Do the extent and direction of arterial remodelling predict subsequent progression of coronary atherosclerosis? A serial intravascular ultrasound study.

OBJECTIVE: Despite the link between positive coronary remodelling and acute ischaemic events, no data exist about the impact of arterial remodelling on subsequent progression of coronary atherosclerosis. The objective of this study was to examine whether extent and direction of arterial remodelling are predictors of progression of coronary atherosclerosis. DESIGN, SETTING AND PATIENTS: From the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, 210 focal coronary lesions (single lesion per patient) were identified with

Control of oral biofilm formation by an antimicrobial decapeptide.

Oral biofilms are mixed-species microbial communities, and their uncontrolled outgrowth can express as oral diseases. Antimicrobial peptides represent alternative classes of antimicrobials that exhibit selectivity for prokaryotes. We wanted to test the effect of a synthetic decapeptide antimicrobial, KSL, on the development of oral biofilms formed by isolated human salivary bacteria. We used differential interference contrast microscopy, coupled with a dual-flow cell system, to determine the effect of KSL on oral biofilm development. We used reductions of viable counts and confocal microscopy to assess the bactericidal activity of KSL on mature oral biofilms. KSL effectively blocked biofilm development. A significant effect on the viability of mature biofilms was observed when KSL was used in the presence of a surface-active agent, or after biofilms were mechanically disrupted. This study shows that KSL may be a useful adjunct for conventional oral hygiene to prevent plaque-mediated dental diseases.

Susceptibility of oral bacteria to an antimicrobial decapeptide.

Naturally occurring antimicrobial peptides have emerged as alternative classes of antimicrobials. In general, these antimicrobial peptides exhibit selectivity for prokaryotes and minimize the problems of engendering microbial resistance. As an alternative method to search for more effective broad-spectrum peptide antimicrobials, investigators have developed peptide libraries by using synthetic combinatorial technology. A novel decapeptide, KKVVFKVKFK (KSL), has been identified that shows a broad range of antibacterial activity. The purpose of this study was to test the efficacy of this antimicrobial peptide in killing selected strains of oral pathogens and resident saliva bacteria collected from human subjects. Cytotoxic activity of KSL against mammalian cells and the structural features of this decapeptide were also investigated, the latter by using two-dimensional NMR in aqueous and DMSO solutions. MICs of KSL for the majority of oral bacteria tested in vitro ranged from 3 to 100 microg ml(-1). Minimal bactericidal concentrations of KSL were, in general, within one to two dilutions of the MICs. KSL exhibited an ED(99) (the dose at which 99 % killing was observed after 15 min at 37 degrees C) of 6.25 microg ml(-1) against selected strains of Lactobacillus salivarius, Streptococcus mutans, Streptococcus gordonii and Actinobacillus actinomycetemcomitans. In addition, KSL damaged bacterial cell membranes and caused 1.05 log units reduction of viability counts of saliva bacteria. In vitro toxicity studies showed that KSL, at concentrations up to 1 mg ml(-1), did not induce cell death or compromise the membrane integrity of human gingival fibroblasts. NMR studies suggest that KSL adopts an alpha-helical structure in DMSO solution, which mimics the polar aprotic membrane environment, whereas it remains unstructured in aqueous medium. This study shows that KSL may be a useful antimicrobial agent for inhibiting the growth of oral bacteria that are associated with caries development and early plaque formation.

Lumen loss in transplant coronary artery disease is a biphasic process involving early intimal thickening and late constrictive remodeling: results from a 5-year serial intravascular ultrasound study.

BACKGROUND: Coronary artery disease is the major cause of late cardiac allograft failure. However, few data exist regarding the natural history of changes in intimal and external elastic membrane (EEM) areas after heart transplantation. METHODS AND RESULTS: In 38 transplant recipients, serial intravascular ultrasound examinations were performed 3.7+/-2.2 weeks after transplantation and annually thereafter for 5 years. In 59 coronary arteries, we compared 135 matched segments among serial studies. In each segment, intravascular ultrasound images were digitized at 1-mm intervals, and mean values of EEM and lumen and intimal areas were analyzed. In the first year after transplantation, the intimal area increased significantly from 1.8+/-1.6 to 3.0+/-2.1 mm(2) (P<0.001). Subsequently, the annual increase in intimal area decreased. EEM area did not change during the first year; however, between years 1 and 3, significant expansion of EEM area occurred (15.4+/-4.6 to 17.2+/-5.4 mm(2), P<0.001). Thereafter, EEM area decreased significantly from 17.2+/-5.4 mm(2) (year 3) to 15.1+/-4.9 mm(2) (year 5, P=0.01). Different mechanisms of lumen loss were observed during 2 phases after transplantation: early lumen loss primarily caused by intimal thickening and late lumen loss caused by EEM area constriction. CONCLUSIONS: This serial ultrasound study revealed that most of the intimal thickening occurred during the first year after heart transplantation. Changes in the EEM area showed a biphasic response, consisting of early expansion and late constriction. Thus, different mechanisms of lumen loss were observed during the early and late phases after transplantation.

Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study.

OBJECTIVES: We sought to determine the role of conventional atherosclerosis risk factors in the development and progression of transplant coronary artery disease (CAD) using serial intravascular ultrasound imaging. BACKGROUND: Transplant artery disease is a combination of allograft vasculopathy and donor atherosclerosis. The clinical determinants for each of these disease processes are not well characterized. Intravascular ultrasound imaging is the most sensitive tool to serially study these processes. METHODS: Baseline intravascular ultrasound imaging was performed 0.9 +/- 0.5 months after transplantation to identify donor atherosclerosis. Follow-up imaging was performed at 1.0 +/- 0.07 year to evaluate progression of donor atherosclerosis and development of transplant vasculopathy. Conventional risk factors for CAD included recipient age, gender, smoking history, diabetes mellitus, hypertension and hypercholesterolemia. RESULTS: Donor-transmitted atherosclerosis was present in 36 patients (39%). At follow-up, progression of donor lesions was seen in 15 patients (42%) and 42 patients (45%) developed transplant vasculopathy, leaving 35 patients (38%) without any disease. There was no difference in any conventional risk factors in patients with and without allograft vasculopathy. However, the severity of allograft vasculopathy was associated with a larger increase in low density lipoprotein (LDL) cholesterol from baseline (p = 0.02). High one-year posttransplant serum triglyceride level and pretransplant body mass index were the only significant predictors (p = 0.03) for progression of donor atherosclerosis. CONCLUSIONS: Conventional atherosclerosis risk factors do not predict development of allograft vasculopathy, but greater change in serum LDL cholesterol level during the first year after transplant is associated with more severe vasculopathy. Therefore, maintenance of LDL cholesterol as close to pretransplant values as possible may help to limit the rate of progression of acquired allograft vasculopathy.

Adventitial hematoma triggering coronary spasm during percutaneous coronary intervention.

During percutaneous coronary intervention of the left anterior descending coronary artery, a lumen narrowing was observed proximal to the stent just deployed. Intravascular ultrasound showed a hematoma localized outside the trilaminar wall structure in absence of a dissection flap or evidence of compression of the lumen. The luminal narrowing resolved after intracoronary administration of vasodilators. This finding is compatible with a coronary spasm triggered by an adventitial hematoma following stent deployment.

Intravascular ultrasound imaging after cardiac transplantation: advantage of multi-vessel imaging.

BACKGROUND: Intravascular ultrasound is a sensitive tool to study transplant vasculopathy. However, there is no consensus regarding the methodology for imaging protocol. The impact of single versus multiple epicardial vessel imaging in determining the prevalence of transplant vasculopathy has not been determined. This study examines the benefit of three-vessel imaging versus one-vessel imaging in detecting transplant vasculopathy. METHODS AND RESULTS: One hundred eleven transplant recipients with intravascular ultrasound imaging at baseline (within 2 months of transplantation) were studied: 107 at 1-year, 53 at 2-year and 41 at 3-year follow-up. A total of 222 arteries, 519 segments and 772 sites were analyzed (94 LAD, 65 LCX and 65 RCA). The prevalence of transplant vasculopathy lesions was 27%, 41% and 58% at 1 year, 39%, 55% and 71% at 2 years and 39%, 55% and 74% at 3 years for patients with one-, two- and three-vessel imaging, respectively. Single- or two-vessel disease was present in 23% (7) and 32% (10) patients with three-vessel imaging, leading to the potential mislabeling of these 17 (55%) patients as "disease free" if they underwent only single-vessel imaging. CONCLUSIONS: Multivessel imaging is more sensitive in detecting the transplant vasculopathy lesions compared to single-vessel imaging. This important variable should be considered when designing and interpreting trials utilizing intravascular imaging derived end-point.

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.

Development of transplantation vasculopathy and progression of donor-transmitted atherosclerosis: comparison by serial intravascular ultrasound imaging.

BACKGROUND: Transplant coronary artery disease is a combination of atherosclerosis transmitted from the donor and new lesions of allograft vasculopathy. We sought to determine the morphological characteristics of allograft vasculopathy and differentiate it from donor-transmitted atherosclerosis with serial intravascular ultrasound. METHODS AND RESULTS: Intravascular ultrasound examination was performed in 93 patients at 27.2+/-15.0 and 369. 7+/-23.9 days after transplantation. The maximally and minimally diseased sites were selected in each segment as defined by Coronary Artery Surgery Study classification. For each matched site, maximal plaque thickness was measured. Lesions (maximum plaque thickness >/=0.5 mm) present at baseline examination were defined as donor lesions. On follow-up, lesions that developed at previously normal sites were defined as de novo lesions. The distribution and severity of donor and de novo lesions were similar in proximal, mid, and distal segments. The de novo lesions were less focal (43% vs 74%) and more circumferential (69% vs 45%) compared with the donor lesions, but there was significant morphological heterogeneity. Similar numbers of patients with and those without donor lesions developed de novo lesions. Moreover, progression of donor lesions was not associated with the presence or absence of de novo lesions. CONCLUSIONS: Differentiation between early allograft vasculopathy from conventional atherosclerosis by distribution and morphology of lesions alone is difficult. Serial intravascular ultrasound imaging with early baseline examination is necessary to make this distinction. This distinction is important because the progression of donor lesions and the development of de novo lesions are independent of each other.

A strategy to arrest and reverse coronary artery disease: a 5-year longitudinal study of a single physician's practice.

BACKGROUND: Animal experiments and epidemiological studies have suggested that coronary disease could be prevented, arrested, or even reversed by maintaining total serum cholesterol levels below 150 mg/dL (3.88 mmol/L). In 1985, we began to study how effective one physician could be in helping patients achieve this cholesterol level and what the associated effect of achieving and maintaining this cholesterol level has on coronary disease. METHODS: The study included 22 patients with angiographically documented, severe coronary artery disease that was not immediately life threatening. These patients took cholesterol-lowering drugs and followed a diet that derived no more than 10% of its calories from fat. Disease progression was measured by coronary angiography and quantified with the percent diameter stenosis and minimal lumen diameter methods. Serum cholesterol was measured biweekly for 5 years and monthly thereafter. RESULTS: Of the 22 participants, 5 dropped out within 2 years, and 17 maintained the diet, 11 of whom completed a mean of 5.5 years of follow-up. All 11 of these participants reduced their cholesterol level from a mean baseline of 246 mg/dL (6.36 mmol/L) to below 150 mg/dL (3.88 mmol/L). Lesion analysis by percent stenosis showed that of 25 lesions, 11 regressed and 14 remained stable. Mean arterial stenosis decreased from 53.4% to 46.2% (estimated decrease = 7%; 95% confidence interval [CI], 3.3 to 10.7, P < .05). Analysis by minimal lumen diameter of 25 lesions found that 6 regressed, 14 remained stable, and 5 progressed. Mean lumen diameter increased from 1.3 mm to 1.4 mm (estimated increase = 0.08 mm; 95% CI, -0.06 to 0.22, P = NS). Disease was clinically arrested in all 11 participants, and none had new infarctions. Among the 11 remaining patients after 10 years, six continued the diet and had no further coronary events, whereas the five dropouts who resumed their prestudy diet reported 10 coronary events. CONCLUSIONS: A physician can influence patients in the decision to adopt a very low-fat diet that, combined with lipid-lowering drugs, can reduce cholesterol levels to below 150 mg/dL and uniformly result in the arrest or reversal of coronary artery disease.

Elimination of nickel, cobalt, and chromium following repeated injections of high dose metal salts.

A study was conducted to determine the ability of hamsters to eliminate in the urine, or store in the organs, large quantities of metal salts given over a period of several months. In addition, the effect of prior immunization on metal ion clearance was determined. The results indicated that nickel was rapidly eliminated in the urine and that the level in the organs was similar to that of control animals. Cobalt was eliminated more slowly than was nickel. The organ levels of cobalt were similar to those of control animals with a slight elevation in the liver of the injected animals. Chromium was eliminated in the urine very slowly, was red cell associated, and the levels were elevated in all the organs (liver, lung, spleen, kidney) compared to control. Prior immunization with metal salts increased the storage of chromium.

In vitro and in vivo metal ion release.

A series of experiments was conducted to study in vitro and in vivo metal ion release and the urine excretion of metal ions. Metal salts were injected and urine analyzed. Anodic potentials were applied to stainless steel and cobalt-chromium-molybdenum (CCM) specimens to cause an acceleration of corrosion rates. Corrosion experiments were done in saline, 10% serum and in a subcutaneous space in hamsters. Corrosion rates were determined by measurements of weight loss and calculations of net charge transfer. Metal ion concentrations were determined with graphite furnace atomic absorption spectroscopy, and were calculated from total charge using Faraday's law. The results with stainless steel showed that the weight loss and metal ion release from stainless steel in vitro and in vivo can be calculated using Faraday's Law, assuming release in proportion to alloy composition. The results with CCM indicated that release rates in vitro can be used to determine the proportionality of release in vivo. All the nickel and most of the cobalt was rapidly excreted, while less than 50% of the chromium was excreted. The excretion of metals following salt injection or in vivo corrosion were very similar.

Cigarette smoke causes acute fluctuations in the cyclic GMP content of the isolated intact lung.

The injection of a single bolus of the gas phase of cigarette smoke into the airway of an isolated, perfused and ventilated, canine lung preparation resulted in a sevenfold increase in lung cyclic GMP content by 2 s after exposure. Recovery of control levels occurred by 2 min after injection. Repeated smoke exposures of the same lung resulted in similar increases. These results indicate that cigarette smoke may activate lung guanylate cyclase when delivered through the airway and suggest that lung cyclic GMP levels may fluctuate acutely during smoking.

Purification of brush border membrane by thiocyanate treatment.

Rat small intestinal brush border membranes are purified from brush borders by homogenization in relatively high concentrations of thiocyanate salts (0.56 M LiSCN, 0.41 M NaSCN, or 0.52 M KSCN), removal of this salt, and differential centrifugation to separate cytoskeletal material from membranes. The marker enzyme, sucrase, is enriched 98-fold in the final membranes over the starting homogenate of intestinal scrapings at a yield of about 20%. The isolated membranes are capable of secondary active sodium-dependent glucose transport as demonstrated by sodium gradient-supported overshooting glucose uptake.