Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Tschoepe, D.
Right arrow Articles by Stratmann, B.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Tschoepe, D.
Right arrow Articles by Stratmann, B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Plaque stability and plaque regression: new insights

Diethelm Tschoepe and Bernd Stratmann

Diabetes Center, Bad Oeynhausen, Heart and Diabetes Center, North Rhine Westfalia, University Clinic, Ruhr University Bochum, Georg Str. 11, 32545 Bad Oeynhausen, Germany

Corresponding author. Tel: +49 5731 972292. E-mail address: ieickhoff{at}hdz-nrw.de


   Abstract
Top
 Abstract
Introduction
 Development and progression of...
 Intervening in patients at...
 HDL and plaque stability
 Conclusions
 References
 
Patients with prior cardiovascular disease and/or diabetes are at the highest risk of a myocardial infarction or stroke. Thus, the majority of morbid cardiovascular events arise in the large population of patients with qualifying risk factors, according to standard risk factor scoring techniques. Angiography studies suggest that a substantial proportion of myocardial infarctions arise in vessels without severe atherosclerotic stenosis on initial examination. The rupture of the fibrous cap of the mature atherosclerotic plaque usually initiates intra-arterial thrombosis and is rendered more likely by additional factors such as inflammation, hyperglycaemic spikes, and mechanical or shear stress in the artery wall. The vulnerability of plaques to rupture is therefore an important determinant of outcome, and treatment strategies in patients with cardiovascular disease should address this issue. Continuing improvements in cardiac-imaging techniques raise the possibility of routine assessment of plaque stability in the future, which will facilitate the identification of vulnerable plaques and the delivery of appropriate treatment. Recent evidence from a large observational study suggests that low HDL-cholesterol not only drives atherosclerosis progression but also increases plaque vulnerability. Correcting low HDL-cholesterol, for example, with nicotinic acid or a fibrate, appears a rational strategy for addressing the continuing burden of atherothrombotic disease.

Key Words: Atherosclerosis • Diabetes • Dyslipidaemia • Cardiovascular risk factors • HDL-cholesterol • Metabolic syndrome


   Introduction
Top
 Abstract
 Introduction
Development and progression of...
 Intervening in patients at...
 HDL and plaque stability
 Conclusions
 References
 
Preventing the progression of atherosclerosis or inducing regression of atherosclerotic plaques is central to strategies aimed at improving cardiovascular prognosis.1,2 However, the extent of atherosclerosis is not the only factor determining the risk of an adverse cardiovascular outcome. The mature atherosclerotic plaque is covered by a thin, fibrous cap that shields the thrombogenic lipid core from the bloodstream, and rupture of this cap is believed to be the terminal event that precipitates the intravascular thrombosis that heralds the onset of a myocardial infarction or stroke.3

Increasing levels of the atheroprotective lipoprotein, HDL-cholesterol, may not only contribute to the inhibition of atherogenesis but may also exert numerous other potentially beneficial actions including stabilization of the atherosclerotic plaque.4 This review describes the pathophysiology of coronary heart disease and considers the potential contribution of elevating HDL-cholesterol to cardiovascular protection through reduced atherosclerotic progression and increased plaque stability.


   Development and progression of coronary heart disease
Top
 Abstract
 Introduction
 Development and progression of...
Intervening in patients at...
 HDL and plaque stability
 Conclusions
 References
 
Epidemiology of sudden cardiac death
Patient populations with evidence of prior coronary disease are at high risk of subsequent coronary events, and cardiovascular management guidelines recommend intensive intervention against coronary risk factors in this population.1,2 However, it is important to understand that although the highest incidence of coronary events occurs in such patients, the greatest number of cardiovascular events overall occurs in the much larger general population with qualifying risk factors, but without a history of manifest ischaemic events or diagnosed organ damage. Conversely, the absolute number of cardiac deaths derives from this much greater fraction in the overall population.5

These considerations are clinically important, as interventions in the highest-risk groups may provide highly significant risk reductions, but actually address only a fraction of the overall burden of cardiovascular risk in the population. Consistent with these observations, angiographic measurement of coronary luminal stenosis has proved a poor predictor of progression to myocardial infarction. In one study, angiograms were reviewed before and after the development of myocardial infarction. Only 22% of one group of patients (n=23) had stenosis >70% on the initial, pre-infarction angiogram in the coronary artery that subsequently occluded.6 A further study in 92 patients showed that 78% of coronary artery segments that gave rise to subsequent myocardial infarction did not display clinically significant stenosis on angiography.7 These and other similar findings8–10 demonstrate that coronary thrombosis often arises from coronary arteries without severe atherosclerotic disease.

Pathophysiology of atherogenesis
Atherogenesis arises through a complex interplay of humoral and molecular factors.11–13 Typically, activation of the arterial endothelium is an early step in atherosclerosis and may arise from a number of cardiometabolic derangements, including oxidative stress (e.g. from smoking or formation of advanced glycation end-products in the setting of hyperglycaemia), mechanical stress due to high blood pressure, or reduced endothelial function secondary to insulin resistance. The activated endothelium expresses adhesion molecules, such as E-selectin, which bind monocytes loosely to the endothelial surface. The chemotactic factor, monocyte chemoattractant protein-1, mediates tight binding of monocytes and infiltration into the vessel wall where they take up lipids avidly (especially oxidized LDL) and differentiate into macrophages under the influence of macrophage colony-stimulating factor and other chemokines. These macrophages, in turn, become foam cells, and then break down to form fatty streaks, thus providing the beginnings of the lipid core of the mature atherosclerotic plaque.

Typically, this accumulation of lipids drives the growth of the atherosclerotic plaque for about three decades.14 However, the inflammatory cells that invade the arterial wall during atherogenesis also secrete a range of inflammatory substances and growth factors, which profoundly influence the properties of the arterial wall. Thus, from about the fourth decade of atherosclerosis onwards, proliferation of smooth muscle cells and deposition of collagen contribute increasingly to the overall formation of the plaque.14 The contents of the plaque are contained within a collagen-rich fibrous cap, which stabilizes the plaque and prevents access of its thrombogenic core to the bloodstream. This cap is itself continually remodelled, with simultaneous removal and replacement of collagen.3,15 Clearly, any reduction in the strength of the fibrous cap during this process may increase the likelihood of plaque rupture, believed to be the most common precipitating event for coronary thrombosis and myocardial infarction, and an important cause of unstable angina pectoris where coronary occlusion is incomplete.3 The likelihood of myocardial infarction therefore depends on a complex balance between the composition (stability) of the plaque and the presence of external stimuli, such as inflammation, mechanical or shear stresses, and hyperglycaemic episodes, which may by themselves or in combination induce plaque rupture.15


   Intervening in patients at risk of adverse cardiovascular outcomes
Top
 Abstract
 Introduction
 Development and progression of...
 Intervening in patients at...
HDL and plaque stability
 Conclusions
 References
 
The metabolic syndrome as a marker of increased atherothrombotic risk
Atherosclerosis and thrombosis contribute importantly to the development of a myocardial infarction, as discussed earlier, and the term ‘atherothrombotic’ describes this process more accurately than either component alone.13,16 In recent years, the concept of the metabolic syndrome (sometimes referred to as the insulin resistance syndrome) has been developed as a practical tool for identifying patients at risk of an atherothrombotic event. The most-used criteria for the diagnosis of the metabolic syndrome, proposed by the US National Cholesterol Education Program/Adult treatment Panel III (NCEP/ATPIII)2 and by the International Diabetes Federation (IDF),17 each depend on the presence of three of five cardiovascular risk factors, based on abdominal obesity (high waist circumference), low HDL-cholesterol, hypertriglyceridaemia, high blood pressure, and hyperglycaemia (high waist circumference is mandatory for diagnosis according to the IDF criteria). However, it is well recognized that a cluster of other cardiovascular risk factors related to thrombosis are also associated with the metabolic syndrome, including impaired endogenous fibrinolysis secondary to increased levels of plasminogen activator inhibitor-1, and increases in circulating fibrinogen, and liquid phase coagulation factors such as factor VII, von Willebrand factor, etc.16,18

The atherothrombotic disturbances associated with the metabolic syndrome are likely to markedly increase the risk of intravascular occlusion at the site of a vulnerable plaque and may account for a substantial proportion of the excess cardiovascular risk associated with the metabolic syndrome. Establishing adequate control of these risk factors therefore remains a principal goal of therapy to prevent or delay the onset of established cardiovascular disease.19 Controlling cardiovascular risk factors is often more difficult in diabetic than in non-diabetic patients, highlighting the need for intensive intervention in this population.20

Quantifying myocardial perfusion disturbances
The standard method for identifying coronary impairment has been the appearance of adverse ECG changes during an exercise test. This test is relatively simple to perform, but is relatively unspecific and may be confounded by pathophysiological variables.21,22 Recent advances in echocardiography or myocardial perfusion-imaging techniques have enabled the detection of defects in regional myocardial perfusion. So, associations with atherothrombotic lesions can be studied directly and non-invasively in patients simultaneously subjected to myocardial stress through exercise or administration of a vasodilator drug.23,24 Although a detailed review of this area is beyond the scope of this review, a brief description of the principal techniques involved is provided subsequently.

ECG-gated single-photon emission computed tomography (SPECT) is a particularly powerful diagnostic tool, as it allows simultaneous measurement of myocardial perfusion and left ventricular (LV) ejection fraction.24,25 These techniques have been found to provide useful additional prognostic information to standard cardiovascular risk assessments on the basis of risk factor scoring. A new generation of hybrid scanners can now combine the anatomical and functional information from SPECT and CT scanning.

Positron emission tomography allows simultaneous measurement of myocardial perfusion and myocardial metabolism by the use of specific tracers for each. A recent study applied this technique to 28 patients with diabetes and ischaemic LV dysfunction and who were managed with medical therapy (i.e. no revascularization).26 Seventeen patients died during a follow-up period of 4.3 years. Patients were stratified according to whether a mismatch was present between LV perfusion and metabolism. The presence of such a mismatch was highly predictive of mortality [risk ratio 3.98 (95% CI 1.33–11.91); P=0.013].

Electron beam computed tomography measures the amount of calcium within the coronary arteries. As calcification of the coronaries accompanies atherosclerosis, this technique provides a quantitative index of the extent of atherosclerosis, which appears to be prognostic and can be used to monitor the atherosclerotic process over time.27–29 These imaging techniques permit visualization of atherosclerosis and promise to contribute importantly to cardiovascular risk stratification, including patients with diabetes and/or less advanced atherosclerosis, for whom conventional risk scoring may underestimate the true cardiovascular risk. In future, advances in tracer technology in combination with these imaging modalities may allow us to distinguish between stable and unstable plaques, for example, by quantitative assessment of inflammatory processes occurring within the coronary artery wall.


   HDL and plaque stability
Top
 Abstract
 Introduction
 Development and progression of...
 Intervening in patients at...
 HDL and plaque stability
Conclusions
 References
 
Antiatherogenic mechanisms of HDL
HDL provides the principal means by which excess cholesterol can be removed from peripheral tissues, including the foam cells of the evolving atherosclerotic plaque, and returned to the liver for catabolism or recycling.30 At the molecular level, HDL inhibits atherosclerosis at multiple sites, including reduced adhesion of inflammatory cells to the endothelium and their migration into the arterial intima, reduced inflammation within the artery wall, and inhibition of LDL oxidation.30 The promotion of reverse cholesterol transport by HDL implies a beneficial effect on atheroma volume, whereas the anti-inflammatory effects of HDL may promote plaque stability and reduced risk of plaque rupture.

This aspect of HDL action was evaluated in the Tromsø study, a 7-year, prospective, population-based observational study of carotid plaque progression measured using ultrasound in 1952 subjects with evidence of carotid atherosclerosis at baseline.31 Patients were stratified into quintiles for a range of cardiovascular risk factors, of which only HDL-cholesterol, age, smoking, and systolic blood pressure were significantly related to atherosclerosis progression in a multivariate analysis, whereas total cholesterol or triglycerides were not. Subjects with HDL-cholesterol in the highest quintile had markedly lower progression of atherosclerosis compared with patients in the other quintiles (Figure 1). Denser plaques that became more echogenic on ultrasound examination during follow-up grew less quickly than plaques that tended to remain more echolucent (Figure 2).


Figure 0391
View larger version (12K):
[in this window]
[in a new window]
  		Figure 1 HDL and stabilization of carotid atherosclerotic plaques in the Tromsø study. Figures in columns are levels of HDL-cholesterol corresponding to each quintile (divide by 0.02586 to convert to mg/dL).31 Reproduced with permission from Lippincott, Williams & Wilkins.

 

Figure 0392
View larger version (12K):
[in this window]
[in a new window]
  		Figure 2 Relationship between echogenicity and stability of plaques in the Tromsø study.31 Reproduced with permission from Lippincott, Williams & Wilkins.

 
The Tromsø study group had previously found that denser, more echogenic plaques were associated with higher levels of HDL-cholesterol.32 The lipid core of an atherosclerotic plaque is echolucent on ultrasound, whereas the fibrous component is echodense. These findings were therefore consistent with enhanced removal of lipid from the atherosclerotic plaque in patients with higher levels of HDL, leading to the formation of denser, slower-growing plaques with a relatively higher proportion of fibrous material. Thus, higher levels of HDL tended to stabilize plaques and inhibit their growth. This important study provides evidence for antiatherogenic effects of HDL, relating to both inhibition of plaque growth and enhanced plaque stability. These findings are further extended by a recent population-based observational cohort study in the UK in 18 815 patients.33

Effectiveness of interventions to increase HDL-cholesterol
Low HDL-cholesterol is an independent risk factor for atherothrombotic coronary events, and correction of low HDL-cholesterol reduced coronary event rates significantly in a number of randomized intervention trials (reviewed elsewhere).34,35 The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) illustrates the benefits of intervening to correct the lipid profile in a patient population with low HDL-cholesterol at baseline.36 Stratification for levels of lipids in this study (Figure 3) showed that the placebo event rate was highest for patients in the highest tertile for LDL-cholesterol and also for patients in the lowest tertile for HDL-cholesterol (or the highest tertile for the ratio of LDL-cholesterol to HDL-cholesterol).37 Interestingly, patients with the lowest HDL-cholesterol appeared to derive greatest benefits from intervention with a statin (Figure 3), consistent with their higher overall cardiovascular risk.


Figure 0393
View larger version (11K):
[in this window]
[in a new window]
  		Figure 3 Relationship between levels of lipoprotein parameters at baseline and subsequent coronary event rates while receiving placebo or a statin in AFCAPS/TexCAPS.37 Reproduced with permission from Lippincott, Williams & Wilkins.

 
Two classes of agents are currently available for increasing levels of HDL-cholesterol: fibrates and nicotinic acid2; randomized trials have evaluated the effects of each class of agent on the lipid profile and on progression of atherosclerosis.35 Figure 4A shows the effects of fenofibrate on these treatment outcomes in the Diabetes Atherosclerosis Intervention Study (DAIS).38 Treatment with the fibrate for at least 3 years increased HDL-cholesterol by ~8%, but the main effect of treatment was a reduction in triglycerides of ~30%. Indices of atherosclerosis progression on angiography were reduced, including the 42% reduction in per cent stenosis shown in Figure 4A.


Figure 0394
Figure 0394
View larger version (24K):
[in this window]
[in a new window]
  		Figure 4 Effects of a fibrate or Niaspan on lipids and atherosclerosis progression in randomized trials. (A) The DAIS. Reprinted from The Diabetes Atherosclerosis Intervention Study.37 Copyright (2001) with permission from Elsevier. (B) The ARBITER 2. Significance values are relative to baseline (NS, not significant). Left-hand panel drawn from data presented by Taylor et al.39 and right-hand panel reproduced from Taylor et al.,39 with permission from Lippincott, Williams & Wilkins.

 
Nicotinic acid is the most powerful agent currently available for increasing HDL-cholesterol.2 The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study39 evaluated the anti-atherogenic effects of Niaspan®, a prolonged-release formulation of nicotinic acid with equivalent HDL-raising efficacy but superior tolerability relative to the immediate-release formulation,40 in patients with low HDL-cholesterol who were already receiving a statin. As expected, a marked increase in HDL-cholesterol of ~20% was observed after treatment with Niaspan (Figure 4B). Carotid ultrasound measurements at baseline and after 1 year of treatment showed that significant progression of atherosclerosis was observed only in the statin-alone group.


   Conclusions
Top
 Abstract
 Introduction
 Development and progression of...
 Intervening in patients at...
 HDL and plaque stability
 Conclusions
References
 
Identifying and managing patients with atherosclerotic plaques that are vulnerable to rupture and thrombosis will receive increasing emphasis in routine cardiovascular care in the future. Improvements in cardiac-imaging methodologies and therapeutic intervention strategies to stabilize plaques are likely to contribute to improved outcomes in these high-risk patients, in addition to interventions to slow or reverse the progression of atherosclerosis itself. We already have strong observational evidence that correcting low HDL-cholesterol is likely to achieve both reduced atherosclerosis burden and improved plaque stability, indicating a marked improvement in overall atherothrombotic risk.

Conflict of interest: D.T. is a member of the speakers bureau of Merck KGaA. B.S. has no conflict of interest to declare.


   References
Top
 Abstract
 Introduction
 Development and progression of...
 Intervening in patients at...
 HDL and plaque stability
 Conclusions
 References
 

  1. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Cats VM, Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D. (2003) European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil 10:Suppl. 1, S1–S78.[CrossRef][ISI][Medline]
  2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. (2001) Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497.[Free Full Text]
  3. Kullo IJ, Edwards WD, Schwartz RS. (1998) Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med 129:1050–1060.[Abstract/Free Full Text]
  4. Moreno PR and Fuster V. (2004) New aspects in the pathogenesis of diabetic atherothrombosis. J Am Coll Cardiol 44:2293–2300.[Abstract/Free Full Text]
  5. Huikuri HV, Castellanos A, Myerburg RJ. (2001) Sudden death due to cardiac arrhythmias. N Engl J Med 345:1473–1482.[Free Full Text]
  6. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. (1988) Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 12:56–62.[Abstract]
  7. Giroud D, Li JM, Urban P, Meier B, Rutishauer W. (1992) Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography. Am J Cardiol 69:729–732.[CrossRef][ISI][Medline]
  8. Ambrose JA, Winters SL, Arora RR, Eng A, Riccio A, Gorlin R, Fuster V. (1986) Angiographic evolution of coronary artery morphology in unstable angina. J Am Coll Cardiol 7:472–478.[Abstract]
  9. Falk E, Shah PK, Fuster V. (1995) Coronary plaque disruption. Circulation 92:657–671.[Free Full Text]
  10. Pasterkamp G, Schoneveld AH, van der Wal AC, Haudenschild CC, Clarijs RJ, Becker AE, Hillen B, Borst C. (1998) Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol 32:655–662.[Abstract/Free Full Text]
  11. Berliner J and Yla-Herttuala S. (1998) The atherosclerotic lesion: a dynamic landscape. Curr Opin Lipidol 9:385–386.[CrossRef][ISI][Medline]
  12. Takahashi K, Takeya M, Sakashita N. (2002) Multifunctional roles of macrophages in the development and progression of atherosclerosis in humans and experimental animals. Med Electron Microsc 35:179–203.[CrossRef][Medline]
  13. Roesen P, Ferber P, Tschoepe D. (2001) Macrovascular disease in diabetes: current status. Exp Clin Endocrinol Diabetes 109:Suppl. 2, S474–S486.
  14. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr., Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. (1995) A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92:1355–1374.[Abstract/Free Full Text]
  15. Pasterkamp C and Falk E. (2000) Atherosclerotic plaque rupture: an overview. J Clin Bas Cardiol 3:81–86.
  16. Kohler HP. (2002) Insulin resistance syndrome: interaction with coagulation and fibrinolysis. Swiss Med Wkly 132:241–252.[Medline]
  17. Alberti KGM, Zimmet P, Shaw J. (2005) The metabolic syndrome—a new worldwide definition. Lancet 366:1059–1062.[CrossRef][ISI][Medline]
  18. Grant PJ. (2003) Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab 29:6S44–6S52.[Medline]
  19. Howard BV, Rodriguez BL, Bennett PH, Harris MI, Hamman R, Kuller LH, Pearson TA, Wylie-Rosett J. (2002) Prevention Conference VI: diabetes and cardiovascular disease: Writing Group I: epidemiology. Circulation 105:e132–e137.[Free Full Text]
  20. Saydah SH, Fradkin J, Cowie CC. (2004) Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 291:335–342.[Abstract/Free Full Text]
  21. Yamazaki T, Myers J, Froelicher VF. (2004) Effect of age and end point on the prognostic value of the exercise test. Chest 125:1920–1928.[Abstract/Free Full Text]
  22. Mora S, Redberg RF, Cui Y, Whiteman MK, Flaws JA, Sharrett AR, Blumenthal RS. (2003) Ability of exercise testing to predict cardiovascular and all-cause death in asymptomatic women: a 20-year follow-up of the lipid research clinics prevalence study. JAMA 290:1600–1607.[Abstract/Free Full Text]
  23. Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ, Davis JL, Douglas PS, Faxon DP, Gillam LD, Kimball TR, Kussmaul WG, Pearlman AS, Philbrick JT, Rakowski H, Thys DM, Antman EM, Smith SC Jr., Alpert JS, Gregoratos G, Anderson JL, Hiratzka LF, Hunt SA, Fuster V, Jacobs AK, Gibbons RJ, Russell RO. American College of Cardiology; American Heart Association; American Society of Echocardiography. (2003) ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation 108:1146–1162.[Free Full Text]
  24. Klocke FJ, Baird MG, Lorell BH, Bateman TM, Messer JV, Berman DS, O'Gara PT, Carabello BA, Russell RO Jr., Cerqueira MD, St John Sutton MG, DeMaria AN, Udelson JE, Kennedy JW, Verani MS, Williams KA, Antman EM, Smith SC Jr., Alpert JS, Gregoratos G, Anderson JL, Hiratzka LF, Faxon DP, Hunt SA, Fuster V, Jacobs AK, Gibbons RJ, Russell RO. American College of Cardiology; American Heart Association; American Society for Nuclear Cardiology. (2003) ACC/AHA/ASNC Guidelines for the clinical use of cardiac radionuclide imaging. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 guidelines for the clinical use of cardiac radionuclide imaging. J Am Coll Cardiol 42:1318–1333.[Free Full Text]
  25. Sabharwal NK and Lahiri A. (2003) Role of myocardial perfusion imaging for risk stratification in suspected or known coronary artery disease. Heart 89:1291–1297.[Abstract/Free Full Text]
  26. Sawada S, Hamoui O, Barclay J, Giger S, Fain R, Foltz J, Fineberg N, Hutchins G. (2005) Usefulness of positron emission tomography in predicting long-term outcome in patients with diabetes mellitus and ischaemic left ventricular dysfunction. Am J Cardiol 96:2–8.[ISI][Medline]
  27. Schmermund A, Mohlenkamp S, Erbel R. (2003) Coronary artery calcium and its relationship to coronary artery disease. Cardiol Clin 21:521–534.[CrossRef][Medline]
  28. Hosoi M, Sato T, Yamagami K, Hasegawa T, Yamakita T, Miyamoto M, Yoshioka K, Yamamoto T, Ishii T, Tanaka S, Itoh A, Haze K, Fujii S. (2002) Impact of diabetes on coronary stenosis and coronary artery calcification detected by electron-beam computed tomography in symptomatic patients. Diabetes Care 25:696–701.[Abstract/Free Full Text]
  29. Mielke CH, Shields JP, Broemeling LD. (2001) Coronary artery calcium, coronary artery disease, and diabetes. Diabetes Res Clin Pract 53:55–61.[CrossRef][ISI][Medline]
  30. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. (2004) Antiinflammatory properties of HDL. Circ Res 95:764–772.[Abstract/Free Full Text]
  31. Johnsen SH, Mathiesen EB, Fosse E, Joakimsen O, Stensland-Bugge E, Njolstad I, Arnesen E. (2005) Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis the Tromsø study. Circulation 112:498–504.[Abstract/Free Full Text]
  32. Mathiesen EB, Bønaa KH, Joakimsen O. (2001) Low levels of high-density lipoprotein cholesterol are associated with echolucent carotid artery plaques: the Tromsø study. Stroke 32:1960–1965.[Abstract/Free Full Text]
  33. Wei L, Murphy MJ, MacDonald TM. (2006) Impact on cardiovascular events of increasing high density lipoprotein cholesterol with and without lipid lowering drugs. Heart 92:746–751.[Abstract/Free Full Text]
  34. Kastelein JJP. (2005) The realities of dyslipidaemia: what do the studies tell us? Eur Heart J 7:Suppl. F, F27–F33.
  35. Brown BG. (2005) Maximizing coronary disease risk reduction using nicotinic acid combined with LDL-lowering therapy. Eur Heart J 7:Suppl. F, F34–F40.
  36. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279:1615–1622.[Abstract/Free Full Text]
  37. Gotto AM Jr., Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. (2000) Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 101:477–484.[Abstract/Free Full Text]
  38. The Diabetes Atherosclerosis Intervention Study (DAIS). (2001) Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 357:905–910.[CrossRef][ISI][Medline]
  39. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. (2004) Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 110:3512–3517.[Abstract/Free Full Text]
  40. McGovern ME. (2005) Niaspan®: creating a new concept for raising HDL-cholesterol. Eur Heart J 7:Suppl. F, F41–F47.[CrossRef]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Tschoepe, D.
Right arrow Articles by Stratmann, B.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Tschoepe, D.
Right arrow Articles by Stratmann, B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?