Grant/research support from: SetPoint Medical, S. Grazio Grant/research support from: SetPoint Medical, S. Sokolovic Grant/research support from: SetPoint Medical, K. Tracey Shareholder of: SetPoint Medical, Consultant for: SetPoint Medical, Y. Levine Shareholder of: SetPoint Medical, Employee of: SetPoint Medical, R. Zitnik Shareholder of: SetPoint Medical, Employee of: SetPoint Medical, P.-P. Tak Grant/research support from: SetPoint Medical, Consultant for: SetPoint Medical

Objective To develop evidence-based recommendations on the use of imaging of the joints in the clinical management of rheumatoid arthritis (RA). Methods The task force comprised an expert group of rheumatologists, radiologists, methodologists and experienced rheumatology practitioners from 13 countries. Thirteen key questions on the role of imaging in RA were generated using a process of discussion and consensus. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, dual-emission x-ray absorptiometry, digital x-ray radiogrammetry, scintigraphy and positron emission tomography. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. The experts used the evidence obtained from the relevant studies to develop a set of 10 recommendations. The strength of recommendation was assessed using a visual analogue scale. Results A total of 6888 references was identified from the search process, from which 199 studies were included in the systematic review. Ten recommendations were produced encompassing the role of imaging in making a diagnosis of RA, detecting inflammation and damage, predicting outcome and response to treatment, monitoring disease activity, progression and remission. The strength of recommendation for each proposition varied according to both the research evidence and expert opinion. Conclusions Ten key recommendations for the role of imaging in the management of RA were developed using research-based evidence and expert opinion.

OBJECTIVE To assess serum levels of tumor marker carbohydrate antigen 125 (CA125) in patients with heart failure (HF) and to investigate possible correlation with echocardiographic parameters and level of brain natriuretic peptide (BNP). PATIENTS AND METHODS We included 76 patients with different cardiac symptoms hospitalized at Clinic for heart disease and rheumatism. Control group (n = 26) was consisted of patients without signs and symptoms of HF, normal left ventricle ejection fraction (LVEF) and normal BNP level. Patients with diagnosis of HF (n = 50) were subdivided into 2 group depending on signs and symptoms of fluid overload: compensated (compHF, n = 10) and decompensated group (decompHF, n = 40). Serum CA125 and BNP were measured on admission and all patient underwent ECG recording and trans thoracic echocardiographic examination. RESULTS The median CA125 level in HF group was significantly higher compared to control group (71.05 [30.70-141.47]U/ml vs 10.75 [8.05- 14.32] U/ml, p < 0.0005). Higher CA125 levels were found in decompHF group compared to compHF group (94.90 [49.75-196.75]U/ml vs 11.90 [10.25-15.80]U/ml, p < 0.0005). In decompHF group 13 of patients had pleural and/or pericardial effusion- their CA125 levels were significantly higher compared to patients without serosal effusion (n = 27) (205.10 [106.50-383.90]U/ml vs. 71.50 [47.30-109.55] U/ml, p < 0.002). We found significant difference in CA125 levels between patients with atrial fibrillation and sinus rhythm (98.40 [48.20-242.70] U/ml vs. 47.30 [12.95-99.05] U/ml, p = 0.015). There was no significant difference in CA125 levels in group with enlarged left atrium compared to normal sized atrium (p = 0.282), as well as in group with moderate/severe mitral regurgitation compared to group with no/mild mitral regurgitation (p = 0.99). Finally, levels of serum CA125 positively correlated with serum level of BNP (r = 0.293, p = 0.039), but not with LVEF (p = 0.369) and left atrium diameter (p = 0.636). CONCLUSION Serum CA125 is elevated in decompensated HF patients: more pronounced elevation was found in patients with pleural and/or pericard effusion compared to patients with no serosal effusion. CA125 level correlated with BNP, but not with left atrium diameter nor with LVEF. Tumor marker CA125 could be used as a marker of systemic congestion and volume overload in decompensated HF. We hypothesized that high CA125 level indicates that measured high BNP is actually wet BNP.

Musculoskeletal ultrasound has become one of the major diagnostic tools in rheumatology for joint examination. Since the inflammatory rheumatic diseases frequently involve all the body systems including the heart, echocardiography plays an important role in the management of rheumatic diseases. Pericardial effusion, pericarditis, infective and non-infective endocarditis (Libman-Sacks), valvular involvement with stenosis and regurgitation, aortic root dilatation, dilated left and right ventricle, and pulmonary arterial hypertension can be routinely checked by a rheumatologist. The article focuses on introduction of basic principles of echocardiography necessary for an internist-rheumatologist in diagnosis and management of autoimmune systemic rheumatic diseases. S t r e s z c z e n i e

Background: Nitric Oxide (NO) participation is recognized in numerous physiological and pathological processes. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease involving joints and other systems including salivary glands. The role of NO in pathogenesis of development of RA is still unknown. Aim & Objectives: We investigated NO concentration in saliva of 63 patients with RA and in 31 healthy control individuals. The aim of the study was also to investigate the correlation between saliva NO concentration and disease activity score (DAS28) in RA patients and to determine whether the statistically significant difference in saliva NO concentrations exists between RA patients with different stages of disease activity. Methods: Patients with RA in this cross;sectional study have been divided, based on the stage of disease activity evaluated by DAS28score, into three subgroups: low disease activity (n=19), moderate disease activity (n=19) and high disease activity (n=25). NO concentration was determined by measuring nitrite concentration by Griess reaction. Conversion of nitrate (NO ;3 ) to nitrite (NO ;2 ) was done with elementary zinc. Absorbance was measured at 546 nm with the use of spectrophotometer.