Evaluating Residual Risk and Long-term Management of the Young CHD Patient. The Arterial Wall

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1 Evaluating Residual Risk and Long-term Management of the Young CHD Patient Patrick M Moriarty, M.D., Professor of Medicine Director of Clinical Pharmacology, Atherosclerosis and Lipoprotein-apheresis Center University of Kansas Medical Center The Arterial Wall External elastic lamina Junqueira L, Carneiro J, Kelley R. Basic Histology, 9th ed 1998

2 Atherosclerosis -A chronic, inflammatory, fibroproliferative disease found in the intima of arterial vessels. -Although the entire vasculature is exposed to the atherogenic effects of risk factors (cholesterol, hypertension, diabetes, ) lesions generally occur in specific areas of the arterial vascular tree. Arterosclerosis A chronic disease characterized by thickening and hardening of the medial walls of elastic arteries with resulting loss of elasticity. Commonly called hardening of the arteries it develops with aging and hypertension.

3 The Cause of Most Heart Attacks: Clot of Disrupted Cholesterol Endothelium Intima Media Endothelial Mechanosensors of Shear Stress Endothelial cell (EC) response to shear stress includes the synthesis of vasoactive mediators to control vascular tone, that is, nitric oxide causing an immediate reduction in shear stress, extracellular matrix proteins and matrix metalloproteinases to promote remodeling and repair, and growth factors expression such as TGF-β to control cell survival and proliferation. Zaragoza, C. et al. Current Opinion in Lipidology. 23(5): , Integrin-linked kinase (ILK) in the cardiovascular system. Overexpression leads to cardiac hypertrophy, whereas ILK suppression leads to dilated cardiomyopathy. ILK also plays a critical role in the recovery after myocardial infarction and atherosclerotic plaque development.

4 Shear stress affects the stability of the cap of a vulnerable plaque Slager CJet al.(2005) Nat Clin Pract Cardiovasc Med2: Proposed Natural History of Atherosclerosis Chatzizisis, Y. S. et al. J Am Coll Cardiol 2007;49:

5 Identifying Those at Risk of Atherothrombosis 1,2 Local factors: Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Generalised disorders Obesity Diabetes Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) Systemic conditions History of CVD Hypertension Hyperlipidemia Hypercoagulable states Genetic Genetic traits Gender Age Lifestyle Smoking Diet Lack of exercise 1. Yusuf S et al. Circulation 2001; 104: Drouet L. Cerebrovasc Dis 2002;13(suppl 1): 1 6. Case #1 Assessment : Premature CVD due to Familial Hypercholesterolemia

6 Overview of Familial ypercholesterolemia An autosomal co-dominant inherited disorder 1. Typically have markedly elevated [LDL-C] 1. FH patients have elevated risk of CHD due to life-long exposure to elevated atherogenic lipoproteins 1. Accelerated atherosclerosis usually develops within the second decade of life 1. Although FH may be diagnosed in childhood, it may also go undiagnosed into adulthood Raal FJ and Santos RD. Atherosclerosis 2012;23: Goldberg A et al. J Clin Lipidol. 2011; 5:S1-S8. Pedigree, Gene Loci and Definitions True homozygote: both mutations are on the same gene, e.g. the LDLR Simple homozygote: both mutations are exactly the same on each allele Compound heterozygote: different mutations from within the same gene (e.g. LDLR) 25% 50% 25% Double heterozygote: mutation alleles are from two different loci (e.g. LDLR and PCSK9 Gain of Function or APOB dysfunction). Mutation LDLR APOB PCSK9 LDLRAP1 Frequency >95% 2 to 5% <1% <1% Cuchel M. et al. Eur Heart J, 2014; 35 (32):

7 Familial Hypercholesterolemia (FH) can be caused by mutations in 4 known genes FH is typically caused by mutations in LDLR, ApoB, PCSK9*, LDLRAP1* or other as yet other unidentified genes 1 LDL Particle Apo B acts as ligand, binding LDL particle to receptor Circulation Liver cell LDL Receptor on hepatocyte, binds to Apo B on LDL particle, inducing endocytosis of LDL PCSK9 Enzyme degrades LDL receptors LDLRAP1* (ARH) mediates internalization via clathrin coated pits *LDLRAP1= LDL receptor adaptor protein 1. *PCSK9 = Proprotein Convertase Subtilisin/Kexin type 9 De Castro-Oros I, et al. Appl Clin Genet. 2010;3: Prevalence of HeFH and HoFH in Founder Populations FOUNDER EFFECT: Occurs when a subpopulation is formed through immigration of a small number of founder subjects followed by population expansion Genetic drift leads to high proportion of affected subjects who share same specific mutations Frequency Population HeFH 1 HoFH 2 General Population 1:500 1:1,000,000 Ashkanazi Jews (Eastern European) 1:67 N/A Lebanese (Christian) 1:85 1:100,000 South African Afrikaners 1:100 1:30,000 French Canadians 1:270 1:275, Austin MA, et al. Am J Epidemiol 2004;160: Raal FJ, Santos RD. Atherosclerosis 2012;223:262-8

8 EAS Consensus Panel: FH is Underdiagnosed Estimated number of individuals worldwide with FH by WHO Regions Entire World African region Region of the Americas South-East Asia region European region Eastern Mediterranean region Western Pacific *Estimated Frequency 1/500 vs. 1/ vs vs vs vs vs vs vs Individuals with familial hypercholesterolemia, in millions Nordesgaard BD et al. Eur Heart J 2013Eur Heart J; /eurheartj/eht273 EAS Position Paper on HoFH: Estimated Number of HoFH Individuals Worldwide by WHO Regions Entire World African region Region of the Americas South-East Asia region European region Eastern Mediterranean region Western Pacific *Estimated Frequency 1/1,000,000 vs. 1/160,000 6,860 vs. 42, vs. 5, vs. 5,810 1,810 vs. 11, vs. 5, vs. 3,690 1,800 vs. 11, ,000 10,000 15,000 Individuals with homozygous familial hypercholesterolemia *Estimates are based upon historical prevalence data (1/1,000,000) as well as directly detected estimates of familial hypercholesterolemia in the Danish general general population (1/160,000). Cuchel M. et al. Eur Heart J Epub available on-line July 22,2014. doi: /eurheartj/ehu274

9 Time to diagnosis of CHD by number of years of hyperlipidemia at baseline among adults not recommended for statin therapy at baseline.* *This figure shows Kaplan Meier curves of future risk of CHD stratified by years of hyperlipidemia experienced by 55 years of age among adults not recommended for statin therapy at 55 years of age. Ann Marie Navar-Boggan et al. Circulation. 2015;131: Mechanism of action of current therapies For FH Class Primary and secondary mechanism of action LDL-lowering response HeFH HoFH Statins LDLR activity (1 O ) >35% 1 Up to 28% 2 Resins Bile acid re-absorption (1 O ), LDLR activity (2 O ) 15% <10% Ezetimibe Cholesterol absorption (1 O ), LDLR activity (2 O ) 15% <10% Stanol esters Cholesterol absorption (1 O ), LDLR activity (2 O ) 10% <10% Nicotinic acid VLDL synthesis (1 O ) 20% NA <10% Lomitapide Inhibits microsomal triglyceride transfer protein NA 50% 28% Mipomersen Antisense oligonucleotide against apob-100 Lipoproteinapheresis 1. Kastelein JJ, et al. N Engl J Med. 2008;358(14); Raal FJ, et al. Atherosclerosis. 2000;150(2): Konrad RJ, et al. Lipids Health Dis. 2011;10: Vohl et al, Atherosclerosis 160 (2002) Removes LDL-c and Lp(a) 5. Chaves et al. lin Endocrinol Metab 86: , Gordon BR, et al. Am J of Card. 1998;81(4): Ito MK, et al. J Clin Lipidol. 2011;5(3 Suppl):S38-S45. Chronically 20-40% (up to 76% acutely) 6,7 NA= not approved

10 Kaplan-Meier Curves for CVD-Free Survival in Subjects With FH According to Lp(a) Levels and Sex Dashed gray line: Male subjects with Lp(a) levels >50 mg/dl. Dashed black line: Male subjects with Lp(a) levels <50 mg/dl. Gray solid line: Female subjects with Lp(a) levels >50 mg/dl. Black solid line: Female subjects with Lp(a) levels <50 mg/dl. JACC. 2014;63(19): Case #1 Plan for FH Elevated CK level with statin. Testing family members. Testing for asymptomatic disease. Treatment.

11 Case #2 Assessment: Premature CVD due to Hypertension and Possible Elevated Heart Rate Mechanism of synergism of hypertension and hyperlipidaemia in the pathogenesis of atherosclerosis. Wayne Alexander Hypertension. 1995;25:

12 Mortality Due to Coronary Heart Disease per Quartile of Usual Systolic Blood Pressure. van den Hoogen PC et al. N Engl J Med 2000;342:1-8. Hypertension Phenotype Association Found in Selected Genetic Epidemiology Studies of the Serbian Population Gene ACE* ACE and angiotensin II type 1 receptor Matrix metalloproteinase 3 Endothelial nitric oxide synthase Polymorphism I/D** I/D and A1166C 5A/6A G894T *ACE = Angiotensin I-converting enzyme; **I/D Insertion/deletion. Alavantic D. Exp Clin. Cardiolo. Vol. 11:

13 Relation Between Resting Heart Rate and Life Expectancy Orso F, et al. Prog. Card. Vasc Dis.52 (2009) Resting heart rate as a risk factor for cardiovascular events. Palatini P. Progress in Cardiovascular Diseases, Volume 52, Issue 1, 2009, 46-60

14 Combined Effect of Heart Rate-Increasing Alleles on Heart rate GPS = genetic predisposition score. a) Combined effects of the 19 available heart rate loci in European adults. b) Combined effect of the 21 available heart rate loci in 12 year old Europeans. Nature genetics. Vol. 45, 2013: Case #2 Plan for Hypertension and possible Elevated Heart Rate BP 160/90, Pulse? Medications BB and Hctz. Serbian decent. Genetic causes of hypertension and increase heart rate. Testing family members. Treatment.

15 Conclusion The young CHD patients origin for severe atherosclerosis is most often related to genetic defects. The etiology for atherosclerosis does not necessarily need to be directly associated with dyslipidemia. The best prognosis is early diagnosis and treatment. After diagnosis of CHD has been made then testing of family members is a major priority. In the future so-called next-generation sequencing methods will be implemented to target specific genes for the management of atherosclerosis.