Learning Objectives. Cholesterol and Lipids in Kids: It s a Matter of the Heart. Is Atherosclerosis a Pediatric Disease?

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Norman Stokes
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understand: Learning Objectives atherosclerosis begins in childhood the role of cholesterol & lipids in children as cardiovascular disease risk factors in adults the causes of hypercholesterolemia in

adult Is Atherosclerosis a Pediatric Disease?

Atherosclerosis in Youth (PDAY) 3000 victims of accidental trauma, suicide, or homicide Atherosclerosis present in most Bogalusa Heart Study Autopsies from accidents or suicide 50% with fatty streaks

1 Scott J. Soifer, MD Professor and Vice Chair Department of Pediatrics University of California, San Francisco UCSF Benioff Children s Hospital Cholesterol and Lipids in Kids: It s a Matter of the Heart To understand: Learning Objectives atherosclerosis begins in childhood the role of cholesterol & lipids in children as cardiovascular disease risk factors in adults the causes of hypercholesterolemia in pediatrics the guidelines for cholesterol screening in children and teens the effectiveness of lipid lowering therapies including lifestyle changes and drugs in children on cardiovascular health in adult Is Atherosclerosis a Pediatric Disease? Coronary Artery Disease Begins in the Young Autopsies of young soldiers who died in the Korean War fatty streaks and atheroma in the aorta and coronary arteries Pathobiological Determinants of Atherosclerosis in Youth (PDAY) 3000 victims of accidental trauma, suicide, or homicide Atherosclerosis present in most Bogalusa Heart Study Autopsies from accidents or suicide 50% with fatty streaks and 8% fibrous plaques by age 15 85% with fatty streaks and 8% fibrous plaques by age 39 Newman et al, NEJM, 1986; Berenson, et al, NEJM, 2001 Risk Factors for the Development of Atherosclerosis and Cardiovascular Disease in Adults Increasing age Male sex Lipids/dyslipidemia Diabetes mellitus Inflammation Obesity Cigarette smoking (+) family history for CVD Hypertension Metabolic syndrome Physical inactivity/ sedentary lifestyle Diet/food preferences Can Modification of Risk Factors in Children affect CVD in the Adult The Cardiovascular Risk in Young Finns Study 3596 children and adolescents 3 18 enrolled in 1980 To determine the effect of childhood lifestyle, biological and psychological measures on the risk of cardiovascular diseases in adulthood 7 health behaviors no smoking, BMI, dietary intake, physical activity, blood pressure, blood glucose and total cholesterol Risk behaviors present in childhood persist into adulthood More low risk behaviors in young adults lower the risk of CVE Maintain cardiovascular health from youth to adulthood 2020 Strategic Impact Goals of the AHA Raitakari et al, JAMA,

Cholesterol is Important in Many Body Functions Forms myelin sheaths and promotes synaptogenesis and neuronal plasticity Why is Cholesterol Important to Children?

2 Cholesterol is Important in Many Body Functions Forms myelin sheaths and promotes synaptogenesis and neuronal plasticity Why is Cholesterol Important to Children? The Good, the Bad and the Ugly Building block of hormones including cortisol, estrogen, testosterone and aldosterone and other important biological molecules (bile salts) A major component of cell membranes and plays an important role in signaling and cell proliferation Causes of Hypercholesterolemia Monogenic dyslipidemias Heterozygous familial hypercholesterolemia (hefh) 1/500 autosomal dominant Total cholesterol < 500 mg/dl ~50% of men experience a CVE by age 50 years Homozygous familial hypercholesterolemia) 1/1 million Total cholesterol > 500 mg/dl Tuberous or tendon xanthomas Symptoms before puberty, death by 2nd decade of life Defect in LDL receptor, little or no response to drugs Treatment is LDL apheresis or liver transplant Familial combined hyperlipidemia 1 2 /100 Markers of Atherosclerosis in Children & Adolescents with Familial HC Carotid artery intima media thickness correlates with total cholesterol and LDL C Electron beam computer tomography (EBCT) detects coronary calcifications in adolescents Multimodal magnetic resonance imaging demonstrates plaque burden & composition in common carotid artery and abdominal aorta Wiegman et al, JAMA, 2004; de Jongh et al, J am Coll of Cardiol, 2002; Gidding et al, Circulation 1998 Causes of Hypercholesterolemia Secondary causes include high fat diet, polygenic disorders and environmental causes Obesity Hypothyroidism Cholestasis Diabetes Systemic lupus erythematosus Use of steroids Immunosuppressive therapy Antiretroviral therapy in HIV infected children Concentrations of Total and LDL Cholesterol Among Children & Adolescents in the US Cholesterol levels at birth TC 70 mg/dl; LDL 30 mg/dl; HDL 35 mg/dl Rapid increase in the first 2 years of life TC decreases during puberty and increases after HDL decreases after puberty There are ethnic differences African Americans higher HDL and lower TG than Hispanics or non Hispanic whites Higher TC, LDL and HDL in girls than boys National Cholesterol Education Program,

3 When Should We Screen for Hyperlipidemia Age Screening < 2 years No screening 2 10 years Selective screening Parent, grandparent, aunt/uncle or sibling with early cardiovascular disease (< 55 in males, < 65 in females) Parent with TC > 240 mg/dl or with dyslipidemia Child has hypertension, obesity or diabetes Child has special risk factor (HIV, chronic inflammatory disease, chronic kidney disease, transplant, Kawasaki, congenital heart disease, cancer 10 years Universal screening years Selective screening > 18 years Universal screening NHLBI, 2012 Non HDL C : A New Screening Method Non HDL C = TC HDL C Estimate of all atherogenic LDL containing lipoproteins in plasma Accurate in non fasting state Better predictor of CVE in adults than LDL C Non HDL C and LDL C predict adult lipid levels Elevated Non HDL C correlate with coronary atheroma and atherosclerosis in children and adults Fasting lipid testing (FLP) for Selective screening Non fasting or fasting for Universal screening Repeat 2 weeks to 3 months if abnormal before treatment NHLBI, Pediatrics 128:supp 5, 2011 Original National Cholesterol Education Program (NCEP) 1992 TC LDL C HDL C Non HDL C Acceptable < 170 < 110 > 45 < 120 Borderline Elevated < Ford ES et al Circulation 2009 National Health and Nutrition Examination Study (NHANES) Lipid profiles measured on children and teens (~10K) Concentration of total cholesterol was mg/dl Concentration of LDL C for was 90.2 mg/dl An elevated total cholesterol (95th% for age & sex: mg/dl) occurred in 10% An elevated LDL C (95th% for age & sex: mg/dl) occurred in 6% Nearly 1% of adolescents (12 to 17) had LDL C high enough for drug treatment With 25M persons in this age group ~ 200,000 should be treated Ford ES et al Circulation 2009 When to start therapy? LDL C Risk factors Therapy < 130 mg/dl No therapy mg/dl None Life style mg/dl Multiple personal risks* Drug therapy mg/dl Family history Life style mg/dl Family history + other Drug therapy risk factors** 190 mg/dl Drug therapy *HDL-C<35, smoking, DM, obesity, HTN, lack of exercise **HIV, chronic inflammatory disease, kidney disease, transplant, etc. Lifestyle Changes For 6 to 12 months before drug therapy Sole therapy for children 2 10 years old Total fat < 30 % of total calories Saturated fat < 10% Dietary cholesterol < 300 mg/day Dietary supplements fiber, antioxidants, fish oil (omega 3 fatty acids) Physical activity 60 min of moderate to strenuous activity Limit screen time to < 2 hours /day Daniels et al. Pediatrics,

4 Statins Most commonly used drugs in the treatment of hypercholesterolemia in adults Decreases cholesterol synthesis by inhibiting HMG CoA reductase Up regulates LDL receptors In children with familial hypercholesterolemia 20 40% decrease in LDL C When to start statins? Boys > 10 years of age Girls should have started menses and have regular periods As young as 8 years of age if severe elevations Use appropriate contraception LDL C >190 mg/dl, no family history or risk factors* LDL C >160 mg/dl, family history or 2 risk factors LDL C >130 mg/dl, special risk factors** Treatment goal: LDL C<110 mg/dl *HDL C<35, smoking, DM, obesity, HTN, lack of exercise **HIV, chronic inflammatory disease, kidney disease, transplant, etc. Statins Several clinical trials in children with FC Efficacy similar to adult patients with LDL C by 18 35% pravastatin 5 20 mg/day lovastatin mg/day simvastatin 10 mg/day atorvastatin mg/day Efficacy similar to adult patients with IMT and other indicators of plaque burden Statins are Safe and Effective in Children and Teens Usual side effects in adults include muscle cramps and myopathy (0.5%), GI symptoms, and elevated liver function tests (0.1%) In several pediatric trials No serious adverse events No significant increases in AST, ALT (1 5%) or CPK No changes in endocrine function No effect on growth and development Wiegman et al, JAMA, 2004 How to Use Statins Learn and use one drug Lowest dose, given at bedtime Target LDL C is <110 mg/dl (optimal) to 130 mg/dl (acceptable) Lower the goal, the more risk factors Repeat labs FLP, CPK, AST/ALT in one month If at goal and no side effects, repeat labs at 2 months then every 6 months How to Use Statins If not at goal, increase dose If there are side effects, stop drug, wait 2 weeks and repeat labs When symptoms and labs normalize, restart and monitor closely Refer to lipid specialist if: LDL C > 250 mg/dl, TG > 500 mg/dl on initial screen LDL C not at goal at maximum dose of the statin Patient needs an additional medication 4

5 Conclusions The development of atherosclerosis and the risk for cardiovascular events in adults begins on our watch This development of atherosclerosis is accelerated by many risk factors Our goal is to maintain cardiovascular health from youth to adulthood Dyslipidemia is one of the most modifiable of the risk factors Selective screening for high risk children should occur between age 2 and 10 Universal screen should occur at age 10 and then at 3 5 year intervals Conclusions Normalizing a child or teen s lipid profile is a primary strategy for the reduction of cardiovascular disease in adults If this cannot be achieved by a heart health lifestyle, statin therapy will normalize the lipid profile with minimal side effects The long term effects of a a lifetime of therapy is unknown on the the development of CVE or other other complications References Shay, CM, et al. Status of Cardiovascular Health in Adolescents: Prevalence Estimates from the National Health and Nutrition Examination Surveys (NHANES) Circulation 127: , 2013 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung and Blood Institute, Publication No , 2012 ( McCrindle, BW, et al. Guidelines for Lipid Screening in Children and Adolescents: Bringing Evidence to the Debate. Pediatrics 130: , 2012 Newman, TB et al. Overly Aggressive New Guidelines for Lipid Screening in Children: Evidence of a Broken Process. Pediatrics 130: ,

Disclosure. Cholesterol and Lipids in Kids: It s a Matter of the Heart. Case Disclosure

Disclosure. Cholesterol and Lipids in Kids: It s a Matter of the Heart. Case Disclosure Sco$ J. Soifer, MD Professor and Vice Chair Department of Pediatrics University of California, San Francisco UCSF Benioﬀ Children s Hospital Cholesterol and Lipids in Kids: Disclosure I have no ﬁnancial