Vedran Velagić

Peripheral Blood Expression Profiles of Bone Morphogenetic Proteins, Tumor Necrosis Factor-superfamily Molecules, and Transcription Factor Runx2 Could Be Used as Markers of the Form of Arthritis, Disease Activity, and Therapeutic Responsiveness

Objective. To assess whether different forms of arthritis and disease activity could be distinguished by peripheral blood expression profiles of bone-regulatory factors including tumor necrosis factor (TNF)-superfamily [TNF-related apoptosis-inducing ligand (TRAIL), the Fas ligand (FasL), and the ligand for herpesvirus entry mediator (LIGHT)] and bone morphogenetic protein (BMP)-family members (BMP-2, BMP-4, BMP-6) as well as osteoblast differentiation gene Runx2. Methods. Blood cells from healthy controls (n = 25) and patients at different disease stages with rheumatoid arthritis (RA; n = 49), osteoarthritis (OA; n = 17), or spondyloarthritis, including ankylosing spondylitis (AS; n = 27) or psoriatic arthritis (PsA; n = 23), were processed for quantitative polymerase chain reaction. Gene expression was assessed in comparison with control samples, correlated with clinical data of different forms of arthritis, and analyzed for discriminative efficacy between groups by receiver-operation characteristic (ROC) curves. Results were confirmed on diagnostic RA (n = 5) and AS (n = 8) samples. Results. BMP-4, BMP-6, and Runx2 expressions were significantly decreased in patients with RA and OA versus controls. Patients with RA also had decreased FasL and LIGHT expression, while patients with AS had increased Runx2 expression. Negative correlation with disease activity was found for BMP-4, FasL, and Runx2 in RA and for Runx2 in PsA, while positive correlation was found for BMP-4 in PsA. Gene expression was higher in the therapy-resistant form of AS (for BMP-4, LIGHT, and Runx2) and in methotrexate-treated patients in RA (for BMP-2 and LIGHT). ROC curve analysis confirmed discrimination between groups, particularly decreased LIGHT and Runx2 for RA and increased Runx2 for AS. Conclusion. Our study identified BMP and Runx2 as possible biomarkers of bone metabolism in several forms of arthritis, while lower FasL and LIGHT were associated with RA. Correlation between gene expression and disease activity may be clinically useful in assessing therapeutic effectiveness and disease monitoring.

Atrial apoptosis and fibrosis adversely affect atrial conduit, reservoir and contractile functions †

OBJECTIVES Chronic atrial volume overload and atrial fibrillation (AF) induce structural changes within atrial myocardium. The aim of this study was to evaluate the effect of adverse cellular remodelling on echocardiographic strain rate (SR) deformation indices of atrial contractile, conduit and reservoir functions. METHODS Forty-four consecutive patients with organic mitral regurgitation were analysed. Twenty-eight patients had long-standing persistent AF (AF group), while 16 were in normal sinus rhythm (NSR group). Left atrial (LA) samples were harvested from all the patients for histological analysis. Postoperative echocardiographic data acquisition was performed exclusively during organized atrial electrical activity in order to assess the contractile reserve of patients from both groups. RESULTS Fibrotic atria had inferior conduit (SR-E: r = -0.36, P = 0.017), reservoir (SR-S: r = -0.31, P = 0.041) and contractile functions (SR-A: r = -0.33, P = 0.027). Analogously, atria with greater apoptotic burdens showed a negative correlation with multiple indices of left atrial functions (SR-E: r = -0.38, P = 0.010; SR-S: r = -0.33, P = 0.028; SR-A: r = -0.28, P = 0.067). The efficiency of atrial contractility was significantly reduced among AF-group patients after conversion to sinus rhythm, when compared with patients in the NSR group (LA active emptying fraction: 20 ± 12 vs 30 ± 10%, P = 0.004; SR-A: 1.1 ± 1.0 vs 2.8 ± 1.9 s(-1), P < 0.001). Superior strain-rate indices of atrial conduit and reservoir functions were noted in the NSR group (SR-E: 3.5 ± 2.3 vs 1.3 ± 1.0 s(-1), P < 0.001; LA expansion index: 86 ± 31 vs 60 ± 42%, P = 0.004). Fibrosis was evident in 7.2 [3.3;9.4]% of the LA tissue sample in the AF group, while it accounted for 3.4 [1.2;8.1]% of atrial tissue in the NSR group (P = 0.054). Apoptosis was documented in 13 (46%) patients in the AF group, whereas none of the patients in the NSR group exhibited signs of programmed cell death (P = 0.001). Myocyte degeneration was more prevalent in the AF group (odds ratio: 7.0, 95% confidence interval: 1.3-36.7, P = 0.021). Age showed a positive correlation with worsening degrees of atrial fibrosis and apoptosis (r = 0.41, P = 0.006; r = 0.49, P = 0.001, respectively). Multiple regression analysis identified SR-S (β = -1.263, P = 0.036) and age (β = 0.144, P = 0.057) as independent predictors of fibrosis. Independent determinants of apoptosis were preoperative AF (β = 4.539, P = 0.007), age (β = 0.188, P = 0.009) and SR-S (β = -1.780, P = 0.002). CONCLUSIONS Atria exhibiting greater fibrotic and apoptotic burdens had impaired conduit, reservoir and contractile function, as evaluated by deformation imaging. Among patients with chronic LA volume overload, exposure to long-standing persistent AF induced more pronounced degrees of adverse atrial cellular remodelling. Strain-rate descriptors of atrial reservoir function harboured potential to predict atrial fibrosis and apoptosis.

Somatic comorbidity, metabolic syndrome, cardiovascular risk, and CRP in patients with recurrent depressive disorders

Aim To investigate the association between depression, metabolic syndrome (MBS), somatic, particularly cardiovascular comorbidity, and low-grade chronic inflammation assessed using C-reactive protein (CRP). Methods This cross-sectional study included 76 patients with recurrent depressive disorder (RDD) and 72 non-depressed medical staff controls from the Department of Psychiatry, University Hospital Center Zagreb between January 2011 and June 2012. Results Seventy-five percent of patients had somatic comorbidity. The most common comorbid conditions were cardiovascular disorders (46.1%), locomotor system diseases (35.5%), carcinoma (15.8%), thyroid diseases (9.2%), and diabetes (9.2%). MTB was more common in RDD patients (31.6%) than in controls (23.6%), but the difference was not significant. Elevated CRP was found to be significantly more frequent in patients with recurrent depressive disorders (RDD) (35.5%; χ2 test, P = 0.001, Cramer V = 0.29) than in controls (12.5%) and was associated with lowered high-density lipoprotein and overweight/obesity. Conclusion We found some intriguing links between stress, depression, metabolic syndrome, and low grade inflammation, which may be relevant for the prevalence of somatic comorbidity in patients with RDD, but further studies are needed to confirm our results.

Propranolol efficiency in prevention of sustained ventricular tachycardia in patients with implanted cardioverter-defibrillator : a case series

Patients with implanted cardioverter-defibrillator (ICD) often have justified ICD activations no matter if the indication for implantation was primary or secondary prophylaxis of sudden death. First line therapy in the prevention of recidivate ventricular arrhythmia in these patients is antiarrhythmic therapy, but if this is inefficient, arrhythmic substrate radiofrequency (RF) ablation is recommended. Ablation treatment is an accepted procedure in patients with ischemic heart disease, but it has rarely been used in patients with idiopathic and particularly polymorphic ventricular tachycardia (VT). It must be emphasized that acute ablation is relatively successful, but because of substrates progression, relapses of VTs are very frequent (35%) (1). Therefore, antiarrhythmic therapy remains an important therapy after the ICD implantation, before, and often after RF ablation (2). We present the cases of five patients in whom the prevention of recidivate VTs was achieved only by an old nonselective beta-blocker propranolol (dose 20 × 40 or 2 × 80mg). Patient 1: a 52 years old woman with ICD implanted as a secondary prevention after out-of-hospital cardiac arrest caused by ventricular fibrillation. There was no structural heart disease, coronarography was normal, and there was only arterial hypertension in patients history. QTc interval was within the reference range, there were no Brugada syndrome elements, and no sudden death in family history. During the first year after the implantation, ICD was activated for more than 10 times because of polymorphic VT in spite of medicaments therapy. On one occasion even an electrical storm occurred. After the implantation, bisoprolol maximum dose was given, and later in combination with mexiletine, which was stopped as a result of intolerance. Combination with amiodarone was used for a short period of time but with no effects. Only after bisoprolol had been replaced with propranolol, there were no tachycardias and ICD stopped activating. Since then the patient has been followed-up for 5 years. Patient 2: a 56 years old man with no family or individual heart disease history, or any other serious disease. ICD was implanted as secondary prophylaxis after relapsing syncopes caused by VTs. The first therapy with amiodarone had not prevented multiple ICD activations, so it was replaced by a combination of bisoprolol and mexiletine. Despite the new therapy, ICD continued to activate for several justified occasions (5 times). Only after bisoprolol had been replaced with propranolol, ICD stopped activating. Since then the patient has been followed-up for 3 years. In the meantime, mexiletine therapy has been stopped (it is unavailable in Croatia), so now he takes propranolol only. Patient 3: a 69 years old man with ICD implanted after relapsing sustained VTs. The patient had no structural heart disease or any signs of ischemia. Coronarography was normal. In spite of the maximum dose of bisoprolol in combination with amiodarone, ICD was reasonably activated on over 20 occasions. On 3 occasions, an electrical storm was detected. Arrhythmia could not have been controlled even by the combination of bisoprolol and mexiletine. Only the replacement of bisoprolol by propranolol led to a complete VT suppression. In the last 3 years, the patient has not had any ICD activation. In the meantime, mexiletine therapy has been stopped. Patient 4: a 86 years old man. Two years ago, he had inferioposterior myocardial infarction with ST-elevation (STEMI) and a year after he was hospitalized for hemodynamically unstable VT. Slightly reduced ejection fraction (EF 45%-50%) was determined, caused by inferioposterior hypokinesia. Coronarography showed an old collateralized occlusion of the right coronary artery (RCA) and irrelevant changes on other coronary arteries. Sustained VTs repeated daily, despite the use of different antiarrhythmics: bisoprolol, lidocaine, amiodarone, and magnesium. After the temporary electrode had been placed, conversion was achieved by overdrive electrostimulation, but only occasionally. However, electrical cardioversion had to be done in most cases (6 times). Only the combination of propranolol and lidocaine in high doses managed to suppress VT. The patient had a successful RF ablation of VT with propranolol therapy only. During the 2 years of follow-up, he has had no arrhythmia. ICD has not been implanted. Patient 5: a 60 years old man. After anteroseptal STEMI with severely reduced left ventricular systolic function, the patient developed frequent VTs that responded neither to combination of bisoprolol and lidocaine nor to overdrive stimulation. The use of amiodarone induced a remarkable extension of the QTc interval without suppressing arrhythmia. On most occasions, arrhythmia had to be stopped by electrical cardioversion (5 times). Only after using propranolol instead of bisoprolol, arrhythmia was completely suppressed. When propranolol had been cancelled, because of septic shock, VT relapsed. After the septic shock had been stabilized, ICD was implanted and propranolol was included to the therapy again. Further follow-up (1 year) has not recorded any ICD activation. In our cases, non-selective propranolol was more effective in suppressing severe VTs than newer selective beta blocker bisoprolol. Unlike bisoprolol, propranolol blocks both beta 1 and beta 2 receptors (20% of beta adrenergic receptors in the heart) and owing to liposolubility also penetrates into the brain (3). Thereby, it can also result in the central inhibition of the sympathetic nervous system. The unique stability effect on the membrane of myocytes has also been described (4). Previous studies showed that propranolol in combination with amiodarone offered the best prevention of VT relapses (5). The reason why propranolol is not widely used in patients with cardiomyopathy is the lack of evidence-based data for these indications. Studies in patients with cardiomyopathy have recently been conducted using only newer beta-blockers (carvedilol, metoprolol, bisoprolol) (6). We believe it could be useful to conduct a study on propranolol, because propranolol possibly has more beneficial effect on the survival of patients with cardiomyopathy than selective beta blockers.

Which clinical variables have the most significant correlation with quality of life evaluated by SF-36 survey in Croatian cohort of patient with ankylosing spondylitis and psoriatic arthritis?

The aim of our study was to assess clinical variables with the best correlation to quality of life (QOL) assessed by medical outcome survey Short-Form 36 (SF-36) in patients with spondyloarthritides, including ankylosing spondylitis (AS) and psoriatic arthritis (PsA). We analyzed the cohort of 54 patients (22 patients with PsA and 32 patients with AS), who filled the Croatian version of SF-36. For each type of arthritis, patients were clinically evaluated using the extensive list of clinical variables categorized into subjective and objective group. For AS patients, subjective and objective variables (spinal mobility measurements, clinical assessment of spinal pain, patient assessments of disease activity and pain) correlated mainly with the physical functioning concept of SF-36. Patients assessments of fatigue correlated with the energy/fatigue subscale, whereas patient assessment of enthesial pain correlated with the pain subscale. Correlations between clinical variables and SF-36 concepts of PsA patients showed more diverse distribution than for AS. Objective variables (spinal mobility measurements, a 76-joint score, clinical assessment of spinal pain) correlated with concepts concerning physical health and pain. Several subjective patient assessments correlated with energy/fatigue, emotional well-being, pain and general health subscales. Both patient and physician assessment of PsA activity correlated with the role limitations due to emotional problems. Bath ankylosing spondylitis functional index (BASFI) had the strongest correlation with the physical functioning concept of SF-36 in both diseases. Our findings provide important information to help selecting the variables with strongest impact on QOL, for better planning the management strategies and achieving better rehabilitation results.

Inducible left-ventricular intracavity gradient during dobutamine stress echocardiography — a condition worth noting

Cardiologia CROATICA Objectives: To evaluate the incidence and left ventricular (LV) morphologic characteristics of patients developing dynamic intraventricular obstruction induced during dobutamine stress echocardiography (DSE). Methods: We studied 77 patients (42 men 55%; mean age 61±12 years) referred for standard high-dose DSE due to exertional dyspnoea or chest pain. The patients were divided into two groups — group I consisted of patients who developed a significant left-ventricular (LV) intracavitary gradient (>20 mmHg) during DSE (33 patients, 45% men, mean age 58.6 ± 12.5 years) and group II consisted of patients without an inducible gradient (44 patients 61% men; mean age 62.5 ± 10.7 years). The intracavitary gradient was defined as a late-peaking left ventricular Doppler velocity profile exceeding basal velocity by 1 m/sec. Results: 43% of the studied patients developed the gradient during high stages of dobutamine infusion (>20 mcg/kg/ min). Mean intracavitary gradient was 75.1 mmHg (range 20-135 mmHg). Patients in group I had statistically smaller LV cavity dimensions (Table 1) but their ejection fraction and fractional shortening were greater. These measurements were done using the Teicholtz method which is based on measuring the radial function of the LV (Table 1). Hypertension was present in a larger percentage of patients in the group I compared to the group II, however not reaching statistical significance (group I 30%, group II 18%, p = 0.28). According to patient histories somewhat more patients in the group I (27%) experienced symptoms like dyspnoea or chest pain during dobutamine infusion than in the group II (18%). The DSE study (Figure 1) was positive for inducible ischaemia in a significantly greater number of patients in the group II, compared to the patients developing the gradient (88% to 12%). Conclusion: An inducible LV intracavitary gradient occurred in a large number (43%) of patients referred to DSE in our centre. These patients had significantly smaller LV cavity dimensions which, together with notably increased radial function, likely contributes to the development of the gradient. Higher values of LV radial function measurements are common in hypertension. Indeed, we noted a higher inciProπireni saæetak / Extended abstract