Lipoprotein-Associated Phospholipase A2 and Risk of Stroke
2008; Elsevier BV; Volume: 101; Issue: 12 Linguagem: Inglês
10.1016/j.amjcard.2008.04.017
ISSN1879-1913
Autores Tópico(s)Cancer, Lipids, and Metabolism
ResumoStroke is the second-leading cause of death worldwide and is a disabling disease of both older and younger adults. Stroke is also among the most highly preventable disorders because there are well-defined risk factors and preventatives. The establishment of new risk markers or factors for stroke risk assessment provides a new avenue for stroke prevention. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that hydrolyzes oxidized phospholipids, releasing lysophosphatidylcholine, which has proinflammatory properties thought to be involved in the development of atherosclerosis and plaque rupture. In 2005, the Lp-PLA2 blood test was approved by the US Food and Drug Administration (FDA) for assessing the risk of ischemic stroke and coronary artery disease. In epidemiologic studies, low-density lipoprotein cholesterol and other lipid factors have not been shown to be consistent predictors of stroke risk. Lp-PLA2 measures, on the other hand, have shown a consistent association with stroke risk, conferring about a 2-fold increase in stroke occurrence. This relation has been studied in both first and recurrent stroke and is reviewed in this article. Importantly, a recent study has now shown that Lp-PLA2 may increase the area under the curve beyond that of traditional cardiovascular risk factors and C-reactive protein. Therefore, Lp-PLA2 determination may provide a pivotal opportunity to appropriately classify previously misclassified persons who are actually at high risk of stroke and in need of aggressive stroke intervention. Stroke is the second-leading cause of death worldwide and is a disabling disease of both older and younger adults. Stroke is also among the most highly preventable disorders because there are well-defined risk factors and preventatives. The establishment of new risk markers or factors for stroke risk assessment provides a new avenue for stroke prevention. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that hydrolyzes oxidized phospholipids, releasing lysophosphatidylcholine, which has proinflammatory properties thought to be involved in the development of atherosclerosis and plaque rupture. In 2005, the Lp-PLA2 blood test was approved by the US Food and Drug Administration (FDA) for assessing the risk of ischemic stroke and coronary artery disease. In epidemiologic studies, low-density lipoprotein cholesterol and other lipid factors have not been shown to be consistent predictors of stroke risk. Lp-PLA2 measures, on the other hand, have shown a consistent association with stroke risk, conferring about a 2-fold increase in stroke occurrence. This relation has been studied in both first and recurrent stroke and is reviewed in this article. Importantly, a recent study has now shown that Lp-PLA2 may increase the area under the curve beyond that of traditional cardiovascular risk factors and C-reactive protein. Therefore, Lp-PLA2 determination may provide a pivotal opportunity to appropriately classify previously misclassified persons who are actually at high risk of stroke and in need of aggressive stroke intervention. The global burden of stroke is immense. Stroke is the second-leading cause of death throughout the world. Of the 5.7 million annual stroke deaths worldwide, 87% occur in low- and middle-income countries. There are about 16 million first-ever strokes annually. Globally, there are >50 million stroke and transient ischemic attack (TIA) survivors, and ≥1 in 5 survivors will have another stroke within 5 years.1Strong K. Mathers C. Bonita R. Preventing stroke: saving lives around the world.Lancet Neurol. 2007; 6: 182-187Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar In the United States, stroke is the third-leading cause of death, after heart disease and cancer. Stroke accounts for 6% of all deaths in the United States, with as many as 150,000 deaths per year.2Heron M. Deaths: leading causes for 2004.National Vital Statistics Reports. 2007; 56: 1-96Google Scholar, 3Rosamond W. Flegal K. Furie K. Go A. Greenlund K. Haase N. Hailpern S.M. Ho M. Howard V. Kissela B. Kittner S. Lloyd-Jones D. McDermott M. Meigs J. Moy C. Nichol G. O'Donnell C. Roger V. Sorlie P. Steinberger J. Thom T. Wilson M. Hong Y. American Heart Association Statistics Committee and Stroke Statistics SubcommitteeHeart Disease and Stroke Statistics—2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2008; 117: e25-e146Crossref PubMed Scopus (3083) Google Scholar There are about 780,000 new strokes annually, of which 600,000 are first attacks and 180,000 are recurrent strokes. There are approximately 5–6 million stroke survivors in the United States. Stroke is the leading cause of adult disability, with 15%–30% of stroke victims experiencing permanent disability and 20% requiring institutional care at 3 months after onset.3Rosamond W. Flegal K. Furie K. Go A. Greenlund K. Haase N. Hailpern S.M. Ho M. Howard V. Kissela B. Kittner S. Lloyd-Jones D. McDermott M. Meigs J. Moy C. Nichol G. O'Donnell C. Roger V. Sorlie P. Steinberger J. Thom T. Wilson M. Hong Y. American Heart Association Statistics Committee and Stroke Statistics SubcommitteeHeart Disease and Stroke Statistics—2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2008; 117: e25-e146Crossref PubMed Scopus (3083) Google Scholar Not surprisingly, stroke is very costly, with recent estimates suggesting that the total direct and indirect costs are $62.7 billion.3Rosamond W. Flegal K. Furie K. Go A. Greenlund K. Haase N. Hailpern S.M. Ho M. Howard V. Kissela B. Kittner S. Lloyd-Jones D. McDermott M. Meigs J. Moy C. Nichol G. O'Donnell C. Roger V. Sorlie P. Steinberger J. Thom T. Wilson M. Hong Y. American Heart Association Statistics Committee and Stroke Statistics SubcommitteeHeart Disease and Stroke Statistics—2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2008; 117: e25-e146Crossref PubMed Scopus (3083) Google Scholar A number of populations are at risk for stroke. It should no longer be considered a disease confined to the elderly because about a third of stroke victims are <65 years of age.4Lucas J.W. Schiller J.S. Benson V. Summary health statistics for US adults: National Health Interview Survey, 2001.Vital Health Stat 10. 2004; 218: 1-134PubMed Google Scholar Blacks have twice the risk of stroke compared with whites.3Rosamond W. Flegal K. Furie K. Go A. Greenlund K. Haase N. Hailpern S.M. Ho M. Howard V. Kissela B. Kittner S. Lloyd-Jones D. McDermott M. Meigs J. Moy C. Nichol G. O'Donnell C. Roger V. Sorlie P. Steinberger J. Thom T. Wilson M. Hong Y. American Heart Association Statistics Committee and Stroke Statistics SubcommitteeHeart Disease and Stroke Statistics—2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2008; 117: e25-e146Crossref PubMed Scopus (3083) Google Scholar Hispanics are also at higher risk. Women are at higher risk of stroke mortality because, on average, they live longer than men. In adults, we have seen an exponential increase in stroke at age 55, with about a doubling of stroke risk for every 5- to 10-year period thereafter.3Rosamond W. Flegal K. Furie K. Go A. Greenlund K. Haase N. Hailpern S.M. Ho M. Howard V. Kissela B. Kittner S. Lloyd-Jones D. McDermott M. Meigs J. Moy C. Nichol G. O'Donnell C. Roger V. Sorlie P. Steinberger J. Thom T. Wilson M. Hong Y. American Heart Association Statistics Committee and Stroke Statistics SubcommitteeHeart Disease and Stroke Statistics—2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2008; 117: e25-e146Crossref PubMed Scopus (3083) Google Scholar However, anyone is at risk for stroke if they have vascular risk factors, a history of other vascular diseases, such as myocardial infarction (MI) or peripheral vascular disease, or if there is a family history of stroke. Interestingly, stroke kills more than twice as many US women every year than breast cancer, and more women than men die of stroke.5National Heart, Lung, and Blood InstituteWhat is the Heart Truth?.www.hearttruth.govGoogle Scholar Black women are also at an increased risk of stroke. Finally, it is estimated that 30% of strokes in women occur in those 55 yrNorthern Manhattan Stroke Study (NOMAS)15Elkind M.S. Tai W. Coates K. Paik M.C. Sacco R.L. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke.Arch Intern Med. 2006; 166: 2073-2080Crossref PubMed Scopus (217) Google Scholar2006Recurrent strokeVeterans Affairs HDL Intervention Trial (VA-HIT)16Robins SJ, Collins D, Nelson JJ, Bloomfield HE, Asztalos BF. Lipoprotein-associated phospholipase A2 predicts cardiovascular events in the low HDL-C and low LDL-C population of the Veterans Affairs HDL Intervention Trial (VA-HIT). Presented at the European Society of Cardiology World Congress of Cardiology; September 2006; Barcelona, Spain. Abstract 3448.Google Scholar2006Recurrent CV events, low LDL and low HDLFurie et al17Furie K.L. Parides M.K. Greer D.M. Camargo E.C.S. Singhal A.B. Lederer M. Hagan N. Dipietro A. Bliss S. McCarthy C.J. et al.Lipoprotein-associated phospholipase A2 activity predicts early stroke recurrence [abstract].Stroke. 2007; 38: 458Google Scholar2007Stroke 6 mo after TIA or first strokeWomen's Health Initiative Observational Study18Wassertheil-Smoller S. Kooperberg C. McGinn A.P. Kaplan R.C. Berger J.S. Lipoprotein-associated phospholipase A2 and risk of ischemic stroke in postmenopausal women: the Women's Health Initiative Observational Study [abstract].Circulation. 2007; 115: e222Google Scholar2007Postmenopausal womenCV = cardiovascular; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TIA = transient ischemic attack. Published or presented in peer-reviewed articles, showing a consistent association between Lp-PLA2 elevation and risk of stroke. Open table in a new tab CV = cardiovascular; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TIA = transient ischemic attack. The Atherosclerosis Risk in Community (ARIC) study was a case-cohort analysis under National Institutes of Health (NIH) sponsorship involving 4 communities in Maryland, Minnesota, Mississippi, and North Carolina. The study population was 45–64 years of age at entry and included 12,773 middle-aged healthy men and women, with both blacks and whites represented.13Ballantyne C.M. Hoogeveen R.C. Bang H. Coresh J. Folsom A.R. Chambless L.E. Myerson M. Wu K.K. Sharrett A.R. Boerwinkle E. Lipoprotein-associated phospholipase A2, high sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.Arch Intern Med. 2005; 165: 2479-2484Crossref PubMed Scopus (261) Google Scholar Lp-PLA2 and C-reactive protein (CRP) were evaluated to determine their ability to predict future stroke. A total of 194 individuals experienced ischemic stroke; there were 766 noncases for comparison, and there was a 6- to 8-year follow-up period. LDL cholesterol levels were similar between the stroke cases and noncases (136.6 mg/dL and 132 mg/dL, respectively; 1 mg/dL = 0.02586 mmol/L). In contrast, elevated Lp-PLA2 in the highest versus the lowest tertile was associated with a hazard ratio (HR) of 1.97 (95% confidence interval [CI], 1.16–3.33; p = 0.01) in relation to stroke.13Ballantyne C.M. Hoogeveen R.C. Bang H. Coresh J. Folsom A.R. Chambless L.E. Myerson M. Wu K.K. Sharrett A.R. Boerwinkle E. Lipoprotein-associated phospholipase A2, high sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.Arch Intern Med. 2005; 165: 2479-2484Crossref PubMed Scopus (261) Google Scholar These results were adjusted for age, sex, race, current smoking status, systolic blood pressure, diabetes, and levels of LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and high-sensitivity C-reactive protein (hs-CRP). Lp-PLA2 was a predictor of stroke, regardless of LDL cholesterol level. Because Lp-PLA2 appears to be independent of traditional risk factors, including hypertension, the ARIC study also examined whether increased Lp-PLA2 and increased blood pressure were synergistic risk factors for stroke (Figure 1). Tertiles of systolic blood pressure were 130 mm Hg. Once patients were identified as having blood pressure values >130–139 mm Hg, their stroke risk was 3.5-fold higher than patients in the bottom tertile for systolic blood pressure. In general, at every level of blood pressure, an Lp-PLA2 value above the median approximately doubled the risk for stroke. In the top tertile of systolic blood pressure, which included patients with prehypertension, stroke risk increased from 3.5-fold to almost 7-fold.13Ballantyne C.M. Hoogeveen R.C. Bang H. Coresh J. Folsom A.R. Chambless L.E. Myerson M. Wu K.K. Sharrett A.R. Boerwinkle E. Lipoprotein-associated phospholipase A2, high sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.Arch Intern Med. 2005; 165: 2479-2484Crossref PubMed Scopus (261) Google Scholar CRP provided additive predictive power in assessing stroke risk, according to the ARIC study.13Ballantyne C.M. Hoogeveen R.C. Bang H. Coresh J. Folsom A.R. Chambless L.E. Myerson M. Wu K.K. Sharrett A.R. Boerwinkle E. Lipoprotein-associated phospholipase A2, high sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.Arch Intern Med. 2005; 165: 2479-2484Crossref PubMed Scopus (261) Google Scholar Generally, as the CRP level increases, there is some increase in the risk of stroke. When used together, Lp-PLA2 and CRP have a synergism and substantially increase the risk of stroke approximately 11-fold when both are elevated in the top tertile versus both at low levels (ie, bottom tertile). Thus, according to the ARIC study findings, Lp-PLA2 levels are higher in individuals who have a stroke; lipid parameters were not predictive of stroke; elevated Lp-PLA2 levels conferred an approximate 2-fold increase in risk independently of traditional risk factors, including lipids; and, elevated Lp-PLA2 and elevated CRP levels were complementary beyond traditional risk factors in identifying individuals at greatly increased risk for ischemic stroke. The Rotterdam Study was the first population-based study to assess the impact of elevated Lp-PLA2 on stroke risk.14Oei H.-H.S. van der Meer I.M. Hofman A. Koudstaal P.J. Stijnen T. Breteler M.M.B. Witteman J.C.M. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study.Circulation. 2005; 111: 570-575Crossref PubMed Scopus (403) Google Scholar This case-cohort study included 7,983 participants with a 6.4-year median follow-up duration for incident ischemic stroke and a 7.2-year median follow-up duration for incident coronary artery disease (CAD). A random cohort of 1,820 subjects was selected for comparison. This group included 308 patients with CAD and 110 patients with incident ischemic stroke. Quartiles of Lp-PLA2 activity were developed, and the lowest quartile served as the reference category. Lp-PLA2 activity showed a graded, stepwise increased risk of stroke risk based on HR. Compared with the first quartile of Lp-PLA2 activity, age- and sex-adjusted HRs for the second, third, and fourth quartiles were 1.06, 1.56, and 1.97, respectively (p for trend = 0.02). After an additional adjustment for cardiovascular risk factors, the corresponding HRs were 1.08, 1.58, and 1.97, respectively (p for trend = 0.03). The study found Lp-PLA2 to be an independent predictor of stroke in the general population, including those patients with non-HDL cholesterol levels below the median. Total cholesterol and non-HDL cholesterol levels were identical in the stroke patients compared with the controls. Thus, the association between Lp-PLA2 activity and stroke suggests that although Lp-PLA2 is carried by LDL particles, it may convey a different risk. Furthermore, adjusting for baseline and incident MI and heart failure did not change the risk estimates, suggesting that these conditions are not intermediate pathways linking Lp-PLA2 to stroke.14Oei H.-H.S. van der Meer I.M. Hofman A. Koudstaal P.J. Stijnen T. Breteler M.M.B. Witteman J.C.M. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study.Circulation. 2005; 111: 570-575Crossref PubMed Scopus (403) Google Scholar The Northern Manhattan Stroke Study looked at how Lp-PLA2 drawn at the time of initial stroke might predict the risk of recurrent stroke (90% of patients had blood drawn within 6 days of their initial stroke).15Elkind M.S. Tai W. Coates K. Paik M.C. Sacco R.L. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke.Arch Intern Med. 2006; 166: 2073-2080Crossref PubMed Scopus (217) Google Scholar The study population was urban, multiethnic, and included 467 patients. Patients were ≥40 years of age, had a first ischemic stroke, and were identified by a surveillance system at Columbia University Medical Center and other local hospitals. The NIH stroke scale at baseline was categorized in the study subjects, and laboratory analyses were performed for both hs-CRP and Lp-PLA2 levels. Laboratory personnel were blinded to patient status and outcomes. The primary outcome was recurrent stroke, and the secondary outcomes included recurrent stroke, MI, and vascular death. Figure 2 shows the association between Lp-PLA2 and recurrent stroke after a first ischemic stroke. CRP and Lp-PLA2 appear to provide complementary prognostic information after a first ischemic stroke. The study showed that although CRP provided information about mortality risk, it was not a good predictor of stroke risk (HR, 0.67; 95% CI, 0.34–1.32). In contrast, Lp-PLA2 conferred about a 2.1-fold increase in recurrent stroke risk (HR, 2.08; 95% CI, 1.04–4.18). In addition, only Lp-PLA2 predicted the combined vascular end point of recurrent stroke, MI, or vascular death (HR, 1.86; 95% CI, 1.01–3.42). There was a nonsignificant trend toward Lp-PLA2 being a more robust recurrent stroke predictor in patients with LDL cholesterol levels <130 mg/dL.15Elkind M.S. Tai W. Coates K. Paik M.C. Sacco R.L. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke.Arch Intern Med. 2006; 166: 2073-2080Crossref PubMed Scopus (217) Google Scholar Furie and colleagues17Furie K.L. Parides M.K. Greer D.M. Camargo E.C.S. Singhal A.B. Lederer M. Hagan N. Dipietro A. Bliss S. McCarthy C.J. et al.Lipoprotein-associated phospholipase A2 activity predicts early stroke recurrence [abstract].Stroke. 2007; 38: 458Google Scholar at the Massachusetts General Hospital studied Lp-PLA2 activity in patients with acute ischemic stroke. The study compared 685 consecutive ischemic stroke/TIA patients and 586 stroke/TIA-free comparably aged control subjects from a primary care clinic. Major outcomes—early recurrent stroke and recurrent stroke, MI, or death—were measured at 6 months. Patients with stroke or TIA were tested at baseline (≤7 days after stroke) and 6 months after stroke (n = 148). Lp-PLA2 enzyme activity was measured using a colorimetric activity method.17Furie K.L. Parides M.K. Greer D.M. Camargo E.C.S. Singhal A.B. Lederer M. Hagan N. Dipietro A. Bliss S. McCarthy C.J. et al.Lipoprotein-associated phospholipase A2 activity predicts early stroke recurrence [abstract].Stroke. 2007; 38: 458Google Scholar When baseline and 6-month Lp-PLA2 levels were compared, the mean difference was not statistically significant, suggesting that there may not be suppression of Lp-PLA2 after stroke as there may be after acute coronary syndromes. There were 23 recurrent strokes in the 6-month short-term follow-up period. However, when cases and controls were compared at baseline, Lp-PLA2 activity levels were 139.7 and 130.2 nmol/min per mL, respectively, which was statistically significant (p <0.001). Lp-PLA2 was a significant predictor of risk of early stroke recurrence at 6 months and remained significant after multivariate adjustment for diabetes, hypertension, hyperlipidemia, atrial fibrillation, smoking, and stroke subtype. The Veterans Affairs HDL Intervention Trial (VA-HIT) examined Lp-PLA2 as a predictor of major cardiovascular events in a high-risk secondary prevention population with a uniformly low LDL cholesterol and low HDL cholesterol (mean LDL cholesterol, 111 mg/dL; mean HDL cholesterol, 32 mg/dL) level.19Rubins H.B. Robins S.J. Collins D. Fye C.L. Anderson J.W. Elam M.B. Faas F.H. Linares E. Schaefer E.J. Schectman G. Wilt T.J. Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.N Engl J Med. 1999; 341: 410-418Crossref PubMed Scopus (3245) Google Scholar The Lp-PLA2 analysis was performed using plasma from 927 subjects attending the 6-month follow-up visit (cardiovascular event rate with placebo, 24.7%) and 1,267 subjects with placebo at baseline (cardiovascular event rate, 25.2%). CAD patients were randomized to gemfibrozil or placebo. In the overall study, the average age was 64 years. Baseline Lp-PLA2 was obtained at the 6-month follow-up visit. The VA-HIT study found that for every standard deviation increase in Lp-PLA2, there was a significant association with an increase in all cardiovascular events (HR, 1.13; p = 0.018).16Robins SJ, Collins D, Nelson JJ, Bloomfield HE, Asztalos BF. Lipoprotein-associated phospholipase A2 predicts cardiovascular events in the low HDL-C and low LDL-C population of the Veterans Affairs HDL Intervention Trial (VA-HIT). Presented at the European Society of Cardiology World Congress of Cardiology; September 2006; Barcelona, Spain. Abstract 3448.Google Scholar For stroke, the results were even more significant compared with coronary events, with a relative risk per standard deviation in Lp-PLA2 mass concentration of 1.38 (p = 0.002). Finally, the Women's Health Initiative (WHI) looked at the risk of ischemic stroke in postmenopausal women. It is the la
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