Coronary Heart Disease


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  • Set C1 – Title Slide
  • Why is font blue? Are the title fonts supposed to be calibri? Some slides have body font as calibri, some have it as Arial
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  • While CHD is not caused by a single gene in most individuals, there are more than 30 single-gene, Mendelian disorders that feature CHD and/or MI. Tests for many of these disorders are available and include DNA-based tests and biochemical analyses. These conditions generally are associated with a substantial risk for coronary disease and heart attack at young ages, and should be included in the differential diagnosis for a family being seen with early onset CHD and MI.
  • The familial dyslipidemias are an important subset of conditions that increase risk for premature CHD. Spacing between major bullets might help
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  • A recent study evaluated the impact on risk of additional family history beyond FDRs with early-onset CHD and found many additional significant associations, shown here as odds ratios, between additional family history characteristics and a personal history of early-onset CHD. This group used data from the national HealthStyles 2003 survey to assess associations between self-reported family history and personal history of early-onset CHD (diagnosed at or before age 60 years). These numbers are adjusted for demographic factors and self-reports of hypercholesterolemia, HTN, and obesity. 4035 respondents, 60% female, 72% white, mean age 48.8 years
  • Also, stratification into average (or weak), moderate, and high (or strong)-risk groups is possible, taking into consideration the degree of relatedness of the affected relatives, the ages of diagnosis, and the number of affected relatives. For example, this is a weak risk family with just one 2 nd degree relative affected at a later age, a moderate risk family with two 2 nd degree relatives affected at later ages, and a strong risk family with one 1 st degree relative affected at an early age, as well as two 2 nd degree relatives affected at later ages.
  • Also using data from the HealthStyles 2003 Survey, Scheuner et al. have published odds ratios for early-onset CHD given different combinations of level of familial risk, strong, moderate or weak and different numbers of CVD risk factors, which included diabetes, hypercholesterolemia, HTN, and obesity. Weak familial risk plus no other condition was the referent group. Early-onset CHD risk increased exponentially as the number of CVD risk factors and familial risk increased. Strong familial risk plus 3 or more risk factors was associated with a 62.2-fold increase in early-onset CHD risk compared with the referent group.
  • In order to assess familial risk for CHD in the clinical setting, personal and family history characteristics of genetic susceptibility to CHD have been determined. These include [Read slide].
  • Refer to a local cardiac genetic counselor or when that’s not possible, refer to a local preventative cardiologist. The components of a genetic evaluation for an individual referred because of concern due to a personal or family history of atherosclerosis include [Read slide].
  • CHD develops as a result of the interplay between an individual’s environment and their genetic predisposition, therefore any genetic test to predict CHD must include such interactions in the algorithm.
  • Set A1 – Content Slide
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  • So, our proband has a strong familial risk for CHD.
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  • Follow-up with our proband and her family showed that our proband [Read slide].
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  • Regarding Michos study: They studied 102 asymptomatic women (mean age 51) who were the sisters of a proband hospitalized with documented premature CHD. 98% were at low risk according to FRE. Based on CAC score percentiles 32% had significant subclinical atherosclerosis and 17% ranked above the 90 th percentile. Sisters of probands with premature CHD appear to be a high-risk group and may warrant non-invasive screening for subclinical disease to appropriately target individuals for more aggressive primary preventive therapy. Other studies have had similar findings.
  • Coronary Heart Disease

    1. 1. Coronary Heart Disease Genetics: An Overview Amy Sturm, MS, CGC Certified Genetic Counselor Clinical Assistant Professor Division of Human Genetics Amy Sturm discloses significant financial interests or other relationships with commercial interests in the following areas: Consultant/Speaker Bureau: Berkeley HeartLab. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device. The following planning committee members have no significant financial interests or relationships with commercial interests to disclose, their educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an organization other than The Ohio State University: Amy Ehrlich, MA and Henry Zheng, PhD, MBA
    2. 2. Some Facts about CHD <ul><li>Most common type of cardiovascular disease </li></ul><ul><li>Leading cause of death in the US for men and women </li></ul><ul><li>Average age of first heart attack </li></ul><ul><ul><li>64.5 for men </li></ul></ul><ul><ul><li>70.3 for women </li></ul></ul><ul><li>Lifetime risk of developing CHD after age 40 </li></ul><ul><ul><li>49% for men and 32% for women (Framingham Heart Study) </li></ul></ul><ul><li>In most cases, no “single gene” as a cause </li></ul><ul><li>Usually multifactorial due to interaction of multiple genetic and environmental risk factors </li></ul>Heart Disease and Stroke Statistics — 2009 Update, American Heart Association
    3. 3. Established CHD Risk Factors <ul><li>Physical inactivity </li></ul><ul><li>Smoking </li></ul><ul><li>High LDL (“bad cholesterol”) </li></ul><ul><li>Low HDL (“good cholesterol”) </li></ul><ul><li>Overweight and obesity </li></ul><ul><li>Diabetes mellitus </li></ul><ul><li>High blood pressure </li></ul><ul><li>Family History </li></ul>
    4. 4. Monogenic versus Polygenic Disease <ul><li>Monogenic </li></ul><ul><ul><li>Disorders caused by a mutation in a single gene </li></ul></ul><ul><ul><li>Also known as Mendelian disorders </li></ul></ul><ul><ul><li>Include CHD as one part of the clinical spectrum </li></ul></ul><ul><ul><li>Example: familial hypercholesterolemia </li></ul></ul><ul><li>Polygenic </li></ul><ul><ul><li>Disorders caused by multiple genetic variants with low penetrance </li></ul></ul><ul><ul><li>Example: common, complex CHD </li></ul></ul>
    5. 5. Mendelian Disorders Featuring CHD and/or MI <ul><li>Abdominal obesity-metabolic syndrome </li></ul><ul><li>Apolipoprotein(a) elevation </li></ul><ul><li>Apolipoprotein A-I deficiency </li></ul><ul><li>Arterial calcification, generalized, of infancy </li></ul><ul><li>Atherosclerosis susceptibility/Atherogenic lipoprotein phenotype </li></ul><ul><li>Cerebrotendinous xanthomatosis </li></ul><ul><li>Coronary artery disease, autosomal dominant 1, MEF2A </li></ul><ul><li>Coronary artery dissection, spontaneous </li></ul><ul><li>Fabry disease </li></ul><ul><li>Familial combined hyperlipidemia </li></ul><ul><li>Familial defective apolipoprotein B-100 </li></ul><ul><li>Familial hypercholesterolemia, autosomal dominant </li></ul><ul><ul><li>LDLR and PCSK9 genes </li></ul></ul><ul><li>Familial hypercholesterolemia, autosomal recessive </li></ul><ul><li>Familial hypertriglyceridemia </li></ul><ul><li>Familial partial lipodystrophy </li></ul><ul><li>Familial pseudohyperkalemia due to red cell leak </li></ul><ul><li>Fibromuscular dysplasia of arteries </li></ul><ul><li>Heparin cofactor II deficiency </li></ul><ul><li>Homocysteinemia </li></ul><ul><li>Homocystinuria </li></ul><ul><li>Hutchinson-Gilford Progeria Syndrome </li></ul><ul><li>Hyperlipoproteinemia, type III </li></ul><ul><li>Niemann-Pick disease, type E </li></ul><ul><li>Pseudoxanthoma elasticum, autosomal dominant and recessive forms </li></ul><ul><li>Sitosterolemia </li></ul><ul><li>Tangier disease </li></ul><ul><li>Werner syndrome </li></ul><ul><li>Williams syndrome </li></ul>Online Mendelian Inheritance in Man
    6. 6. Familial Dyslipidemias <ul><li>Inherited conditions that cause high levels of cholesterol and, in some cases, triglycerides </li></ul><ul><ul><li>Familial hypercholesterolemia </li></ul></ul><ul><ul><li>Familial hypertriglyceridemia </li></ul></ul><ul><ul><li>Familial combined hyperlipidemia </li></ul></ul><ul><ul><ul><li>All three are common, autosomal dominant disorders </li></ul></ul></ul><ul><ul><li>Polygenic dyslipidemia </li></ul></ul><ul><ul><ul><li>Most common form of elevated serum cholesterol </li></ul></ul></ul><ul><li>Often result in the premature onset of CHD </li></ul><ul><li>Typically underdiagnosed </li></ul>Crouch MA and Gramling R, Prim Care Clin Office Pract 2005
    7. 7. In Most Cases CHD is a Complex, Multifactorial Disease <ul><li>Hundreds of modifier genes likely influence the risk for CHD, each with an incremental effect on risk </li></ul><ul><li>These modifier genes have the potential to interact with other traits that are also polygenic (e.g. diabetes, blood pressure) </li></ul><ul><li>Numerous dietary, environmental and lifestyle risk factors and their interactions also impact CHD risk </li></ul>
    8. 8. Most CHD-Associated Gene Variants Have Low Penetrance <ul><li>Genome-wide association (GWA) studies of large populations have identified gene variants that contribute to an individual's risk for CHD </li></ul><ul><li>These variants only exert a small influence on the individual's CHD risk (i.e. low penetrance) </li></ul>
    9. 9. 9p21 Example <ul><li>GWA analyses have revealed strong associations with the 9p21 locus and CHD, as well as other types of cardiovascular disease, such as abdominal aortic aneurysm </li></ul><ul><li>SNP rs1333049 </li></ul><ul><ul><li>An individual's status for the rs1333049 SNP influences his/her risk for CHD </li></ul></ul><ul><ul><li>Heterozygotes (possess one copy of the rs1333049 risk-increasing allele [the C allele]) have a relative risk of 1.3 for CHD </li></ul></ul><ul><ul><li>Homozygotes have a relative risk of 1.7 </li></ul></ul>
    10. 10. Familial Hypercholesterolemia (FH) <ul><li>In contrast to polygenic, common, complex CHD, FH is inherited in an autosomal dominant fashion </li></ul><ul><li>FH affects 1 in 500 individuals </li></ul><ul><li>In the heterozygous form of FH, elevated plasma levels of LDL-C and total cholesterol lead to excessive deposition of cholesterol in the arterial walls, accelerated atherosclerosis and premature CHD </li></ul><ul><li>Most commonly caused by germline mutations in the LDL receptor gene, LDLR </li></ul><ul><li>High penetrance </li></ul><ul><li>Lifetime penetrance is close to 100% in males and approximately 70% in females </li></ul>
    11. 11. Family History of Coronary Heart Disease <ul><li>Important and independent risk factor for both </li></ul><ul><ul><li>CHD events </li></ul></ul><ul><ul><li>Atherosclerosis in asymptomatic adults </li></ul></ul><ul><li>First Degree Relative (FDR) with CHD: 2-3 fold increase in risk </li></ul><ul><ul><li>Risk increases </li></ul></ul><ul><ul><ul><li>As number of affected FDRs increases </li></ul></ul></ul><ul><ul><ul><ul><li>3-6 fold increase in risk if > 2 FDRs with CHD </li></ul></ul></ul></ul><ul><ul><ul><li>With younger ages of CHD onset in relatives </li></ul></ul></ul>
    12. 12. Odds Ratios for Various Definitions of a “Positive Family History of CHD” <ul><li>First Degree Relatives (FDR) </li></ul><ul><ul><li>> 1 FDR with early-onset CHD (5.0) </li></ul></ul><ul><ul><li>> 1 FDR with late-onset CHD (2.5) </li></ul></ul><ul><ul><li>1 FDR with CHD at any age of onset (3.0) </li></ul></ul><ul><ul><li>> 2 FDRs with CHD at any age of onset (5.1) </li></ul></ul><ul><ul><li>> 1 sibling with CHD at any age of onset (3.1) </li></ul></ul><ul><ul><li>> 1 parent with CHD at any age of onset (3.8) </li></ul></ul><ul><ul><li>Parent and sibling pair with CHD at any age of onset (5.0) </li></ul></ul><ul><ul><li>Both parents with CHD (6.2) </li></ul></ul><ul><li>Second Degree Relatives (SDRs) </li></ul><ul><ul><li>> 1 SDR with early-onset CHD (4.6) </li></ul></ul><ul><ul><li>> 2 SDRs with CHD at any age of onset (2.8) </li></ul></ul><ul><li>Related conditions </li></ul><ul><ul><li>> 1 FDR with early-onset stroke (2.9) </li></ul></ul><ul><ul><li>> 1 sibling with stroke at any age of onset (3.2) </li></ul></ul><ul><ul><li>FDRs and SDRs with stroke at any age of onset (2.7) </li></ul></ul><ul><ul><li>> 1 FDR with diabetes (2.4) (women only) </li></ul></ul>Scheuner MT et al, Genet Med 2006
    13. 13. Familial Risk Stratification MI d. 85 MI d. 85 CAD dx. 67 MI dx. 53 MI d. 85 Diabetes dx. 45 Weak Risk Moderate Risk Strong Risk Published Risk Stratification Guidelines in Scheuner MT. Genet Med 2003 CAD dx. 67
    14. 14. Risk for Early-Onset CHD Given Familial CHD Risk and Number of CVD Risk Factors CVD risk factors = diabetes, hypercholesterolemia, hypertension and obesity Adjusted for age, gender, ethnicity/race, educational level, income, and marital status. Adapted from Table 4, Scheuner MT et al. Genet Med 2006 Familial CHD Risk Three or more n=376 OR a (95% CI) Two n=740 OR a (95% CI) One n=1203 OR a (95% CI) None n=1716 OR a (95% CI) Strong (n=1273) 62.2 (18.5-209.1) 48.6 (14.8-160.0) 17.9 (5.3-61.0) 4.3 (1.1-17.6) Moderate (n=471) 24.9 (5.2-119.7) 27.8 (7.2-106.8) 2.1 (0.21-20.0) 3.6 (0.6-21.9) Weak (n=2291) 16.5 (4.4-61.2) 12.6 (3.6-44.4) 3.7 (1.0-13.9) 1.0 (referent)
    15. 15. Genetic Susceptibility to CHD Be on the Watch for… <ul><li>Early onset CHD (men < 55, women < 65) </li></ul><ul><li>Angiographic severity (degree of blockage) </li></ul><ul><li>Multi-vessel disease (coronaries, carotids, aorta) </li></ul><ul><li>>1 close relative with CHD, especially female relatives </li></ul><ul><li>Absence of risk factors in family members with CHD </li></ul><ul><li>Family history of related disorders (diabetes, hypertension, stroke, peripheral vascular disease) </li></ul>
    16. 16. Genetic Counseling for CHD <ul><li>Same goals as other types of adult genetic counseling, </li></ul><ul><li>like cancer genetic counseling… </li></ul><ul><li>We just don’t have a genetic test for “ CHD1 and CHD2” ! </li></ul><ul><li>Pedigree risk assessment </li></ul><ul><li>Medical history </li></ul><ul><li>Physical examination </li></ul><ul><li>Differential diagnosis, including Mendelian disorders featuring CHD </li></ul><ul><li>Genetic counseling and education regarding risk level </li></ul><ul><li>Laboratory testing (biochemical testing for traditional and emerging CHD risk factors) </li></ul><ul><li>Screening for early detection of atherosclerosis </li></ul><ul><li>Based on results make recommendations for targeted risk factor modification and prevention strategies </li></ul><ul><li>Follow-up on response to therapy </li></ul><ul><li>Identify at-risk family members </li></ul>
    17. 17. What about Genetic Testing for CHD? <ul><li>Currently available, but is it clinically useful? </li></ul><ul><li>Does it add value to current risk prediction tools? </li></ul><ul><li>For any gene variant the effect on risk is likely to be relatively small </li></ul><ul><ul><li>Most relative risks in range of 1.2-1.4 </li></ul></ul><ul><ul><li>Given the low penetrance of these variants, genetic tests will have limited predictive power and clinical utility </li></ul></ul><ul><li>What about reclassification of risk level as more is learned about additional genetic modifiers of risk ? </li></ul><ul><li>What about complex gene-gene and gene-environment interactions? </li></ul><ul><li>Family history remains the “gold standard” in familial risk assessment for CHD </li></ul><ul><li>Genetic testing appropriate if Mendelian disorder(s) in differential </li></ul>
    18. 18. Case Example: Is This Woman at Increased Risk? d. 47 Heart Attack P Breast ca dx 35 40 35 61 d. 6 mo SIDS 10
    19. 19. Expanding the Pedigree… d. 47 Heart Attack P Breast ca dx 35 40 35 61 d. 6 mo SIDS 10 65 CABGx3, 62 Non-smoker 67 DM dx 55 HTN dx 45 d. 61 Heart attack Now what???
    20. 20. Familial Risk for Patient: Strong d. 47 Heart Attack P Breast ca dx 35 40 35 61 d. 6 mo SIDS 10 65 CABGx3, 62 Non-smoker 67 DM dx 55 HTN dx 45 d. 61 Heart attack
    21. 21. CardioGenetic Consultation <ul><li>Proband and sister go through risk assessment </li></ul><ul><li>Proband’s physical exam and bloodwork okay, but… </li></ul><ul><li>Sister diagnosed with borderline HTN; medication started </li></ul><ul><li>CT coronary angiography also ordered </li></ul><ul><ul><li>Shows 50-75% luminal narrowing in the left anterior descending (LAD) coronary artery </li></ul></ul><ul><ul><li>Results reviewed with sister, who is still symptom-free; statin, beta-blocker and aspirin added to medical therapy </li></ul></ul><ul><li>Invasive cardiac catheterization/coronary angiography scheduled </li></ul><ul><ul><li>Balloon angioplasty and stents placed across LAD lesion </li></ul></ul><ul><li>Cardiac Rehabilitation/Secondary Prevention </li></ul>
    22. 22. Long-term Proband and Family Follow-up P Breast ca dx 35 40 35 10 <ul><li>Proband’s husband also came in for genetic </li></ul><ul><li>risk assessment based </li></ul><ul><li>on his own strong familial risk; evaluation did not show increased personal risk; managing weight </li></ul><ul><li>and lipid levels with </li></ul><ul><li>diet and exercise </li></ul><ul><li>Proband’s sister continues follow-up with her cardiologist and stops smoking half pack of cigarettes per day </li></ul><ul><li>Proband joined women’s hockey league </li></ul><ul><li>and gym and began losing weight; also changed </li></ul><ul><li>diet and food she prepares for family </li></ul>
    23. 23. Family History as a Guide for Early Detection and Prevention Modified from Scheuner MT. Genet Med 2003 Collect family history every 1-2 years High Moderate Average Possible Mendelian disorder? Assessment of established and emerging CHD risk factors every 1-2 yrs Consider early detection strategies every 2-3 yrs beginning 10 yrs before earliest CHD onset in family Provide personalized prevention strategies tailored to CHD risk factors and presence of subclinical disease Identify at-risk relatives Assessment of established CHD risk factors every 2-3 yrs If multiple risk factors identified, assign high risk Provide personalized prevention strategies tailored to CHD risk factors Assessment of established CHD risk factors every 5 yrs Provide public health prevention messages
    24. 24. Useful Online Programs to Estimate CHD Risk <ul><li>Framingham Risk Score ( ) </li></ul><ul><ul><li>Family history not included in Framingham risk score </li></ul></ul><ul><ul><li>Recent study concluded that a third of women classified as low risk by Framingham had significant subclinical atherosclerosis (Michos et al, Am Heart J , 2005) </li></ul></ul><ul><li>CardioSmart Risk Assessment Tool ( ) </li></ul><ul><ul><li>Patient education site based on findings from the Framingham Heart Study </li></ul></ul><ul><li>Reynolds Risk Score ( ) </li></ul><ul><ul><li>Also incorporates serum C-Reactive Protein level and family history of CHD prior to age 60 in the parents of the user </li></ul></ul><ul><li>Your Disease Risk ( ) </li></ul><ul><ul><li>Assesses CHD risk using medical and smoking history, diet, physical activity measures and family history of affected first-degree relatives </li></ul></ul><ul><li>Family Health Link ( ) </li></ul><ul><ul><li>Risk triage tool that assesses risk for CHD based on family history </li></ul></ul><ul><ul><li>Stratifies risk into average, moderate and high risk categories </li></ul></ul>