What a vascular surgeon should know and do about atherosclerotic risk factors
2009; Elsevier BV; Volume: 49; Issue: 5 Linguagem: Inglês
10.1016/j.jvs.2008.12.046
ISSN1097-6809
AutoresChristos D. Liapis, Efthymios D. Avgerinos, Nikolaos P.E. Kadoglou, John D. Kakisis,
Tópico(s)Peripheral Artery Disease Management
ResumoAtherosclerosis is a systematic disease presenting with a significant overlapping of cardiovascular disorders implicating coronary heart disease and its equivalents, peripheral arterial disease, carotid arterial disease, and aneurysm disease. Evaluating patient's atherosclerotic risk profile is essential to guide primary and secondary prevention. Atherosclerotic risk factor modifications reduce, significantly, cardiovascular disease mortality and morbidity, particularly in high-risk patients. This article provides a reference guide for all conventional (eg, smoking, dyslipidemia, hypertension) and evolving (eg, homocysteine, C-reactive protein, fibrinogen, inflammatory markers) risk factors of atherosclerosis and recommends the currently effective strategies for an overall cardiovascular risk reduction. As vascular surgeons, by definition, conduct the overall management of patients with vascular disease understanding of the development, assessment, and management of atherosclerotic risk factors should remain among their highest priorities. Atherosclerosis is a systematic disease presenting with a significant overlapping of cardiovascular disorders implicating coronary heart disease and its equivalents, peripheral arterial disease, carotid arterial disease, and aneurysm disease. Evaluating patient's atherosclerotic risk profile is essential to guide primary and secondary prevention. Atherosclerotic risk factor modifications reduce, significantly, cardiovascular disease mortality and morbidity, particularly in high-risk patients. This article provides a reference guide for all conventional (eg, smoking, dyslipidemia, hypertension) and evolving (eg, homocysteine, C-reactive protein, fibrinogen, inflammatory markers) risk factors of atherosclerosis and recommends the currently effective strategies for an overall cardiovascular risk reduction. As vascular surgeons, by definition, conduct the overall management of patients with vascular disease understanding of the development, assessment, and management of atherosclerotic risk factors should remain among their highest priorities. Atherosclerosis is a systematic disease frequently presenting with a significant overlapping of disorders implicating coronary heart disease (CHD) and its equivalents, peripheral arterial disease (PAD), carotid arterial disease (CAD), and aneurysms. Under this prism, risk reduction in atherosclerotic patients is not targeting CHD, PAD, CAD, or aneurysmal disease individually—but all of them—towards improvement of the quality of life and long-term survival. Evaluating a patient's global atherosclerotic risk profile has been proven essential to accurately predict the cardiovascular risk and guide primary and secondary prevention.1Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. et al.European guidelines on cardiovascular disease prevention in clinical practice: Executive summary.Atherosclerosis. 2007; 194: 1-45Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar All patients presenting with angina, claudication, stroke, or aneurysm should undergo rigorous assessment of the entire cardiovascular system and of the potentially affected organs. As vascular surgeons, conduct by definition, the overall management of patients with vascular disease understanding of the development and assessment of atherosclerotic risk factors should remain among their highest priorities. During recent years, the establishment of conventional and predisposing risk factors and the concurrent evolution of multiple emerging risk factors have raised cardiovascular risk reduction to a considerable challenge; however, few vascular surgeons are adequately assessing risk of atherosclerosis and patients fail to achieve desired treatment targets.2Leon Jr, L.R. Labropoulos N. Lebda P. Kalman P.G. The vascular surgeon's role in risk factor modification: results of a survey.Perspect Vasc Surg Endovasc Ther. 2005; 17: 145-153Crossref PubMed Scopus (11) Google Scholar, 3Bianchi C. Montalvo V. Ou H.W. Bishop V. Abou-Zamzam Jr, A.M. Pharmacologic risk factor treatment of peripheral arterial disease is lacking and requires vascular surgeon participation.Ann Vasc Surg. 2007; 21: 163-166Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar This review addresses current knowledge about atherosclerotic risk factors and their contemporary management. The prevalence and severity of atherosclerosis among individuals and groups are related to several "old" and "new" risk factors. So far, there is no universal agreement on the exact classification of the various cardiovascular risk factors and markers. A reasonable classification system was proposed by the American Heart Association (AHA) Prevention Conference statement in 1999 that divided risk factors into the following three categories:1the traditional and conventional risk factors that appear to have a direct causal role in atherogenesis,2the predisposing factors that mediate some risk through the causal factors but may also have independent effects, and3the conditional risk factors that have "an association with an increased risk of coronary artery disease although their causative, independent, and quantitative contributions to coronary artery disease are not well documented." These factors may enhance risk in the presence of the causative risk factors, hence the term conditional.4Grundy S.M. Pasternak R. Greenland P. Smith Jr, S. Fuster V. Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology.Circulation. 1999; 100: 1481-1492Crossref PubMed Scopus (914) Google Scholar, 5Smith Jr, S.C. Greenland P. Grundy S.M. Prevention conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary.Circulation. 2000; 101: 111-116Crossref PubMed Google Scholar To adapt this classification system into current knowledge and practice, significant changes need to be applied and not only within the three proposed categories. A novel category of emerging risk factors is now necessary to cover the entire spectrum of evolving markers of atherosclerosis, particularly biomarkers. These emerging risk factors, although extensively assessed, still need further confirmatory studies to pass into clinical practice.6Kullo I.J. Ballantyne C.M. Conditional risk factors for atherosclerosis.Mayo Clin Proc. 2005; 80: 219-230Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar As soon as the evidence is sufficient, some of these will transit to the category of conditional risk factors, but it remains to be elucidated which ones will ever prove to be predisposing or even conventional. Thus, a contemporary classification of risk factors is proposed in the Table.1Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. et al.European guidelines on cardiovascular disease prevention in clinical practice: Executive summary.Atherosclerosis. 2007; 194: 1-45Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 4Grundy S.M. Pasternak R. Greenland P. Smith Jr, S. Fuster V. Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology.Circulation. 1999; 100: 1481-1492Crossref PubMed Scopus (914) Google Scholar, 5Smith Jr, S.C. Greenland P. Grundy S.M. Prevention conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary.Circulation. 2000; 101: 111-116Crossref PubMed Google Scholar, 6Kullo I.J. Ballantyne C.M. Conditional risk factors for atherosclerosis.Mayo Clin Proc. 2005; 80: 219-230Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 7Pearson T.A. Mensah G.A. Alexander R.W. Anderson J.L. Cannon 3rd, R.O. Criqui M. et al.Markers of inflammation and cardiovascular disease Application to clinical and public health practice. A statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association.Circulation. 2003; 107: 499-511Crossref PubMed Scopus (4874) Google Scholar, 8Liapis C.D. Atherosclerosis risk factor treatment–general considerations.in: Cronenwett J. Johnston D. Rutherford's vascular surgery. 7th ed. W.B. Saunders, Philadelphia, PA2009Google Scholar, 9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google ScholarTableCategories of risk factors for atherosclerosis and cardiovascular diseases8Liapis C.D. Atherosclerosis risk factor treatment–general considerations.in: Cronenwett J. Johnston D. Rutherford's vascular surgery. 7th ed. W.B. Saunders, Philadelphia, PA2009Google ScholarConventionalPredisposingConditionalEmerging (Novel)SmokingAdvanced ageHomocysteineInflammatory markers: Serum amyloid A, WBC count, cytokines (IL-1β, IL-6, IL-10, IL-18, MCP-1 etc), cell adhesion molecules (ICAM-1, VCAM-1, P-selectin, etc), soluble CD40 ligand, protease activated receptors, ESR, lipoprotein-associated PLA2DiabetesGender: male sex, postmenopausal womenCRP (hsCRP)Infectious agents: Chlamydia pneumoniae, CMV, HSV 1 and 2, Helicobacter pylori, hepatitis ADyslipidemiaOverweight/obesityFibrinogenVascular calcification markers: osteopontin, osteoprotegerin, setuinHypertensionInsulin resistanceLipoprotein (a)Hypercoagulable states and hemostatic factors: lupus anticoagulant, D-dimers, markers of platelet activation, TPA, PAI-1, prothrombin 1 and 2, protein ZPhysical inactivityHypertriglyceridemiaMatrix metalloproteinasesFamily history/geneticsEndothelial progenitor cellsSocioeconomic factors, race, and ethnicityAdipokines: leptin, adiponectinMicroalbuminuria, creatinine, urateOxidative stress: ox-LDL, LOX-1, myeloperoxidase, oxidant capacity, ROS, etcMiscellaneous: alcohol, PAPPA-A, asymmetric dimethylarginine, HSP sdLDLCMV, Cytomegalovirus; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; hsCRP, high-sensitivity C-reactive protein; HSP, heat-shock proteins; HSV, herpes simplex virus; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; MCP-1, monocyte chemotactic protein-1; ox-LDL, oxidized low-density lipoprotein; PAI-1, plasminogen activator inhibitor-1; PAPPA, pregnancy-associated plasma protein-A; PLA2, phospholipase A2; ROS, reactive oxygen species; sdLDL, small dense low-density lipoprotein; TPA, tissue plasminogen activator; VCAM-1, vascular cell adhesion molecule-1; WBC, white blood cell. Open table in a new tab CMV, Cytomegalovirus; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; hsCRP, high-sensitivity C-reactive protein; HSP, heat-shock proteins; HSV, herpes simplex virus; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; MCP-1, monocyte chemotactic protein-1; ox-LDL, oxidized low-density lipoprotein; PAI-1, plasminogen activator inhibitor-1; PAPPA, pregnancy-associated plasma protein-A; PLA2, phospholipase A2; ROS, reactive oxygen species; sdLDL, small dense low-density lipoprotein; TPA, tissue plasminogen activator; VCAM-1, vascular cell adhesion molecule-1; WBC, white blood cell. Four major risk factors for vascular disease (all four modifiable!) have been confirmed: smoking, diabetes mellitus, dyslipidemia, and hypertension. Smoking is associated with a marked twofold increased risk for cerebrovascular and fourfold increased risk for peripheral vascular disease. The number of pack-years is associated with global atherosclerotic disease severity, including a higher risk of stroke, and an increased risk of amputation, peripheral graft occlusion, and death.9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar Recommended practice1Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. et al.European guidelines on cardiovascular disease prevention in clinical practice: Executive summary.Atherosclerosis. 2007; 194: 1-45Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar•All patients should be strongly advised to stop smoking•Suggest referral to a smoking cessation clinic•Suggest antidepressant drug therapy (bupropion or nortriptyline) and nicotine replacement therapy (gum, patch, inhaler, etc), as single or combined therapies Diabetes, predominately type 2, is a clear risk factor for stroke, particularly ischemic stroke, with prospective studies reporting up to a threefold increase of the relative risk and a more severe stroke-related disability and mortality. Although diabetes has been found to be associated with angiographically demonstratable extracranial carotid and basilar artery occlusion, few reports have clarified the influence of diabetes on large vessel cranial atherosclerosis.11Kameyama M. Fushimi H. Udaka F. Diabetes mellitus and cerebral vascular disease.Diabetes Res Clin Practice. 1994; 24: S205-S208Abstract Full Text PDF PubMed Scopus (42) Google Scholar Diabetes is one of the strongest predictors for PAD (twofold increase of relative risk of intermittent claudication) and its associated complications, including higher amputation (up to 10-fold increase) and mortality rates.9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar Recommended practice1Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. et al.European guidelines on cardiovascular disease prevention in clinical practice: Executive summary.Atherosclerosis. 2007; 194: 1-45Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 12Gaede P. Vedel P. Larsen N. Jensen J.V. Parving H.H. Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3699) Google Scholar, 13ADAStandards of medical care in diabetes.Diabetes Care. 2006; 29: S4-S42PubMed Google Scholar•Aim hemoglobin A1C <7.0%•Aim hemoglobin A1C <6.0% for high-risk patients•Encourage lifestyle changes, such as diet and exercise•Control other risk factors such as smoking, hypertension, and dyslipidemia Several epidemiologic studies have clearly shown that total hypercholesterolemia is among the most important risk factors for CHD and PAD; however, whether serum cholesterol levels are related to stroke and CAD incidence is not yet established. Particularly for PAD, independent lipidemic risk factors include elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein (a). Elevated levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (a-1), the major protein component of HDL-C, seem to confer a protective effect.9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar Low HDL-C, high triglycerides, and more recently, high lipoprotein (a) levels have been also associated with an increased risk of CHD and stroke.9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar Recommended practice1Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. et al.European guidelines on cardiovascular disease prevention in clinical practice: Executive summary.Atherosclerosis. 2007; 194: 1-45Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar, 14HPSCGMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial.Lancet. 2002; 360: 7-22Abstract Full Text Full Text PDF PubMed Scopus (7461) Google Scholar, 15Grundy S.M. Cleeman J.I. Merz C.N. Brewer Jr, H.B. Clark L.T. Hunninghake D.B. et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation. 2004; 110: 227-239Crossref PubMed Scopus (4950) Google Scholar, 16Smith Jr, S.C. Allen J. Blair S.N. Bonow R.O. Brass L.M. Fonarow G.C. et al.AHA/ACC Guidelines for secondary prevention of patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung and Blood Institute.Circulation. 2006; 113: 2363-2372Crossref PubMed Scopus (1500) Google Scholar Primary targets •Aim LDL-C <2.6 mmol/L (100 mg/dL)•Aim LDL-C 1.0 mmol/L (∼40 mg/dL) in men and >1.2 mmol/L (∼45 mg/dL) in women•Aim triglycerides <1.7 mmol/L (∼150 mg/dL)•Consider fibrates•Consider niacin Hypertension is associated with all forms of cardiovascular disease and the associated mortality increases progressively and linearly with increasing blood pressure levels.17Lewington S. Clarke R. Qizilbash N. Peto R. Collins R. Prospective Studies CollaborationAge-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Abstract Full Text Full Text PDF PubMed Scopus (7183) Google Scholar Recommended practice1Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. et al.European guidelines on cardiovascular disease prevention in clinical practice: Executive summary.Atherosclerosis. 2007; 194: 1-45Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar, 18ESH/ESC2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.J Hypertens. 2003; 21: 1011-1053Crossref PubMed Scopus (3722) Google Scholar•Aim blood pressure <140/90 mm Hg for nondiabetic hypertensive patients•Aim blood pressure <130/80 mm Hg for diabetic hypertensive patients•Encourage lifestyle changes, such as diet and exercise•Prescribe thiazides as the initial drugs to lower blood pressure•Prescribe angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), particularly in patients with diabetic renal disease (but not renal artery stenosis) or congestive heart failure•Prescribe β-adrenergic blockers in patients with concomitant CHD•Prescribe calcium channel blockers for uncontrolled hypertension•Use multiple agents, if needed to achieve desired blood pressure goals Predisposing risk factors for atherosclerosis are those that confer their risk through conventional factors and through potentially independent effects. Those that are nonmodifiable include advanced age, gender (male sex; postmenopausal women), family history and genetics, and race (eg, blacks) and ethnicity (eg, non-Hispanic blacks). Those that are modifiable include overweight and obesity, physical inactivity, insulin resistance (even without diabetes), and socioeconomic-behavioral factors such as social isolation, depression, type A personality, work, and family stress. Recommended practice1Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. et al.European guidelines on cardiovascular disease prevention in clinical practice: Executive summary.Atherosclerosis. 2007; 194: 1-45Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 5Smith Jr, S.C. Greenland P. Grundy S.M. Prevention conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary.Circulation. 2000; 101: 111-116Crossref PubMed Google Scholar, 8Liapis C.D. Atherosclerosis risk factor treatment–general considerations.in: Cronenwett J. Johnston D. Rutherford's vascular surgery. 7th ed. W.B. Saunders, Philadelphia, PA2009Google Scholar, 9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar•Encourage lifestyle changes such as diet and exercise•Control other risk factors, such as smoking, hypertension, and dyslipidemia Conditional risk factors have an association with an increased risk of cardiovascular disease, although their independent contribution is not well documented. They include homocysteine, C-reactive protein (CRP), fibrinogen, lipoprotein (a), and hypertriglyceridemia. Reports from prospective and retrospective studies suggest that elevated homocysteine levels are an independent risk factor for vascular disease associated with a mildly increased risk of CHD, stroke, PAD, and venous thromboembolism.10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar Recommended practice8Liapis C.D. Atherosclerosis risk factor treatment–general considerations.in: Cronenwett J. Johnston D. Rutherford's vascular surgery. 7th ed. W.B. Saunders, Philadelphia, PA2009Google Scholar, 9Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2347) Google Scholar, 10Liapis C.D. Bell P.F. Michailidis D. Sivenius J. Nicolaides A. Fernandes e Fernandes J. et al.ESVS guidelines Prevention and diagnosis of carotid artery disease stenosis.Curr Vasc Pharmacol. 2009; ([in press])Google Scholar•Supplementation with B-vitamins or folate, although regulating homocysteine plasma levels, does not have a proven benefit in cardiovascular risk reduction. Observational and prospective studies have consistently reported that elevated CRP serum levels definitely have prognostic value for cardiovascular events and death. To date, CRP is the only inflammatory marker used in clinical practice, but it needs to be emphasized that the predictive value of CRP can be estimated only through high-precision assays for high-sensitivity CRP. It is within these lower, previously "normal" ranges that the high-sensitivity CRP levels seem to have predictive abilities for cardiovascular events. Recommended practice8Liapis C.D. Atherosclerosis risk factor treatment–general considerations.in: Cronenwett J. Johnston D. Rutherford's vascular surgery. 7th ed. W.B. Saunders, Philadelphia, PA2009Google Scholar, 19Ikonomidis I. Stamatelopoulos K. Lekakis J. Vamvakou G.D. Kremastinos D.T. Inflammatory and non-invasive vascular markers: The multimarker approach for risk stratification in coronary artery disease.Atherosclerosis. 2008; 199: 3-11Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar•Statins, cyclooxygenase inhibitors (eg, aspirin), ACE inhibitors, and ARBs reduce CRP levels, but yet, no proven benefit in cardiovascular risk reduction has been shown. Several prospective studies have associated fibrinogen levels and subsequent cardiovascular disease risk, particularly for CHD and cerebrovascular disease. Some have advocated that fibrinogen may have equal effectiveness as total cholesterol in predicting future risk. However, whether elevated fibrinogen levels are a cause or consequence of atherosclerosis remains unclear. Recommended practice8Liapis C.D. Atherosclerosis risk factor treatment–general considerations.in: Cronenwett J. Johnston D. Rutherford's vascular surgery. 7th ed. W.B. Saunders, Philadelphia, PA2009Google Scholar, 20The Bezafibrate Infarction Prevention (BIP) Study GroupSecondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease.Circulation. 2000; 102: 21-27Crossref PubMed Scopus (1144) Google Scholar•Bezafibrate has been found to reduce fibrinogen levels compared with placebo, but yet no proven benefit in cardiovascular risk reduction has been shown. See the section for dyslipidemia. The list of emerging risk factors for atherosclerosis is expanding, and their detailed analysis goes beyond the scope of the current review because their clinical value remains to be elucidated. Several treatment strategies have been proposed to control these factors; but yet, no proven benefit in cardiovascular risk reduction has been shown. A raw classification of these factors is summarized in the Table. Apart from CRP and fibrinogen, several other inflammatory markers have been associated with atherosclerosis and cardiovascular disease. Serum amyloid A (an apolipoprotein associated with HDL-C), high white blood cell count, cytokines (interleukins 6 and 18, tumor necrosis factor-α [TNF-α], monocyte chemotactic protein-1 [MCP-1]), endothelial adhesion molecules (intercellular adhesion molecule 1, P-selectin, etc), circulating soluble CD40 ligand (an immune mediator), protease-activated receptors (PARs), and lipoprotein-associated phospholipase A2 have been all associated with CHD, CAD, stroke, or PAD. Because of their involvement in the atherosclerotic process, some inflammatory markers became important therapeutic targets. Trials using TNF-α antagonists, such as infliximab and etanercept, failed to show any improvement in cardiac function. Statins have been found to have an independent effect on reducing MCP-1 levels, but not TNF-α.8Liapis C.D. Atherosclerosis risk factor treatment–general considerations.in: Cronenwett J. Johnston D. Rutherford's vascular surgery. 7th ed. W.B. Saunders, Philadelphia, PA2009Google Scholar Several infectious agents have been associated with the formation of atherosclerotic plaque and its complications. Of bacteria, Chlamydia pneumoniae, a human respiratory pathogen, has been most strongly associated with cardiovascular disease, particularly with acute myocardial infarction (MI), cerebrovascular symptoms, PAD, and abdominal aortic aneurysm expansion.21Kaperonis E.A. Liapis C.D. Kakisis J.D. Dimitroulis D. Papavassiliou V.G. Perrea D. et al.Inflammation and Chlamydia pneumoniae infection correlate with the severity of peripheral arterial disease.Eur J Vasc Endovasc Surg. 2006; 31: 509-515Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 22Kaperonis E.A. Liapis C.D. Kakisis J.D. Perrea D. Kostakis A.G. Karayannakos P.E. The association of carotid plaque inflammation and Chlamydia pneumoniae infection with cerebrovascular symptomato
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