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Lipid Screening AAP Recommendations 2008. Henaro Sabino Pediatric Cardiology. STUDIES. Autopsy Study of Korean War (men 18-24yo). Bogalusa Heart Study RF in children, then followed to adulthood Cardiovascular Health in Children NC: Blacks highest prevalence of Tot chol >200
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Lipid Screening AAP Recommendations 2008 Henaro Sabino Pediatric Cardiology
STUDIES • Autopsy Study of Korean War (men 18-24yo). • Bogalusa Heart Study • RF in children, then followed to adulthood • Cardiovascular Health in Children • NC: Blacks highest prevalence of Tot chol >200 • NHANES (National Health & Nutrition Examination Surveys) • Children & adolescents over 12yrs • Blacks had higher HDL, lower TG • PDAY (Pathobiological Determinants of Atherosclerosis in Youth) • 15-34 yo. with accidental death (autopsy)
STUDIES • Results: • Pathologic process beginning with fatty streaks as early as school-aged children. • 13% of 4th graders & 10% of adolescents have tot chol > 200. • 75% of school-aged kids with high total chol have tot chol > 200 as young adults. • Longitudinal tracking is important to identify these patients. • RF for CV disease: Diabetes, obesity, hypertension, smoking, hyperlipidemia.
Pathobiology • Fatty streaks accumulation of lipid-filled macrophages • smooth muscle proliferation FIBROUS PLAQUE
In Vivo STUDIES • Risk Factors for increased intima-media thickness of the carotid arteries (cIMT): • increased LDL-c • Increased apolipoprotein B • Increased fibrinogen, homocysteine, and C-reactive protein • low HDL-c • hypertension • family history of early myocardial infarction Davis et al Circulation 2001
Lipid Metabolism • Three sources of Cholesterol: • Dietary: Fat ingested, absorbed & reprocessed (bile acids & VLDL in bloodstream) by liver. VLDL LDL to receptor sites. • Intracellular Production: either produce cholesterol or esterify cholesterol for recycle. • Recycle via GI pathway.
Classes of Plasma Lipoproteins • Chylomicrons- origin is from dietary fat & is high in TG. • VLDL- from de novo synthesis (liver) & is high in TG. • LDL- from catabolism of VLDL & is major carrier of cholesterol. • HDL- synthesized in liver and gut, & is composed of cholesterol & proteins.
Mechanism of HDL? • In Vitro: attenuate oxidation of LDL & inhibits endotelian expression of inflammatory markers. • Enhances reverse transport of cholesterol, promotes efflux of cholesterol from plaque, stabilizes plaque (less thrombogenic). • ?Vasorelaxation and increased endothelial NO synthase expression. Tsujika Maki, J Lipid Research, Kuvin JT, Am Heart J 2002.
Medications for Hyperlipidemia • Cholesterol-Absorption Inhibitor: lowers LDL (as much as 20% below baseline). • Example: Ezetimibe • Mechanism: Like bile acid resins, thought to act on intestinal border to prevent absorption, but enter into the enterohepatic system. • Side-effects: G.I. upset (but tablet form better tolerated).
Treatment in Pediatrics • cIMT decreased in children with FH treated with pravastatin over 2 years while it increased in the placebo group (Weigman et. al. JAMA 2004; 292: 331) • Flow mediated dilatation of the brachial artery improved to normal with early simvastatin (40 mg) treatment in 50 children with FH after 28 weeks vs. no improvement in the placebo group (de Jongh et. al. JACC 2002; 40: 2117)
Safety of Statins in Pediatrics • Docubu et. al. Lancet 1992; 339:1488. • Simvastatin (to 40 mg/d) in 32 children • F/U 24 mos. • 1 pt. increased transaminases and 2 transient elevations in CK • Development normal • De Jongh et. al. Circ. 2002;106:2231 • Simvastatin (to 40 mg/d) in 173 children with FH • 3 transient increases in CK (one on erythromycin) • No change growth and development
Safety of Statins in Pediatrics • Knipscheer et. al. Ped. Research 1996; 39: 867. • Pravastatin (20-40 mg) in 72 children with FH • Transient increases in transaminases and CK = in both placebo and pravastatin • Clauss et. al. Pediatrics 2005; 116: 682. • Lovastatin (20-40 mg) in 54 postmenarchal girls with FH • No diff. vs. placebo in safety, hormone levels, & menstrual cycle length.
Safety of Statins in Pediatrics • McCrindle et. al. J. Pediatrics 2003; 143: 74. • Atorvastatin (10-20 mg) in 187 children with FH or severe hypercholesterolemia • Excellent safety • 6 mos. extension (10 mg) safe and no effect on growth and development • Routine monitoring of CK is problematic • Psychological concerns-44% reported concerns for disease, but 62% felt safer with medications.
Controversy With Statins • New York Times February 13, 2008, 11:45 am • Do Statins Make You Stupid? • By Tara Parker-Pope Cholesterol-lowering statin drugs have had a rough time of it lately. • There was the headline-making trial of the statin-combination drug Vytorin, which rattled conventional wisdom about the value of lowering cholesterol. Business Week weighed in with a report that asked: “Do Cholesterol Drugs Do Any Good?” And my Well column in Science Times last month pointed out that there’s no data to show that statins prolong the lives of many people who use them. • Now, The Wall Street Journal has joined the fray. Health Journal columnist Melinda Beck revisited questions about whether statin drugs have cognitive side effects that leave users, particularly women, with muddled thinking and forgetfulness. “This drug makes women stupid,” Dr. Orli Etingin, vice chairman of medicine at New York-Presbyterian Hospital, declared at a recent luncheon, according to the Journal. • Over the years, there’s been a lot of discussion about whether statins affect thinking and memory, but drug makers point out that hundreds of studies haven’t shown a causal link between statins and memory problems. However, anecdotal reports continue to suggest that some patients do develop memory loss while taking the drugs. • After I wrote about the issue several years ago, a colleague who had once memorized poetry as a hobby told me he was unable to remember poems once he started taking statins. Dr. Beatrice A. Golomb, assistant professor at the University of California at San Diego, has collected thousands of stories from patients about statin side effects. She has said common complaints from patients taking statins include being unable to remember the name of a grandchild, walking into a room and forgetting why you are there, or starting a sentence and being unable to finish. Some complain of personality changes or irritability.
Use Of Statins • Initiation and titration • Lowest dose qDay; baseline CK, AST, ALT • Report all adverse effects • Pregnancy counseling • Drug interactions-EES, azoles • After 4 wks.-FLP, CK, AST, ALT (concern CK > 10 ULN; trans. > 3 ULN) • Target LDL (min 130; ideal 110) achieved-recheck 8 wk. and 3 months • Target not met-double dose-recheck in 4 wks.
Cost of Statins • $4 Generic Drug Program: • Lovastatin 10 or 20 mg (#30) • Pravastatin 10, 20, or 40 mg (#30)
Metabolic Syndrome • Atherogenic dyslipidemia • (elevated apo B, TG ≥ 110, increased small dense LDL particles, HDL ≤ 40) • Raised blood pressure • Insulin resistance +/- glucose intolerance • Fasting glucose ≥ 110 • Proinflammatory state (TNF-alpha & IL-6 CRP) • Prothrombotic state • (fibrinogen, plasminogen activators, antithrombin, von Willebrand factor, factor V Leiden, and protein C) • Obesity (BMI ≥ 95%ile, waist circ ≥ 90%ile)
Concerns about 2008 AAP Guidelines • Family hx not effective screening tool: • In population-based survey of 3,048 parents in Canada: • Positive history of early CV dz (i.e <55yo) had 33% sensitivity (23.7% PPV) for detection of borderline elevated LDL, and 41% (8% PPV) for detection of high LDL (>130). O’Loughlin j, Ped 2004 • Positive family hx AND elevated BMI increased sensitivity for detection of abnormal lipid profile (but no change in PPV). Eissa MA, Am J Prev Med 2009
Concerns about 2008 AAP Guidelines • LDL and HDL not sufficient for risk-stratification: • Elevated ApoB and low ApoA-1 in children & adolescents were related to increased adult IMT and worse brachial artery flow-mediated dilatation (FMD). • ApoB/ApoA-1 ratio better than LDL/HDL ratio (PPV 0.62 vs. 0.57, p=0.03) in detection of progression to subclinical atherosclerosis. Juonala M (Young Finn Study), J Am Coll Cardiol 2008
Concerns about 2008 AAP Guidelines • BMI vs. Waist Circumference • Children with waist circumference >90%ile compared to smaller waist controls are: • 3.6 times more likely to have low HDL • 3 times more likely to have high TG • 3.7 times more likely to have high fasting insulin Bassali R, Am J Prev Med Jul 2009.
