Changes In Plaque Morphology Research Articles

Lipoprotein-associated phospholipase A2 as a biomarker of coronary heart disease and a therapeutic target

Lipoprotein-associated phospholipase A2 (Lp PLA2) is postulated to occupy a key position in the pathogenic sequence leading to formation of complex atherosclerotic lesions. This study reviews evidence supporting its role as a biomarker of vascular disease and as a possible therapeutic target. Evidence continues to build supporting the usefulness of Lp PLA2 as a predictor of coronary events in the general population and in those with established coronary heart disease. Elevated Lp PLA2 is also associated with stroke and heart failure. The crystal structure of Lp PLA2 is now available and offers insight into the links between structure, function and atherogenic properties. Recently completed studies on the efficacy of darapladib, a specific Lp PLA2 inhibitor, show beneficial changes in plaque morphology in animal models and in humans. Lp PLA2 is gaining acceptance as a useful biomarker of chronic inflammation and as a predictor of vascular disease. Early results with darapladib offer promise, but not definitive proof, of a potential role for Lp PLA2 inhibition in coronary heart disease prevention.

Progression of atherosclerosis in the Apo E−/− model: 12-Month exposure to cigarette mainstream smoke combined with high-cholesterol/fat diet

This study was performed to gain information about the influence of two cardiovascular risk factors, cigarette mainstream smoke (MS) and high-cholesterol/fat diet, on the progression of atherosclerosis in apolipoprotein E-deficient (Apo E−/−) mice. Eight to 12-week-old mice were whole-body exposed for up to 12 months (6h/day, 5days/week) to diluted cigarette mainstream smoke at total particulate matter (TPM) concentrations of 100 or 200mg/m3, or to filtered fresh air (sham) in combination with a normal chow diet or a high-cholesterol/fat diet. Cholesterol in the aortic arch was elevated in the high-cholesterol/fat diet groups exposed to 200mgTPM/m3 compared to sham at all time points. In the brachiocephalic artery (BA), absolute plaque size and fraction area of plaques was elevated over the 12-month time course in mice exposed to 200mgTPM/m3 compared to sham (both diets). Exposure to 100 and 200mgTPM/m3 altered the number of elastin-rich layers in the BA in mice fed a high-cholesterol/fat diet, indicating changes in plaque morphology at 6 and 9 months. This study shows for the first time the influence of two different risk factors, MS and high-cholesterol/fat diet, both alone and in combination over a period of 12 months, on the progression of atherosclerosis in Apo E−/− mice. Data suggest that long-term exposure to cigarette mainstream smoke accelerates the development of atherosclerosis in Apo E−/− mice, particularly in combination with a high-cholesterol/fat diet.

NUCLEOTIDE AND AMINO ACID CHANGES IN WEST NILE VIRUS STRAINS EXHIBITING RENAL TROPISM IN HAMSTERS

Recent studies have shown that West Nile virus (WNV) can induce an asymptomatic persistent infection in the kidneys of experimentally infected hamsters. The chronically infected rodents shed virus in their urine for up to 8 months, despite the disappearance of viremia and the development of high levels of neutralizing antibodies. WNV, like most members of the Japanese encephalitis virus complex (Flavivirus; Flaviviridae), is assumed to be mainly neurotropic; little is known about the genetic basis for its renal tropism. In this study, complete sequence analyses were done to compare four WNV isolates from the urines of persistently infected hamsters with the wild-type parent virus (NY 385-99). Nucleotide changes, ranging from 0.05% to 0.09%, were identified in all of the WNV isolates from urine; most of the changes were in coding regions, causing amino acid substitutions in the E, NS1, NS2B, and NS5 proteins. The genetic changes associated with renal tropism were also accompanied by a loss of virulence for hamsters and a change in plaque morphology.

Carotid artery disease

Stroke is the principal cause of persisting neurological disability in the ‘developed’ world. The most common cause of ischaemic carotid territory stroke is thromboembolism, usually from stenoses in the extracranial internal carotid artery. In the majority of patients, embolism is preceded by an acute change in plaque morphology, thus predisposing to overlying thrombus formation. The management of symptomatic atherosclerotic carotid artery disease requires modification of risk factors, and antiplatelet and statin therapy. There is grade-A level evidence that selected patients (usually those with a stenosis >70%) gain significant benefit from carotid endarterectomy (despite the small risk of perioperative stroke). Two level-I randomized clinical trials have also provided grade-A evidence that patients with asymptomatic carotid stenoses >60% gain significant benefit from carotid endarterectomy (although the overall reduction in late stroke is less than that observed in symptomatic patients). Emerging as a possible alternative to carotid surgery is angioplasty; the extracranial stenosis is dilated and primarily stented via the Seldinger approach through the common femoral artery (thereby potentially avoiding some of the complications associated with carotid surgery). Most practitioners of angioplasty use a cerebral protection device to minimize the risk of embolic stroke during the procedure.

How best to combat the enemies? Lipid lowering

The evidence linking elevated plasma low-density lipoprotein cholesterol to atherosclerosis and its clinical consequences is overwhelming. Similarly, there is now compelling evidence that the risk of these complications can be reduced by lipid-lowering therapies. Research reported during the past few years has helped to clarify the apparent paradox of substantial reductions in the risk for cardiovascular events in the presence of minor changes in the extent of coronary artery stenosis. It is clear that lipid reduction results in favourable changes in plaque morphology and composition, reflecting a reduction in the inflammatory content and an increase in the smooth muscle content that favour stability. In addition, changes in endothelial function, platelet adhesiveness and rheology all potentially play a role in the beneficial effects of lipid lowering.

The clinical course of residual carotid arterial disease

Over a 5-year period 642 patients underwent 686 carotid endarterectomies with patch closure and intraoperative surveillance with continuous-wave Doppler. The perioperative stroke rate was 1.5%. Patients were screened with duplex scans immediately after operation for the presence of residual carotid lesions, and followed every 3 to 6 months for either the development of a true recurrent lesion or a change in a residual one. Five hundred thirty-nine arteries (84%) had no postoperative abnormalities. The incidence of recurrent carotid lesions in this groups was 1.5%, 3.4%, and 5.2% at 1, 2, and 3 years, respectively. The incidence of symptoms in this group was 0.2%, 0.7%, and 1.4% at 1, 2, and 3 years, respectively. The earliest recurrence or symptom occurred 8 months from operation. One hundred forty-seven arteries had residual lesions that were more common when either a temporary shunt was used or the operation was carried out above the hypoglossal nerve or below the omohyoid muscle. Sixty-one patients who had plaque proximal to the arteriotomy without a significant stenosis were followed an average of 21 months. There were no changes in plaque morphology and no proven symptoms related to the residual lesion. Fifty-six patients with both plaque and significant hemodynamic abnormalities in the carotid bulb were followed an average of 18 months. Seven of these patients (12.5%) had either a significant deterioration of the lesion or a symptom from it. Each event occurred within 6 months of operation. Thirty patients had significant flow abnormalities but no visible plaque. None of these lesions deteriorated. Although common, residual carotid lesions are benign unless the lesion is characterized by both plaque within the artery and a hemodynamically significant stenosis. These lesions should be further investigated and treated when discovered.

The role of plaque morphology and diameter reduction in the development of new symptoms in asymptomatic carotid arteries

To determine the natural history of changes in plaque morphology and luminal diameter of atherosclerotic carotid arteries, we used duplex scanning to follow-up (1) the contralateral artery in 289 patients who had undergone carotid endarterectomy, with a mean follow-up 22 months and a range of 0 to 48 months and (2) the carotid arteries in 130 patients who had no surgical treatment and had been symptom free, with a mean follow-up period of 15 months and a range of 0 to 48 months. Plaques were graded as to the ratio of echolucency to echogenicity, with type 1 being most echolucent and type 4 being most echogenic. A normal-appearing artery was classified as type 5. Heterogeneous plaques (types 1 and 2) occurred significantly more (p < 0.001) in symptomatic preoperative arteries than in asympatomatic arteries. Follow-up of the asymptomatic vessels showed that the majority of plaques either remained the same or became more echogenic (fibrous). Approximately one fourth of plaques in each group degenerated (more echolucent). Thirty-one patients (10.7%) developed new symptoms in the contralateral asymptomatic group, with 10 patients (3.5%) having strokes. Fourteen of 130 (10.8%) patients, or 5.4% of vessel territories at risk, in the primary asymptomatic group developed new symptoms, with only two strokes occurring. In the contralateral asymptomatic group those patients who initially had >75% stenoses fared worse than those with primary asymptomatic disease with >75% stenosis. Although the overall development of new symptoms is low in both populations, our data indicate that those patients with heterogeneous plaques or whose plaques have undergone change may be at risk for new symptoms. Longer follow-up studies are needed to define the role of plaque changes in the development of symptoms. For now we advocate a conservative “wait and see” approach to symptom-free patients with >75% stenoses and calcified plaques. We suggest a more aggressive approach, recommending early surgical intervention, to those few patients with heterogeneous plaques.

The role of plaque morphology and diameter reduction in the development of new symptoms in asymptomatic carotid arteries

To determine the natural history of changes in plaque morphology and luminal diameter of atherosclerotic carotid arteries, we used duplex scanning to follow-up (1) the contralateral artery in 289 patients who had undergone carotid endarterectomy, with a mean follow-up 22 months and a range of 0 to 48 months and (2) the carotid arteries in 130 patients who had no surgical treatment and had been symptom free, with a mean follow-up period of 15 months and a range of 0 to 48 months. Plaques were graded as to the ratio of echolucency to echogenicity, with type 1 being most echolucent and type 4 being most echogenic. A normal-appearing artery was classified as type 5. Heterogeneous plaques (types 1 and 2) occurred significantly more (p less than 0.001) in symptomatic preoperative arteries than in asympatomatic arteries. Follow-up of the asymptomatic vessels showed that the majority of plaques either remained the same or became more echogenic (fibrous). Approximately one fourth of plaques in each group degenerated (more echolucent). Thirty-one patients (10.7%) developed new symptoms in the contralateral asymptomatic group, with 10 patients (3.5%) having strokes. Fourteen of 130 (10.8%) patients, or 5.4% of vessel territories at risk, in the primary asymptomatic group developed new symptoms, with only two strokes occurring. In the contralateral asymptomatic group those patients who initially had greater than 75% stenoses fared worse than those with primary asymptomatic disease with greater than 75% stenosis. Although the overall development of new symptoms is low in both populations, our data indicate that those patients with heterogeneous plaques or whose plaques have undergone change may be at risk for new symptoms. Longer follow-up studies are needed to define the role of plaque changes in the development of symptoms. For now we advocate a conservative "wait and see" approach to symptom-free patients with greater than 75% stenoses and calcified plaques. We suggest a more aggressive approach, recommending early surgical intervention, to those few patients with heterogeneous plaques.

Growth cycle of fowlpox virus and change in plaque morphology and cytopathology by contaminating mycoplasma

Studies of the multiplication of fowlpox virus (FP) in chick embryo (CE) monolayers indicate that the eclipse period in this system extends for 24–36 hours and the increase of infectious virus is exponential from 36 to 72 hours with a decline in titer by 120 hours. Most of the virus remains cell-associated throughout this period. The kinetics of the in vitro growth curve in cultures dually infected with FP and Mycoplasma gallisepticum are very similar to pure FP infection, but the in vivo infectivity is markedly decreased. Whereas the pock count of FP alone was approximately 1 log lower than the plaque titer, the pock count of the FP- Mycoplasma mixture was at least 5–6 logs lower. The mechanism of this effect of Mycoplasma on the in vivo infectivity of FP has not been elucidated.

The mutability of small-plaque-forming encephalomyocarditis virus.

Summary Sixty-four single plaque subclones of a small-plaque-forming mutant of encephalomyocarditis virus, EMC/r+, were isolated and titrated. In addition to EMC/r+ virus, some contained large-plaque-forming virus, EMC/r. The selective conditions which prevailed during the growth and isolation of the subclones were analysed in detail. All the evidence suggests that only negligible differential selection favouring either the parental (EMC/r+) or the newly arisen plaque type (EMC/r) could have taken place. The changing selective conditions which operate during the growth of EMC/r mutants arising during the plaque assay of EMC/r+, and which slow down their emergence, are discussed. The changes in plaque morphology were shown to be genetically determined. For estimation of the mutation rate the subclones were placed a priori into one of three groups according to their total virus (infectivity) content. The mutation rate from r+ → r was calculated by four methods from each of the 3 groups and found to be 1–2 × 10−1 per particle per duplication.

Properties of foot-and-mouth disease virus in tissue culture I. Changes in plaque morphology and antigenicity following passage in tissue culture

By passage of the Brussels-O strain of foot-and-mouth disease virus through tissue cultures, variants were obtained which differed from the original virus in antigenicity, antigenic character, and rate of neutralization by homologous and probably also heterologous antibodies. Further, a variant forming a plaque-pattern different from that of the parental strain was obtained. An increase in cytopathogenicity was also observed during tissue-culture passages. The nature of the variance is discussed, and it seems probable that passage through tissue culture selectively favours the virus of the variant type in the heterogenous original population.