Cleland J.G.F.,University of Hull |
Teerlink J.R.,University of California at San Francisco |
Senior R.,Royal Brompton Hospital |
Nifontov E.M.,St. Petersburg State Medical University |
And 17 more authors.
The Lancet | Year: 2011
Background Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. Methods We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. Findings 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. Interpretation Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. Funding Cytokinetics Inc. © 2011 Elsevier Ltd.
Zhebrun D.,Blood and Endocrinology Center |
Kudryashova Y.,Institute of Endocrinology |
Babenko A.,Institute of Endocrinology |
Maslyansky A.,Blood and Endocrinology Center |
And 6 more authors.
Aging | Year: 2011
The protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) is an important negative regulator of signal transduction through the T-cell receptors (TCR). Recently a single-nucleotide polymorphism (SNP) 1858 C/T within this gene was shown to be a risk factor for several autoimmune diseases, such as rheumatoid arthritis (RA), Graves' Disease (GD), systemic lupus erythematosus (SLE), Wegener's granulomatosis (WG) and type 1 diabetes mellitus (T1D). The aim of this study was to analyze a possible association between 1858 C/T SNP and a number of autoimmune diseases, including RA, GD and T1D in Russian population. Patients with T1D, GD, RA and healthy controls were genotyped for the 1858 C/T SNP in PTPN22 gene. We found a significant association between PTPN22 1858 C/T SNP and T1D and GD. 1858T/T genotype was observed more frequently in T1D and GD patients compared to control subjects. No such association was observed for RA. In concordance with a previous data establishing PTPN22 1858 C/T SNP association with several autoimmune diseases, our findings provide further evidence that the PTPN22 gene may play an important role in the susceptibility to some autoimmune diseases. © Zhebrun et al.
Sonin D.L.,Medical College of Wisconsin |
Sonin D.L.,Blood and Endocrinology Center |
Wakatsuki T.,Invivosciences, Inc. |
Routhu K.V.,Medical College of Wisconsin |
And 4 more authors.
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2013
Purpose: Fibroblast activity promotes adverse left ventricular (LV) remodeling that underlies the development of ischemic cardiomyopathy. Transforming growth factor-b (TGF-b) is a potent stimulus for fibrosis, and the extracellular signal-regulated kinases(ERK) 1/2 pathway also contributes to the fibrotic response. The thrombin receptor, protease-activated receptor 1 (PAR1), has been shown to play an important role in the excessive fibrosis in different tissues. The aim of this study was to investigate the influence of a PAR1 inhibitor, SCH79797, on cardiac fibrosis, tissue stiffness and postinfarction remodeling, and effects of PAR1 inhibition on thrombin-induced TGF-b and (ERK) 1/2 activities in cardiac fibroblasts. Methods: We used a rat model of myocardial ischemia-reperfusion injury, isolated cardiac fibroblasts, and 3-dimensional (3D) cardiac tissue models fabricated to ascertain the contribution of PAR1 activation on cardiac fibrosis and LV remodeling. Results: The PAR1 inhibitor attenuated LV dilation and improved LV systolic function of the reperfused myocardium at 28 days. This improvement was associated with a nonsignificant decrease in scar size (%LV) from 23+% in the control group (n = 10) to 16%+5.5% in the treated group (n = 9; P = .052). In the short term, the PAR1 inhibitor did not rescue infarct size or LV systolic function after 3 days. The PAR1 inhibition abolished thrombin-mediated ERK1/2 phosphorylation, TGF-b and type I procollagen production, matrix metalloproteinase-2/9 activation, myofibroblasts transformation in vitro, and abrogated the remodeling of 3D tissues induced by chronic thrombin treatment. Conclusion: These studies suggest PAR1 inhibition initiated after ischemic injury attenuates adverse LV remodeling through late-stage antifibrotic events. © The Author(s) 2012.
Golovanova T.A.,RAS Sechenov Institute of Evolutionary Physiology and Biochemistry |
Belostotskaya G.B.,Blood and Endocrinology Center
Cellular Transplantation and Tissue Engineering | Year: 2011
In mammalian heart, cardiac myocyte division ceases within the first week of postnatal life posing one of the most intriguing questions of evolution. Stimulation of cardiac myocyte proliferation during postnatal period would have profound impact on cardiac regeneration in humans. It has been shown that the primary culture of cardiac myocytes obtained from newborn rat could serve as an appropriate model for the investigation of the processes taking place in the heart during early postnatal ontogenesis. Similarly to the in vivo situation, the increased mitotic activity observed during the first 2-4 days after birth is diminished in cardiac myocyte culture within 4-5 days of culturing. Besides, 60% of cultured cells underwent mitotic division followed by increase in their volume which also closely resembles the process of cardiac myocyte hypertrophy in vivo. The cardiac myocyte volume was progressively increased during culturing and equaled to 819±68, 1532±212, and 3246±190 μm 3 on the 1 st, 3 rd, and 6 th day of culture, respectively. Furthermore, the rate of cardiac myocyte growth in culture was similar to the pattern of myocyte hypertrophy observed in the in vivo settings. Myocyte hypertrophy in culture was associated with the formation of polyploid and multinucleated, most commonly binucleated, cells which is generally analogous to the in vivo myocyte hypertrophy. The analysis of myocyte volume distribution suggested that during cultivation nearly 60% of cells are switched from hyperplasia to hypertrophy, stopping at the G 2/M boundary of the cell cycle. The results obtained indicate that cell growth patterns in primary cardiac myocyte culture share a lot of similarity with the in vivo cardiac myocyte growth. Primary cardiac myocyte culture is a valuable tool for investigation of the processes responsible for cessation of cardiac myocyte division in adult mammals.
Anisimov S.V.,Blood and Endocrinology Center
Advances in Gerontology | Year: 2012
Any spinal pathology is accompanied by a significant loss in the quality of life and a high disability rate. The rate of occurrence of spinal impairments increases with advancing age. Spinal impairments may be etiologically different and characterized by a wide range of significant and very diverse clinical symptoms. At the same time, the "lower back pain" (as well as the back pain) syndrome is the most common complaint. The main cause for the development of the syndrome is degenerative disc disease (DDD) of a nonspecific nature that leads to irreversible structural damage to intervertebral discs. Surgical DDD treatment methods, including those based on bone tissue autografting, are not radical; this compels researchers to search for alternative approaches. This review analyzes the principles of regenerative cellular and cell-replacement therapies that are based on the use of a variety of cell types, in the treatment of intervertebral pathologies and compares various cell substrates for these therapies. © Pleiades Publishing, Ltd., 2012.
Mikhaylov E.N.,Blood and Endocrinology Center |
Bhagwandien R.,Electrophysiology Unit |
Janse P.A.,Electrophysiology Unit |
Theuns D.A.M.J.,Electrophysiology Unit |
Szili-Torok T.,Electrophysiology Unit
Europace | Year: 2013
AimsCryoballoon ablation (CBA) is a well-used technique when performing pulmonary vein (PV) isolation in patients with paroxysmal atrial fibrillation (AF). Our aim is to describe incidence, characteristics, and clinical predictors for developing atrial tachycardias (ATs) after cryoballoon PV isolation in patients with paroxysmal AF.Methods and resultsThe study population consisted of 181 consecutive patients undergoing a first CBA. All patients received an event-recorder before cryoablation and transmitted daily electrocardiogram (ECG) during 1 month before ablation and 3 months after. Further follow-up consisted of 24 h Holter monitoring and ECG registration every 3 months and also in patients presenting with symptoms. A mean follow-up period was 497.9 ± 283.9 days, and 175 patients completed follow-up. In 14 (8%) patients regular ATs were registered. In multivariate logistic regression model, the following parameters were independently associated with ATs after ablation: an additional right PV, treatment with beta-blockers, and presence of AT on event-recording strips before ablation. Seven (4%) patients with registered AT underwent a redo procedure. In two (1.1%) patients ATs were originated in reconnected PVs. In other patients no left AT was induced. No macro re-entrant left AT was documented in any patient. During follow-up, after a redo ablation, no AT was registered.ConclusionThe incidence of left AT after CBA is low, and no left atrial macro re-entrant tachycardia was found. The following independent predictors of AT development have been identified: an additional right PV, regular AT registered before ablation, and the use of beta-blockers. © 2013 The Author.
Mikhaylov E.,Blood and Endocrinology Center |
Kanidieva A.,Blood and Endocrinology Center |
Sviridova N.,Blood and Endocrinology Center |
Abramov M.,Blood and Endocrinology Center |
And 3 more authors.
Europace | Year: 2011
Aims: A new strategy for anatomically based ganglionated plexi (GP) ablation for the treatment of paroxysmal atrial fibrillation (AF) has been proposed recently. We aimed to assess the long-term outcome of patients undergoing anatomic GP ablation for paroxysmal AF, in comparison with circumferential pulmonary vein (PV) isolation. Methods and results: The study population consisted of 70 patients (mean age 56.6 ± 10.9 years; 41 males) with paroxysmal AF and no history of structural heart disease: 35 subjects underwent anatomic GP ablation, while 35 consecutive patients had circumferential PV isolation (CPVI) (control group). The groups were not different in demographic and clinical parameters. Anatomic GP ablation required more ablation points (85.6 ± 5.5 vs. 74.4 ± 6.2, P < 0.05) and equal duration of total procedure and fluoroscopy times. During a mean follow-up period of 36.3 ± 2.3 months, freedom from any atrial tachyarrhythmia without antiarrhythmics was achieved in 34.3% patients after anatomic GP ablation and 65.7% patients after CPVI (log-rank test P = 0.008). Early arrhythmia recurrences and anatomic GP ablation were independent predictors of late recurrence [HR 6.44 (CI 95%; 3.14-13.18; P < 0.001) and HR 2.08 (CI 95%; 1.03-4.22; P = 0.04), respectively]. Six patients in the group of GP ablation underwent subsequent CPVI, plus peri-mitral flutter ablation in two of them, with no further arrhythmia episodes in five patients. Conclusion: Anatomic GP ablation yields a significantly lower success rate over the long-term follow-up period, when compared with CPVI. Recurrences include AF and macro re-entrant atrial tachycardias. © The Author 2010.
Korostovtseva L.S.,Blood and Endocrinology Center
Medical science monitor : international medical journal of experimental and clinical research | Year: 2011
To assess the impact of obstructive sleep apnea-hypopnea syndrome (OSAHS) on prognosis and cardiovascular morbidity and mortality in relation to other major cardiovascular risk factors. This prospective study recruited 234 patients from an out-patient clinic. Based on the Berlin questionnaire, 147 patients (90 males, mean age 52.1 ± 10.4 years) with highly suspected sleep breathing disorders were included in the study. Based on cardiorespiratory monitoring, patients were divided into 2 groups: 42 patients without sleep breathing disorders (SBD), and 105 patients with OSAHS. Among these, 12 patients started CPAP therapy and formed the third group. The mean follow-up period was 46.4 ± 14.3 months. Event-free survival was lowest in the untreated OSAHS patients (log rank test 6.732, p = 0.035). In the non-adjusted regression model, OSAHS was also associated with a higher risk of cardiovascular events (OR = 8.557, 95% CI 1.142-64.131, p = 0.037). OSAHS patients demonstrated higher rates of hospitalization compared to the control group without SBD (OR 2.750, 95%CI 1.100-6.873, p = 0.04). OSAHS hypertensive patients, and in particular, according to our model, patients with severe OSAHS (AHI ≥ 30/h), are at higher risk of fatal and non-fatal cardiovascular events. Moreover, untreated OSAHS patients demonstrate higher rates of hospitalization caused by the onset or deterioration of cardiovascular disease.
Platonov P.G.,Lund University |
Mitrofanova L.B.,Blood and Endocrinology Center |
Orshanskaya V.,Blood and Endocrinology Center |
Ho S.Y.,Imperial College London
Journal of the American College of Cardiology | Year: 2011
Objectives: The purpose of this study was to assess the association between structural changes in human atria, age, and history of atrial fibrillation (AF). Background: Development of fibrosis in atrial walls is associated with deterioration of atrial conduction and predisposes to AF in experiment. Human data, however, are scarce, and whether fibrosis is a cause or consequence of AF is not known. Methods: Medical records for consecutive autopsies were checked for AF history and duration. Atrial specimens from 30 patients (ages 64 ± 12 years) were collected in 3 equal age-matched groups as patients without AF history, with paroxysmal AF, or with permanent AF. Tissue samples were obtained at the level of superior pulmonary veins, inferior pulmonary veins, center of posterior left atrial wall, terminal crest, and Bachmann's bundle. Histology sections were assessed for extent of fibrosis, fatty tissues, and inflammatory infiltration at each location. Results: No correlation was observed between age and fibrosis at any location. Fibrosis extent and fatty infiltration were twofold to threefold higher at all locations in patients with history of AF and correlated with lymphomononuclear infiltration. Patients with permanent AF had greater fibrosis extent than did patients with paroxysmal AF. Conclusions: In post-mortem material, structural changes in the atria were not associated with age, but were significantly correlated with presence of AF and its severity. Our findings suggest that age-related changes per se are unlikely to be the sole cause of advanced fibrosis underlying AF. © 2011 American College of Cardiology Foundation.
Mikhaylov E.N.,Blood and Endocrinology Center |
Orshanskaya V.S.,Blood and Endocrinology Center |
Lebedev A.D.,Blood and Endocrinology Center |
Szili-Torok T.,Erasmus University Rotterdam |
Lebedev D.S.,Blood and Endocrinology Center
Journal of Cardiovascular Electrophysiology | Year: 2013
Hyperthyroidism and AF Ablation Introduction Many patients with atrial fibrillation (AF) receive amiodarone. Amiodarone-induced hyperthyroidism (AIH) may develop as a complication. We hypothesized that pulmonary vein (PV) isolation in patients with paroxysmal AF and history of AIH may yield a lower success rate. Methods and Results Among 704 patients who underwent AF ablation in our center between 2007 and 2010, we identified 20 patients (mean age 58.3 ± 5.0 years; 11 males) with paroxysmal AF and overt AIH in the past. The control group consisted of 40 patients with amiodarone-refractory AF and no thyroid dysfunction. All patients underwent circumferential PV isolation. During redo procedures all tachycardias were targeted for ablation. During a 12-month follow-up, in the AIH group 6 (30%) patients were arrhythmia free after a single procedure, in comparison to 25 (62.5%) controls (P = 0.01). Atrial tachycardia (AT) was registered in 7 (35%) AIH patients and in 1 (2.5%) control patient (P = 0.001). AF recurred in 10 (50%) AIH versus 15 (37.5%) control patients (P = 0.2). Redo ablation was performed in 7 (35%) AIH patients and in 3 (7.5%) non-AIH patients (P = 0.01). During a redo procedure a PV-unrelated tachycardia was diagnosed in 5 (25%) AIH patients (vs 0 in the controls, P = 0.003). After the last performed ablation, 12 (60%) AIH patients and 28 (70%) controls had no recurrence, P = 0.56. AIH was an independent predictor of ATs. Conclusion PV isolation alone has a lower efficacy for preventing recurrence in paroxysmal AF in AIH patients. After repeat ablations, overall freedom from tachyarrhythmias is similar to patients with no history of thyroid dysfunction. © 2013 Wiley Periodicals, Inc.