ABSTRACT
This study investigated treatment trends and major adverse events in patients hospitalized for osteoporotic vertebral fracture (OVF). The frequency of surgical interventions for OVF increased significantly, but this did not decrease major adverse events. The findings underscore the necessity for reevaluating OVF management strategies. PURPOSE: Osteoporotic vertebral fracture (OVF) is a common condition in the aging population, often leading to increased morbidity and mortality. Here, we analyzed treatment trends and incidence of major adverse events in patients hospitalized for OVF. METHODS: We conducted a cross-sectional descriptive study, using a large Japanese hospital administrative database. The cohort included hospitalized patients aged 65 years or older, admitted for OVF from January 2015 to December 2021. The primary outcomes were the trend in the proportion of the patients undergoing surgery for OVF and the incidence of major adverse events within 30 days of admission. As a secondary outcome, we evaluated the trend in hospitalization costs. RESULTS: The study cohort consisted of 14,714 patients, with a mean age of 82.4 years. There was a significant increase in surgical interventions for OVF, from 3.7% of patients in 2015 to 9.8% in 2021 (p < 0.001). The incidence of major adverse events remained unchanged, with a risk ratio of 1.09 (95% confidence interval, 0.88 to 1.35) in 2021 compared to 2015. Average hospitalization costs increased significantly, from $7,570.6 (SD 6,047.0) in 2015 to $9,502.9 (SD 7,231.5) in 2021 (p < 0.001). CONCLUSION: Despite a significant increase in the proportion of surgical intervention for OVF, no reduction in the risk of major adverse events was observed between 2015 and 2021. Surgeons and policy makers need to interpret these findings and work towards an optimized approach to the management of OVF in the aging population.
Subject(s)
Hospitalization , Osteoporotic Fractures , Postoperative Complications , Spinal Fractures , Humans , Male , Aged , Female , Aged, 80 and over , Spinal Fractures/surgery , Spinal Fractures/epidemiology , Incidence , Osteoporotic Fractures/surgery , Osteoporotic Fractures/epidemiology , Cross-Sectional Studies , Japan/epidemiology , Hospitalization/statistics & numerical data , Postoperative Complications/epidemiologyABSTRACT
BACKGROUND: Patients with spinal meningioma may present preoperatively with paralysis and sensory deficits. However, there is a paucity of detailed evaluations and a lack of consensus regarding imaging findings that are predictive of neurological symptoms in patients with spinal meningioma. METHODS: Herein, a total of 55 patients who underwent surgical resection of spinal meningiomas in eight hospitals between 2011 and 2021 were enrolled. Patient characteristics, degree of muscle weakness, sensory disturbances, and the presence of bowel/bladder dysfunction (BBD) before surgical treatment were evaluated using medical records. Patients with American Spinal Injury Impairment Scale grades A-C and the presence of BBD were classified into the paralysis (+) group. Patients with sensory disturbances were assigned to the sensory disturbance (+) group. Based on magnetic resonance (MR) and computed tomography images, the tumor location was classified according to the spinal level and its attachment to the dura mater. To evaluate tumor size, the tumor occupation ratio (OR) was calculated using the area and distance measurement method in horizontal MR images, and the maximum length and area of the tumor in the sagittal plane were measured. RESULTS: Of all patients, 85 % were women. The mean age of patients at surgery was 69.7 years. Twenty-eight (51 %) and 41 (75 %) patients were classified into the paralysis (+) and sensory disturbance (+) groups, respectively. The average tumor length and area in the sagittal plane were 19.6 mm and 203 mm2, respectively; OR-area and diameters were 70.3 % and 72.3 %, respectively. In univariate analyses, tumor length and area in the sagittal plane were significant risk factors for paralysis. OR-diameter, symptom duration, and a low MIB-1 index correlated with sensory disturbances. Multivariate logistic regression analysis demonstrated that the area and length of the tumor in the sagittal plane were significantly correlated with paralysis, whereas the OR-diameter and symptom duration significantly correlated with sensory disturbances. The cut-off values for the area and length of the tumor in the sagittal plane to predict paralysis were 243 mm2 and 20.1 mm, respectively. CONCLUSIONS: Preoperative paralysis in patients with spinal meningiomas was significantly associated with sagittal tumor size than with high tumor occupancy in the horizontal plane. Sensory disturbances were associated with high occupancy in the horizontal plane. Patients with spinal meningiomas > 20 mm in length or 243 mm2 in area in the sagittal plane are at risk of developing paralysis and could be considered for surgery even in the absence of paralysis.
Subject(s)
Meningeal Neoplasms , Meningioma , Humans , Meningioma/surgery , Meningioma/diagnostic imaging , Meningioma/complications , Female , Male , Aged , Retrospective Studies , Middle Aged , Risk Factors , Meningeal Neoplasms/surgery , Meningeal Neoplasms/diagnostic imaging , Meningeal Neoplasms/complications , Magnetic Resonance Imaging , Aged, 80 and over , Adult , Paralysis/etiology , Sensation Disorders/etiologyABSTRACT
STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To elucidate the factors related to progression of scoliosis in patients with rheumatoid arthritis (RA) using longitudinal cohort data. SUMMARY OF BACKGROUND DATA: Thirty percent of patients with RA have lumbar scoliosis. However, the effectiveness of current treatment methods in preventing the progression of scoliosis is not well-understood due to a lack of longitudinal studies. METHODS: We enrolled 180 patients with RA who were followed up for over two years, all of whom underwent standing spinal X-rays. These patients were categorized based on their disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR) into two groups: those in remission (n=76) and those in non-remission (n=104). We evaluated various radiographic measures, including C7 center sacral vertical line (C7-CSVL), pelvic obliquity, major Cobb angle, and curve location. RESULTS: Fifty-three (29.4%) patients presented progression of scoliosis during a mean follow-up period of 4.8 years. Patients in the non-remission showed larger Cobb angle at baseline and final follow-up, compared to those in remission. The annual progression rate of the curve was also greater in the non-remission group (1.04 degree /year), than in the remission group (0.59 degree /year, P=0.001). There was no difference in the incidence of new vertebral fractures. The presence of a baseline cobb angle of 10 degree or more (OR: 3.14; 95% CI: 1.38-7.13; P=0.006), glucocorticoid use (OR: 2.88; 95% CI: 1.18-7.06; P=0.021), and non-remission at baseline (OR: 2.83; 95% CI: 1.25-6.41; P=0.012) were significant risk factors for progression of scoliosis. CONCLUSION: RA disease activity is linked to progression of scoliosis in patients with RA. Patients with RA who present with an initial scoliosis of 10 degrees or greater, require glucocorticoids for treatment and are in non-remission at baseline may be at high risk for scoliosis progression.
ABSTRACT
OBJECTIVE: Atlantoaxial subluxation is a well-known serious complication encountered in patients with rheumatoid arthritis (RA). However, it is unknown whether RA affects global spinal alignment. The aim of this study was to investigate whether high disease activity in patients with RA exacerbates spinal sagittal malalignment. METHODS: The authors included 197 patients with RA who were followed up for > 2 years; standing spinal radiographs were obtained in all patients. Patients were divided into persistent moderate disease activity/high disease activity (pMDA/HDA; n = 64) and non-pMDA/HDA (n = 133) groups based on the disease activity at follow-up visits. Radiographic parameters assessed included pelvic incidence, pelvic tilt (PT), lumbar lordosis (LL), thoracic kyphosis (TK), and C7 sagittal vertical axis (SVA). RESULTS: Over an average 5-year follow-up, increases in SVA, PT, and TK and a decrease in LL were observed. The pMDA/HDA group had a larger increase in PT and a higher incidence of vertebral fractures than the non-pMDA/HDA group. After adjusting variables using propensity score matching, the authors still found a higher rate of increase in PT (0.79°/year vs 0.01°/year, p = 0.001) in the pMDA/HDA group than in the non-pMDA/HDA group. This trend remained consistent even when patients who developed vertebral fractures were excluded. CONCLUSIONS: Spinal sagittal alignment deteriorates over time in patients with RA. High disease activity in RA exacerbates spinal deformity.
Subject(s)
Arthritis, Rheumatoid , Humans , Female , Male , Arthritis, Rheumatoid/complications , Middle Aged , Aged , Follow-Up Studies , Lordosis/diagnostic imaging , Adult , Kyphosis/diagnostic imaging , Kyphosis/etiology , Spine/diagnostic imagingABSTRACT
The ideal bone implant would effectively prevent aseptic as well as septic loosening by minimizing stress shielding, maximizing bone ingrowth, and preventing implant-associated infections. Here, a novel gradient-pore-size titanium scaffold was designed and manufactured to address these requirements. The scaffold features a larger pore size (900 µm) on the top surface, gradually decreasing to small sizes (600 µm to 300 µm) towards the center, creating a gradient structure. To enhance its functionality, the additively manufactured scaffolds were biofunctionalized using simple chemical and heat treatments so as to incorporate calcium and iodine ions throughout the surface. This unique combination of varying pore sizes with a biofunctional surface provides highly desirable mechanical properties, bioactivity, and notably, long-lasting antibacterial activity. The target mechanical aspects, including low elastic modulus, high compression, compression-shear, and fatigue strength, were effectively achieved. Furthermore, the biofunctional surface exhibits remarkable in vitro bioactivity and potent antibacterial activity, even under conditions specifically altered to be favorable for bacterial growth. More importantly, the integration of small pores alongside larger ones ensures a sustained high release of iodine, resulting in antimicrobial activity that persisted for over three months, with full eradication of the bacteria. Taken together, this gradient structure exhibits obvious superiority in combining most of the desired properties, making it an ideal candidate for orthopedic and dental implant applications.
Subject(s)
Iodine , Titanium , Titanium/pharmacology , Protective Devices , Anti-Bacterial Agents/pharmacology , Iodine/pharmacology , IonsABSTRACT
The treatment of critical-sized bone defects has long been a major problem for surgeons. In this study, an intramedullary nail shaped three-dimensional (3D)-printed porous titanium implant that is capable of releasing strontium ions was developed through a simple and cost-effective surface modification technique. The feasibility of this implant as a stand-alone solution was evaluated using a rabbit's segmental diaphyseal as a defect model. The strontium-loaded implant exhibited a favorable environment for cell adhesion, and mechanical properties that were commensurate with those of a rabbit's cortical bone. Radiographic, biomechanical, and histological analyses revealed a significantly higher amount of bone ingrowth and superior bone-bonding strength in the strontium-loaded implant when compared to an untreated porous titanium implant. Furthermore, one-year histological observations revealed that the strontium-loaded implant preserved the native-like diaphyseal bone structure without failure. These findings suggest that strontium-releasing 3D-printed titanium implants have the clinical potential to induce the early and efficient repair of critical-sized, load-bearing bone defects.
Subject(s)
Internal Fixators , Titanium , Animals , Rabbits , Titanium/pharmacology , Prostheses and Implants , Cell Adhesion , Strontium/pharmacologyABSTRACT
Porous structures are frequently used in surgical implants to strengthen the interlocking power produced by bone ingrowth. Therefore, we aimed to elucidate the mechanism underlying bone ingrowth into a porous structure accompanied by vascularization. A nonbioactive polyetheretherketone implant with a 3D-printed porous structure was prepared and implanted in a bone hole created in the tibias of rabbits. We observed bone ingrowth in the same individual specimens immediately and at 2, 4, 8, and 12 weeks post-implantation using in-vivo computed tomography (CT). Furthermore, a detailed evaluation with blood vessels of each specimen at 2, 4, and 12 weeks was performed with ex-vivo CT and histological specimen. Additional histological evaluation was performed using thin sections of an implant made with thermoplastic polyurethane having the same structure. As a result, the bone invasion began after four weeks, when the construction of fibrous tissue and the spread of new blood vessels within the voids matured. As the bone matured in the load-bearing area, new blood vessels outside the bone matrix regressed. This longitudinal evaluation study suggests that preceding fibrogenesis and vascularization may be key in developing bone ingrowth. STATEMENT OF SIGNIFICANCE: A porous structure is an essential structure for dental and orthopedic implants because it provides strong fixation through bone invasion. Although it was known that vascularization was involved in this, the details were not known. This in vivo study revealed that in order for bone ingrowth to begin, a preparatory period of approximately 4 weeks was required to establish blood flow inside and outside the implant. Furthermore, it was confirmed that by spreading the fibrous structure in advance, it has an advantageous effect on the migration of cells involved in the formation of bones and blood vessels. We pointed out that it is necessary to consider fibrogenesis and vascularization when creating future implants.
Subject(s)
Bone and Bones , Prostheses and Implants , Animals , Rabbits , Porosity , Polyethylene Glycols/chemistry , Ketones/pharmacology , Ketones/chemistry , Neovascularization, Pathologic , Titanium/chemistry , Osseointegration/physiologyABSTRACT
Pulse rate variability (PRV), derived from Laser Doppler flowmetry (LDF) or photoplethysmography, has recently become widely used for sleep state assessment, although it cannot identify all the sleep stages. Peripheral blood flow (BF), also estimated by LDF, may be modulated by sleep stages; however, few studies have explored its potential for assessing sleep state. Thus, we aimed to investigate whether peripheral BF could provide information about sleep stages, and thus improve sleep state assessment. We performed electrocardiography and simultaneously recorded BF signals by LDF from the right-index finger and ear concha of 45 healthy participants (13 women; mean age, 22.5 ± 3.4 years) during one night of polysomnographic recording. Time- and frequency-domain parameters of peripheral BF, and time-domain, frequency-domain, and non-linear indices of PRV and heart rate variability (HRV) were calculated. Finger-BF parameters in the time and frequency domains provided information about different sleep stages, some of which (such as the difference between N1 and rapid eye movement sleep) were not revealed by finger-PRV. In addition, finger-PRV patterns and HRV patterns were similar for most parameters. Further, both finger- and ear-BF results showed 0.2-0.3 Hz oscillations that varied with sleep stages, with a significant increase in N3, suggesting a modulation of respiration within this frequency band. These results showed that peripheral BF could provide information for different sleep stages, some of which was complementary to the information provided by PRV. Furthermore, the combination of peripheral BF and PRV may be more advantageous than HRV alone in assessing sleep states and related autonomic nervous activity.
ABSTRACT
BACKGROUND: There is a lack of evidence on spinal subarachnoid hematomas because of the rarity of their spontaneous development and difficulty in diagnosis. The aim of this study was to identify the characteristics and outcomes of surgically confirmed acute non-traumatic spinal subarachnoid hematomas from a multicenter surgical database and conduct a systematic review of existing literature. METHODS: Five surgically confirmed cases of acute non-traumatic spinal subarachnoid hematomas were identified from our multicenter database with 22 cases from a systematic review of existing literature. RESULTS: The mean age of the 27 patients was 59 years. The length of the hematoma was longer than five vertebrae in 70% of the patients, most commonly distributed in the thoracic spine; 63% of all cases were idiopathic, 30% were under anticoagulant therapy, and the remaining 7% presented with coagulation abnormalities. As many as 70% of the patients showed some improvement in neurological symptoms after surgery during a mean follow-up period of 14 months. CONCLUSIONS: This study elucidated the characteristics of acute non-traumatic spinal subarachnoid hematomas in patients who were surgically confirmed. Most patients were middle-aged, complained of back pain, and had the hematoma located in the thoracic spine. Seventy percent of the patients in this study had some improvement in their neurological status, most likely due to surgical decompression and hematoma evacuation.
Subject(s)
Nervous System Diseases , Spinal Cord Diseases , Middle Aged , Humans , Hematoma/diagnostic imaging , Hematoma/etiology , Hematoma/surgery , Spine , Decompression, Surgical , Multicenter Studies as TopicABSTRACT
BACKGROUND: Limitations of gait function persist in some patients with knee osteoarthritis after total knee arthroplasty. This study aimed to identify preoperative muscle composition variables of the operated limb associated with postoperative gait function. METHODS: Longitudinal data from 45 patients who underwent unilateral primary total knee arthroplasty were retrospectively analyzed. Timed Up-and-Go test and gait speed were measured preoperatively and at 3 and 6 months postoperatively. Preoperative muscle composition in the glutei medius and minimus, the quadriceps, the hamstrings, and combination of the hamstrings and quadriceps were evaluated by computed tomography. The area ratio of the individual muscle composition to the total muscle was calculated. The factors associated with Timed Up-and-Go test and gait speed were identified using stepwise regression analysis. RESULTS: Shorter Timed Up-and-Go test and faster gait speed at each time point correlated with higher lean muscle mass area of the total hamstrings, higher area ratio of lean muscle mass to the total hamstrings or to combination of the hamstrings and quadriceps, and lower area ratio of low density lean tissue or intramuscular adipose tissue to the total hamstrings. Shorter Timed Up-and-Go test at each time point also correlated with higher combined area of lean muscle mass of the hamstrings and quadriceps. Faster gait speed at each time point additionally correlated with lower area ratio of intramuscular fat to the total hamstrings and lower area ratio of lean tissue mass or intramuscular adipose tissue to combination of the hamstrings and quadriceps. Regression analysis using the significant muscle composition variables revealed that the area ratio of lean muscle mass to the total hamstrings was the only predictor of Timed Up-and-Go test and gait speed after operation. CONCLUSIONS: Preoperative area ratio of ipsilateral lean muscle mass to the total hamstrings could predict gait function after total knee arthroplasty.
Subject(s)
Arthroplasty, Replacement, Knee , Osteoarthritis, Knee , Humans , Retrospective Studies , Muscle Strength/physiology , Gait/physiology , Osteoarthritis, Knee/surgery , Lower Extremity , Quadriceps Muscle/physiologyABSTRACT
PURPOSE: This study aimed to elucidate the severity of neurological deficits in a large series of patients with acute spontaneous spinal epidural haematoma (SSEH) using magnetic resonance imaging (MRI). METHODS: We included 57 patients treated for acute SSEH at 11 institutions and retrospectively analysed their demographic and MRI data upon admission. We investigated MRI findings, such as the haematoma length and canal occupation ratio (COR). The neurological severity of SSEH was assessed based on the American Spinal Injury Association score on admission. RESULTS: Of the 57 patients, 35 (61%) presented with severe paralysis. The MRI analysis showed that SSEH was often located in the cervical spine, dorsal to the spinal cord, and spread over more than three vertebrae. No differences in age, sex, and aetiology were found between patients with and without severe paralysis. The hypo-intensity layer encircling the haematoma, intra-haematoma heterogeneity, and increased CORs were observed more frequently in the severe paralysis group. Furthermore, pathological examination of a dissected haematoma from one patient with a hypo-intensity layer revealed a collagen layer around the haematoma, and patients with intra-haematoma heterogeneity were more likely to have a bleeding predisposition. CONCLUSIONS: In this large series of patients with SSEH, we identified some MRI features associated with severe paralysis, such as the hypo-intensity layer, intra-haematoma heterogeneity, and increased COR. Accordingly, patients with these MRI characteristics should be considered for early surgical intervention.
Subject(s)
Hematoma, Epidural, Spinal , Cervical Vertebrae , Hematoma, Epidural, Spinal/diagnostic imaging , Hematoma, Epidural, Spinal/etiology , Humans , Magnetic Resonance Imaging , Paralysis/diagnostic imaging , Paralysis/etiology , Retrospective StudiesABSTRACT
Objectives: Fragility fractures of the pelvis (FFP) commonly occur in the frail elderly. Displacement in the posterior pelvic ring is recognized as the key sign of instability. This study aims to elucidate the relationship between computer tomography (CT)-based frailty markers and displacement of the posterior pelvic ring within 7 days after injury. Methods: This retrospective study included 49 patients (42 females, 7 males) with FFP (type I 10, type II 24, type III 12, type IV 3). On a CT slice at the level of the third lumbar vertebra, skeletal muscle area, skeletal muscle radiation attenuation, and skeletal muscle index (SMI) were calculated as sarcopenia markers. Osteopenia was measured with trabecular region of interest attenuation technique on the same CT slice. Results: There was no difference in the demographics between non-displaced and displaced FFP. CT-based data showed that patients with FFP had osteopenia. However, no difference was found between non-displaced and displaced FFP. SMI was higher in FFP types III/IV than non-displaced FFP when CT-based data on sarcopenia were compared among all patients. Female patients with FFP demonstrated similar results. Logistic regression analysis using the demographics and CT-based markers on sarcopenia and osteopenia revealed that SMI was a potential determinant of displacement of the posterior pelvic ring fractures. Conclusions: There was inverse association between sarcopenia and displacement of the posterior pelvic ring in the early phase of FFP. Relatively preserved muscle may develop displacement in the elderly with osteopenia.
ABSTRACT
BACKGROUND: Although the mortality related to hip fracture and osteoporotic vertebral fracture have been reported, few studies have examined the mortality related to atlas and/or axis fractures. The aim of this study was to assess the association between mortality and atlas and/or axis fractures retrospectively and to elucidate the efficacy of surgical treatment. METHODS: A total of 33 elderly patients who were treated for atlas and/or axis fractures at our institution between January 2012 and December 2018 were included in this study. These patients were divided into two groups: surgical treatment and conservative treatment. Fracture types, comorbidities, neurological status, treatment types, and walking ability at follow-up were reviewed. Mortality was assessed using medical records or via phone interviews. RESULTS: The mean age at injury was 79.9 ± 8.0 years, and the mean follow-up period was 2.3 years. The overall mortality rates at 1 and 5 years were 21.4% and 48.4%, respectively. During the observation period, 12 (36%) patients died. Twenty-two patients were treated conservatively (14 were treated with a cervical collar, 8 were treated with a halo vest). Surgical procedures included occipital-cervical fixation, osteosynthesis of C2 fractures, C1-2 fixation, and C1-4 fixation using a posterior approach. Surgical treatment correlated with better survival rates. There was no significant difference between the two groups in terms of ambulatory ability and functional recovery. CONCLUSION: Upper cervical spine fractures appear to have a worse prognosis compared to hip and osteoporotic vertebral fractures. This study indicates the efficacy of surgical treatment for upper cervical spine fractures in the elderly for improving survival prognosis.
Subject(s)
Osteoporotic Fractures , Spinal Fractures , Aged , Cervical Vertebrae/surgery , Fracture Fixation, Internal/methods , Humans , Osteoporotic Fractures/diagnostic imaging , Osteoporotic Fractures/mortality , Osteoporotic Fractures/surgery , Retrospective Studies , Spinal Fractures/diagnostic imaging , Spinal Fractures/mortality , Spinal Fractures/surgery , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: Macrophage differentiation is associated with the development of atherosclerosis and plaque vulnerability and is regulated by transcription factor MafB. We previously reported that MafB attenuates macrophage apoptosis, which is associated with atherosclerotic plaque instability. The aim of this study was to elucidate the role of MafB in the progression of atherosclerotic plaque. METHODS: We generated macrophage-specific dominant-negative (DN) MafB transgenic mice and intercrossed DN-MafB mice with apolipoprotein E (ApoE) knockout (KO) mice. RESULTS: There was no significant difference in advanced atherosclerotic lesion area between DN-MafB/ApoE KO mice and littermate control ApoE KO mice 9 weeks after high-cholesterol diet. However, DN-MafB/ApoE KO mice showed significantly larger necrotic cores and lower collagen content in atherosclerotic plaques than ApoE KO mice. Although there was no difference in intraplaque macrophage infiltration and efferocytosis, DN-MafB/ApoE KO mice showed significantly more apoptotic macrophages at the plaque edges than did ApoE KO mice. Real-time PCR analysis revealed that peritoneal macrophages of DN-MafB/ApoE KO mice had a greater increase in matrix metalloproteinase-9 and mRNA expression of inflammatory/M1 macrophage markers (tissue necrosis factor-α, interleukin-6, CD11c, and p47phox) after lipopolysaccharide stimulation than those of ApoE KO mice. CONCLUSION: Macrophage-specific inhibition of MafB may destabilize atherosclerotic plaques in advanced lesions.
Subject(s)
Apoptosis , Macrophages/metabolism , Matrix Metalloproteinase 9/metabolism , Oxidative Stress , Plaque, Atherosclerotic/metabolism , Animals , Atherosclerosis/pathology , Cell Differentiation , Cell Nucleus/metabolism , Female , Inflammation , Interleukin-6/metabolism , MafB Transcription Factor/genetics , MafB Transcription Factor/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout, ApoE , Mice, Transgenic , RAW 264.7 Cells , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: The homologous to the E6-AP carboxyl terminus (HECT)-type ubiquitin E3 ligase ITCH is an enzyme that plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin-interacting protein (TXNIP) is a negative regulator of the thioredoxin system and an endogenous reactive oxygen species scavenger. In the present study, we focused on the functional role of ubiquitin E3 ligase ITCH and its interaction with TXNIP to elucidate the mechanism of cardiotoxicity induced by reactive oxygen species, such as doxorubicin and hydrogen peroxide. METHODS AND RESULTS: Protein interaction between TXNIP and ITCH in cardiomyocyte was confirmed by immunoprecipitation assays. Overexpression of ITCH increased proteasomal TXNIP degradation and augmented thioredoxin activity, leading to inhibition of reactive oxygen species generation, p38 MAPK, p53, and subsequent intrinsic pathway cardiomyocyte apoptosis in reactive oxygen species-induced cardiotoxicity. Conversely, knockdown of ITCH using small interfering RNA inhibited TXNIP degradation and resulted in a subsequent increase in cardiomyocyte apoptosis. Next, we generated a transgenic mouse with cardiac-specific overexpression of ITCH, called the ITCH-Tg mouse. The expression level of TXNIP in the myocardium in ITCH-Tg mice was significantly lower than WT littermates. In ITCH-Tg mice, cardiac dysfunction and remodeling were restored compared with WT littermates after doxorubicin injection and myocardial infarction surgery. Kaplan-Meier analysis revealed that ITCH-Tg mice had a higher survival rate than WT littermates after doxorubicin injection and myocardial infarction surgery. CONCLUSION: We demonstrated, for the first time, that ITCH targets TXNIP for ubiquitin-proteasome degradation in cardiomyocytes and ameliorates reactive oxygen species-induced cardiotoxicity through the thioredoxin system.
Subject(s)
Cardiomyopathies/enzymology , Carrier Proteins/metabolism , Myocardial Infarction/enzymology , Myocytes, Cardiac/enzymology , Oxidative Stress , Reactive Oxygen Species/metabolism , Thioredoxins/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Animals, Newborn , Apoptosis , Cardiomyopathies/chemically induced , Cardiomyopathies/genetics , Cardiomyopathies/pathology , Cardiomyopathies/physiopathology , Cardiotoxicity , Carrier Proteins/genetics , Cell Cycle Proteins , Cells, Cultured , Disease Models, Animal , Doxorubicin , Mice, Transgenic , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Proteasome Endopeptidase Complex , Protein Binding , Proteolysis , RNA Interference , Rats, Sprague-Dawley , Signal Transduction , Thioredoxins/genetics , Time Factors , Transfection , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination , Ventricular Function, Left , Ventricular Remodeling , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
AIMS: Apoptosis of cardiomyocytes is thought to account for doxorubicin cardiotoxicity as it contributes to loss of myocardial tissue and contractile dysfunction. Given that high-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein capable of inhibiting apoptosis, we aimed to clarify the role of HMGB1 in heat shock protein beta 1 (HSPB1) expression during doxorubicin-induced cardiomyopathy. METHODS AND RESULTS: Mitochondrial damage, cardiomyocyte apoptosis, and cardiac dysfunction after doxorubicin administration were significantly attenuated in mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) compared with wild type (WT) -mice. HSPB1 levels after doxorubicin administration were significantly higher in HMGB1-Tg mice than in WT mice. Transfection with HMGB1 increased the expression of HSPB1 at both the protein and mRNA levels, and HMGB1 inhibited mitochondrial dysfunction and apoptosis after exposure of cardiomyocytes to doxorubicin. HSPB1 silencing abrogated the inhibitory effect of HMGB1 on cardiomyocyte apoptosis. Doxorubicin increased the binding of HMGB1 to heat shock factor 2 and enhanced heat shock element promoter activity. Moreover, HMGB1 overexpression greatly enhanced heat shock element promoter activity. Silencing of heat shock factor 2 attenuated HMGB1-dependent HSPB1 expression and abrogated the ability of HMGB1 to suppress cleaved caspase-3 accumulation after doxorubicin stimulation. CONCLUSIONS: We report the first in vivo and in vitro evidence that cardiac HMGB1 increases HSPB1 expression and attenuates cardiomyocyte apoptosis associated with doxorubicin-induced cardiomyopathy. Cardiac HMGB1 increases HSPB1 expression in cardiomyocytes in a heat shock factor 2-dependent manner.
Subject(s)
Apoptosis/genetics , Gene Expression Regulation , HMGB1 Protein/metabolism , HSP27 Heat-Shock Proteins/genetics , Mitochondria/metabolism , Animals , Animals, Newborn , Cardiomyopathies/chemically induced , Cardiomyopathies/diagnosis , Cardiomyopathies/genetics , Cardiomyopathies/metabolism , Cardiomyopathies/mortality , Cell Line , Cells, Cultured , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/pharmacology , HMGB1 Protein/genetics , Humans , Membrane Potential, Mitochondrial , Mice , Mice, Transgenic , Myocardium/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/ultrastructure , Promoter Regions, Genetic , Rats , Transcriptional ActivationABSTRACT
AIM: Pentraxin 3 (PTX3) is a novel marker for the primary local activation of innate immunity and inflammatory responses. Although clinical and experimental evidence suggests that PTX3 is associated with atherosclerosis, the relationship between PTX3 and vascular remodeling after wall injury remains to be determined. We investigated the effects of PTX3 on neointimal hyperplasia following wire vascular injury. METHODS: PTX3 systemic knockout (PTX3-KO) mice and wild-type littermate (WT) mice were subjected to wire-mediated endovascular injury. At four weeks after wire-mediated injury, the areas of neointimal and medial hyperplasia were evaluated. RESULTS: The PTX3-KO mice exhibited higher hyperplasia/media ratios than the WT mice after wire injury, and the degree of Mac-3-positive macrophage accumulation was significantly higher in the PTX3-KO mice than in the WT mice. Furthermore, the PTX3-KO mice showed a much greater increase in the number of PCNA-stained cells in the vascular wall than that observed in the WT mice. CONCLUSIONS: A deficiency of PTX3 results in deteriorated neointimal hyperplasia after vascular injury via the effects of macrophage accumulation and vascular smooth muscle cell proliferation and migration.
Subject(s)
C-Reactive Protein/physiology , Cell Proliferation , Hyperplasia/etiology , Macrophages/pathology , Muscle, Smooth, Vascular/pathology , Neointima/etiology , Nerve Tissue Proteins/physiology , Vascular System Injuries/complications , Animals , Cell Movement , Hyperplasia/metabolism , Hyperplasia/pathology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/metabolism , Neointima/metabolism , Neointima/pathology , Vascular System Injuries/metabolism , Vascular System Injuries/pathologyABSTRACT
Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild-type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI)-1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-κB (NF-κB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFκB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF.
Subject(s)
Atrial Fibrillation/complications , Endothelial Cells/metabolism , Heart Failure/complications , Thrombosis/etiology , Toll-Like Receptor 4/metabolism , Animals , Atrial Fibrillation/blood , Atrial Fibrillation/genetics , Atrial Fibrillation/metabolism , Atrial Fibrillation/physiopathology , Case-Control Studies , Chaperonin 60/metabolism , Disease Models, Animal , Heart Atria/metabolism , Heart Failure/blood , Heart Failure/genetics , Heart Failure/metabolism , Heart Failure/physiopathology , Hemodynamics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Proteins/metabolism , NF-kappa B/metabolism , Nitric Oxide Synthase Type III/metabolism , Phosphorylation , Plasminogen Activator Inhibitor 1/metabolism , Signal Transduction , Thrombosis/blood , Thrombosis/genetics , Thrombosis/metabolism , Thrombosis/physiopathology , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/genetics , Vascular Cell Adhesion Molecule-1/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
OBJECTIVE: The response-to-tissue-injury theory is currently the favorite paradigm to investigate valve pathology. To the best of our knowledge, there are currently no in vivo valve injury models. There are few calcific aortic valve stenosis (AVS) models that develop hemodynamically significant stenosis. Here, we investigated the effect of direct mechanical injury on aortic valves in vivo and developed a novel mouse model of calcific AVS. APPROACH AND RESULTS: Aortic valve injury was created by inserting and moving a spring guidewire under echocardiographic guidance into the left ventricle of male C57/BL6 mice via right common carotid artery. Serial echocardiographic measurements revealed that aortic velocity was increased 1 week after injury and persistently increased until 16 weeks after injury. AVS mice showed a higher heart weight/body weight ratio and decreased left ventricular fractioning shortening 4 weeks after injury, compared with sham mice. We found remarkable proliferation of valve leaflets 4 weeks after injury. Proliferative valves showed increased production of reactive oxygen species and expression of inflammatory cytokines and osteochondrogenic factors. Alizarin red staining showed valvular calcification 12 weeks after injury. CONCLUSIONS: We report a novel calcific AVS model to support the response-to-tissue-injury theory. This model may be a valuable tool for analyzing the mechanism of AVS and assessing therapeutic options.
Subject(s)
Aortic Valve Stenosis/etiology , Aortic Valve/injuries , Aortic Valve/pathology , Calcinosis/etiology , Heart Injuries/etiology , Animals , Aortic Valve/diagnostic imaging , Aortic Valve/metabolism , Aortic Valve/physiopathology , Aortic Valve Stenosis/diagnostic imaging , Aortic Valve Stenosis/metabolism , Aortic Valve Stenosis/pathology , Aortic Valve Stenosis/physiopathology , Calcinosis/diagnostic imaging , Calcinosis/metabolism , Calcinosis/pathology , Calcinosis/physiopathology , Cell Proliferation , Chondrogenesis , Cytokines/metabolism , Disease Models, Animal , Fibrosis , Heart Injuries/diagnostic imaging , Heart Injuries/metabolism , Heart Injuries/pathology , Heart Injuries/physiopathology , Hemodynamics , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred C57BL , Osteogenesis , Oxidative Stress , Reactive Oxygen Species/metabolism , Severity of Illness Index , Stroke Volume , Time Factors , Ultrasonography , Ventricular Function, LeftABSTRACT
BACKGROUND: Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular disease and is associated with heart failure development. The Cornell product is an easily measured electrocardiographic parameter for assessing LVH. However, it is undetermined whether the Cornell product can predict the cardiac prognosis of chronic heart failure (CHF) patients. METHODS AND RESULTS: We performed standard 12-lead electrocardiography and calculated the Cornell product in 432 consecutive CHF patients. LV geometry was assessed as normal, concentric remodeling, concentric or eccentric hypertrophy. The Cornell product was significantly higher in patients with eccentric hypertrophy, and increased with advancing New York Heart Association functional class. During a median follow-up of 660 days, there were 121 cardiac events including 36 cardiac deaths and 85 re-hospitalizations for worsening heart failure. Multivariate Cox proportional hazard analysis showed that the Cornell product was an independent predictor of cardiac events in CHF patients. Patients in the highest quartile of Cornell product had a higher prevalence of LV eccentric hypertrophy (22, 29, 33 and 67 % for quartiles one through four). Kaplan-Meier analysis demonstrated that the highest quartile of Cornell product was associated with the greatest risk among CHF patients. CONCLUSION: The Cornell product is associated with LV eccentric hypertrophy and can be used to predict future cardiac events in CHF patients.