Relation between coronary artery remodelling (compensatory dilatation) and stenosis in human native coronary arteries

OBJECTIVES—To investigate the contribution of plaque size and vessel remodelling to coronary artery stenosis and to assess the role of vessel shrinkage (negative remodelling) across a wide range of lesions.
DESIGN—Postmortem study of coronary remodelling in perfusion fixed hearts.
SUBJECTS—24 men and 24 women who died suddenly with coronary artery disease.
MAIN OUTCOME MEASURES—Percentage stenosis, percentage plaque burden, percentage remodelling, and arc of normal vessel were measured and related to age, sex, smoking status, and history of hypertension.
RESULTS—There was a positive relation between percentage stenosis and percentage plaque burden (r = 0.6, p < 0.0001) and an inverse relation between percentage stenosis and percentage remodelling (r = -0.4, p < 0.0001). Multilinear regression modelling showed that luminal stenosis = 1.0 (plaque burden) − 0.4 (vessel remodelling). Remodelling was greater in lesions that would not have been significant at angiography ( 25% stenosis) than in the remaining lesions (25.9 (26)% v 10.0 (21.1)%, p < 0.0001, respectively) and was reduced in segments with circumferential plaques (12.7 (24.5)% v 20.7 (24.3)% in eccentric plaques, p = 0.001). Remodelling did not correlate with age, sex, or smoking. Negative remodelling was present in 62 lesions with a stenosis > 25% versus 10 lesions with  25% stenosis (p < 0.0001). Lesions with negative remodelling had greater plaque burden and luminal stenosis and a reduced arc of normal segment.
CONCLUSION—Outward arterial remodelling negates the stenosing effect of increasing plaque size. Significant coronary stenoses arise from a failure of this outward remodelling in the face of a large plaque burden. Coronary arterial remodelling is unrelated to sex or smoking and is plaque specific.


Keywords: coronary artery disease; vessel remodelling; pathology     

The role of charged residues mediating low affinity protein–protein recognition at the cell surface by CD2

Insights into the structural basis of protein–protein recognition have come principally from the analysis of proteins such as antibodies, hormone receptors, and proteases that bind their ligands with relatively high affinity (K_a ≈ 10⁹ M⁻¹). In contrast, few studies have been done on the very low affinity interactions mediating cell adhesion and cell–cell recognition. As a site of protein–protein recognition, the ligand binding face of the T lymphocyte cell–cell recognition molecule, CD2, which binds its ligands 10⁴- to 10⁵-fold more weakly than do antibodies and proteases, is unusual in being both very flat and highly charged. An analysis of the effect of mutations and ionic strength on CD2 binding to its ligand, CD48, indicates that these charged residues contribute little, if any, binding energy to this interaction. However, the loss of these charged residues is shown to markedly reduce ligand-binding specificity. Thus, the charged residues increase the specificity of CD2 binding without increasing the affinity. This phenomenon is likely to result from a requirement for electrostatic complementarity between charged binding surfaces to compensate for the removal, upon binding, of water interacting with the charged residues. It is proposed that this mode of recognition is highly suited to biological interactions requiring a low affinity because it uncouples increases in specificity from increases in affinity.     

Complex stenosis morphology and vasomotor responses to inhibition of nitric oxide synthesis

OBJECTIVE—To assess the relation between coronary vasomotor effects of N^G-monomethyl-L-arginine (LNMMA) administration and coronary stenosis morphology, length, and severity in patients with stable angina.DESIGN—In 28 patients (24 male, four female) with coronary artery disease and chronic stable angina, intracoronary normal saline and 4 µmol/min LNMMA were infused for four minutes each, followed by an intracoronary bolus of 250 µg glyceryl trinitrate. Coronary stenoses were classified as concentric (smooth), eccentric (smooth), or complicated (irregular). The diameters of these stenoses and their adjacent reference proximal segments were measured by quantitative angiography.RESULTS—During LNMMA infusion a significantly larger proportion of complicated stenoses than concentric and eccentric stenoses constricted by ? 5% (p < 0.01) and the magnitude of vasoconstriction was greater in complicated than in concentric and eccentric stenoses (p < 0.05). For complicated stenoses the magnitude of constriction (in mm) with reference to normal saline was greater than that of the concentric and eccentric stenoses (p < 0.05), whereas concentric and eccentric stenoses constricted similarly. Irrespective of the type of morphology, there was a correlation (p < 0.05) between both the severity and the length of stenoses and the magnitude of vasoconstriction to LNMMA. A similar proportion of concentric, eccentric, and complicated stenoses showed ? 5% increase in diameter with glyceryl trinitrate, and the magnitude of the response was similar in the three groups.CONCLUSIONS—In patients with coronary artery disease, the response to LNMMA is greater when stenosis morphology is complex, indicating greater nitric oxide activity. This provides further evidence that plaques with complex morphology are in an active state.     

Captopril in clinical hypertension. Changes in components of renin-angiotensin system and in body composition in relation to fall in blood pressure with a note on measurement of angiotensin II during converting enzyme inhibition.

The effect of the converting enzyme inhibitor captopril on arterial pressure, the components of the renin-angiotensin-aldosterone system, and body sodium and potassium content was studied in eight hypertensive patients with renal artery stenosis and, in conjunction with diuretics, in seven patients with hypertension unresponsive to previous treatment. Two hours after the first dose, captopril caused significant falls in systolic and diastolic pressures, plasma angiotensin II, and aldosterone, with converse increases in angiotensin I and both active and total renin; the initial fall in diastolic pressure was significantly related to the drop in plasma angiotensin II. The biochemical changes were sustained during prolonged treatment, even when diuretics were added. One untreated patient with renal artery occlusion had severe secondary aldosterone excess, was sodium and potassium depleted, and severely hyponatraemic and hypokalaemic; captopril restored blood pressure, plasma electrolyte concentrations, and exchangeable sodium and total body potassium to normal. In one man with renal artery stenosis and overall renal impairment captopril led to sodium retention, and blood pressure did not fall until a diuretic was added. In the remaining patients with renal artery stenosis, pretreatment renin, angio tensin II, and aldosterone concentrations were either normal or only modestly raised, and plasma electrolyte concentrations and body content of sodium and potassium were normal. Captopril alone controlled arterial pressure in all, three cases showing a gradual fall of pressure over the first six weeks of treatment; no significant changes in exchangeable sodium or total body potassium were seen. The group of patients with previously intractable hypertension were all controlled with a combination of captopril and diuretic.     

Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes

Conventional treatment for nasopharyngeal carcinoma (NPC) frequently fails and is accompanied by severe long-term side effects. Since virtually all undifferentiated NPCs are associated with Epstein-Barr virus (EBV), this tumor is an attractive candidate for cellular immunotherapy targeted against tumor-associated viral antigens. We now demonstrate that EBV-specific cytotoxic T-cell (CTL) lines can readily be generated from individuals with NPC, notwithstanding the patients' prior exposure to chemotherapy/radiation. A total of 10 patients diagnosed with advanced NPC were treated with autologous CTLs. All patients tolerated the CTLs, although one developed increased swelling at the site of pre-existing disease. At 19 to 27 months after infusion, 4 patients treated in remission from locally advanced disease remain disease free. Of 6 patients with refractory disease prior to treatment, 2 had complete responses, and remain in remission over 11 to 23 months after treatment; 1 had a partial remission that persisted for 12 months; 1 has had stable disease for more than 14 months; and 2 had no response. These results demonstrate that administration of EBV-specific CTLs to patients with advanced NPC is feasible, appears to be safe, and can be associated with significant antitumor activity.     

Ecstasy induced acute myocardial infarction

A 23 year old man presented with a clinical history and ECG compatible with acute myocardial infarction, having taken a single tablet of ecstasy (3,4-methylenedioxymetamphetamine) 18 hours previously. He was treated with aspirin and thrombolytic therapy; however, cardiac catheterisation showed angiographically normal coronary arteries and left ventricular function. Sympathomimetic drugs are freely available and widely abused in Britain, but there is little evidence of the mechanisms or management of cardiac complications. In such cases the use of standard treatment for acute myocardial infarction is recommended with agents such as glyceryl trinitrate and phentolamine to reduce coronary artery spasm. Early coronary angiography may help to determine the relative contribution of spasm, thrombus, and underlying atherosclerotic disease.


Keywords: ecstasy; 3,4-methylenedioxymetamphetamine; acute myocardial infarction     

Which patients stop working because of rheumatoid arthritis? Results of five years' follow up in 732 patients from the Early RA Study (ERAS)

OBJECTIVES: To assess the occurrence and prognostic factors for the ability to maintain paid work in patients with rheumatoid arthritis (RA). SETTING: Inception cohort of patients with RA recruited from rheumatology departments in nine NHS Hospital Trusts in England. PATIENTS: All consecutive patients with RA of less than two years' duration, before any second line (disease modifying) drug treatment, and followed up for five years. METHODS: Clinical, laboratory, and radiological assessments, and all treatments were recorded prospectively using a standardised format at presentation and yearly. OUTCOME MEASURES: Changes in, and loss of paid work by five years' follow up. RESULTS: 732 patients completed the five year follow up. 353/721 (49%) were gainfully employed at the onset of RA, 211 (60%) were still working at five years, 104 (29%) stopped because of the disease, and 31 (9%) retired for reasons other than RA. Work disability at five years was more likely in manual workers (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.4 to 3.8) and worse baseline Health Assessment Questionnaire (HAQ>1.5, OR 2.26, 95% CI 1.38 to 3.7). In combination with other baseline variables (erythrocyte sedimentation rate, sex, age of onset, and radiological erosions), employment outcome was predicted in 78% using multivariate analysis. CONCLUSIONS: Nearly half of the patients with RA were in paid employment at onset, work disability was an adverse outcome for a third of these patients by five years, and manual work and high baseline HAQ were important predictors for this. These details are likely to be useful to clinicians, health professionals, and patients in order to plan medical, orthopaedic, and remedial treatments in early RA. Future disease modifying treatments could be compared with this cohort of patients who were treated with conventional second line drugs.     

Hematopoietic growth factors for graft failure after bone marrow transplantation: a randomized trial of granulocyte-macrophage colony- stimulating factor (GM-CSF) versus sequential GM-CSF plus granulocyte- CSF

Delay in hematologic recovery after bone marrow transplantation (BMT) can extend and amplify the risks of infection and hemorrhage, compromise patients' survival, and increase the duration and cost of hospitalization. Because current studies suggest that granulocyte- macrophage (GM) colony-stimulating factor (CSF) may potentiate the sensitivity of hematopoietic progenitor cells to G-CSF, we performed a prospective, randomized trial comparing GM-CSF (250 micrograms/m2/d x 14 days) versus sequential GM-CSF x 7 days followed by G-CSF (5 micrograms/kg/d x 7 days) as treatment for primary or secondary graft failure after BMT. Eligibility criteria included failure to achieve a white blood cell (WBC) count > or = 100/microL by day +21 or > or = 300/microL by day +28, no absolute neutrophil count (ANC) > or = 200/microL by day +28, or secondary sustained neutropenia after initial engraftment. Forty-seven patients were enrolled: 23 received GM-CSF (10 unrelated, 8 related allogeneic, and 5 autologous), and 24 received GM- CSF followed by G-CSF (12 unrelated, 7 related allogeneic, and 5 autologous). For patients receiving GM-CSF alone, neutrophil recovery (ANC > or = 500/microL) occurred between 2 and 61 days (median, 8 days) after therapy, while those receiving GM-CSF+G-CSF recovered at a similar rate of 1 to 36 days (median, 6 days; P = .39). Recovery to red blood cell (RBC) transfusion independence was slow, occurring 6 to 250 days (median, 35 days) after enrollment with no significant difference between the two treatment groups (GM-CSF: median, 30 days; GM-CSF+G- CSF; median, 42 days; P = .24). Similarly, platelet transfusion independence was delayed until 4 to 249 days (median, 32 days) after enrollment, with no difference between the two treatment groups (GM- CSF: median, 28 days; GM-CSF+G-CSF: median, 42 days; P = .38). Recovery times were not different between patients with unrelated donors and those with related donors or autologous transplant recipients. Survival at 100 days after enrollment was superior after treatment with GM-CSF alone. Only 1 of 23 patients treated with GM-CSF died versus 7 of 24 treated with GM-CSF+G-CSF who died 16 to 84 days (median, 38 days) after enrollment, yielding Kaplan-Meier 100-day survival estimates of 96% +/- 8% for GM-CSF versus 71% +/- 18% for GM-CSF+G-CSF (P = .026). These data suggest that sequential growth factor therapy with GM-CSF followed by G-CSF offers no advantage over GM-CSF alone in accelerating trilineage hematopoiesis or preventing lethal complications in patients with poor graft function after BMT.(ABSTRACT TRUNCATED AT 400 WORDS)     

Functions of vasopressin and oxytocin in bone mass regulation

Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr^−/− mice have osteopenia, and Avpr1α^−/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr^−/−:Avpr1α^−/− double-mutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avp-stimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α^−/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.Over the past decade, we have described direct actions of anterior and posterior pituitary hormones on the skeleton (1–8). We have shown that these actions are exerted via G protein-coupled receptors resident on both osteoblasts and osteoclasts. We also find that the skeleton is highly sensitive to the action of posterior pituitary hormones; for example, mice haploinsufficient in oxytocin (Oxt) have osteopenic bones, but lactation is normal; lactation is impaired only in Oxt^−/− mice (2). Likewise, Tshr haploinsufficient mice are completely euthyroid with normal thyroid follicles but display significant osteopenia (4). The exquisite sensitivity of the skeleton to pituitary hormones comes as no surprise, considering that the pituitary gland and the skeleton are both evolutionarily more primitive than target endocrine organs (7).Apart from the known actions of growth hormone on the skeleton, Tsh, Fsh, Acth, Oxt, and vasopressin (Avp) have all been shown to regulate the formation and/or function of both osteoblasts and osteoclasts and thus to control bone remodeling in vivo (2–4, 6–8). The two neurohypophyseal hormones Oxt and Avp have opposing functions (2, 3). Oxt stimulates and Avp inhibits osteoblast formation. Consequently, the genetic deletion of the Oxt receptor (Oxtr) and Avp receptor 1α (Avpr1α) yields opposing phenotypes, notably osteopenia in Oxtr^−/− mice and high bone mass in Avpr1α^−/− mice (2, 3). These findings may explain the rapid recovery of bone loss at weaning when plasma Oxt levels are high (9) and also the profound loss of bone noted in chronic hyponatremic states, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in which serum Avp levels are elevated (3).We find high levels of Oxtr expression on both osteoclasts and osteoblasts (2, 10), in addition to their abundant expression in breast and uterine tissue, where they regulate lactation and parturition, respectively (11). Avpr1αs, in contrast, are distributed more ubiquitously, whereas Avpr2s are localized mainly in the kidney, where they regulate free water excretion (12). Osteoblasts express both Avpr1α and Avrpr2 (3). The only other known isoform, Avpr1β, is expressed predominantly in the pancreas and pituitary; it regulates ACTH secretion from pituitary corticotrophs (13). Sequence alignment shows that the binding sites of the Oxtr and Avprs are highly conserved, with specific amino acids within the predicted binding pocket providing ligand selectivity (14–16). The respective ligands Oxt and Avp also are homologous nonapeptides, differing in only two amino acids, and are known to interact with the other’s receptor with different affinities (17).To our knowledge, osteoblasts and osteoclasts are the only cells in which Oxtr, Avpr1α, and Avpr2 are coexpressed. We also have shown that osteoblastic Oxtrs undergo internalization and nuclear translocation upon binding to Oxt and that this action is independent of cytosolic Erk phosphorylation (18). Avpr1α activation by Avp also activates Erk phosphorylation within minutes (3). The homology between the ligands and their respective receptors and converging downstream signals suggest that Avp and Oxtr may share receptors with opposing or convergent signals. Here, we have explored these interactions in the regulation of osteoblastic bone formation by using mice lacking one or both receptors, chemical inhibitors, and physiological models of high bone turnover.