Minimally invasive versus conventional methods for aortic root surgery: Choosing the right approach.

OBJECTIVE: Partial upper sternotomy is preferred for isolated aortic valve replacement because of its optimal surgical visibility and favorable cosmetic outcomes; however, it is not commonly used for aortic root surgery, and the conventional median sternotomy is still the preferred method for most surgeons. We aimed to compare the safety and effectiveness of a minimally invasive approach (partial sternotomy [PS]) and conventional approach (median sternotomy [FS]) for aortic root surgery. METHODS: Patients who underwent aortic root surgery at our hospital from 2016 to 2021 were retrospectively enrolled and divided into two groups. After propensity score matching, the conventional group included 156 patients and the minimally invasive group-57 patients. RESULTS: Bicuspid aortic valves were observed in 63 (40.4%) and 33 (57.9%) patients in the FS and PS groups, respectively. Valve-sparing surgery was performed on 69 (44.2%) and 30 (52.6%) patients in the FS and PS groups, respectively. The minimally invasive approach was beneficial in terms of blood loss during the first 24 h after surgery (p = 0.029) and postoperative blood transfusion (p = 0.023). The survival rates and freedom from reoperation or severe aortic regurgitation after the David procedure were comparable between the standard and minimally invasive groups (p = 0.25; p = 0.66) at mid-term follow-up. CONCLUSIONS: A minimally invasive approach for aortic root surgery can be safely performed as the standard approach. Partial upper sternotomy has the advantage of lower blood loss in the early postoperative period and does not negatively affect the results of valve-sparing root replacement.

Diagnosis and Treatment Patterns of Chronic Thromboembolic Pulmonary Hypertension in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia: A Registry Study.

BACKGROUND: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) in countries with limited resources have, to date, been poorly represented in registries. OBJECTIVE: This work assesses the epidemiology, diagnosis, hemodynamic and functional parameters, and treatment of CTEPH in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia. METHODS: A prospective, cohort, phase IV, observational registry with 3-year follow-up (n = 212) in patients aged ≥ 18 years diagnosed with CTEPH was created. Clinical, hemodynamic, and functional parameters were obtained at an initial visit, follow-up visits, and a final visit at the end of 3 years' observation or end of follow-up. Data were recorded on electronic case report forms. Parameters evaluated included 6-minute walking distance (6MWD), use of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), pulmonary hypertension (PH)-targeted therapy, and survival. All statistical analyses were exploratory and descriptive, and were performed in the overall population. RESULTS: The most common symptoms were typical of those expected for CTEPH. Almost 90% of patients underwent right heart catheterization at diagnosis or initial study visit. In total, 66 patients (31%) underwent PEA before the initial visit; 95 patients (45%) were considered operable, 115 (54%) were inoperable, and two (1%) had no operability data. Only 26 patients (12%) had been assessed for BPA at their initial visit. PH-targeted therapy was documented at diagnosis for 77 patients (36%), most commonly a phosphodiesterase type 5 inhibitor (23%). Use of PH-targeted therapy increased to 142 patients (67%) at the initial visit, remaining similar after 3 years. Use of riociguat increased from 6% of patients at diagnosis to 38% at 3 years. Between baseline and end of observation, results for patients with paired data showed an increase in 6MWD. Survival at the end of observation was 88%. CONCLUSIONS: These data highlight the current diagnosis and management of CTEPH in the participating countries. They show that early CTEPH diagnosis remains challenging, and use of off-label PH-targeted therapy is common. CLINICALTRIALS: gov: NCT02637050; registered December 2015.

Redo aortic root surgery post-Ross procedure.

Background: Despite numerous advantages of the Ross procedure, it presents a risk of late autograft and right ventricular outflow tract conduit failure. This study aimed to analyze the outcomes of autograft dysfunction reoperations using autograft-sparing and root replacement techniques. Methods: Between 2015 and 2023, 49 patients underwent redo root surgery in our institution. Autograft valve-sparing procedures (VSP) were performed in 20 cases and the Bentall procedure (BP) in 29 patients. The short and long-term clinical outcomes along with echocardiographic results of VSP and BP were investigated. Results: Overall early mortality rate was 2.0% with no significant difference between the groups. Severe autograft valve insufficiency at the time of redo (OR 4.07, P = 0.03) and patient age (OR 1.07, P = 0.04) were associated with a valve replacement procedure instead of VSP. The median follow-up duration was 34 months. No late deaths occurred in either group. Freedom from VSP failure and aortic prosthesis dysfunction were 93.8% and 94.1% in the VSP and BP groups, respectively. No reoperations were necessary in either group. Conclusion: Redo aortic root surgery can be safely performed in patients with autograft failure. Both root replacement and autograft valve-sparing procedures demonstrated acceptable results at mid-term follow-up. Early redo surgery pre-empting severe aortic insufficiency increases the likelihood of preservation of the dilated autograft valve.

Adipokine-Cytokine Profile in Patients with Unstable Atherosclerotic Plaques and Abdominal Obesity.

The goal of the research was to study the levels of adipokines and their associations with unstable atherosclerotic plaques in patients with coronary atherosclerosis and abdominal obesity (AO). METHODS: The study included 145 men aged 38-79 with atherosclerosis of the coronary arteries (CA) and stable angina pectoris II-III FC who were hospitalized for coronary bypass surgery (2011-2022). The final analysis included 116 patients. Notably, 70 men had stable plaques in the CA (of which 44.3% had AO), and 46 men had unstable plaques in the CA (of which 43.5% had AO). Adipocytokine levels were determined using multiplex analysis (Human Metabolic Hormone V3 panel). RESULTS: In the subgroup of patients with unstable plaques, patients with AO had a GLP-1 level that was 1.5 times higher and a lipocalin-2 level that was 2.1 times lower, respectively. GLP-1 is direct, and lipocalin-2 is inversely associated with AO in patients with unstable plaques. Among patients with AO, the level of lipocalin-2 in patients with unstable plaques was 2.2 times lower than in patients with stable plaques in the CA. The level of lipocalin-2 was inversely associated with the presence of unstable atherosclerotic plaques in the CA. CONCLUSION: GLP-1 is directly associated with AO in patients with unstable atherosclerotic plaques. Lipocalin-2 is inversely associated with unstable atherosclerotic plaques in patients with AO.

Existing and Emerging Approaches to Risk Assessment in Patients with Ascending Thoracic Aortic Dilatation.

Ascending thoracic aortic aneurysm is a life-threatening disease, which is difficult to detect prior to the occurrence of a catastrophe. Epidemiology patterns of ascending thoracic aortic dilations/aneurysms remain understudied, whereas the risk assessment of it may be improved. The electronic databases PubMed/Medline 1966-2022, Web of Science 1975-2022, Scopus 1975-2022, and RSCI 1994-2022 were searched. The current guidelines recommend a purely aortic diameter-based assessment of the thoracic aortic aneurysm risk, but over 80% of the ascending aorta dissections occur at a size that is lower than the recommended threshold of 55 mm. Moreover, a 55 mm diameter criterion could exclude a vast majority (up to 99%) of the patients from preventive surgery. The authors review several visualization-based and alternative approaches which are proposed to better predict the risk of dissection in patients with borderline dilated thoracic aorta. The imaging-based assessments of the biomechanical aortic properties, the Young's elastic modulus, the Windkessel function, compliance, distensibility, wall shear stress, pulse wave velocity, and some other parameters have been proposed to improve the risk assessment in patients with ascending thoracic aortic aneurysm. While the authors do not argue for shifting the diameter threshold to the left, they emphasize the need for more personalized solutions that integrate the imaging data with the patient's genotypes and phenotypes in this heterogeneous pathology.

Adipokine Levels in Men with Coronary Atherosclerosis on the Background of Abdominal Obesity.

Background. Obesity is associated with dyslipidemia, and excess body fat is associated with unfavorable levels of adipokines and markers of inflammation. The goal of research. To study the level of adipokines and markers of inflammation, their associations with unstable atherosclerotic plaques in men with coronary atherosclerosis on the background of abdominal obesity. Materials and methods. The study involved 82 men aged 40-77 years with coronary atherosclerosis after endarterectomy from the coronary arteries. We divided all men into two groups: 37 men (45.1%) with unstable atherosclerotic plaques, and 45 men (54.9%) who had stable plaques. Obesity was established at a BMI of ≥30 kg/m2. The levels of adipokines and markers of inflammation in the blood were determined by multiplex analysis. Results. In patients with obesity and unstable plaques, the levels of C-peptide, TNFa and IL-6 were 1.8, 1.6, and 2.8 times higher, respectively, than in patients with obesity and stable plaques. The chance of having an unstable plaque increases with an increase in TNFa by 49% in obese patients and decreases with an increase in insulin by 3% in non-obese patients. Conclusions. In men with coronary atherosclerosis and obesity, unstable atherosclerotic plaques in the coronary arteries are directly associated with the level of TNF-α.

Mitomycin-Treated Endothelial and Smooth Muscle Cells Suitable for Safe Tissue Engineering Approaches.

In our previous study, we showed that discarded cardiac tissue from the right atrial appendage and right ventricular myocardium is an available source of functional endothelial and smooth muscle cells for regenerative medicine and tissue engineering. In the study, we aimed to find out what benefits are given by vascular cells from cardiac explants used for seeding on vascular patches engrafted to repair vascular defects in vivo. Additionally, to make the application of these cells safer in regenerative medicine we tested an in vitro approach that arrested mitotic division to avoid the potential tumorigenic effect of dividing cells. A tissue-engineered construction in the form of a patch based on a polycaprolactone-gelatin scaffold and seeded with endothelial and smooth muscle cells was implanted into the abdominal aorta of immunodeficient SCID mice. Aortic patency was assessed using ultrasound, MRI, immunohistochemical and histological staining. Endothelial and smooth muscle cells were treated with mitomycin C at a therapeutic concentration of 10 µg/ml for 2 h with subsequent analysis of cell proliferation and function. The absence of the tumorigenic effect of mitomycin C-treated cells, as well as their angiogenic potential, was examined by injecting them into immunodeficient mice. Cell-containing patches engrafted in the abdominal aorta of immunodeficient mice form the vessel wall loaded with the appropriate cells and extracellular matrix, and do not interfere with normal patency. Endothelial and smooth muscle cells treated with mitomycin C show no tumorigenic effect in the SCID immunodeficient mouse model. During in vitro experiments, we have shown that treatment with mitomycin C does not lead to a decrease in cell viability. Despite the absence of proliferation, mitomycin C-treated vascular cells retain specific cell markers, produce specific extracellular matrix, and demonstrate the ability to stimulate angiogenesis in vivo. We pioneered an approach to arresting cell division with mitomycin C in endothelial and smooth muscle cells from cardiac explant, which prevents the risk of malignancy from dividing cells in vascular surgery. We believe that this approach to the fabrication of tissue-engineered constructs based on mitotically inactivated cells from waste postoperative material may be valuable to bring closer the development of safe cell products for regenerative medicine.

Results of concomitant cryoablation for atrial fibrillation during mitral valve surgery.

OBJECTIVES: Concomitant atrial fibrillation ablation during mitral valve (MV) surgery using radio frequency energy sources has been reported previously with excellent outcomes. However, data regarding the effectiveness of concomitant cryoablation remain limited. This study aimed to assess the efficacy of concomitant cryoablation in patients scheduled for MV surgery. METHODS: Between 2012 and 2020, 242 adult patients who underwent MV surgery and concomitant cryoablation were included. Data on rhythm, medication status and clinical events were assessed at 3, 6 and 12 months, then annually thereafter. RESULTS: Early mortality was 0.4%. The mean follow-up period duration was 43.9 months. The survival rates at 1, 3 and 5 years were 97.3%, 94.3% and 87.7%, respectively. The rates of freedom from atrial arrhythmia paroxysms at 1, 3 and 5 years were 79.0%, 64.0% and 60.5%, respectively. Atrial arrhythmia recurrence was associated with isolated left atrial lesion set (P = 0.038), large right atrial size (P = 0.002), lower surgeon experience (P = 0.003) and atrial fibrillation paroxysms in the early postoperative period (P = 0.002). CONCLUSIONS: Concomitant cryoablation during MV surgery is a safe and reproducible technique. The procedure provides acceptable freedom from atrial arrhythmias recurrences during long-term follow-up. The biatrial lesion set has advantages over the left atrium pattern in terms of atrial arrhythmias freedom. Surgeon experience significantly influences atrial fibrillation ablation success. Randomized trials are needed to compare radiofrequency and cryoablation.

Deep Hypothermic Circulatory Arrest vs. Antegrade Cerebral Perfusion in Cerebral Protection during the Surgical Treatment of Chronic Dissection of the Ascending and Arch Aorta.

Circulatory arrest during aortic surgery presents a risk of neurological complications. The present study aimed to investigate the effectiveness of deep hypothermic circulatory arrest (DHCA) vs. antegrade cerebral perfusion (ACP) in cerebral protection during the surgical treatment of chronic dissection of the ascending and arch aorta and to assess the quality-of-life (QoL) in the long-term postoperative period with respect to the used cerebral protection method. In a prospective, randomized study, 58 patients with chronic type I aortic dissection who underwent ascending aorta and aortic arch replacement surgery were included. Patients were allocated in two groups: 29 patients who underwent surgery under moderate hypothermia (24°C) combined with ACP and 29 patients who underwent surgery under DHCA (18°C) with craniocerebral hypothermia. The regional hemoglobin oxygen saturation (rSO2, %) were compared during surgery, neurological complications were analyzed during the early postoperative period, QoL was compared in the long-term postoperative period (1-year follow-up). During the early postoperative period, 37.9% of patients in the DHCA group exhibited neurological complications, compared with 13.8% of those in the ACP group (p < .05). The risk of neurological complications in the early postoperative period was dependent on the extent of rSO2 decrease during circulatory arrest. In the ACP group, rSO2 decreased by ≤17% from baseline during circulatory arrest. In the DHCA group, a more profound decrease in rSO2 (>30%) was recorded (p < .05). QoL in the long-term period after surgery improved, but it was not dependent on the cerebral protection method used during surgery. ACP during aortic replacement demonstrated the most advanced properties of cerebral protection that can be evidenced by a lesser degree of neurological complications, compared with patients who underwent surgery under conditions of DHCA. QoL after surgery was not dependent on the cerebral protection method used during surgery.

Associated bare stenting of distal aorta with a Djumbodis(®) system versus conventional surgery in type A aortic dissection.

BACKGROUND: The effectiveness of additional stenting of the distal aorta as compared to conventional surgery alone in type A aortic dissection (TAD) has yet to be proven. METHODS: We conducted this multicenter comparative study to evaluate the effects of antegrade bare stenting of the dissected aorta beyond the distal anastomosis with a Djumbodis(®) device system (DDS). Outcomes that were measured included early outcomes, overall mortality from aortic cause and late aortic events including re-interventions. A consecutive series of 134 patients operated on in two participating centers were distributed into study and control groups according to the treatment received: conventional surgery with DDS (DJ group, n=42) or without (control group, n=92). RESULTS: Operative mortality was 21.4% and 17.6% in the DJ and control groups, respectively (P=0.9), and was within pre-specified alarm lines for both groups. In multivariate analysis, the only independent predictor of operative mortality was the presence of any complication (cardiac tamponade or malperfusion, P=0.05), which occurred more in the DJ group (OR =1.3; non-significant). Sixty patients were included into the matched survivors cohorts study (propensity scoring). The aortic event-free survival at 7 years for early survivors was 77%±10% and 48%±11% in the matched DJ group and control group, respectively (HR =0.66). Late mortality from an aortic cause was 10% and 20% in the matched DJ group and control group, respectively (RR =0.5). Actuarial freedom from aortic or vascular interventions was 71%±10% and 67%±9% in the matched DJ and control group, respectively. Operative mortality was not influenced by the use of DDS as compared to conventional surgery alone for TAD. CONCLUSIONS: We observed a trend towards better organ perfusion in the DJ group postoperatively, and more aortic events and deaths of aortic cause in the control group during follow-up.

Molecular mechanisms of synergy of corneal muscarinic and nicotinic acetylcholine receptors in upregulation of E-cadherin expression.

Corneal epithelial erosion is one of the most common problems in clinical ophthalmology. Despite significant progress in understanding how the cornea heals, clinically available pharmacological therapies that can promote repair and prevent visual complications remain limited. We have recently demonstrated that the acetylcholine (ACh) axis of corneal epithelium plays an important role in regulation and coordination of distinct activities of corneal epithelial cells (CEC) mediating re-epithelialization, but mechanisms remained unclear. We hypothesized that the grounds for synergistic effects of corneal ACh receptors lie within the signaling pathways linking different receptors to specific elements of the CEC pro-epithelialization activities. In this study, we sought to elucidate the molecular mechanisms of cooperation of corneal muscarinic and nicotinic ACh receptors (mAChRs and nAChRs) in upregulation of E-cadherin expression. The roles of individual corneal mAChRs and nAChRs subtypes were investigated by in-cell western assay of the ACh-treated CEC, in which different ACh receptor genes were silenced by receptor-specific shRNAs. Functional inactivation of M3, but not M4, mAChR subtype, or α3 or α7, but not α9, nAChR subunit significantly inhibited E-cadherin expression. To gain a mechanistic insight, we blocked the key steps of the downstream signaling pathways. Results demonstrated that cholinergic agonists can upregulate E-cadherin expression by activating M3 mAChR, and α3ß2 and α7 nAChRs via the common signaling cascade Ca(2+)-CaMKII-PKC-Ras-Raf-MEK-ERK. Activation of α7 nAChR can launch the Ras-Raf-MEK-ERK cascade both indirectly, through the Ca(2+)-CaMKII-PKC step, and directly, perhaps, due to its direct interaction with Ras. Although the biological significance of such redundancy remained to be elucidated, results of the present study point to a new direction to pharmacologically accelerate corneal re-epithelialization, and should have salient clinical implication.

Muscle sarcomas and alopecia in A/J mice chronically treated with nicotine.

AIMS: To evaluate the pathobiologic effects of long-term treatment with nicotine of A/J mice susceptible to tobacco-induced lung carcinogenesis. MAIN METHODS: Experimental group of mice received subcutaneous injections of the LD(50) dose of (-)nicotine hydrogen tartrate of 3 mg/kg/day, 5 days per week for 24 months, and control group received the vehicle phosphate-buffered saline. KEY FINDINGS: Nicotine treated mice, 78.6%, but none of control of mice, developed neoplasms originating from the uterus or skeletal muscle. Examination of the uterine neoplasms revealed leiomyosarcomas, composed of whorled bundles of smooth-muscle like cells with large and hyperchromatic nuclei. Sections of the thigh neoplasms revealed densely cellular tumors composed of plump spindle cells, with occasional formation of 'strap' cells, containing distorted striations. Both neoplasms were positive for desmin staining. A solitary pulmonary adenoma with papillary architecture also occurred in one nicotine treated mouse. Experimental mice also developed transient balding starting as small patches of alopecia that progressed to distinct circumscribed areas of complete hair loss or large areas of diffuse hair loss. SIGNIFICANCE: We demonstrate for the first time that chronic nicotine treatment can induce the development of muscle sarcomas as well as transient hair loss. These findings may help explain the association of childhood rhabdomyosarcoma with parental smoking and earlier onset of balding in smokers. It remains to be determined whether the pathobiologic effects of nicotine result from its receptor-mediated action and/or its tissue metabolites cotinine and N'-nitrosonornicotine, or toxic effects of reactive oxygen species activated due to possible intracellular accumulation of nicotine.

Novel cholinergic peptides SLURP-1 and -2 regulate epithelialization of cutaneous and oral wounds.

It is well established that auto/paracrine acetylcholine (ACh) is essential for wound epithelialization, and that the mechanisms include regulation of keratinocyte motility and adhesion via nicotinic ACh receptors (nAChRs). Keratinocyte nAChRs can be also activated by non-canonical ligands, such as secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related protein (SLURP)-1 and -2. In this study, we determined effects of recombinant (r)SLURP-1 and-2 on migration of human epidermal and oral keratinocytes under agarose and epithelialization of cutaneous and oral mucosal excisional wounds in mice, and also identified nAChRs mediating SLURP signals. Both in vitro and in vivo, rSLURP-1 decreased and SLURP-2 increased epithelialization rate. The mixture of both peptides accelerated epithelialization even further, indicating that their simultaneous signaling renders an additive physiologic response. The specificity of rSLURP actions was illustrated by similar effects on cutaneous and oral wounds, which feature distinct responses to injury, and also by abrogation of rSLURP effects with neutralizing antibodies. rSLURP-1 acted predominantly via the α7 nAChR-coupled up-regulation of the sedentary integrins α2 and α3 , whereas SLURP-2--through α3, and α9 nAChRs up-regulating migratory integrins α5 and αV . The biologic effects of rSLURPs required the presence of endogenous ACh, indicating that auto/paracrine SLURPs provide for a fine tuning of the physiologic regulation of crawling locomotion via the keratinocyte ACh axis. Since nAChRs have been shown to regulate SLURP production, cholinergic regulation of keratinocyte migration appears to be mediated by a reciprocally arranged network. The cholinergic peptides, therefore, may become prototype drugs for the treatment of wounds that fail to heal.

Cytokine-induced alterations of α7 nicotinic receptor in colonic CD4 T cells mediate dichotomous response to nicotine in murine models of Th1/Th17- versus Th2-mediated colitis.

Ulcerative colitis (UC) and Crohn's disease (CD) are two forms of chronic inflammatory bowel disease. CD4 T cells play a central role in the pathogenesis of both diseases. Smoking affects both UC and CD but with opposite effects, ameliorating UC and worsening CD. We hypothesized that the severity of gut inflammation could be modulated through T cell nicotinic acetylcholine receptors (nAChRs) and that the exact clinical outcome would depend on the repertoire of nAChRs on CD4 T cells mediating each form of colitis. We measured clinical and immunologic outcomes of treating BALB/c mice with oxazolone- and trinitrobenzene sulfonic acid (TNBS)-induced colitides by nicotine. Nicotine attenuated oxazolone colitis, which was associated with an increased percentage of colonic regulatory T cells and a reduction of Th17 cells. TCR stimulation of naive CD4(+)CD62L(+) T cells in the presence of nicotine upregulated expression of Foxp3. In marked contrast, nicotine worsened TNBS colitis, and this was associated with increased Th17 cells among colonic CD4 T cells. Nicotine upregulated IL-10 and inhibited IL-17 production, which could be abolished by exogenous IL-12 that also abolished the nicotine-dependent upregulation of regulatory T cells. The dichotomous action of nicotine resulted from the up- and downregulation of anti-inflammatory α7 nAChR on colonic CD4 T cells induced by cytokines characteristic of the inflammatory milieu in oxazolone (IL-4) and TNBS (IL-12) colitis, respectively. These findings help explain the dichotomous effect of smoking in patients with UC and CD, and they underscore the potential for nicotinergic drugs in regulating colonic inflammation.

Cardiac resynchronization therapy and bone marrow cell transplantation in patients with ischemic heart failure and electromechanical dyssynchrony: a randomized pilot study.

Most studies have confirmed the beneficial effects of autologous bone marrow mononuclear cell (BMMC) transplantation on angina, myocardial perfusion, regional wall motion, and LV ejection fraction (LVEF). Cardiac resynchronization therapy (CRT) has also shown a beneficial effect in patients with heart failure (HF) and electrical/mechanical dyssynchrony. However, the relative contribution of BMMC and CRT in patients with ischemic HF and electromechanical dyssynchrony has never been investigated. The aim of this study was to evaluate the benefit of combining BMMC transplantation with CRT in patients with severe ischemic HF, left bundle branch block (LBBB), and mechanical dyssynchrony. Patients with ischemic HF, LVEF < 35%, LBBB, and mechanical dyssynchrony underwent intramyocardial transplantation of BMMC and CRTD system implantation. This randomized, single-blind, crossover study compared clinical and echocardiographic parameters during two follow-up periods: 6 months of active CRT (BMMC + CRTact) and 6 months of inactive CRT (BMMC + CRTinact). Physical performance was assessed by means of a 6-min walking test. Myocardial perfusion was evaluated by SPECT. Quality of Life (QoL) was assessed through the Minnesota Living with HF Questionnaire (MLwHFQ). Twenty-six patients (64 ± 7 years) were enrolled in the study. The distance covered by the patients during the 6-min walking test significantly increased in the BMMC + CRTinact phase (BMMC therapy only) in comparison with the baseline (269 ± 68 vs 206 ± 51; p = 0.007) and in the BMMC + CRTact phase (BMMC therapy + CRT) in comparison with the BMMC + CRTinact (378 ± 59 vs 269 ± 68; p < 0.001). The summed rest and stress score (SPECT) decreased significantly in the BMMC + CRTact and BMMC + CRTinact phases in comparison with the baseline (p ≤ 0.03). Both phases showed equivalent myocardial perfusion in the segments into which BMMC had been injected. QoL score was significantly lower in the BMMC + CRTinact phase than at the baseline (44.1 ± 14 vs 64.8 ± 19; p < 0.001), and in the BMMC + CRTact phase than in the BMMC + CRTinact phase (26.4 ± 12 vs 44.1 ± 14; p = 0.004). BMMC and CRT seem to act independently on myocardial perfusion and electromechanical dyssynchrony, respectively. Combining these two complementary therapies can significantly improve LV performance in patients with severe HF and electromechanical dyssynchrony.

Results of coronary artery bypass grafting alone and combined with surgical ventricular reconstruction for ischemic heart failure.

In this study, we included 236 patients with ischemic heart failure and ejection fraction (EF) <35% who underwent surgical treatment. Patients were randomized in two groups. There were 116 patients who underwent coronary artery bypass grafting (CABG) with surgical ventricular reconstruction (SVR) and 120 patients who underwent CABG alone. The hospital mortality rate was 5.8% after isolated CABG and 3.5% after CABG combined with SVR. All survivors had follow-up investigation from four months to five years, with a mean follow-up time of 31±13 months. The mean New York Heart Association (NYHA) functional class decreased from 2.9±0.5 to 2.2±0.7 one year after CABG and from 3.1±0.4 to 2.0±0.6 one year after CABG with SVR. We showed that left ventricular reconstruction significantly decreased EDV from 237±52 to 176±30 and correspondingly increased EF from 32±6 to 39±9. However, after isolated CABG EF did not increase significantly (32±7 preoperatively and 34±11 postoperatively). One- and three-year rates were 95% and 78% after SVR with CABG and 83% and 78% after CABG alone. Despite the more aggressive surgical strategy, left ventricular reconstruction did not increase operative mortality and early results were significantly effective compared with coronary artery bypass grafting alone.

Differential involvement of α4ß2, α7 and α9α10 nicotinic acetylcholine receptors in B lymphocyte activation in vitro.

Mouse B lymphocytes express several nicotinic acetylcholine receptor (nAChR) subtypes, their exact functions being not clearly understood. Here we show that α7 nAChR was present in about 60%, while α4ß2 and α9(α10) nAChRs in about 10% and 20% of mouse spleen B lymphocytes, respectively; Balb/c and C57Bl/6 mice possessed different relative amounts of these nAChR subtypes. α4ß2 and α7, but not α9(α10) nAChRs, were up-regulated upon B lymphocyte activation in vitro. Flow cytometry and sandwich ELISA studies demonstrated that α7 and α9(α10) nAChRs are coupled to CD40, whereas α4ß2 nAChR is coupled to IgM. B lymphocytes of both α7(-/-) and ß2(-/-) mice responded to anti-CD40 stronger than those of the wild-type mice, whereas the cells of ß2(-/-) mice responded to anti-IgM worse than those of the wild-type or α7(-/-) mice. Inhibition of α7 and α9(α10) nAChRs with methyllicaconitine resulted in considerable augmentation of CD40-mediated B lymphocyte proliferation in cells of all genotypes; stimulation of α4ß2 nAChRs with epibatidine increased the IgM-mediated proliferation of the wild-type and α7(-/-), but not ß2(-/-) cells. Inhibition of α9(α10) nAChRs with α-conotoxin PeAI exerted weak stimulating effect on CD40-mediated proliferation. This nAChR subtype was up-regulated in α7(-/-) B-cells. α7 nAChRs were found recruited to immune synapses between human T and B lymphocytes, both of which produced acetylcholine. It is concluded that α7 nAChR fulfills inhibitory CD40-related mitogenic function, α4ß2 nAChR produces a stimulatory IgM-related effect, while α9α10 nAChR is a "reserve" receptor, which partly compensates the absence of α7 nAChR in α7(-/-) cells. Acetylcholine is an additional mediator to modulate activation of interacting T and B lymphocytes.

Upregulation of nuclear factor-kappaB expression by SLURP-1 is mediated by alpha7-nicotinic acetylcholine receptor and involves both ionic events and activation of protein kinases.

SLURP-1 (secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein-1) is a novel auto/paracrine cholinergic peptide that can bind to α(7)-nicotinic acetylcholine receptor (nAChR), a high Ca(2+)-permeable ion channel coupled to regulation of nuclear factor-κB (NF-κB) expression. Elucidation of intracellular signaling events elicited by SLURP-1 is crucial for understanding the molecular mechanism of functioning of this novel hormone-like peptide that alters vital cell functions and can protect from tumorigenic transformation. In this study, we sought to dissect out the role of α(7)-nAChR in mediating the biologic effects of recombinant SLURP-1 on the immortalized line of human oral keratinocytes Het-1A. A multifold upregulation of the NF-κB expression at the mRNA and protein levels by SLURP-1 was only slightly diminished due to elimination of Na(+), whereas in Ca(2+)-free medium the effect of SLURP-1 was inhibited by >50%. Both in the absence of extracellular Ca(2+) and in the presence of Cd(2+) or Zn(2+), the SLURP-1-dependent elevation of NF-κB was almost completely blocked by inhibiting MEK1 activity. Downstream of α(7)-nAChR, the SLURP-1 signaling coupled to upregulation of NF-κB also involved Jak2 as well as Ca(2+)/calmodulin-dependent kinase II (CaMKII) and protein kinase C (PKC), whose inhibition significantly (P < 0.05) reduced the SLURP-1-induced upregulation of NF-κB. The obtained results indicated that activation of α(7)-nAChR by SLURP-1 leads to upregulation of the NF-κB gene expression due to activation of the Raf-1/MEK1/ERK1/2 cascade that proceeds via two complementary signaling pathways. One is mediated by the Ca(2+)-entry dependent CaMKII/PKC activation and another one by Ca(2+)-independent involvement of Jak2. Thus, there exists a previously not appreciated network of noncanonical auto/paracrine ligands of nAChR of the Ly-6 protein family, which merits further investigations.

Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: a randomized study.

Intramyocardial transplantation of autologous bone marrow mononuclear cells (BMMC) is believed to be a promising method for the treatment of patients with chronic ischemic heart disease. The aim of this study was to evaluate long-term results of intramyocardial bone marrow cell transplantation in patients with severe ischemic heart failure. One hundred nine patients with chronic myocardial infarction and end-stage chronic heart failure were randomized into two groups: 55 patients received intramyocardial BMMC injection and 54 received optimal medical therapy. The NOGA system (Biosense-Webster) was used to administer 41 +/- 16 x 106 BMMC into the border zone of myocardial infarction. None of the patients developed periprocedural complications following BMMC injections. The injections led to improvement of CCS class (3.1 +/- 0.4 to 1.6 +/- 0.6 after 6 months and 1.6 +/- 0.4 after 12 months; p = 0.001) and NYHA functional class (3.3 +/- 0.2 to 2.3 +/- 0.2 after 6 months and 2.5 +/- 0.1 after 12 months; p = 0.006). Left ventricular ejection fraction increased significantly in the BMMC group (27.8 +/- 3.4% vs 32.3 +/- 4.1%; p = 0.04) while it tended to decrease in the control group (26.8 +/- 3.8% to 25.2 +/- 4.1%; p = 0.61). Summed rest score improved in the BMMC group after 12 months (30.2 +/- 5.6 to 27.8 +/- 5.1; p = 0.032). The improvement of stress score was more noticeable (34.5 +/- 5.4 to 28.1 +/- 5.2; p = 0.016). Neither stress nor rest score changed in patients numbers on medical therapy. In BMMC group 6 (10.9%) patients died at 12-month follow-up compared with 21 (38.9%) in control group (log-rank test, p = 0.0007). Intramyocardial bone marrow cell transplantation to patients with ischemic heart failure is safe and improved survival, clinical symptoms, and has beneficial effect on LV function.