CONGESTIVE HEART FAILURE, Issue 3 2010
Rose S. Cohen MD
A prospective, open-label, 3-month study was conducted to evaluate the feasibility and short-term clinical effect of subcutaneous erythropoietin injections in patients with anemia and heart failure with preserved ejection fraction (ejection fraction, 55%±2%). Using a dose-adjusted algorithm to effect a rate of rise in hemoglobin not to exceed 0.4 g/dL,/wk, hemoglobin (10.8±0.3 to 12.2±0.3 g/dL) and red blood cell volume (1187±55 to 1333±38 mL) increased with an average weekly dose of 3926 units. Functional measures increased from baseline (6-minute walk test [289±24 to 331±22 m], exercise time [432±62 to 571±51 s], and peak oxygen consumption [8.2±0.7 to 9.4±0.9 mL/kg/min], all P<.05). End-diastolic volume declined significantly (8% volumetric decrease, 108±3 to 100±3 mL, P =.03), but there were no significant changes in left ventricular mass or estimated left ventricular end-diastolic pressure. Pressure-volume analysis demonstrated a reduction in ventricular capacitance at an end-diastolic pressure of 30 mm Hg without significant changes in contractile state. Congest Heart Fail. 2010;16:96,103. © 2009 Wiley Periodicals, Inc. [source]

Optimal Left Ventricular Lead Position Predicts Reverse Remodeling and Survival After Cardiac Resynchronization Therapy

CONGESTIVE HEART FAILURE, Issue 2 2009
David Tepper MD
Background., A nonoptimal LV pacing lead position may be a potential cause for nonresponse to CRT. Methods., The site of latest mechanical activation was determined by speckle tracking radial strain analysis and related to the LV lead position on chest x-ray in 244 CRT candidates. Echocardiographic evaluation was performed after 6 months. Long-term follow-up included all-cause mortality and hospitalizations for heart failure. Results., Significant LV reverse remodeling (reduction in LV end-systolic volume from 189±83 mL to 134±71 mL, P<.001) was noted in the group of patients with a concordant LV lead position (n=153, 63%), whereas patients with a discordant lead position showed no significant improvements. In addition, during long-term follow-up (32±16 months), less events (combined for heart failure hospitalizations and death) were reported in patients with a concordant LV lead position. Moreover, a concordant LV lead position appeared to be an independent predictor of hospitalization-free survival after long-term CRT (hazard ratio: 0.22, P=.004). Conclusions., Pacing at the site of latest mechanical activation, as determined by speckle tracking radial strain analysis, resulted in superior echocardiographic response after 6 months of CRT and better prognosis during long-term follow-up. [source]

Baseline Characteristics of Patients Randomized in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) Study

CONGESTIVE HEART FAILURE, Issue 2 2008
Cecilia Linde MD
The Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study is a randomized controlled trial currently assessing the safety and efficacy of cardiac resynchronization therapy in patients with asymptomatic left ventricular (LV) dysfunction with previous symptoms of mild heart failure. This paper describes the baseline characteristics of randomized patients; 610 patients with New York Heart Association (NYHA) class II (82.3%) heart failure or asymptomatic (NYHA class I) LV dysfunction with previous symptoms (17.7%) were randomized in 73 centers. The mean age was 62.5±11.0 years, the mean LV ejection fraction was 26.7%±7.0%, and the mean LV end-diastolic diameter was 66.9±8.9 mm. A total of 97% of patients were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and 95.1% were taking ,-blockers, which were at the target dose in 35.1% of patients. Compared with previous randomized cardiac resynchronization therapy trials, REVERSE patients are on better pharmacologic treatment, are younger, and have a narrower QRS width despite similar LV dysfunction. [source]

Feasibility of Biventricular Pacing in Patients With Recent Myocardial Infarction: Impact on Ventricular Remodeling

CONGESTIVE HEART FAILURE, Issue 1 2007
Eugene S. Chung MD
To test the hypothesis that biventricular pacing after a myocardial infarction with reduced ejection fraction can attenuate left ventricular (LV) remodeling, the authors studied 18 patients (myocardial infarction within 30,45 days, ejection fraction ,30%, narrow QRS) randomized to biventricular therapy (biventricular therapy + defibrillator) (biventricular group) or implantable cardioverter-defibrillator alone (control group). At 1, 6, and 12 months, there were no differences in functional or clinical parameters (New York Heart Association, quality of life, 6-minute walk). Twelve-month LV volume remained stable in the biventricular group, but increased in the control group (median LV end-diastolic volume increase, 6.5 mL in biventricular vs 35 mL in control; P=.03; median LV end-diastolic volume decrease, 5.5 mL in biventricular vs 30.5-mL increase in control; P=.11). Biventricular therapy also prevented an increase in sphericity index at 12 months (median, ,2% in biventricular vs 37% in control; P=.06). Delivery of biventricular therapy early after myocardial infarction appears safe and feasible and may attenuate subsequent LV dilation. [source]

Remodeling of the actin cytoskeleton of target hepatocytes and NK cells during induction of apoptosis

CYTOSKELETON, Issue 2 2001
W. Marty Blom
Abstract Natural Killer cells are immune cells that recognize and eliminate altered and non-self cells from the circulation. To study the interaction between NK cells and target cells, we set up an experimental system consisting of rat Interleukin-2 activated Natural Killer cells (A-NK cells) and rat hepatocytes with a masked Major Histocompatibility Complex (MHC). The masking of the MHC induces recognition of the hepatocytes by the NK cells as non-self. We showed that in vitro apoptosis is rapidly induced in the hepatocytes [Blom et al., 1999] after co-incubation with A-NK cells. Now we describe the morphological changes that occur during and after interaction of A-NK cells with hepatocytes. Confocal laser scanning microscopy showed that the actin cytoskeleton of the NK cells was remodeled during attack of hepatocytes. Some NK cells were in close contact with the hepatocytes while others had formed actin-containing dendrites of varying length that made contact with the hepatocytes. However, dendrite formation is not obligatory for induction of apoptosis because cells that were unable to form these did induce FAS-dependent apoptosis in hepatocytes. Apparently both direct as well as distant contact resulted in apoptosis. Formation of the dendrites was calcium-dependent as EGTA largely prevented it. Importantly, chelation of the calcium also suppressed killing of the hepatocytes. Within 1 h after addition of the A-NK cells, morphological changes in hepatocytes that are characteristic of apoptosis, such as the formation of apoptotic bodies and fragmented nuclei, became apparent. Specifically, the actin cytoskeleton of the hepatocytes was remodeled resulting in the formation of the apoptotic bodies. Inhibition of caspase activity by z-Val-Ala-DL-Asp-fluoromethylketone (100 ,M) partly protected against the rearrangement of the actin filaments in the hepatocytes. Cell Motil. Cytoskeleton 49:78,92, 2001. © 2001 Wiley-Liss, Inc. [source]

Collagen Remodeling After 585-nm Pulsed Dye Laser Irradiation: An Ultrasonographic Analysis

DERMATOLOGIC SURGERY, Issue 10 2003
Brent R. Moody MD
Background and Objectives. Nonablative dermal remodeling is an evolving technology that has generated great interest among both laser surgeons and patients. Evidence indicates that dermal collagen formation is the key mechanism of action for the nonablative techniques. We studied, with ultrasound, new collagen formation after nonablative laser irradiation. Methods. Ten patients with facial rhytids underwent a single treatment with a 585-nm pulsed dye laser. The patients were all female, ranging in age from 47 to 67, and were Fitzpatrick skin types I,III. Laser parameters were as follows: an energy fluence of 2.4 to 3.0 J/cm2, a pulse duration of 350 ,sec, and a spot size of 5 mm with no overlap. Ultrasonographic assessments of dermal collagen were taken at baseline and at 30 and 90 days after treatment. Results. Ultrasonography demonstrated an increase in dermal collagen after a single treatment with the 585-nm pulsed dye laser. The greatest degree of neocollagenesis occurred periocularly. Conclusion. A single treatment with a 585-nm pulsed dye laser appears to increase dermal collagen. This increase in dermal collagen can be assessed with noninvasive cutaneous ultrasound. [source]

Microtubule-dependent organization of subcortical microfilaments in the early Drosophila embryo

DEVELOPMENTAL DYNAMICS, Issue 3 2007
Maria Giovanna Riparbelli
Abstract Dynamic alterations in the spatial organization of cytoskeletal elements constitute a prominent morphological feature of the early, syncytial stages of embryogenesis in Drosophila. Here, we describe and characterize the dynamic behavior of cytoplasmic, subcortical microfilaments, which form a series of nucleus-associated structures, at different phases of the simultaneous nuclear division cycles characteristic of early Drosophila embryos. Remodeling of the cytoplasmic microfilament arrays takes place in parallel to the established cyclic reorganization of cortical microfilament structures. We provide evidence that the cortical and subcortical microfilament populations organize independently of each other, and in response to distinct instructive cues. Specifically, formation of subcortical microfilament structures appears to rely on, and spatially mirror, the organization of polarized microtubule arrays, while cortical microfilament restructuring constitutes a centrosome-dependent process. Genetic analysis identifies a requirement for SCAR, a key mediator of Arp2/3-based microfilament dynamics, in organization of subcortical microfilament structures. Developmental Dynamics 236:662,670, 2007. © 2007 Wiley-Liss, Inc. [source]

Remodeling of an identified motoneuron during metamorphosis: central and peripheral actions of ecdysteroids during regression of dendrites and motor terminals

DEVELOPMENTAL NEUROBIOLOGY, Issue 2 2002
Laura M. Knittel
Abstract During metamorphosis of the moth Manduca sexta, an identified leg motoneuron, the femoral depressor motoneuron (FeDe MN), undergoes reorganization of its central and peripheral processes. This remodeling is under the control of two insect hormones: the ecdysteroids and juvenile hormone (JH). Here, we asked whether peripheral or central actions of the ecdysteroids influenced specific regressive aspects of MN remodeling. We used stable hormonal mimics to manipulate the hormonal environment of either the FeDe muscle or the FeDe MN soma. Our results demonstrate that motor-terminal retraction and dendritic regression can be experimentally uncoupled, indicating that central actions of ecdysteroids trigger dendritic regression whereas peripheral actions trigger terminal retraction. Our results further demonstrate that discrete aspects of motor-terminal retraction can also be experimentally uncoupled, suggesting that they also are regulated differently. © 2002 Wiley Periodicals, Inc. J Neurobiol 52: 99,116, 2002 [source]

Right Ventricular Adaptations Along with Left Ventricular Remodeling in Older Athletes

ECHOCARDIOGRAPHY, Issue 3 2009
Oner Ozdogan M.D.
Background: Afterload changes and anatomic interaction between the ventricles cause right ventricle (RV) adaptation along with left ventricle (LV) remodeling. This study was designed to evaluate RV adaptations along with LV remodeling and to determine the effect of aging on both ventricles in a population of older athletes. Methods: Echocardiographic characteristics of 48 endurance trained older athletes were examined by tissue Doppler imaging (TDI) and integrated backscatter (IBS). Results: Mean LV mass index was calculated as 107.8±17.0 g/m2. Twenty-two athletes were > 55 years old. Age was found to be a risk factor for diastolic dysfunction regarding lateral TDI velocities (Em < Am) (r = 0.385, P < 0.001). RV long-axis (LAX) diameters were associated with LA volumes and LV masses (r = 0.380, P < 0.01 and r = 0.307, P < 0.05). RV LAX diameters were correlated with RV TDI E-wave (r =,0.285, P < 0.05), RV LAX average, and peak IBS values (r = 0.36, P < 0.05 and r = 0.348, P < 0.05). Conclusions: TDI and IBS are applicable methods to evaluate the relationship between the two ventricles in athletes' heart. Increased RV LAX IBS values indicate increased LV mass and LA volume as a result of RV changes along with LV remodeling. Our data suggest that RV TDI E-wave and average RV IBS values reflect cardiac adaptations of both RV and LV in older athletes. [source]

An Echocardiographic Analysis of the Long-Term Effects of Carvedilol on Left Ventricular Remodeling, Systolic Performance, and Ventricular Filling Patterns in Dilated Cardiomyopathy

ECHOCARDIOGRAPHY, Issue 7 2005
Peter S. Rahko M.D.
Background: The long-term clinical benefit of beta blockade is well recognized, but data quantifying long-term effects of beta blockade on remodeling of the left ventricle (LV) is limited. Methods: This consecutive series evaluates the long-term response of the LV to the addition of carvedilol to conventional therapy for dilated cardiomyopathy. There were 33 patients who had a LV ejection fraction <45%, LV enlargement and symptomatic heart failure. Quantitative Doppler echocardiography was performed at baseline 6, 12, 24, and 36 months after initiation of carvedilol to evaluate LV ejection fraction, LV volume, wall stress, mass, regional function, and diastolic performance. Results: Compared to baseline there was a significant and sustained reduction in end-systolic volume and end-systolic wall stress with a corresponding improvement in LV ejection fraction. The LV mass did not decline but relative wall thickness increased toward normal. An analysis of regional wall motion responses showed an improvement in all areas, particularly the apical, septal, and lateral walls that was significantly more frequent in patients with a nonischemic etiology. Filling patterns of the LV remained abnormal throughout the study but changed with therapy suggesting a decline in filling pressures. These changes were sustained for 3 years. Conclusion: (1) The addition of carvedilol to conventional therapy for a dilated cardiomyopathy significantly improves LV ejection fraction and reduces LV end-systolic volume and wall stress for at least 3 years, (2) the response to 6 months of treatment predicts the long-term response, (3) the typical response is partial improvement of the LV, complete return to normal size, and function is uncommon, and (4) abnormalities of LV filling persist in virtually all patients throughout the course of treatment. [source]

Remodeling of extracellular matrix and epileptogenesis

EPILEPSIA, Issue 2010
Alexander Dityatev
Summary Extracellular matrix (ECM) in the brain is composed of molecules synthesized and secreted by neurons and glial cells, which form stable aggregates of diverse composition in the extracellular space. In the mature brain, ECM undergoes a slow turnover and restrains structural plasticity while supporting multiple physiologic processes, including perisomatic ,-aminobutyric acid (GABA)ergic inhibition, synaptic plasticity, and homeostatic regulations. Seizures lead to striking remodeling of ECM, which may be essentially engaged in different aspects of epileptogenesis. This view is supported by human genetic studies linking ECM molecules and epilepsy, by data showing altered epileptogenesis in mice deficient in ECM molecules, and by evidence that ECM may shape seizure-induced sprouting of mossy fibers, granule cell dispersion, and astrogliosis. Therefore, restraining seizure-induced remodeling of ECM or suppressing the signaling triggered by the remodeled ECM might provide effective therapeutic strategies to antagonize the progression of epileptogenesis. [source]

Gene and Cell Therapy for Heart Disease

IUBMB LIFE, Issue 2 2002
Regina M. Graham
Abstract Heart disease is the most common cause of morbidity and mortality in Western society and the incidence is projected to increase significantly over the next few decades as our population ages. Heart failure occurs when the heart is unable to pump blood at a rate to commensurate with tissue metabolic requirements and represents the end stage of a variety of pathological conditions. Causes of heart failure include ischemia, hypertension, coronary artery disease, and idiopathic dilated cardiomyopathy. Hypertension and ischemia both cause infarction with loss of function and a consequent contractile deficit that promotes ventricular remodeling. Remodeling results in dramatic alterations in the size, shape, and composition of the walls and chambers of the heart and can have both positive and negative effects on function. In 30-40% of patients with heart failure, left ventricular systolic function is relatively unaffected while diastolic dysfunction predominates. Recent progress in our understanding of the molecular and cellular bases of heart disease has provided new therapeutic targets and led to novel approaches including the delivery of proteins, genes, and cells to replace defective or deficient components and restore function to the diseased heart. This review focuses on three such strategies that are currently under development: (a) gene transfer to modulate contractility, (b) therapeutic angiogenesis for the treatment of ischemia, and (c) embryonic and adult stem cell transfer to replace damaged myocardium. [source]

Morphologic changes associated with functional adaptation of the navicular bone of horses

JOURNAL OF ANATOMY, Issue 5 2007
V. A. Bentley
Abstract Failure of functional adaptation to protect the skeleton from damage is common and is often associated with targeted remodeling of bone microdamage. Horses provide a suitable model for studying loading-related skeletal disease because horses are physically active, their exercise is usually regulated, and adaptive failure of various skeletal sites is common. We performed a histologic study of the navicular bone of three groups of horses: (1) young racing Thoroughbreds (n = 10); (2) young unshod ponies (n = 10); and (3) older horses with navicular syndrome (n = 6). Navicular syndrome is a painful condition that is a common cause of lameness and is associated with extensive remodeling of the navicular bone; a sesamoid bone located within the hoof which articulates with the second and third phalanges dorsally. The following variables were quantified: volumetric bone mineral density; cortical thickness (Ct.Th); bone volume fraction, microcrack surface density; density of osteocytes and empty lacunae; and resorption space density. Birefringence of bone collagen was also determined using circularly polarized light microscopy and disruption of the lacunocanalicular network was examined using confocal microscopy. Remodeling of the navicular bone resulted in formation of transverse secondary osteons orientated in a lateral to medial direction; bone collagen was similarly orientated. In horses with navicular syndrome, remodeling often led to the formation of intracortical cysts and development of multiple tidemarks at the articular surface. These changes were associated with high microcrack surface density, low bone volume fraction, low density of osteocytes, and poor osteocyte connectivity. Empty lacunae were increased in Thoroughbreds. Resorption space density was not increased in horses with navicular syndrome. Taken together, these data suggest that the navicular bone may experience habitual bending across the sagittal plane. Consequences of cumulative cyclic loading in horses with navicular syndrome include arthritic degeneration of adjacent joints and adaptive failure of the navicular bone, with accumulation of microdamage and associated low bone mass, poor osteocyte connectivity, and low osteocyte density, but not formation of greater numbers of resorption spaces. [source]

If bone is the answer, then what is the question?

JOURNAL OF ANATOMY, Issue 2 2000
R. HUISKES
In the 19th century, several scientists attempted to relate bone trabecular morphology to its mechanical, load-bearing function. It was suggested that bone architecture was an answer to requirements of optimal stress transfer, pairing maximal strength to minimal weight, according to particular mathematical design rules. Using contemporary methods of analysis, stress transfer in bones was studied and compared with anatomical specimens, from which it was hypothesised that trabecular architecture is associated with stress trajectories. Others focused on the biological processes by which trabecular architectures are formed and on the question of how bone could maintain the relationship between external load and architecture in a variable functional environment. Wilhelm Roux introduced the principle of functional adaptation as a self-organising process based in the tissues. Julius Wolff, anatomist and orthopaedic surgeon, entwined these 3 issues in his book The Law of Bone Remodeling (translation), which set the stage for biomechanical research goals in our day. ,Wolff's Law' is a question rather than a law, asking for the requirements of structural optimisation. In this article, based on finite element analysis (FEA) results of stress transfer in bones, it is argued that it was the wrong question, putting us on the wrong foot. The maximal strength/minimal weight principle does not provide a rationale for architectural formation or adaptation; the similarity between trabecular orientation and stress trajectories is circumstantial, not causal. Based on computer simulations of bone remodelling as a regulatory process, governed by mechanical usage and orchestrated by osteocyte mechanosensitivity, it is shown that Roux's paradigm, conversely, is a realistic proposition. Put in a quantitative regulatory context, it can predict both trabecular formation and adaptation. Hence, trabecular architecture is not an answer to Wolff's question, in the sense of this article's title. There are no mathematical optimisation rules for bone architecture; there is just a biological regulatory process, producing a structure adapted to mechanical demands by the nature of its characteristics, adequate for evolutionary endurance. It is predicted that computer simulation of this process can help us to unravel its secrets. [source]

Targeting Bone Remodeling for the Treatment of Osteoporosis: Summary of the Proceedings of an ASBMR Workshop,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2009
John P Bilezikian
First page of article [source]

Editorial: Positive Effects of Intravenous Zoledronic Acid on Bone Remodeling and Structure: Are Different Effects on Osteoblast Activity to Other Oral Bisphosphonates Responsible?,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2008
Peter R Ebeling MD
No Abstracts. [source]

Remodeling and Vascular Spaces in Bone

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2007
Erik Fink Eriksen
Abstract In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed. [source]

Bone Remodeling: Biochemical Markers or Bone Biopsy?

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2006
Pascale M Chavassieux
No abstract is available for this article. [source]

Differential Effects of Teriparatide and Alendronate on Bone Remodeling in Postmenopausal Women Assessed by Histomorphometric Parameters,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005
Monique Arlot MD
Abstract An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 ,g with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment. Introduction: Alendronate and teriparatide increased BMD, assessed by DXA, by different mechanisms of action, supported by changes in biochemical markers of bone turnover. The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment. Materials and Methods: Patients were a cohort from a randomized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 ,g and alendronate 10 mg in postmenopausal women with osteoporosis. Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months (n = 23) or 18 months (n = 14); 5 additional patients were biopsied from contralateral sides at 6 and 18 months. Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months (teriparatide, n = 8; alendronate, n = 9) and 15 patients at 18 months (teriparatide, n = 8; alendronate, n = 7). Data were analyzed by two-sample tests. Results: Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months, whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months. Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group, returning to levels comparable with untreated postmenopausal women. In the teriparatide group, the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen, a biochemical marker of bone formation. The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups. Conclusions: These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide. [source]

Drugs Used to Treat Osteoporosis: The Critical Need for a Uniform Nomenclature Based on Their Action on Bone Remodeling,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2005
B Lawrence Riggs MD
Abstract There continues to be uncertainty about the classification of available drugs for treating osteoporosis. We find that grouping them into anti-catabolic and anabolic classes based on the mechanisms of their action on bone remodeling and fracture reduction removes ambiguities and provides a relatively straightforward classification. The recent introduction of teriparatide into clinical practice initiated the era of anabolic therapy for osteoporosis, but it is still unclear how to define an anabolic drug. All drugs that increase bone mass do so by affecting bone remodeling. When their mechanisms of action on bone remodeling and on fracture reduction are considered, we find that anti-osteoporotic drugs fall naturally into either anti-catabolic or anabolic classes. Anti-catabolic drugs increase bone strength and reduce fractures mainly by decreasing the number of bone multicellular units (BMUs). This reduces perforative resorption and preserves skeletal microarchitecture (by preventing further structural damage to trabecular bone and increased porosity in cortical bone induced by high bone remodeling). Reduction in bone remodeling by anti-catabolic drugs may increase bone mass moderately during the interval in which previously initiated BMUs are completing mineralization. Some anti-catabolic drugs may also enhance the formation phase of the remodeling cycle, but their major action is to reduce overall bone turnover (i.e., the number of BMUs in bone). In contrast, anabolic drugs increase bone strength and reduce fractures by substantially increasing bone mass as a result of an overall increase in the number of BMUs combined with a positive BMU balance (the magnitude of the formation phase is greater than that of the resorption phase). Some anabolic drugs also induce renewed modeling, increase periosteal apposition and repair of trabecular microstructure. We hope that this classification will serve as a starting point for continued discussion on the important issue of nomenclature. [source]

Adrenarche and Bone Modeling and Remodeling at the Proximal Radius: Weak Androgens Make Stronger Cortical Bone in Healthy Children,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2003
Thomas Remer
Abstract Adrenarche, the physiological increase in adrenal androgen secretion, may contribute to better bone status. Proximal radial bone and 24-h urinary steroid hormones were analyzed cross-sectionally in 205 healthy children and adolescents. Positive adrenarchal effects on radial diaphyseal bone were observed. Obviously, adrenarche is one determinant of bone mineral status in children. Introduction: Increased bone mass has been reported in several conditions with supraphysiological adrenal androgen secretion during growth. However, no data are available for normal children. Therefore, our aim was to examine whether adrenal androgens within their physiological ranges may be involved in the strengthening of diaphyseal bone during growth. Methods: Periosteal circumference (PC), cortical density, cortical area, bone mineral content, bone strength strain index (SSI), and forearm cross-sectional muscle area were determined with peripheral quantitative computed tomography (pQCT) at the proximal radial diaphysis in healthy children and adolescents. All subjects, aged 6,18 years, who collected a 24-h urine sample around the time of their pQCT analysis (100 boys, 105 girls), were included in the present study, and major urinary glucocorticoid (C21) and androgen (C19) metabolites were quantified using gas chromatography-mass spectrometry. Results and Conclusions: We found a significant influence of muscularity, but not of hormones, on periosteal modeling (PC) before the appearance of pubic hair (prepubarche). Similarly, no influence of total cortisol secretion (C21) was seen on the other bone variables. However, positive effects of C19 on cortical density (p < 0.01), cortical area (p < 0.001), bone mineral content (p < 0.001), and SSI (p < 0.001),reflecting, at least in part, reduction in intracortical remodeling,were observed in prepubarchal children after muscularity or age had been adjusted for. This early adrenarchal contribution to proximal radial diaphyseal bone strength was further confirmed for all cortical variables (except PC) when, instead of C19 and C21, specific dehydroepiandrosterone metabolites were included as independent variables in the multiple regression model. During development of pubic hair (pubarche), muscularity and pubertal stage rather than adrenarchal hormones seemed to influence bone variables. Our study shows that especially the prepubarchal increase in adrenal androgen secretion plays an independent role in the accretion of proximal radial diaphyseal bone strength in healthy children. [source]

Cancellous Bone Remodeling Occurs in Specialized Compartments Lined by Cells Expressing Osteoblastic Markers

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2001
Ellen M. Hauge
Abstract We describe a sinus, referred to as a bone remodeling compartment (BRC), which is intimately associated with cancellous bone remodeling. The compartment is lined on its marrow side by flattened cells and on its osseous side by the remodeling bone surface, resembling a roof of flattened cells covering the bone surface. The flat marrow lining cells are in continuity with the bone lining cells at the margins of the BRC. We examined a large number of diagnostic bone biopsy specimens received during recent years in the department. Furthermore, 10 patients (8 women and 2 men, median age 56 [40,69] years) with the high turnover disease of primary hyperparathyroidism who were treated with parathyroidectomy and followed for 3 years were included in the histomorphometric study. Bone samples for the immuno-enzyme staining were obtained from an amputated extremity of child. The total cancellous bone surface covered by BRC decreases by 50% (p < 0.05) following normalization of turnover and is paralleled by a similar 50% decrease in remodeling surface (p < 0.05). The entire eroded surface and two-thirds of the osteoid surface are covered by a BRC. BRC-covered uncompleted walls are 30% (p < 0.05) thinner than those without a BRC. This indicates that the BRC is invariably associated with the early phases of bone remodeling, that is, bone resorption, whereas it closes during the late part of bone formation. Immuno-enzyme staining shows that the flat marrow lining cells are positive for alkaline phosphatase, osteocalcin, and osteonectin, suggesting that they are bone cells. The first step in cancellous bone remodeling is thought to be the lining cells digesting the unmineralized matrix membrane followed by their disappearance and the arrival of the bone multicellular unit (BMU). We suggest that the lining cell barrier persists during bone remodeling; that the old lining cells become the marrow lining cells, allowing bone resorption and bone formation to proceed under a common roof of lining cells; that, at the end of bone formation, new bone lining cells derived from the flattened osteoblasts replace the marrow lining cells thereby closing the BRC; and that the two layers of lining cells eventually becomes a single layer. The integrity of the osteocyte-lining cell system is reestablished by the new generation of lining cells. The BRC most likely serves multiple purposes, including efficient exchange of matrix constituents and minerals, routing, monitoring, or modulating bone cell recruitment, and possibly the anatomical basis for the coupling of bone remodeling. [source]

A Three-Dimensional Simulation of Age-Related Remodeling in Trabecular Bone,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2001
J. C. Van Der Linden
Abstract After peak bone mass has been reached, the bone remodeling process results in a decrease in bone mass and strength. The formation deficit, the deficit of bone formation compared with previous resorption, results in bone loss. Moreover, trabeculae disconnected by resorption cavities probably are not repaired. The contributions of these mechanisms to the total bone loss are unclear. To investigate these contributions and the concomitant changes in trabecular architecture and mechanical properties, we made a computer simulation model of bone remodeling using microcomputed tomography (micro-CT) scans of human vertebral trabecular bone specimens. Up to 50 years of physiological remodeling were simulated. Resorption cavities were created and refilled 3 months later. These cavities were not refilled completely, to simulate the formation deficit. Disconnected trabeculae were not repaired; loose fragments generated during the simulation were removed. Resorption depth, formation deficit, and remodeling space were based on biological data. The rate of bone loss varied between 0.3% and 1.1% per year. Stiffness anisotropy increased, and morphological anisotropy (mean intercept length [MIL]) was almost unaffected. Connectivity density increased or decreased, depending on the remodeling parameters. The formation deficit accounted for 69,95%, disconnected trabeculae for 1,21%, and loose fragments for 1,17% of the bone loss. Increasing formation deficit from 1.8% to 5.4% tripled bone loss but only doubled the decrease in stiffness. Increasing resorption depth from 28 to 56 ,m slightly increased bone loss but drastically decreased stiffness. Decreasing the formation deficit helps to prevent bone loss, but reducing resorption depth is more effective in preventing loss of mechanical stiffness. [source]

High-Turnover Periprosthetic Bone Remodeling and Immature Bone Formation Around Loose Cemented Total Hip Joints

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2001
Michiaki Takagi
Abstract Aseptic loosening and periprosthetic osteolysis are the major problems awaiting solution in total hip surgery. The clinical investigation focused on the analysis of periprosthetic bone remodeling to clarify one important key event in the cascade of periprosthetic connective tissue weakening and osteolysis around loose artificial hip joints. Twelve acetabular bone samples adjacent to granulomatous synovial-like membrane of loose hip prosthesis were retrieved at revision surgery and processed for Villanueva bone staining for morphological observation and bone histomorphometric analysis. Eight well-fixed bony samples were used as control. Although osteoclastic surface and eroded surface by osteoclasts were evident in the periprosthetic bone from loose hip joints (p = 0.003 and p = 0.027), increased osteoid/low-mineralized bone matrix (p < 0.001) and osteoid width (p < 0.001) also were significant findings in structural analysis. In addition, not only elevated mineral apposition rate (MAR; p = 0.044) but also increased mineralizing surface (p = 0.044) and bone formation rate (BFR; p = 0.002) in loose periprosthetic bones were shown in dynamic data analysis. These results were confirmed by precise morphological observation by confocal laser scanning microscopy. Active coupling of bone formation and resorption and increased osteocytes with abundant bone canalicular projections were found in combined with the presence of immature bone matrices (osteoid and low-mineralized bone areas) in periprosthetic bones from loose hip joints. These results indicated that active osteoclastic bone resorption and/or defective bone formation are coupled with monocyte/macrophage-mediated foreign body-type granuloma in the synovial-like interface membrane of loose hip joints. Thus, this unique high-turnover periprosthetic bone remodeling with bad bone quality probably is caused by the result of cellular host response combined with inappropriate cyclic mechanical loading. The fragile periprosthetic bone may contribute to hip prosthesis loosening. [source]

Loss of Osteocyte Integrity in Association with Microdamage and Bone Remodeling After Fatigue In Vivo,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000
Olivier Verborgt
Abstract As a result of fatigue, bone sustains microdamage, which is then repaired by bone-remodeling processes. How osteoclastic activity is targeted at the removal of microdamaged regions of bone matrix is unknown. In the current studies, we tested the hypothesis that changes in osteocyte integrity, through the initiation of regulated cell death (apoptosis), are associated with fatigue-related microdamage and bone resorption. Ulnae of adult rats were fatigue-loaded to produce a known degree of matrix damage. Osteocyte integrity was then assessed histomorphometrically from terminal deoxynucleotidyl transferase,mediated deoxyuridine triphosphate,nick end labeling (TUNEL),stained sections to detect cells undergoing DNA fragmentation associated with apoptosis; toluidine blue,stained sections were used for secondary morphological confirmation. Ten days after loading, large numbers of TUNEL-positive osteocytes were found in bone surrounding microcracks and in bone surrounding intracortical resorption spaces (,300% increases over controls, p < 0.005). TUNEL labeling in loaded ulnae at sites distant from microcracks or resorption foci did not differ from that in control bone. Osteocytes in toluidine blue,stained sections showed equivalent trends to TUNEL-stained sections, with significant increases in pyknotic nuclei and empty lacunae associated with microcracks and intracortical resorption spaces. TUNEL-positive osteocytes were observed around bone microdamage by 1 day after loading (p < 0.01 relative to baseline), and their number remained elevated throughout the entire experimental period. Increases in empty lacunae and decreases in normal osteocyte numbers were observed over time as well. These studies show that (1) osteocyte apoptosis is induced by bone fatigue, (2) this apoptosis is localized to regions of bone that contain microcracks, and (3) osteoclastic resorption after fatigue also coincides with regions of osteocyte apoptosis. The strong associations between microdamage, osteocyte apoptosis, and subsequent bone remodeling support the hypothesis that osteocyte apoptosis provides a key part of the activation or signaling mechanisms by which osteoclasts target bone for removal after fatigue-induced matrix injury. [source]

Left Ventricle and Left Atrium Remodeling after Mitral Valve Replacement in Case of Mixed Mitral Valve Disease of Rheumatic Origin

JOURNAL OF CARDIAC SURGERY, Issue 4 2010
n Ender Topal M.D.
Methods: Thirty consecutive elective patients with MVR for mixed mitral disease of rheumatic origin formed the study group. Of these, 21 (70%) were women and the mean age was 37 years. Transthoracic echocardiography was performed prior to surgery, at three-month follow-up, and at three-year follow-up except for the latest nine patients. Results: The mean duration of follow-up was 3.6 ± 1.8 years. MVR surgery improved the functional class (mean New York Heart Association [NYHA] class) at three-year follow-up (p = 0.008). LV end-diastolic diameter and LA sizes decreased after MVR. Total chordal preservation causes better outcome, regarding to LV ejection fraction (LVEF) and NYHA functional class of patients. Preoperative high NYHA class, low LVEF, and high LV end-systolic diameter (LVESd) resulted with postoperative LV dysfunction (p were < 0.001, < 0.001, and 0.006, respectively). Conclusion: In patients with mixed mitral valve disease, MVR enhanced LV and LA remodeling resulting in better NYHA function. Preoperative NYHA, LVEF, and LVESd were significant predictors of postoperative LV function. (J Card Surg 2010;25:367-372) [source]

Partial Aortic Root Remodeling with an Adventitial Inversion Technique for an Acute Type A Aortic Dissection

JOURNAL OF CARDIAC SURGERY, Issue 3 2010
Junji Yunoki M.D.
Postoperative computed tomography at six months showed no dissection or pseudoaneurysm in the aortic root.,(J Card Surg 2010;25:327-329) [source]

Atrial Remodeling After Mitral Valve Surgery in Patients with Permanent Atrial Fibrillation

JOURNAL OF CARDIAC SURGERY, Issue 5 2004
Fernando Hornero M.D., Ph.D.
Mitral surgery allows an immediate surgical auricular remodeling and besides in those cases in which sinus rhythm is reached, it is followed by a late remodeling. The aim of this study is to investigate the process of postoperative auricular remodeling in patients with permanent atrial fibrillation undergoing mitral surgery. Methods: In a prospective randomized trial, 50 patients with permanent atrial fibrillation and dilated left atrium, submitted to surgical mitral repair, were divided into two groups: Group I contained 25 patients with left auricular reduction and mitral surgery, and Group II contained 25 patients with isolated valve surgery. Both groups were considered homogeneous in the preoperative assessment. Results: After a mean follow-up of 31 months, 46% of patients included in Group I versus 18% of patients included in Group II restarted sinus rhythm (p = 0.06). An auricular remodeling with size regression occurred in those patients who recovered from sinus rhythm, worthy of remark in Group II (,10.8% of left auricular volume reduction in Group I compared to ,21.5% in Group II; p < 0.05). A new atrial enlargement took place in those patients who remained with atrial fibrillation (+16.8% left auricular volume in Group I vs. +8.4% in Group II; p < 0.05). Conclusions: Mitral surgery produces an atrial postoperative volume that decrease especially when reduction techniques are employed. Late left atrial remodeling depended on the type of atrial rhythm and postoperative surgical volume. [source]

Bepridil Reverses Atrial Electrical Remodeling and L-Type Calcium Channel Downregulation in a Canine Model of Persistent Atrial Tachycardia

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2007
KUNIHIRO NISHIDA M.D.
Introduction: This study tested whether bepridil, a multichannel blocker, would reverse electrical remodeling induced by persistent atrial tachycardia. Methods and Results: Fourteen dogs were subjected to rapid atrial pacing at 400 bpm for 6 weeks after atrioventricular block was created to control the ventricular rate. During the study period, seven dogs were given placebo for 6 weeks (Control group), and seven were given placebo for 3 weeks, followed by 3 weeks of bepridil (10 mg/kg/day, Bepridil group). The atrial effective refractory period (ERP) and the inducibility and duration of atrial fibrillation (AF) were determined on a weekly basis. After 6 weeks, expression of L-type calcium channel ,1C messenger ribonucleic acid (mRNA) was quantified by real-time reverse transcription-polymerase chain reaction. In the Control group, ERP was shortened and the inducibility and duration of AF increased through the 6-week period. In the Bepridil group, the same changes occurred during the first 3 weeks, but were gradually reversed with bepridil. After 6 weeks, ERP was longer, AF inducibility was lower, and AF duration was shorter in Bepridil group than in the Control group. Expression of ,1C mRNA was decreased by 64% in the Control group (P < 0.05 vs sham), but in the Bepridil group, it was not different compared with the sham dogs. As a whole group of dogs, ERP was positively correlated with ,1C mRNA expression. Conclusion: Bepridil reverses the electrophysiological consequences of atrial remodeling to some extent and L-type calcium channel downregulation in a canine model of atrial tachycardia. [source]

Is Atrial Remodeling a Viable Target for Prevention of Atrial Fibrillation Recurrence?

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2004
STANLEY NATTEL M.D.
[source]