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Results for “Remodeling”

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PubMed2001

Counteracting regulation of chromatin remodeling at a fission yeast cAMP response element-related recombination hotspot by stress-activated protein kinase, cAMP-dependent kinase and meiosis regulators.

In fission yeast, an ATF/CREB-family transcription factor Atf1-Pcr1 plays important roles in the activation of early meiotic processes via the stress-activated protein kinase (SAPK) and the cAMP-dependent protein kinase (PKA) pathways. In addition, Atf1-Pcr1 binds to a cAMP responsive element (CRE)-like sequence at the site of the ade6-M26 mutation, which results in local enhancement of meiotic recombination and chromatin remodeling. Here we studied the roles of meiosis-inducing signal transduction pathways in M26 chromatin remodeling. Chromatin analysis revealed that persistent activation of PKA in meiosis inhibited M26 chromatin remodeling, suggesting that the PKA pathway represses M26 chromatin remodeling. The SAPK pathway activated M26 chromatin remodeling, since mutants lacking a component of this pathway, the Wis1 or Spc1/Sty1 kinases, had no M26 chromatin remodeling. M26 chromatin remodeling also required the meiosis regulators Mei2 and Mei3 but not the subsequently acting regulators Sme2 and Mei4, suggesting that induction of M26 chromatin remodeling needs meiosis-inducing signals before premeiotic DNA replication. Similar meiotic chromatin remodeling occurred meiotically around natural M26 heptamer sequences. These results demonstrate the coordinated action of genetic and physiological factors required to remodel chromatin in preparation for high levels of meiotic recombination and eukaryotic cellular differentiation.

Cell Differentiation↗

PubMed1998

Prolonged inhaled NO attenuates hypoxic, but not monocrotaline-induced, pulmonary vascular remodeling in rats.

UNLABELLED: In concentrations of 10-20 ppm, inhaled nitric oxide (NO) decreases pulmonary artery pressure and attenuates vascular remodeling in pulmonary hypertensive rats. Because NO is potentially toxic, it is important to know whether lower concentrations attenuate vascular remodeling produced by different etiologies. Therefore, we determined the effects of prolonged, small-dose inhaled NO administration on hypoxic and monocrotaline (MCT)-induced pulmonary vascular remodeling. Rats were subjected to normoxia, hypoxia (normobaric 10% oxygen), or hypoxia plus NO in concentrations of 50 ppb, 200 ppb, 2 ppm, 20 ppm, and 100 ppm for 3 wk. A second group of normoxic rats was given MCT (60 mg/kg intraperitoneally) alone or in the presence of 2, 20, and 100 ppm of NO. Subsequently, pulmonary artery smooth muscle thickness and the number of muscular arteries (percentage of total arteries) were determined. Right ventricular hypertrophy was determined by right to left ventricle plus septum weight ratio (RV/LV + S). Pulmonary artery smooth muscle thickness and the percent muscular arteries were increased by hypoxia and MCT. The hypoxic increase in thickness was attenuated by all concentrations of NO, with 100 ppm being greatest, whereas NO had no effect on MCT rats. NO attenuated the increase in percent muscular arteries in hypoxic but not MCT rats. The RV/LV + S was increased by hypoxia and MCT compared with normoxia. Hypoxia-induced RV hypertrophy was decreased by all concentrations of inhaled NO, although attenuation with 50 ppb was less than with 200 ppb, 20 ppm, and 100 ppm. In MCT rats 2 and 100 ppm NO increased RV hypertrophy, whereas 20 ppm had no effect. In conclusion, inhaled NO in concentrations as low as 50 ppb attenuates the pulmonary vascular remodeling and RV hypertrophy secondary to hypoxia. In contrast, concentrations as high as 100 ppm do not attenuate MCT-induced pulmonary remodeling. These results demonstrate that extremely low concentrations of NO may attenuate remodeling but that the effectiveness is dependent on the mechanism inducing pulmonary remodeling. IMPLICATIONS: The authors determined whether inhaled NO, a selective pulmonary vasodilator, attenuates pulmonary vascular remodeling caused by two models of pulmonary hypertension: chronic hypoxia and monocrotaline injection. Analysis of pulmonary vascular morphology suggests that very low concentrations of NO effectively attenuate hypoxic remodeling but that NO is not effective in monocrotaline-induced pulmonary remodeling.

Administration, Inhalation↗

PubMed2004

Remodeling of coronary arteries in diabetic patients-an intravascular ultrasound study.

BACKGROUND: Coronary artery remodeling is a structural change in the vessel wall and typically in response to atherosclerotic plaque. The nature of coronary remodeling has been described in different clinical situations. However, remodeling characteristics of coronary arteries of diabetic patients have never been studied. HYPOTHESIS: We tested the hypothesis that positive remodeling of coronary artery in response to atherosclerotic plaque in diabetic patients would be less compared to nondiabetic patients. METHODS: Coronary intravascular ultrasound analysis of data in 26 consecutive patients (12 diabetic and 14 nondiabetic) was performed. Linear regression analyses of vessel area versus plaque area were carried out to establish a relation between the degree of plaque and the extent of remodeling in diabetic and nondiabetic groups. RESULTS: The positive remodeling quantified as the slope of the regression line was similar in both the groups (diabetic group 1.32 and nondiabetic group 0.80) when all segments with different plaque areas were considered (P > 0.05). However, the diabetic group had greater positive remodeling in segments with plaque area less than 55%, as the slope for diabetic group was 2.01 and nondiabetic group was 1.40 (P < 0.05). CONCLUSIONS: Both the diabetic and nondiabetic patients had positive remodeling in response to atherosclerotic plaque formation. Diabetics had greater positive remodeling in the early stages of atherosclerosis compared to nondiabetics, thus providing evidence against our hypothesis. The adverse clinical outcomes in diabetics may not be due to inadequate positive remodeling of coronary arteries as previously thought.

Coronary Angiography↗

PubMed2006

Association of coronary plaque composition and arterial remodelling: a virtual histology analysis by intravascular ultrasound.

BACKGROUND: Conflicting data have been reported about the correlation between plaque composition assessed by virtual histology (VH) and remodelling index (RI). AIM: To evaluate, in a larger patient population, the relationship between plaque morphology obtained by VH and arterial remodelling. METHODS AND RESULTS: VH intravascular ultrasound was performed on 95 non-bifurcation native significant lesions (>75% stenosis) in 85 patients. Positive remodelling (defined as RI > or =1.05) was present in 28 lesions, whereas intermediate/negative remodelling (RI <1.05) was present in 67 lesions. Compared with intermediate/negative remodelling, positive remodelling was associated with an increased frequency of patients with acute coronary syndrome (n = 13 (52%) vs n = 15 (25%); p = 0.017), and with a greater plaque burden (mean (SD) 78.3 (6.3)% vs 73.2 (6.8)%, p = 0.001). At the minimal lumen site, necrotic core was significantly smaller in lesions with positive remodelling (median (interquartile range) 5.0% (2.2-11.0%)) than in lesions with intermediate/negative remodelling (median (interquartile range) 9.0% (4.0-16.0%); p = 0.048). No differences were observed in the rate of thin-cap fibroatheroma or in the presence of multiple necrotic core layers, and there were no statistical differences for fibrous, fibro fatty and dense calcium percent plaque area at the minimum lumen diameter (MLD), or for the entire lesion length between both groups. CONCLUSIONS: In vivo VH analysis shows that lesions with positive remodelling have statistically less necrotic core percent area at the MLD site compared with intermediate/negative remodelling lesions.

Aged↗

PubMed2000

Extent and direction of arterial remodeling in stable versus unstable coronary syndromes : an intravascular ultrasound study.

BACKGROUND: The morphological characteristics of coronary plaques in patients with stable versus unstable coronary syndromes have been described in vivo with intravascular ultrasound, but the relationship between arterial remodeling and clinical presentation is not well known. METHODS AND RESULTS: We studied 85 patients with unstable and 46 patients with stable coronary syndromes using intravascular ultrasound before coronary intervention. The lesion site and a proximal reference site were analyzed. The remodeling ratio (RR) was defined as the ratio of the external elastic membrane (EEM) area at the lesion to that at the proximal reference site. Positive remodeling was defined as an RR >1.05 and negative remodeling as an RR <0.95. Plaque area (13.9+/-5.5 versus 11.1+/-4.8 mm(2); P=0.005), EEM area (16.1+/-6.2 versus 13.0+/-4.8 mm(2); P=0. 004), and the RR (1.06+/-0.2 versus 0.94+/-0.2; P=0.008) were significantly greater at target lesions in patients with unstable syndromes than in patients with stable syndromes. Positive remodeling was more frequent in unstable than in stable lesions (51. 8% versus 19.6%), whereas negative remodeling was more frequent in stable lesions (56.5% versus 31.8%) (P=0.001). CONCLUSIONS: Positive remodeling and larger plaque areas were associated with unstable clinical presentation, whereas negative remodeling was more common in patients with stable clinical presentation. This association between the extent of remodeling and clinical presentation may reflect a greater tendency of plaques with positive remodeling to cause unstable coronary syndromes.

Aged↗

PubMed1995

31P nuclear magnetic resonance spectroscopic imaging of regions of remodeled myocardium in the infarcted rat heart.

BACKGROUND: The clinical course of a patient with a myocardial infarction (MI) depends largely on the ability of the noninfarcted region to remodel and compensate for the loss of the infarcted region. Previous studies have shown that the remaining viable myocardium remodels morphologically, functionally, and biochemically. The purpose of this study was to define the regional distribution of the biochemical remodeling that occurs after MI in rat hearts by use of a technique that could be applied noninvasively to human subjects. METHODS AND RESULTS: Infarcts of the left ventricular apex and anterolateral wall were induced by occluding a coronary artery. Eight to 10 weeks after infarction, one-dimensional chemical shift imaging (CSI) was used to obtain 31P nuclear magnetic resonance (NMR) spectra of eight 2.5-mm-thick cross-sectional slices along the long axis (from base to apex) of isolated buffer-perfused rat hearts. Regional ATP and phosphocreatine (PCr) contents were compared in remodeled versus normal (sham) myocardium. Spin-echo 1H MR images identified the mass of each slice, allowing calculations of metabolite amount per unit myocardium in each slice. 1H MR images identify the hypertrophy of remodeled myocardium but do not discriminate between scar and viable tissue. In contrast, 31P CSI does distinguish viable tissue. Compared with shams, there was less 31P signal in the slices distal to the occlusion containing mainly scar tissue and increased signal intensity in slices proximal to the occlusion because of myocyte hypertrophy. The ATP signal intensity changed in direct proportion to the viable tissue mass in the slice, suggesting that the amount of ATP per unit mass in viable remodeled myocardium is the same as that of the shams. In contrast, the amount of PCr per unit mass in remodeled myocardium decreased. This decrease is uniform across the slices, correlates with infarct size, and parallels a similar decrease in tissue creatine content. CONCLUSIONS: 31P CSI of post-MI hearts shows that (1) PCr decreases uniformly (ie, independent of the distance from the scar) in the noninfarcted remodeled myocardium, and its amount inversely correlates with infarct size; and (2) the ATP signal provides a profile of viable myocardium and is a biochemical marker of morphological remodeling and hypertrophy that has occurred in noninfarcted regions. Thus, 31P CSI provides both a marker that tissue injury has occurred (decreased PCr) and a marker of the extent of remodeling in response to injury (ATP distribution) in a single set of noninvasive measurements.

Adenosine Triphosphate↗

PubMed2001

Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis.

Remodeling of large and small arteries contributes to the development and complications of hypertension. The focus of this review is some of the mechanisms involved in the remodeling of small arteries in hypertension. In hypertension, changes in small artery structure are basically of 2 kinds: (1) inward eutrophic remodeling, in which outer and lumen diameters are decreased, media/lumen ratio is increased, and cross-sectional area of the media is unaltered; and (2) hypertrophic remodeling, in which the media thickens to encroach on the lumen, resulting in increased media cross-sectional area and media/lumen ratio. Growth, apoptosis, inflammation, and fibrosis contribute to vascular remodeling in hypertension. Apoptosis is gene-regulated cell death, with minimal membrane disruption and inflammation, that counters cell proliferation and fine-tunes developmental growth. Apoptosis has been reported in hypertension to be both increased and decreased in different tissues, including blood vessels. Inflammation, which may be low grade, probably plays an important role in triggering fibrosis in cardiovascular disease and hypertension. Vascular fibrosis entails accumulation of collagen, fibronectin, and other extracellular matrix components in the vessel wall and is an important aspect of extracellular matrix remodeling in hypertension. Associated with this, there may be increases in cell-matrix attachment sites (integrins) and changes in their topographical localization that may modulate arterial structure. Imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to alteration in collagen turnover and extracellular matrix remodeling. Chronic vasoconstriction may lead to embedding of the contracted vessel structure in a remodeled extracellular matrix, contributing to the inward remodeling of the blood vessel as smooth muscle cells are rearranged around a smaller lumen. The resulting remodeling of small arteries may initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension.

Animals↗

PubMed2001

Intravascular ultrasound analysis of arterial remodeling in the double-injury swine coronary artery model of restenosis.

BACKGROUND: Vascular remodeling is a major component of atherosclerotic and restenotic processes. The aim of this study was to evaluate remodeling at two different axial loci in a restenotic (double-injury) coronary artery model in the hypercholesterolemic minipig. METHODS: The cross-sectional area (CSA) of the lumen, artery and neointima following a single stenotic injury (SI) and second restenotic injury (RI) was measured by serial intravascular ultrasound (IVUS). IVUS CSAs were determined before, immediately after and 4 weeks after each injury. Analyses were performed at two selected axial loci, defined as: 1) locus of the minimal luminal area (MLA) 4 weeks after SI (measured immediately prior to the RI); and 2) locus of the MLA at 4 weeks after RI. Loci were selected to mimic diverse approaches used in studies of remodeling. RESULTS: Restenotic remodeling, defined by locus 1, was unchanged 4 weeks following the RI and neointima formation accounted for the chronic lumen loss. In contrast, constrictive remodeling was the prominent arterial response defined by locus 2. Regardless of the MLA analysis, artery wall enlargement occurred in more than half of the pigs at 4 weeks following the SI. Balloon/artery ratios were comparable during the two injuries and could not account for observed differences in remodeling. Remodeling results obtained by comparison of artery CSA to a reference CSA differed from serial IVUS analysis. CONCLUSIONS: In the presence of a pre-established stenosis, vascular remodeling depends on the axial locus of interest. In contrast, remodeling following injury of a naïve artery is independent of defined axial locations used here and is predominantly one of outward remodeling.

Animals↗

PubMed2001

Super-osteons (remodeling clusters) in the cortex of the femoral shaft: influence of age and gender.

Previous studies of cortical remodeling in the fractured femoral neck indicated that the merging of spatially clustered remodeling osteons could result in the formation of deleteriously large cavities associated with femoral neck fracture. This study aimed to identify whether remodeling osteons in the femoral shaft were also clustered and to assess the influence of age and gender. Microradiographic images of femoral mid-shaft cross-sections from 66 subjects over 21 years of age were analyzed to determine the number, size and location of all Haversian canals. Those most recently remodeled were identified using an edge-detection algorithm highlighting the most marked differential gradients in grey levels. Cluster analysis (JMP software) of these osteons identified the proportion of recently remodeled osteons that were within 0.75 mm clusters. As in the femoral neck, remodeling osteons were significantly more clustered than could occur by chance (real, 59.4%; random, 39.4%; P < 0.0001). The density of these clusters (number/mm(2)) was not significantly associated with subject age or gender but was greatest near the periosteum and decreased toward the marrow cavity (periosteal 0.043 +/- 0.004; mid-cortex 0.028 +/- 0.003; endosteal 0.017 +/- 0.002). Cortical porosity increased with age. The presence of giant canals (diameter >385 microm) was inversely related to the presence of clusters (R(2) = 0.237, P < 0.0001). This data suggest that remodeling osteons tend to be spatially colocalized in the shaft as they are in the neck of the femur and their presence is independent of age or gender. We propose that these remodeling clusters be termed super-osteons. The negative relationship between super-osteons and giant canals raises the intriguing possibility that loss of the control of remodeling depth results in the merging of osteonal systems to form deleteriously large cortical cavities with a marked reduction in bone strength.

Adult↗

PubMed1993

Streaming potentials in healing, remodeling, and intact cortical bone.

Electrical fields have been implicated in accelerated bone healing and as a transduction mechanism for mechanically driven bone remodeling. Applied mechanical or electrical stimulation of bone remodeling suggests that this depends on the magnitude, frequency, and duration of the stimulus. The magnitude of endogenous electrical fields, manifest by streaming potentials (SPs) across canine cortical bone, were measured as a function of bending frequency in vivo and then in vitro at healing drill holes and at remodeling (ipsilateral) and normal, intact (contralateral) control sites in canine tibia. SP magnitudes normalized to periosteal strain were smaller for drill holes at 2 and 4 weeks postsurgery relative to either remodeling (P < 0.05 at 10 Hz) or normal intact (P < 0.001 at 10 Hz) controls both in vivo and in vitro. SPs of 12 week drill holes were similar to SPs of remodeling controls and tended to be smaller than SPs of normal intact controls. Mean SP normalized to bone impedance was approximately the same for all sites, suggesting that the smaller SPs during healing and remodeling relate to smaller bone impedance and/or larger porosity. SP as a function of bending frequency for normal sites was similar to that observed previously. SP versus frequency for drill holes and remodeling controls was more variable, probably because of variations in bone microstructure, and displayed a higher frequency content. The observed differences in SP magnitude and frequency response to loading associated with stages of healing indicate that endogenous electrical fields do indeed respond to the structural changes in healing and remodeling and are therefore capable of providing structural feedback information for the repair and remodeling process.

Animals↗

PubMed1992

An analytical and numerical study of the stability of bone remodelling theories: dependence on microstructural stimulus.

The origin of unstable bone remodelling simulations using strain-energy-based remodelling rules was studied mathematically in order to assess whether the unstable behavior was due to the mathematical rules proposed to characterize the processes, or to the numerical approximations used to exercise the mathematical predictions. A condition which is necessary for the stability of a strain-energy-based remodelling theory was derived analytically using the calculus of variation. The analytical result was derived using a simple elastic model which consists of a long beam loaded by an axial force and a bending moment. This loading situation mimics the coupling between local density and global density distributions seen in vivo. A condition necessary for a stable remodelling scheme is arrived at, but the conditions necessary to guarantee a stable remodelling scheme are not. In this remodelling scheme, the elastic modulus is proportional to volumetric density raised to an exponent n, and the microstructural stimulus is taken as the strain energy density divided by volumetric density raised to an exponent m. In order for a remodelling scheme to be stable in this loading situation, m must be greater than n. Finite-difference time-stepping is used to verify the predictions of the analytical study. These numerical studies appear to confirm the analytical studies. Physiologic interpretation of the behavior found with n greater than m indicates that this type of unstable behavior is unlikely to be observed in vivo. Since numerical approximations are not made in deriving this stability condition, we conclude that the mathematical rules proposed to characterize bone remodelling based on strain energy density should meet this condition to be relevant to physiologic bone remodelling.

Bone Density↗

PubMed1996

Cortical bone remodeling in autosomal dominant osteopetrosis: a study of two different phenotypes.

Previous analyses of cancellous bone remodeling in autosomal dominant osteopetrosis (ADO) have suggested a diminished osteoclastic resorption at the endocortical surface. Consequently, cortical width increases with age in both ADO type I and II. By means of histomorphometric methods, the remodeling cycle of the Haversian surface in the iliac crest has recently been reconstructed in normal individuals. The aim of the present investigation was to study cortical bone remodeling in ADO type I and II. Transcortical iliac crest bone biopsies obtained from 21 ADO patients were studied. Of these, 14 had ADO type I and seven had ADO type II. Twenty of the patients had received intravital double labeling with tetracycline before the biopsies were obtained. The static histomorphometric parameters for cortical bone mass and structure were compared with a control group of 21 sex- and age-matched individuals. Regarding the dynamic histomorphometric parameters for reconstruction of the cortical bone remodeling cycle, the ADO type I material was compared with control material from 14 sex- and age-matched individuals, whereas the ADO type II material was compared with control material from six sex-matched but younger individuals. Significant increases were seen in absolute as well as fractional cortical widths in both ADO types. Furthermore, an age-related increase was observed in both absolute and fractional cortical widths in ADO type I, whereas ADO type II was nonsignificant with regard to age. The fractional cancellous width was reduced in both type I and type II. However, only in ADO type I did the fractional cancellous width significantly correlate inversely with age. In the control group, neither cortical dimensions nor cancellous width correlated significantly with age. No significant differences were observed between patients and the control group in osteon dimensions; fractional resorptive, formative, or quiescent sites; resorptive or formative remodeling rates; remodeling periods; or activation frequency. An age-related increase in cortical porosity was seen in the group of normal individuals, but not in the two patient groups. The fractional remodeling space was increased in the ADO type II group. In conclusion, cortical dimensions are increased in both ADO type I and II and positively correlated to age in type I. However, cortical remodeling at the Haversian surface is essentially normal in both ADO type I and II. This could be explained by a defective endocortical bone resorption, as no periosteal accretion was observed, and because cancellous bone remodeling previously has been described to be normal.

Adult↗

PubMed2005

Early postinfarction ventricular restraint improves borderzone wall thickening dynamics during remodeling.

BACKGROUND: Early infarct expansion impairs function of normally perfused borderzone myocardium (BZM), initiates adverse remodeling, and portends a poor long-term outcome. Early ventricular restraint has been demonstrated to improve global remodeling but its effect on BZM function has not been assessed. Using an ovine model of infarct induced remodeling and MRI, we tested the hypothesis that ventricular restraint early after MI preserves BZM function and reduces remodeling. METHODS: Six sheep had a large anterior infarction after ligation of all diagonal branches. One week after infarction 3 sheep had placement of a cardiac support device (CSD) to restrain infarct expansion. Global remodeling and borderzone wall thickening strain were assessed using tagged MRI before and 8 weeks after infarction. RESULTS: Global remodeling was greatly reduced in the CSD group compared with control. The BZM systolic wall thickening was similar in both groups at baseline (13.5% +/- 2.0%, control; 12.8% +/- 2.0%, CSD, p = 0.8). After 8 weeks of infarction-induced remodeling, systolic wall thickening strain decreased significantly to 4.9% +/- 0.7% in the control group (p = 0.03). In contrast, systolic wall thickening was preserved in the CSD group at 8 weeks (11.0% +/- 1.6%, p = 0.3). In the control group all thickening occurred during isovolemic contraction, plateauing during ejection. The CSD improved late systolic borderzone wall thickening, although dynamics remained perturbed. CONCLUSIONS: Ventricular restraint early after MI improves both contractile function of the BZM and global ventricular remodeling. The dynamics of BZM wall thickening are impaired during remodeling. The CSD significantly improves but does not completely maintain baseline BZM wall thickening dynamics.

Animals↗

PubMed2004

Early identification of left ventricular remodelling after myocardial infarction, assessed by transthoracic 3D echocardiography.

AIMS: The usefulness of 3D echocardiography (3DE) for accurate evaluation of left ventricular (LV) remodelling after acute myocardial infarction (AMI), and early identification of remodelling in the subacute phase, was assessed. METHODS AND RESULTS: Thirty-three AMI patients (21 anterior AMIs) underwent 3DE prospectively at baseline (6+/-4 days) and at 3, 6, and 12 months post-AMI. Remodelling was defined as >20% increase in end-diastolic volume (EDV) at 6 or 12 months in relation to baseline. In patients with remodelling (n = 13) at baseline, EDV and end-systolic volume (ESV), but not ejection fraction (EF), were significantly increased compared to patients without subsequent remodelling (n = 20). At 12 months, EDV and ESV increased further and significantly, and EF was unchanged in patients with remodelling, whilst LV volumes were unchanged and EF slightly increased in patients without remodelling. Clinical, electrocardiographic, and echocardiographic variables were analysed for the early identification of LV remodelling. Of these, at baseline the 3D sphericity index (EDV divided by the volume of a sphere, the diameter of which is the LV major end-diastolic long axis) was, by far, the most predictive variable with a sensitivity, specificity, and positive and negative predictive value for a cutoff value of >0.25 of 100%, 90%, 87% and 100%, respectively. CONCLUSIONS: Three-dimensional echocardiography can differentiate patients with and without subsequent development of LV remodelling accurately and early on the basis of the 3D sphericity index, a new and highly predictive variable.

Adult↗

PubMed2003

Experimental investigation of bone remodelling using composite femurs.

OBJECTIVE: To determine the load transfer patterns of femurs in the intact, immediate post-operative and long-term (remodelled) post-operative implanted conditions for Lubinus SPII and Müller-Curved cemented hip prostheses, and to examine to what extent remodelling may influence the long-term outcome. DESIGN: Experimental and finite element (FE) methods were applied to composite femurs under loads representing the heel-strike phase of gait, determining cortical bone and cement strains for the different femur conditions. BACKGROUND: The authors previously developed protocols to measure bone and cement strains, and to produce remodelled femur specimens, yet these have not been applied together to compare strain patterns of different femur conditions. The Lubinus SPII is clinically more successful than the Müller-Curved stem, with failure mainly due to aseptic loosening. METHODS: Cortical bone strains were determined in intact femurs. Six femurs each were implanted with the two stem types and cortical bone and cement strains were measured. Bone remodelling was recreated using a validated CAD-CAM procedure to remove a layer of proximal cortical bone, replicating a typical scenario found in stable clinical retrievals. Strains were remeasured. FE methods were used to compliment the experiments. RESULTS: Stress shielding was reduced with remodelling, though bone strains did not return to their intact values, particularly around the calcar. Cement strains increased with remodelling. Differences occurred between the two stems; the Müller-Curved produced a more severe strain transition. CONCLUSIONS: Procedures were successfully combined together to investigate in vitro the performance of two cemented stems, in immediate and long-term post-operative conditions. The increase of cement strains with remodelling is a potential indicator for in vivo cement failure. RELEVANCE: The consequences of femoral bone remodelling on the long-term success of joint replacements are not well understood, where remodelling may lead to increased bone and cement stresses.

Bone Remodeling↗

PubMed2003

Mathematical model predicts a critical role for osteoclast autocrine regulation in the control of bone remodeling.

Bone remodeling occurs asynchronously at multiple sites in the adult skeleton and involves resorption by osteoclasts, followed by formation of new bone by osteoblasts. Disruptions in bone remodeling contribute to the pathogenesis of disorders such as osteoporosis, osteoarthritis, and Paget's disease. Interactions among cells of osteoblast and osteoclast lineages are critical in the regulation of bone remodeling. We constructed a mathematical model of autocrine and paracrine interactions among osteoblasts and osteoclasts that allowed us to calculate cell population dynamics and changes in bone mass at a discrete site of bone remodeling. The model predicted different modes of dynamic behavior: a single remodeling cycle in response to an external stimulus, a series of internally regulated cycles of bone remodeling, or unstable behavior similar to pathological bone remodeling in Paget's disease. Parametric analysis demonstrated that the mode of dynamic behavior in the system depends strongly on the regulation of osteoclasts by autocrine factors, such as transforming growth factor beta. Moreover, simulations demonstrated that nonlinear dynamics of the system may explain the differing effects of immunosuppressants on bone remodeling in vitro and in vivo. In conclusion, the mathematical model revealed that interactions among osteoblasts and osteoclasts result in complex, nonlinear system behavior, which cannot be deduced from studies of each cell type alone. The model will be useful in future studies assessing the impact of cytokines, growth factors, and potential therapies on the overall process of remodeling in normal bone and in pathological conditions such as osteoporosis and Paget's disease.

Autocrine Communication↗

PubMed2002

Ventricular remodeling without cellular contractile dysfunction.

BACKGROUND: A number of factors may contribute to progressive left ventricular (LV) remodeling and global LV dysfunction after myocardial damage. Important among these are loss of myocytes from necrosis or apoptosis, changes in the extracellular matrix (ECM), myocyte contractile dysfunction, and the purely geometric or mechanical effects of structural alterations in the LV. Which of these components is more important at a particular stage in the natural history of LV remodeling is unclear. Nor is it known whether global LV dysfunction can occur in the absence of isolated myocyte contractile dysfunction. METHODS AND RESULTS: We studied the natural history of LV remodeling in the rat infarct model to address the question of whether structural alterations in the heart can contribute directly to LV dysfunction or whether the presence of myocyte contractile dysfunction is essential for the development of systolic LV dysfunction. Over 6 weeks, post-MI rats developed progressive LV remodeling and dysfunction, with alterations in several biochemical markers such as a decrease in sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and an increase in brain natriuretic peptide (BNP) and Na(+)-Ca(2+) exchanger. Myocytes isolated from the remote noninfarcted LV of the remodeled hearts were hypertrophied. Changes in length of the remodeled myocytes correlated well with indices of global LV remodeling. However, no significant defects were seen in any of the contractile or intracellular calcium transient parameters of the remodeled myocytes in the unloaded state, after viscous loading or during increased stimulation frequency. CONCLUSIONS: These data suggest that myocyte hypertrophy may be dissociated from myocyte contractile defect and that global LV systolic dysfunction can occur in the absence of significant myocyte contractile dysfunction. Factors such as loss of muscle mass from necrosis or apoptosis, increased wall stress, and alterations in the ECM may play a more important role early in the natural history of LV remodeling, before myocyte contractile dysfunction has become apparent.

Animals↗

PubMed2003

Effects of cardiovascular risk factors on coronary artery remodeling in patients with mild atherosclerosis.

BACKGROUND: Vascular remodeling counteracts luminal encroachment during the progression of coronary artery disease (CAD) and modulates the manifestation of hemodynamically significant lesions. However, the role of cardiovascular risk factors for coronary remodeling has not been fully clarified. METHODS: Therefore, we investigated the role of local plaque burden and systemic risk factors on coronary vascular remodeling in 25 patients (49 segments) with angiographically normal or minimally diseased coronary arteries by intravascular ultrasound. In an additional 12 patients without coronary atherosclerosis, physiological vessel tapering was determined and used to calculate the extent of remodeling in diseased segments. RESULTS: An increase in local plaque burden was directly correlated with positive vascular remodeling (r = 0.54, P<0.001). However, cardiovascular risk factors like hypertension (P<0.001) and hypercholesterolemia (P = 0.03) were associated with reduced positive or even negative remodeling. Moreover, the total number of classical cardiovascular risk factors was a strong predictor for reduced positive remodeling (P for trend <0.001). In contrast, coronary flow reserve, a measure of shear stress imposed on the vessel wall, positively correlated with compensatory enlargement (r = 0.44, P = 0.002). By multivariate analysis, plaque burden (P = 0.001), hypertension (P = 0.001) and coronary flow reserve (P = 0.018) proved to be independent determinants of vascular remodeling of epicardial coronary arteries. CONCLUSIONS: Cardiovascular risk factors impair compensatory arterial enlargement and even predispose to shrinkage of epicardial arteries during the initial stage of atherosclerosis. Reduced positive vascular remodeling might contribute to the clinical manifestation of CAD by facilitating the development of flow-limiting stenoses in patients at risk.

Aged↗