Evidence Of Remodeling Research Articles

Novel Cardiac Troponin I S43/45N Substitution does not Cause Aberrant Cardiac Remodeling or Dysfunction in Mice

Elevated protein kinase C (PKC) expression and activity, along with downstream phosphorylation of cardiac troponin I (cTnI) are linked to cardiac dysfunction. Specifically, elevated cTnI S43/45 phosphorylation is reported in human and rodent models of heart failure, but the exact role of phosphorylation at this site is still debated. Transgenic (tg) mice expressing cardiac-specific phospho-mimetic S43/45D develop contractile dysfunction, followed by cardiac hypertrophy, fibrosis, and progressive heart failure. Thus, S43/45 phosphorylation is postulated to be a sarcomeric node for modulating contractile function in the heart. To further test this idea, it is critical to show that a phospho-null substitution at this site does not alter wild-type function. Multiple groups have used the conventional nonpolar alanine (A) phospho-null substitution at S43/45 and report diminished myocyte and contractile function, which resembles the outcome after phosphorylation. We postulate the nonpolar properties of A potentially alter interactions between cTnI, troponin T (TnT) and C (TnC). As a result, the amide R side chain in asparagine (N), with a polarity somewhat similar to the hydroxyl group in S, could make N a reasonable non-phosphorylatable residue without overt effects on wild-type function. Previously, adult rat myocytes virally transduced with S43/45N (SN)in our laboratory did not display overt changes in contractile function compared to wild-type myocytes. In ongoing experiments, generation of tg mice expressing a cardiac-specific cTnISN also show no changes in in vivo cardiac contractile function or evidence of remodeling in mice up to at least four months of age. These findings suggest the novel N substitution acts as a “functionally conservative” phospho-null substitution at cTnIS43/45 in myocardium.

Repetitive nasal allergen challenge in allergic rhinitis: Priming and Th2-type inflammation but no evidence of remodelling.

Local tissue eosinophilia and Th2 cytokines are characteristic features of seasonal allergic rhinitis. Airway remodelling is a feature of asthma whereas evidence for remodelling in allergic rhinitis (AR) is conflicting. By use of a novel human repetitive nasal allergen challenge (RAC) model, we evaluated the relationship between allergic inflammation and features of remodelling in AR. Twelve patients with moderate-severe AR underwent 5 alternate day challenges with diluent which after 4weeks were followed by 5 alternate day challenges with grass pollen extract. Nasal symptoms, Th1/Th2 cytokines in nasal secretion and serum were evaluated. Nasal biopsies were taken 24hours after the 1st and 5th challenges with diluent and with allergen. Sixteen healthy controls underwent a single challenge with diluent and with allergen. Using immunohistochemistry, epithelial and submucosal inflammatory cells and remodelling markers were evaluated by computed image analysis. There was an increase in early and late-phase symptoms after every allergen challenge compared to diluent (both P<.05) with evidence of both clinical and immunological priming. Nasal tissue eosinophils and IL-5 in nasal secretion increased significantly after RAC compared to corresponding diluent challenges (P<.01, P=.01, respectively). There was a correlation between submucosal mast cells and the early-phase clinical response (r=0.79, P=.007) and an association between epithelial eosinophils and IL-5 concentrations in nasal secretion (r=0.69, P=.06) in allergic rhinitis. No differences were observed after RAC with regard to epithelial integrity, reticular basement membrane thickness, glandular area, expression of markers of activation of airway remodelling including α-SMA, HSP-47, extracellular matrix (MMP7, 9 and TIMP-1), angiogenesis and lymphangiogenesis for AR compared with healthy controls. Novel repetitive nasal allergen challenge in participants with severe persistent seasonal allergic rhinitis resulted in tissue eosinophilia and increases in IL-5 but no structural changes. Our data support no link between robust Th2-inflammation and development of airway remodelling in AR.

Architectural and ultrastructural features of tessellated calcified cartilage in modern and extinct chondrichthyan fishes.

Tessellated calcified cartilage (TCC) is a distinctive kind of biomineralized perichondral tissue found in many modern and extinct chondrichthyans (sharks, rays, chimaeroids and their extinct allies). Customarily, this feature has been treated somewhat superficially in phylogenetic analyses, often as a single "defining" character of a chondrichthyan clade. TCC is actually a complex hard tissue with numerous distinctive attributes, but its use as a character complex for phylogenetic analysis has not yet been optimized. This study attempts to improve this situation by presenting new terminology for certain aspects of tesseral architecture, including single-monolayered, multiple-monolayered, polylayered and voussoir tesserae; new histological data, including thin sections of TCC in several Palaeozoic taxa, and new proposals for ways in which various characters and states (many of which are defined here for the first time) could be applied in future phylogenetic analyses of chondrichthyan fishes. It can be concluded that many, but not all, of the unique attributes of modern TCC evolved by the Early Devonian (ca. 400 before present (bp)). The globular calcified cartilage reported in Silurian sinacanthids and the so-called subtessellated perichondral biomineralization (with irregular and ill-defined geometries of a layer or layers of calcified cartilage blocks) of certain extinct "acanthodians" (e.g., Climatius, Ischnacanthus, Cheiracanthus) could represent evolutionary precursors of TCC, which seems to characterize only part of the chondrichthyan total group. It is hypothesized that heavily biomineralized "layer-cake" TCC in certain Palaeozoic chondrichthyans perhaps served a dual physiological role, as a phosphate sink and in providing increased skeletal density in very large (>7 m) Devonian-Permian marine sharks such as ctenacanths and as an adaptation to calcium-deficient environments among Permo-Carboniferous non-marine sharks such as xenacanths. By contrast, the equivalent tissue in modern elasmobranchs probably serves only to reinforce regions of cartilage (mostly in the jaws) subjected to high loading. It is also noted that much of the variation observed in tesseral architecture (including localized remodelling), ultrastructure and histology in modern and extinct chondrichthyans is confined to the perichondrally facing cap zone (where Type-1 collagen matrix predominates in modern TCC), whereas the main body of the tessera (where Type-2 collagen matrix predominates) exhibits comparatively little evidence of remodelling and histological or structural variation.

Quantitative 129Xe MRI detects early impairment of gas-exchange in a rat model of pulmonary hypertension

Hyperpolarized 129Xe magnetic resonance imaging (MRI) is capable of regional mapping of pulmonary gas-exchange and has found application in a wide range of pulmonary disorders in humans and animal model analogs. This study is the first application of 129Xe MRI to the monocrotaline rat model of pulmonary hypertension. Such models of preclinical pulmonary hypertension, a disease of the pulmonary vasculature that results in right heart failure and death, are usually assessed with invasive procedures such as right heart catheterization and histopathology. The work here adapted from protocols from clinical 129Xe MRI to enable preclinical imaging of rat models of pulmonary hypertension on a Bruker 7 T scanner. 129Xe spectroscopy and gas-exchange imaging showed reduced 129Xe uptake by red blood cells early in the progression of the disease, and at a later time point was accompanied by increased uptake by barrier tissues, edema, and ventilation defects—all of which are salient characteristics of the monocrotaline model. Imaging results were validated by H&E histology, which showed evidence of remodeling of arterioles. This proof-of-concept study has demonstrated that hyperpolarized 129Xe MRI has strong potential to be used to non-invasively monitor the progression of pulmonary hypertension in preclinical models and potentially to also assess response to therapy.

Bony lesions in early tetrapods and the evolution of mineralized tissue repair

AbstractBone healing is an important survival mechanism, allowing vertebrates to recover from injury and disease. Here we describe newly recognized paleopathologies in the hindlimbs of the early tetrapodsCrassigyrinus scoticusandEoherpeton watsonifrom the early Carboniferous of Cowdenbeath, Scotland. These pathologies are among the oldest known instances of bone healing in tetrapod limb bones in the fossil record (about 325 Ma). X-ray microtomographic imaging of the internal bone structure of these lesions shows that they are characterized by a mass of trabecular bone separated from the shaft's trabeculae by a layer of cortical bone. We frame these paleopathologies in an evolutionary context, including additional data on bone healing and its pathways across extinct and extant sarcopterygians. These data allowed us to synthesize information on cell-mediated repair of bone and other mineralized tissues in all vertebrates, to reconstruct the evolutionary history of skeletal tissue repair mechanisms. We conclude that bone healing is ancestral for sarcopterygians. Furthermore, other mineralized tissues (aspidin and dentine) were also capable of healing and remodeling early in vertebrate evolution, suggesting that these repair mechanisms are synapomorphies of vertebrate mineralized tissues. The evidence for remodeling and healing in all of these tissues appears concurrently, so in addition to healing, these early vertebrates had the capacity to restore structure and strength by remodeling their skeletons. Healing appears to be an inherent property of these mineralized tissues, and its linkage to their remodeling capacity has previously been underappreciated.

Two Year Clinical Outcomes of the Subchondroplasty® Procedure for Treatment of Symptomatic Bone Marrow Lesions of the Knee

Objectives: Bone Marrow Lesions (BML) are a common finding on knee MRI. In the knee, BML have a strong correlation to patient-reported pain, function, joint deterioration and rapid progression to TKR. Histologic analyses of BML have demonstrated findings consistent with fracture and bony remodeling of the trabeculae. The Subchondroplasty (SCP®) Procedure aims to treat the bone defects present in the BML by percutaneously filling them with a bone substitute material, designed to flow through intact bone, harden at body temperature and then heal through natural bone turnover. Previous retrospective, single-center case series have demonstrated improvements in patient-reported outcomes. The purpose of this prospective, multi-center study is to evaluate the 2-year clinical and radiographic outcomes of patients with BML of the knee treated with the Subchondroplasty Procedure. Methods: Seventy patients were treated between 2012 and 2017 for BML of the tibial plateau and/or femoral condyle. Self-drilling cannulas were inserted into the BML using arthroscopic and fluoroscopic guidance, then injected with AccuFill® Bone Substitute Material. All patients also underwent arthroscopy to aid in targeting the underlying bony lesion and address intra-articular pathology. MRIs and radiographs were obtained pre-operatively, at 6, 12 and 24 months, with additional radiographs collected at 6 weeks and 3 months. Patient-reported outcomes, including VAS pain, IKDC and KOOS were collected pre-operatively, 2 and 6 weeks, and 3, 6, 12 and 24 months post-operatively. Results: Seventy patients (36 males and 34 females), average age 57 were consented and enrolled in the study. Preoperative K-L grade included 1.4% Grade 0, 2.9% Grade 1, 27.1% Grade 2, 55.7% Grade 3 and 7.1% Grade 4. Fifty eight tibial plateaus and 41 femoral condyles were treated (29 bipolar lesions treated). VAS Pain scores improved from a mean of 6.2/10 pre-op to 2.9/10 at 1 year. IKDC scores improved from mean 33.9 pre-op to 61.3 at 1 year. KOOS scores improved from baseline to 1 year (Fig. 1) with mean KOOS Pain from 45.8 to 73.9, ADL 52.9 to 79.2, Symptoms 49.7 to 71.9, Sports 21.2 to 49.9 and Quality of Life 18.1 to 52.3. All patient-reported outcomes showed statistically significant improvement at one year. Two year outcomes collected to date appear to follow the same trend. The last study subject is due to return in January 2019 at which point the final 2 year analysis will be completed. Six patients (8.6%) converted to arthroplasty (1 UKA and 5 TKA) at one year. To date, the 24 month conversion rate is 16.1% out of 62 subjects. The final conversion rate for 24 months will be calculated after the final subject returns. Radiographs and MRIs demonstrated good incorporation of the AccuFill material through 12 months with evidence of early remodeling and a lack of OA progression in the majority of subjects. Twenty-four month MRIs demonstrate continued remodeling of the AccuFill material. Conclusion: This study presents statistically and clinically-meaningful evidence of improvements in clinical outcomes following Subchondroplasty procedure for BML of the knee. The low conversion rate suggests this less-invasive procedure may delay the need for knee arthroplasty. MR imaging demonstrates good incorporation of the BSM and evidence of remodeling and reduction in material volume over time. [Figure: see text][Table: see text]

The Diversity of the Postclassic Mimbres Periods (AD 1150–1450): Insights from Las Animas Village in Southwestern New Mexico

The Postclassic period (ca. AD 1150–1450) in the Mimbres region is diverse and variable. Excavation data from Las Animas Village (LA3949) is used to explore this variability and better delineate the regional sequence. Las Animas Village is a large multicomponent site with Pithouse, Classic, and Postclassic occupations. Focus here is on the Postclassic component, a roughly oval adobe pueblo, two-story in parts, that surrounded a plaza. There was extensive evidence of remodeling; some lower story rooms were filled in and use of the second story continued, in one case the second story was remodeled into small storage units. Both ceramic and chronometric dates indicate that the adobe pueblo was used in the AD 1300s and probably after 1400; it has numerous late types though little Roosevelt Red Ware. Las Animas Village is one of the only eastern Mimbres sites known for this time period, and it may have been where remaining populations gathered in late prehispanic times.

Reconstruction of large mandibular defects using autologous tissues generated from in vivo bioreactors.

A significant clinical challenge in craniofacial surgery is the reconstruction of large mandibular defects. In this work, we demonstrated that vascularized tissues of large volume and custom geometry can be generated from in vivo bioreactors implanted against the rib periosteum in an ovine model. The effects of different bioreactor scaffold material on tissue ingrowth were measured. To minimize donor site morbidity, tissues generated from bioreactors filled with synthetic graft were transferred as either vascularized free flaps or avascular grafts to a large mandibular defect. It was demonstrated that synthetic graft in an in vivo bioreactor is sufficient to produce free tissue bone flaps capable of integrating with native tissues when transferred to a large mandibular defect in an ovine model.

Variation in large ectocranial lesions from pre-Columbian Kuelap, Peru

This paper analyses a diverse collection of previously undescribed cranial lesions observed from 42 individuals from the pre-Columbian site of Kuelap, eastern montane, Peru. I describe the presence of cranial lesions, their location on the vault location, shape, and size of affected area, and evidence of remodeling. Seventeen percent of the total cranial sample demonstrates similar superficial cranial lesions including males (25/117, 21.4%) and females (14/74, 18.9%), and adolescents (3/27, 11%). Most lesions are narrow ovals or long and leaf-shaped, with depression of the external cranial vault. While some are well-healed and smooth-surfaced, others are more irregular with variable degrees of remodeling. The highest frequency is on the superior and posterior aspects of the vault, usually along the sagittal plane. Differential diagnoses are considered but no single pathology is clear for all cases. There are some common features consistent with active and healing osteitis and a few are directly associated with trepanation. General patterning suggests intentional treatment, perhaps even possible cauterization of scalp injuries or healed infections. These large cranial “scars” have not been observed at coastal Peruvian sites and may reflect specific regional conditions related to highland environmental factors, local medical treatments of cranial injuries, or population specific malformations.

СРАВНИТЕЛЬНЫЙ АНАЛИЗ ОСТЕОИНТЕГРАЦИИ АЛЮМООКСИДНЫХ БИОКЕРАМИЧЕСКИХ ГРАНУЛ В ЭКСПЕРИМЕНТЕ

Objective. To perform comparative analysis of osseointegration of bioceramic alumina-based granules, hydroxyapatite-based granules, and granules of deproteinized bone tissue. Material and Methods. The experiment was conducted on 52 adult male Kyoto-Wistar laboratory rats weighing 350 to 520 g. Animals were divided into five matched groups, which differed only in the type of implanted material. Granules were implanted in lumbar vertebral bodies and in distal right femur of each laboratory animal. Two months after surgery animals were euthanized with subsequent tissue sampling for morphological studies. Results. Examination of specimens from groups with implantation of alumina granules revealed the formed trabecular bone with evidence for remodeling. Bone tissue filled the space between granules fitting closely to their surfaces. There was no connective tissue capsule on the border between the bone tissue and alumina granules. Conclusion. Bioceramic alumina-based granules in the form of cylinders with a through inner channel have high strength surpassing that of analogs and ability for osseointegration close to that of hydroxyapatite and deproteinized bone granules.

Longitudinal heterogeneity of arterial remodeling and endothelial shear stress in human coronary artery plaques and their effects on the natural history of atherosclerosis

Purpose: Expansive remodeling (ER) and low endothelial shear stress (ESS) critically determine the natural history of atherosclerosis, but they have only been investigated in a cross-sectional arterial axis. In this study, we assessed the longitudinal variation of remodeling and ESS along the length of individual plaques in human coronary arteries and their relation to subsequent plaque growth. Methods: We performed 3D coronary reconstruction by angiography/IVUS at baseline and at 6-10 months follow-up as part of the PREDICTION Study. In discrete baseline plaques (max thickness >0.5 mm, length 9 to 30 mm), we assessed arterial remodeling and ESS (using computational fluid dynamics) in 3mm-long segments. Plaque growth was evaluated in the same locations at follow-up. Results: In 313 arteries from 220 patients, 371 plaques (average length 16.6±0.4 mm) were identified. Of these plaques, 237 (63.9%) had evidence of remodeling while the remaining 134 (36.1%) showed no remodeling. The vast majority of remodeled plaques (93.2%) displayed heterogeneous remodeling patterns along their length: 52 plaques (23.5%) exhibited two remodeling patterns, 14 (6.3%) exhibited three remodeling patterns and 155 plaques (70.1%) showed a combination of one remodeling pattern in some areas of the plaque with absence of remodeling elsewhere (p<0.001). Of plaques with homogeneous remodeling, 18.8% had Excessive ER, 6.2% Compensatory ER, 12.5% Inadequate ER and 62.5% Constrictive remodeling (p<0.05). Similarly, 75.7% of all plaques demonstrated heterogeneous ESS profiles along their length: 20 plaques (7.1%) exhibited both low and high ESS, 79 (28.1%) both low and moderate ESS, 67 (23.8%) both moderate and high ESS; and 115 plaques (40.9%) showed all three ESS patterns (p<0.001). Of plaques with homogeneous ESS, 40% had low ESS, 20% moderate ESS and 40% high ESS. Segments with Excessive ER were associated with low ESS while constrictively remodeled segments with high ESS (p<0.001). Plaque growth at follow-up was primarily evident in segments with baseline low ESS (OR 1.4, 95% CI 1.1-1.7, p<0.05). Conclusions: Arterial remodeling and ESS patterns are not homogeneously distributed along the length of individual coronary plaques, but show significant longitudinal heterogeneity. Since Excessive ER is related to low ESS and subsequent plaque growth, the detailed characterization of remodeling and ESS profiles along the longitudinal aspect of lesions may enhance early identification of highest-risk plaques.

PTU-116 Transplantation for ALD: Lessons from the Explant

IntroductionAlcoholic liver disease (ALD) remains one of the commonest indications for liver transplantation in Europe. The histological features of ALD vary, depending on extent and stage of injury, No features...

Evaluation of elastin-derived vascular grafts in a circulatory model

Purpose: To evaluate pentagalloyl-glucose (PGG) stabilized elastinderived vascular grafts (EDVGs) in terms of their suitability as vascular substitutes. Methods: EDVGs were prepared by alkaline decellularization (0.1 M NaOH at 37°C for 3 h), rinsing and sterilization in 0.1% peracetic acid. Batches of EDVG scaffolds were treated with sterile 0.1% PGG (pH 5.5) containing 20% isopropanol for 24 h, rinsed and stored in sterile PBS. A subset of PGG and non-PGG samples were additionally covalently heparinized via diamine coupling and reductive amination using nitrous acid degraded heparin. Grafts were implanted in a rat infrarenal aortic model for 4 and 8 weeks. Remodeling, patency, endothelialization and healing of the explants were determined by gross and histological evaluation. Results: While PGG treatment did not significantly affect the denaturation temperature (DT) of the tissue, heparinization resulted in significant increases in DT (from 52°C to 81–82°C) and heparin content (from baseline noise levels of b10 mg/g to N100 mg/g). Overall the nonheparinized groups showed strong evidence of remodeling and recellularization, with a high patency rate of 82%. At 8 weeks, only small fragments of the original grafts were preserved with good neovessel formation and moderate intimal hyperplasia (IH). The heparinized groups showed 100% patency, but with little remodeling, presumably due to the increased crosslink density resulting from the amination of the tissue prior to heparin attachment. Some surface endothelialization was observed in all treatment groups. Conclusions: EDVGs are promising candidates as vascular grafts, either as substrates for remodeling, or in more highly cross-linked and heparinized forms.

Tissue engineering of aortic valve leaflets using biomimetic composite poly(ethylene glycol) diacrylate hydrogels

Purpose: To evaluate pentagalloyl-glucose (PGG) stabilized elastinderived vascular grafts (EDVGs) in terms of their suitability as vascular substitutes. Methods: EDVGs were prepared by alkaline decellularization (0.1 M NaOH at 37°C for 3 h), rinsing and sterilization in 0.1% peracetic acid. Batches of EDVG scaffolds were treated with sterile 0.1% PGG (pH 5.5) containing 20% isopropanol for 24 h, rinsed and stored in sterile PBS. A subset of PGG and non-PGG samples were additionally covalently heparinized via diamine coupling and reductive amination using nitrous acid degraded heparin. Grafts were implanted in a rat infrarenal aortic model for 4 and 8 weeks. Remodeling, patency, endothelialization and healing of the explants were determined by gross and histological evaluation. Results: While PGG treatment did not significantly affect the denaturation temperature (DT) of the tissue, heparinization resulted in significant increases in DT (from 52°C to 81–82°C) and heparin content (from baseline noise levels of b10 mg/g to N100 mg/g). Overall the nonheparinized groups showed strong evidence of remodeling and recellularization, with a high patency rate of 82%. At 8 weeks, only small fragments of the original grafts were preserved with good neovessel formation and moderate intimal hyperplasia (IH). The heparinized groups showed 100% patency, but with little remodeling, presumably due to the increased crosslink density resulting from the amination of the tissue prior to heparin attachment. Some surface endothelialization was observed in all treatment groups. Conclusions: EDVGs are promising candidates as vascular grafts, either as substrates for remodeling, or in more highly cross-linked and heparinized forms.

BrdU Pulse LabellingIn Vivoto Characterise Cell Proliferation during Regeneration and Repair following Injury to the Airway Wall in Sheep

The response of S-phase cells labelled with bromodeoxyuridine (BrdU) in sheep airways undergoing repair in response to endobronchial brush biopsy was investigated in this study. Separate sites within the airway tree of anaesthetised sheep were biopsied at intervals prior to pulse labelling with BrdU, which was administered one hour prior to euthanasia. Both brushed and spatially disparate unbrushed (control) sites were carefully mapped, dissected, and processed to facilitate histological analysis of BrdU labelling. Our study indicated that the number and location of BrdU-labelled cells varied according to the age of the repairing injury. There was little evidence of cell proliferation in either control airway tissues or airway tissues examined six hours after injury. However, by days 1 and 3, BrdU-labelled cells were increased in number in the airway wall, both at the damaged site and in the regions flanking either side of the injury. Thereafter, cell proliferative activity largely declined by day 7 after injury, when consistent evidence of remodelling in the airway wall could be appreciated. This study successfully demonstrated the effectiveness of in vivo pulse labelling in tracking cell proliferation during repair which has a potential value in exploring the therapeutic utility of stem cell approaches in relevant lung disease models.

Short-Axis 2D Strain from Speckle Tracking Predicts Echocardiographic Response to Cardiac Resynchronization Therapy

Two-dimensional (2D) strain imaging from speckle tracking is a Doppler independent technique allowing assessment of left ventricular (LV) strain (ɛ); systolic strain rate (SRs') and early diastolic strain rate (SRe') in the radial and circumferential planes. We set out to investigate whether (i) these parameters facilitated assessment of dyssynchronous contraction and (ii) these measures could predict response to cardiac resynchronization therapy (CRT). Forty-one patients with severe, symptomatic heart failure on optimal medical therapy were recruited. Thirty-two healthy subjects were used as controls. Time to peak ɛ, SRs', and SRe' of 6 LV segments were measured in the parasternal short axis prior to and 6 weeks post CRT implantation. Time delays between segments were then calculated and ANOVA assessed for prediction of response, classified as reduction in LV end systolic volume of >15%. 2D strain demonstrated significantly more dyssynchronous contraction in the heart failure population at baseline compared to healthy controls. Significant reduction in dyssynchrony was seen in ɛ and SRs' following CRT, largely confined to those with evidence of remodeling. The time delay between peak circumferential SRs' of opposing walls was the best predictor of reverse remodeling. 2D strain imaging appears to be a useful measure to predict response to CRT. The time to peak circumferential SR is a new predictor of response.

Comparison of Ventricular Structure and Function in Chinese Patients With Heart Failure and Ejection Fractions >55% Versus 40% to 55% Versus

Subjects with heart failure (HF) and a preserved ejection fraction (EF) are heterogenous and the EF used to define this syndrome varies considerably among studies. We sought to determine if physiologic differences exist between subjects with a normal EF (>55%) or mildly decreased EF (40% to 55%). 357 consecutive Chinese patients who were healthy (n = 93) or had HF (n = 264) underwent comprehensive echocardiography, Doppler analysis, and measurement of neurohormones. Subjects with HF were stratified by EF into those with normal EF (>55%, n = 128), mildly decreased EF (40% to 55%, n = 38), or moderate to severely decreased EF (<40%, n = 100). Employing noninvasive pressure-volume analysis, estimated end-systolic and end-diastolic pressure-volume relations were calculated. Subjects with HF and an EF 40% to 55% more often had a previous myocardial infarction and diabetes than those with HF and an EF >55%. Physiologically, the cohort with a mildly decreased EF had eccentrically enlarged ventricles with evidence of remodeling (rightward shifted end-diastolic pressure-volume relation) and decreased chamber contractility (downward shifted end-systolic pressure-volume relation) most comparable to subjects with overt systolic HF. In conclusion, in subjects with HF and a preserved EF, there are distinct physiologic differences between those with a normal (>55%) and a mildly decreased (40% to 55%) EF.

Remodeling of cardiovascular system and function of parathyroid glands in patients with arterial hypertension

Features of structural and functional remodeling of the left ventricular and brachial artery and parathyroid hormone blood levels are studied in 95 patients with arterial hypertension. It was shown that increased parathyroid hormone blood levels correlate with increased frequency and evidence of remodeling of left ventricular and brachial artery, also significant decrease in diastolic function and endothelium-dependent vasodilatation. 21.6 % of hypertensive patients have asymptomic of parathyroid hormone hyper secretion. Pathological type of circadian blood pressure profile was observed in these patients.

New insights into the pathophysiology of the small airways in asthma

Asthma is a lung disease characterized by inflammation and remodeling of the airways, which leads to airflow obstruction and symptoms of wheeze, chest tightness, cough and dyspnea. It is now widely accepted that airway inflammation and remodeling occur not only in the central airways but also in the small airways and even in the lung parenchyma. Inflammation of the distal lung can be observed even in mild asthmatics with normal or noncompromised lung function. Moreover, the small airways and the lung parenchyma can produce many Th2 cytokines and chemokines involved in initiation and perpetuation of the inflammatory process. In addition, the distal parts of the lung have been recognized as a predominant site of airflow obstruction in asthmatics. In fact, the inflammation at this distal site has been described as more severe when compared to the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance, highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease.

Evidence of remodeling in peripheral airways of patients with mild to moderate asthma: Effect of hydrofluoroalkane-flunisolide

We have shown previously that inflammation in asthma is not restricted to central airways but can also be demonstrated in peripheral airways. It is not clear whether inflammation of the peripheral airways is associated with structural changes and whether this remodeling process can be modulated by deposition of inhaled corticosteroids (ICSs). To compare remodeling in peripheral and central airways and to investigate the effects of hydrofluoroalkane (HFA)-ICS on remodeling at these sites. Transbronchial and endobronchial biopsies were obtained from 12 patients with mild to moderate asthma before and after a 6-week course of HFA-ICS (flunisolide). Total collagen deposition, expression of collagen III, TGF-beta, and alpha-smooth muscle actin were examined by using Van Gieson staining and immunocytochemistry, respectively. Total collagen occupied 37.7% of the wall area of peripheral airways, compared with 54.5% of the wall area of central airways (P = .04). There was no significant difference in central versus peripheral airways for collagen III or alpha-smooth muscle actin immunoreactivity and in the number of TGF-beta(+) cells in the submucosa. The only significant effect of HFA-flunisolide was a decrease in alpha-smooth muscle actin area in peripheral airways (13.4% vs 4.6%; P = .01) that correlated with the percentage increase in forced expiratory flow at 25% to 75% of vital capacity (r(s) = -1.00; P = .00). Our data show that there is a considerable degree of airway remodeling in peripheral airways in patients with asthma and confirm the inability of ICS to modulate collagen deposition and TGF-beta expression. Treatment with HFA-flunisolide is associated with a significant decrease in the expression of alpha-smooth muscle actin in peripheral airways, which correlated with improvement in peripheral airway function.