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

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s Hospital Cholesterol and Lipids in Kids: Disclosure I have no ﬁnancial interest, arrangement, or aﬃliahon with any

1 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 interest, arrangement, or aﬃliahon with any commercial company who has provided products or services relahng to this presentahon or support for this conhnuing medical educahon achvity, but It s a Matter of the Heart Disclosure Scholar athlete - DM, HT & smoking.i DO TAKE STATINS! 1

2 Scholar athlete - DM, HT & smoking Family History- Father takes stahns Scholar athlete - DM, HT & smoking Family History- Father takes stahns + Family history for early CVE Learning ObjecHves To understand: Scholar athlete - DM, HT & smoking Family History- Father takes stahns + Family history for early CVE Total Cholesterol 276 LDL Cholesterol 190 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 eﬀechveness of lipid lowering therapies including lifestyle changes and drugs in children on cardiovascular health in adult 2

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

3 Is Atherosclerosis a Pediatric Disease? Coronary Artery Disease Begins in the Young Autopsies of young soldiers who died in the Korean War fa$y streaks and atheroma in the aorta and coronary arteries Pathobiological Determinants of Atherosclerosis in Youth (PDAY) 3000 vichms of accidental trauma, suicide, or homicide Atherosclerosis present in most Bogalusa Heart Study Autopsies from accidents or suicide 50% with fa$y streaks and 8% ﬁbrous plaques by age 15 85% with fa$y streaks and 38% ﬁbrous plaques by age 39 Newman et al, NEJM, 1986; Berenson, et al, NEJM, 2001 Risk Factors for the Development of Atherosclerosis and Cardiovascular Disease in Adults Increasing age Male sex Lipids/dyslipidemia Diabetes mellitus InﬂammaHon Obesity Cigare$e smoking (+) family history for CVD Hypertension Metabolic syndrome Physical inachvity/ sedentary lifestyle Diet/food preferences Can ModiﬁcaHon 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 achvity, 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 FuncHons Causes of Hypercholesterolemia Gene mutahons in the LDL receptor or achvity Homozygous familial hypercholesterolemia (hofh) Forms myelin sheaths and

4 Cholesterol is Important in Many Body FuncHons Causes of Hypercholesterolemia Gene mutahons in the LDL receptor or achvity Homozygous familial hypercholesterolemia (hofh) Forms myelin sheaths and promotes synaptogenesis and neuronal plashcity Building block of hormones including corhsol, 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 proliferahon Markers of Atherosclerosis in Children & Adolescents with Familial HC Heterozygous familial hypercholesterolemia (hefh) 1/1 million Total cholesterol > 500 mg/dl, very elevated LDL- C Tuberous or tendon xanthomas Symptoms before puberty, death by 2nd decade of life Li$le or no response to drugs Treatment is LDL- apheresis or liver transplant 1/500 autosomal dominant Total cholesterol < 500 mg/dl, elevated LDL- C ~50% of men have a CVE by age 50, 25% of females Familial combined hyperlipidemia 1-2 /100 Associated with obesity and insulin resistance, elevated TG, HDL-C CaroHd artery inhma- media thickness correlates with total cholesterol and LDL- C Electron beam computer tomography (EBCT) detects coronary calciﬁcahons in adolescents MulHmodal magnehc resonance imaging demonstrates plaque burden & composihon in common carohd artery and abdominal aorta Wiegman et al, JAMA, 2004; de Jongh et al, J am Coll of Cardiol, 2002; Gidding et al, CirculaHon

5 ConcentraHons of Total and LDL Cholesterol Among Children & Adolescents in the US 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 AnHretroviral therapy in HIV- infected children Cholesterol levels at birth Rapid increase in the ﬁrst 2 years of life TC decreases during puberty and increases axer HDL decreases axer 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 NaHonal Cholesterol EducaHon Program, 1992 When Should We Screen for Hyperlipidemia Age < 2 years Screening No 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 SelecHve screening > 18 years Non HDL- C : A New Screening Method 2 10 years SelecHve screening Universal screening NHLBI, 2012 TC 70 mg/dl; LDL 30 mg/dl; HDL 35 mg/dl Non- HDL- C = TC HDL- C EsHmate of all atherogenic LDL- containing lipoproteins in plasma Accurate in non- fashng state Be$er 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 FasHng lipid teshng (FLP) for SelecHve screening Non- fashng or fashng for Universal screening Repeat 2 weeks to 3 months if abnormal before treatment NHLBI, Pediatrics 128:supp 5,

6 Original NaHonal Cholesterol EducaHon Program (NCEP) NaHonal Health and NutriHon ExaminaHon Study (NHANES) Acceptable TC LDL- C HDL- C Non HDL- C < 170 < 110 > 45 < < Borderline Elevated Lipid proﬁles measured on children and teens (~10K) ConcentraHon of total cholesterol was mg/dl ConcentraHon 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 CirculaHon 2009 NaHonal Cholesterol EducaHon Program, AHA AAP and NHLBI Treatment RecommendaHons When to start therapy? LDL- C < 130 mg/dl Risk factors Therapy - No therapy mg/dl None Life- style mg/dl MulHple personal risks* Drug- therapy mg/dl mg/dl 190 mg/dl Family history Life- style Family history + other risk factors** - Drug- therapy Drug therapy *HDL-C<35, smoking, DM, obesity, HTN, lack of exercise **HIV, chronic inflammatory disease, kidney disease, transplant, etc. Ford ES et al CirculaHon 2009 NaHonal Cholesterol EducaHon Program, AHA AAP and NHLBI Treatment RecommendaHons 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, anhoxidants, ﬁsh oil (omega- 3 fa$y acids) Physical achvity 60 min of moderate to strenuous achvity Limit screen Hme to < 2 hours /day Daniels et al. Pediatrics,

7 NaHonal Cholesterol EducaHon Program, AHA AAP and NHLBI Treatment RecommendaHons StaHns Most commonly used drugs in the treatment of hypercholesterolemia in adults When to start stamns? Decreases cholesterol synthesis by inhibihng HMG- CoA reductase Up regulates LDL receptors In children with familial hypercholesterolemia 20-40% decrease in LDL- C *HDL- C<35, smoking, DM, obesity, HTN, lack of exercise **HIV, chronic inﬂammatory disease, kidney disease, transplant, etc. StaHns are Safe and EﬀecHve in Children and Teens StaHns Boys > 10 years of age Girls should have started menses and have regular periods As young as 8 years of age if severe elevahons Use appropriate contracephon 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 Several clinical trials in children with FC Eﬃcacy similar to adult pahents with LDL- C by 18-35% pravastahn 5-20 mg/day lovastahn mg/day simvastahn 10 mg/day atorvastahn mg/day Usual side eﬀects in adults include muscle cramps and myopathy (0.5%), GI symptoms, and elevated liver funchon tests (0.1%) In several pediatric trials Eﬃcacy similar to adult pahents with IMT and other indicators of plaque burden No serious adverse events No signiﬁcant increases in AST, ALT (1-5%) or CPK No changes in endocrine funchon No eﬀect on growth and development Wiegman et al, JAMA,

How to Use StaHns How to Use StaHns Learn and use one drug Lowest dose, given at bedhme Target LDL- C is <110 mg/dl (ophmal) to 130 mg/dl (acceptable) Lower the goal, the more risk factors Repeat

8 How to Use StaHns How to Use StaHns Learn and use one drug Lowest dose, given at bedhme Target LDL- C is <110 mg/dl (ophmal) 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 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: Conclusions Scholar athlete + Family history for early CVD Lifestyle changes only Total Cholesterol 234 LDL Cholesterol 149 LDL- C > 250 mg/dl, TG > 500 mg/dl on inihal screen LDL- C not at goal at maximum dose of the stahn PaHent needs an addihonal medicahon 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 SelecHve 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 8

9 Conclusions Normalizing a child or teen s lipid proﬁle is a primary strategy for the reduchon of cardiovascular disease in adults If this cannot be achieved by a heart healthy lifestyle, stahn therapy will normalize the lipid proﬁle with minimal side eﬀects The long- term eﬀects of a a lifehme of therapy is unknown on the the development of CVE or other other complicahons References Shay, CM, et al. Status of Cardiovascular Health in Adolescents: Prevalence EsHmates from the NaHonal Health and NutriHon ExaminaHon Surveys (NHANES) CirculaHon 127: , 2013 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk ReducHon in Children and Adolescents. NaHonal Heart, Lung and Blood InsHtute, PublicaHon No , 2012 ( cvd_ped/index.htm) 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: ,

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

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