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Cardiovascular risk factors of first degree relatives with family history of premature atherosclerotic… Wu, Evelyn Pui See 2005

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C A R D I O V A S C U L A R RISK F A C T O R S OF FIRST D E G R E E R E L A T I V E S W I T H F A M I L Y H I S T O R Y OF P R E M A T U R E A T H E R O S C L E R O T I C D I S E A S E  by  E V E L Y N PUI SEE W U  B.Sc. (Biochemistry), The University o f British Columbia, 2003  A T H E S I S S U B M I T T E D IN P A R T I A L F U L F I L L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E OF M A S T E R OF S C I E N C E in T H E F A C U L T Y OF G R A D U A T E S T U D I E S (Pathology and Laboratory Medicine)  T H E U N I V E R S I T Y OF BRITISH C O L U M B I A July 2005  © Evelyn Pui See W u , 2005  ABSTRACT  The presence o f premature (men <50 years; women <60 years) coronary heart disease ( C H D ) in a first-degree relative is a significant and independent risk factor for cardiovascular, peripheral vascular and cerebrovascular disease. First-degree relatives (FDRs) o f patients with premature C H D (index patients) have increased risk o f death from cardiovascular disease compared to those without a family history. The purpose o f this study was to determine whether F D R s had higher prevalence and severity o f traditional and non-traditional cardiovascular risk factors compared to the general Canadian population.  Index patients and their F D R s (parents, siblings, and children) were recruited for the Family Atherosclerosis Counseling and Testing Study ( F A C T S ) . Cardiovascular risk assessment included measurements o f lipid and biochemical markers, sociodemographic factors, anthropometry measures, as well as dietary, exercise, and smoking histories. Cardiovascular risk factors in F D R s were compared to a case-matched M - C H A T (Multicultural  Community  Health  Assessment Trial) control population.  Male index patients had significantly higher median values o f body-mass-index ( B M I ; p = 0.002), waist circumference (p <0.001), systolic blood pressure (p = 0.026) and diastolic blood pressure (p = 0.001) than male F D R s . Median lipoprotein(a) values were higher in male index patients than their male F D R s (p = 0.014); no differences were observed between female index patients and female F D R s (p = 0.238). Though both groups were comparable in age (p = 0.130), F D R siblings had similar risk factors as index patients, except more F D R siblings were non-  smokers {p = 0.048) and F D R siblings were more educated (p = 0.044). Index patients and their F D R siblings had comparable median lipoprotein(a) values at 176 m g / L (102 - 476 mg/L) and 182 m g / L (59 - 474 mg/L), respectively (p = 0.516). A l s o , there was a higher prevalence o f abdominal obesity in F D R siblings than in the index patients, which did not reach statistical significance.  In general, F D R s had similar prevalence and severity o f traditional lifestyle habits and cardiovascular risk factors as the M - C H A T controls. Both the F D R s and the controls were relatively healthy: over 92% o f the female and 85% o f the male F D R s were classified as ' l o w risk' according to the Framingham risk score, even after adjusting for positive family history.,  However, there were distinct differences between F D R s and controls in the frequency o f elevated non-traditional risk factors, even after adjusting for age. Median lipoprotein(a) values were comparable between female F D R s at 218 (63 - 483) mg/L and female controls at 177 (96 270) m g / L (p - 0.331). Male F D R s , on the other hand, had significantly lower lipoprotein(a) than male controls at 105 (45 - 238) m g / L and 192 (88 - 377) m g / L , respectively (p = 0.022). Mean serum homocysteine levels were higher in both male and female F D R s at 10.9 ± 0.5 plM and 9.0 ± 0.3 | J M , compared to 8.5 ± 0.2 \xM and 7.3 ± 0.2 \xM for male and female controls, respectively (p <0.001). Mean C-reactive protein values were 1.8 ± 0.2 m g / L in male and 2.5 ± 0.2 m g / L in female F D R s ; they did not differ significantly from the controls at 1.7 ± 0.3 m g / L for men and 1.7 ± 0.3 m g / L for women (p = 0.272).  In total, 86% o f the F D R s and 78% o f the controls had at least one modifiable risk factor (smoking, physical inactivity, B M I >25 kg/m , diabetes, or blood pressure >140/90 mmHg), comparable to the 80% found in the general population from the Canadian Community  Health  Survey in 2000. Despite the many similarities in traditional cardiovascular risk factors between the F D R s and the controls, however, 87% o f the F D R s had at least one non-traditional risk factor. This was significantly different than the 59% o f the controls ( p O . O O l ) ; moreover, 92% o f the i o w - r i s k ' female F D R s had at least one non-traditional risk factor.  Therefore, though the F D R s have similar traditional risk factors as the general population and were thus classified as low-risk, these individuals with strong family histories o f premature C H D have frequent increases in homocysteine values that may put F D R s at increased risk for C V D . Traditional cardiovascular risk factor profile alone may not be sufficient in assessing risk in these individuals.  TABLE OF CONTENTS Abstract  ii  List o f Tables  viii  List o f Figures  x  Acknowledgements  xi  Dedication  xiii  INTRODUCTION  1  Research Problem  1  Purpose o f the Study  2  Definition o f Terms  3  CHAPTER I 1.1  LITERATURE REVIEW  Prevalence o f Cardiovascular Disease  '..  5 5  1.2  Non-traditional Risk Factors 1.2.1 Abdominal Obesity and the Metabolic Syndrome 1.2.2 C-Reactive Protein 1.2.3 Lipoprotein(a) 1.2.4 Homocysteine  8 8 9 11 12  1.3  Family History o f Cardiovascular Disease 1.3.1 Genetics Versus Environment 1.3.2 I N T E R H E A R T  13 13 15  CHAPTER II  METHODS AND PROCEDURES  16  2.1  Summary o f Research Project  16  2.2  Research Design  16  2.3  F A C T Study 2.3.1 Background  17 17  2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7  Research Objectives Research Design Recruitment o f Index Patients Recruitment o f First-Degree Relatives Initial Appointment for First-Degree Relatives Data Collection  '.  18 18 19 21 22 23  2.4  Multicultural Community Health Assessment Trial ( M - C H A T )  26  2.5  Canadian Community Heart Health Survey  26  2.6  Data Analysis  26  2.7  Research Questions  27  2.8  Ethical Considerations  29  C H A P T E R III  RESULTS  30  3.1  Efficiency o f Sampling  30  3.2  Baseline Characteristics  32  3.2.1 3.2.2 3.2.3  Characteristics o f Index Patients Characteristics o f First-Degree Relatives Characteristics o f Controls  32 35 38  3.3  Comparison O f Index Patients A n d Their First-Degree Relatives  42  3.4  Comparison O f First-Degree Relatives A n d Their Controls  50  C H A P T E R IV  DISCUSSION  63  5.1 .  Index Patients and F D R Siblings  64  5.2  First-Degree Relatives Compared To Controls  65  5.2.1 5.2.2 5.2.3 5.3 5.3.1 5.3.2 5.3.3 5.3.4  Traditional cardiovascular risk factors Non-traditional cardiovascular risk factors Risk assessment o f F D R s - are they necessary? Limitations Sample size Selection o f F D R s and controls Selection bias Comparing data with the Canadian population  65 68 70 72 73 74 76 77  5.3.5  Family history  78  5.3.6  Biochemical measurements  78  5.4  Summary  Reference  79 ;  Appendix  80 91  Appendix A : General Consent Form - Index Patients  91  Appendix Appendix Appendix Appendix  96 100 108 110  B : General Consent Form - First-Degree Relatives C : General Questionnaire for F A C T S D : Modifiable Activity Questionnaire E : Framingham Risk Score  LIST OF TABLES  Table 3.1 .  Inclusion and Exclusion Criteria for Index Patient Recruitment  Table 3.2  Inclusion and Exclusion Criteria for First Degree Relative Recruitment  Table 3.3  Recruitment and Enrollment o f Index Patients  Table 3.4  Recruitment and Enrollment o f First-Degree Relatives  Table 3.5  Ethnicity o f Index Patients  Table 3.6  General Baseline Characteristics o f Index Patients  Table 3.7  General Baseline Characteristics o f First-Degree Relatives  Table 3.8  Biochemical Measurements o f First-Degree Relatives  Table 3.9  General Baseline Characteristics o f Controls  Table 3.10  Comparison o f Physical Activity Between Controls and the General Population in British Columbia  Table 3.11  Biochemical Measurements o f Controls  Table 3.12  Gender and Relation o f First-Degree Relatives to Index Patients  Table 3.13  Comparison o f General Characteristics Between Index Patients and First-Degree Relatives  Table 3.14  Comparison o f Index Patients With Their First-Degree Relatives  Table 3.15  Comparison o f Index Patients With Their Siblings  Table 3.16  Comparison o f General Characteristics Between First-Degree Relatives and Controls  Table 3.17  Categorical Comparisons Between First-Degree Relatives and Controls  Table 3.18  Comparisons o f Biochemical Measurements Between First-Degree Relatives and Controls  Table 3.19  Prevalence o f Elevated Apolipoprotein B in First-Degree Relatives and Controls  viii  Table 3.20  Comparison o f the Prevalence o f Elevated Non-traditional Risk Factors Between First-Degree Relatives and Controls  Table 3.21  Framingham Risk Scores for First-Degree Relatives and Controls After Adjusting for Positive Family History  Table 3.22  Number o f Non-traditional Risk Factors in First-Degree Relatives and Controls  Table 3.23  Number o f Major Modifiable Cardiovascular Risk Factors in First-Degree Relatives and Controls  IX  LIST OF FIGURES  Figure 4.1.  Prevalence of Cardiovascular Diseases in Americans A g e 20 Years and Older by Age and Sex  X  ACKNOWLEDGEMENTS  I have so many people to acknowledge for their help and support - without them, this thesis would definitely not have been possible!  First, I wish to acknowledge my supervisor, Dr. Jiri Frohlich, for his excellent guidance and mentorship throughout my studies. H i s vast wealth o f knowledge, whether it is regarding current cardiovascular treatment guidelines or the best places to visit in Prague, is definitely indispensable. H e provided me with unique learning experiences that have contributed to m y development not only as a researcher, but also as an individual.  I also want to offer m y sincere thanks to Dr. Rajashree Devarakonda for her invaluable advice and contribution throughout the F A C T study. A s well, I am very appreciative o f Dr. Scott Lear for the controls in the M - C H A T study.  Throughout m y time at St. Paul's Hospital, 1 was privileged to meet and work with wonderful staff at the Healthy Heart Program, including my fellow colleagues at the Atherosclerosis Specialty Laboratory, including Lubomira Czermakova, Simi K o h l i , Amber Zutz, Guosong Qiu, and Susanne Burns. Besides their unfaltering support through the project, they also made the last two years an unforgettable experience, with plenty o f 'healthy' food and laughter!  A l s o , heartfelt thanks to Jonathan H i i for his help, both academically and in life - 1 would never have gotten this far without all your support.  XI  A n d finally, I would like to acknowledge other members o f m y thesis committee, including Dr. John H i l l , Dr. Karin Humphries, D r . Greg M i l l e r and Dr. Haydn Pritchard, forproviding insightful suggestions and guidance throughout the project. A l s o , thank you to Pfizer for funding the F A C T study.  DEDICATION  This thesis is dedicated to my parents, Anita and David, who have always encouraged me to pursue my dreams and have always given me their unwavering support. Without you, mommy and daddy, I would not be where I am now -  thankyoul  I also want to dedicate this to my grandmother ('Granny') for her worldly wisdom and especially for her patience and understanding while I was writing m y thesis.  \  Xlll  INTRODUCTION  Premature atherosclerosis in a first-degree relative is a significant and independent risk factor for the development o f cardiovascular, peripheral vascular or cerebrovascular disease . 1  Compared to individuals without family history, first-degree relatives o f coronary heart disease patients have an increased risk o f death from coronary heart disease ' . Apart from genetics, the 1 2  prevalence o f other cardiovascular risk factors, including both modifiable and non-modifiable factors, are also higher in these families . Therefore, early identification and reduction o f risk 3  factors in this higher-risk group is a key strategy for coronary heart disease p r e v e n t i o n ' ' . 1  4  5  Research P r o b l e m  First-degree relatives o f patients with premature C H D are considered a higher-risk group ' . Few researchers have examined apparently healthy first-degree relatives o f affected 4  5  individuals. Even fewer studies have investigated family cohorts with a history o f premature CHD.  Purpose of the Study  The purpose o f the study is to examine the prevalence and severity o f traditional and nontraditional cardiovascular risk factors in first-degree relatives o f index patients (patients with premature C V D at <50 years in men and ^ 6 0 years i n women) as compared to the general population.  •  W e hypothesized that:  Index patients and their first-degree relatives (parents, siblings, and children) w i l l have similar traditional and non-traditional cardiovascular risk factors.  •  First-degree relatives w i l l have higher prevalence and severity o f traditional and nontraditional cardiovascular risk factors as compared to a control ( M - C H A T ) population.  •  The gender (men versus women) and the type o f relation (parental versus sibling history) to the index patient w i l l affect the prevalence and severity o f traditional and nontraditional C V D risk factors in first-degree relatives.  2  Definition of Terms  •  Atherosclerosis: " A process in which deposits o f yellowish plaques (atheromas) containing cholesterol, lipid material and lipophages are formed within large- and medium-sized arteries. A n atheroma can increase in size and harden over time reducing blood flow and can potentially result in a thrombosis or bleeding into and subsequently clotting o f an artery resulting in a myocardial infarction" . 6  •  Body Mass Index (BMI): A measure o f human body size and proportion. It is defined as weight (kilograms) divided by height (meters) squared.  •  Cardiovascular diseases (CVD): For the purposes o f this study, all diseases o f the circulatory system including acute myocardial infarction, ischemic heart disease, peripheral vascular disease, and stroke . 1  •  Cardiovascular disease risk (CVD risk): The probability o f an unfavourable cardiovascular event.  •  Coronary heart disease (CHD): A n acute or chronic disease affecting the blood vessels o f the heart, and involving an insufficient supply o f oxygenated blood to the myocardium. For this study, coronary heart disease involved those with coronary artery disease, peripheral vascular disease, as well as cerebrovascular disease.  •  First-degree relative (FDR): A n immediate, biological family member including parents (mother or father), siblings (brother or sister), and children (daughter or son).  •  Modifiable risk factor: A determinant that can be modified by intervention, thereby reducing the probability o f disease.  3  •  Non-modifiable risk factor: A determinant that cannot be changed. This includes age, gender, and genetics.  •  Non-traditional risk factor: A n attribute that may be associated with an increased probability o f developing disease, but has not been well-validated by evidence-based studies.  •  Risk assessment: identification o f an individual's risk for coronary heart disease.  •  Risk factor: an environmental, behavioral, or biologic factor confirmed by temporal sequence, usually in longitudinal studies, which i f present directly increases the probability o f a disease occurring, and i f absent or removed reduces the probability. Risk factors are part o f the causal chain, or expose the host to the causal chain. Once disease occurs, removal o f a risk factor may not result in a cure . 8  •  Traditional risk factor: A generally accepted risk factor for cardiovascular disease, including smoking, high blood pressure, high cholesterol, diabetes, obesity/sedentary lifestyle, alcohol, stress, age and certain aspects o f socio-economic status . 6  4  C H A P T E R I: L I T E R A T U R E R E V I E W  A search o f the literature was conducted on traditional and non-traditional cardiovascular disease risk factors, as well as family history o f premature atherosclerosis. This included both theoretical and evidenced-based materials published from 1987 to 2005. Search terms included cardiovascular  disease, atherosclerosis, family history, cardiovascular  risk assessment,  emerging cardiac risk factors, C-reactive protein, lipoprotein(a), homocysteine, gender, and metabolic  syndrome.  >  Prevalence of C a r d i o v a s c u l a r Disease  Cardiovascular disease ( C V D ) is the leading cause o f mortality and morbidity in developed countries, and rapidly increasing in developing nations. In Canada, C V D (heart attacks and strokes) accounted for 36% o f total mortality and cost $18.5 billion annually in direct and indirect costs to the Canadian economy . Though mortality rates due to C V D have 6  decreased by 56% since 1969, the actual number o f deaths has remained steady since the m i d 1990s . Moreover, similar to other developed countries, Canada is currently facing increased 6  prevalence o f obesity (including adolescent obesity), diabetes mellitus, and an increasingly aging population.  The majority o f C V D manifests as atherosclerotic disease, which encompasses coronary heart disease ( C H D ) , cerebrovascular disease, and peripheral vascular disease.  5  Since the observation that increased cholesterol is correlated to C V D mortality by Anitschkow in 1913, important advances have been made through the identification o f major C V D risk factors . This has been aided by large prospective cohort studies such as the 9  Framingham Heart Study . Non-modifiable C V D risk factors include age, gender, genetics, and 10  previous family history o f C V D . Major modifiable risk factors include dyslipidemia (low H D L cholesterol, high total cholesterol-to-HDL-cholesterol ratio), smoking, hypertension (>140/90 mmHg), and diabetes mellitus. It is now well accepted that the reduction o f these modifiable risk factors can lower both the incidence and prevalence o f the atherosclerotic disease. Certainly, many current risk assessment strategies and treatment guidelines target these modifiable risk factors.  However, it is also evident that a substantial proportion o f C V D events occur in individuals who do not have these traditional risk factors. For example, though cholesterol is routinely screened in the C V D risk assessment, approximately half o f those who develop C V D do not have high cholesterol levels". This could be partially explained by that fact most C V D patients do not have extreme levels o f modifiable C V D risk factors: even slight elevations in cholesterol and blood pressure can increase one's risk for C V D ' ' . 1 0  The Working Group on Hypercholesterolemia  1 2  1 3  and Other Dyslipidemias  published  Canadian recommendations for the management and treatment o f dyslipidemias in 2000 to provide health care providers with standardized guidelines for evaluating C V D risk in patients . 5  Since the publication o f the Canadian guidelines, the National Cholesterol Education Program  6  Adult Treatment Panel-Ill ( N C E P ATP-III) has also published a report in 2 0 0 2 . 14  In light o f the  American report, revised Canadian recommendations were published in 2 0 0 3 . l5  Using N C E P ATP-III risk algorithm, cardiovascular disease ( C V D ) risk is based on Framingham risk equations to estimate 10-year risk o f C H D mortality or occurrence o f myocardial infarction. The Framingham Risk Score considers traditional C V D risk factors including age, gender, smoking, total cholesterol, HDL-cholesterol, blood pressure, and diabetes . Risk is classified into three levels o f risk (low, moderate, high); LDL-cholesterol 10  ( L D L - C ) and total cholesterol to HDL-cholesterol ratio ( T C : H D L - C ) targets vary depending on the level o f risk. However, the Framingham Risk Score does not take into account family history of C H D , and is likely to underestimate C V D risk, especially at younger ages; therefore, the guidelines recommend multiplying the risk estimate by 1.7- to 2-fold for those with positive family history o f premature C H D . People with established C H D and those with diabetes are considered high r i s k . Finally, the guidelines also recommend new non-invasive assessment o f 15  preclinical atherosclerosis (exercise stress testing, nuclear perfusion scans, and carotid ultrasonography) and measurement o f non-traditional risk factors such as C-reactive protein, lipoprotein(a), homocysteine, and fibrinogen to aid in early identification o f individuals at high risk . 15  7  N o n - T r a d i t i o n a l R i s k Factors  Abdominal Obesity and the Metabolic Syndrome  The metabolic syndrome is defined as a cluster o f C V D risk factors, including insulin resistance, abdominal obesity, elevated plasma triglycerides, low H D L - C levels, and high blood pressure. The N C E P ATP-III guidelines define metabolic syndrome as having at least three o f the above C V D risk factors, with waist circumference cut-offs o f 102 cm for men and 88 cm for w o m e n . In contrast, in the International Diabetes Federation (IDF) consensus worldwide 14  definition, a person must have abdominal obesity, in addition to two o f the other four risk factors. The IDF also have more stringent definitions o f abdominal obesity, at > 94 cm for Caucasian men and > 80 cm for women; for South Asian and Chinese men, cut-offs are even lower at > 90 c m . 1 6  Studies have shown that abdominal obesity is observed in about half o f the patients with metabolic syndrome. Individuals with abdominal obesity also have small, dense L D L particles and elevated apolipoprotein B levels. Adipose tissue synthesizes and secretes a variety o f proteins that trigger systemic responses, including adiponectin, leptin, TNF-oc, and C-reactive protein (CRP). Increases in adipose tissue size and distribution can cause changes in insulin sensitivity. In particular, visceral adipocytes, which are predominately deposited around the abdomen, leads to higher lipolytic activity. A s a result, the levels o f circulating triglycerides and free fatty acids w i l l increase; i f the increased load on the portal system is not effectively cleared  by the liver, insulin resistance w i l l result. Therefore, waist circumference is a simple and useful estimate o f abdominal obesity . 15  Obesity, especially abdominal obesity, is associated with increased risk o f diabetes, hypertension, low HDL-cholesterol ( H D L - C ) , symptoms o f the metabolic syndrome, as well as increased inflammatory markers including C-reactive protein ( C R P ) and interleukin-6 ( I L - 6 ) ' . 1 7  l 8  C-Reactive Protein  Inflammation is widely acknowledged as an integral process throughout the pathogenesis o f atherosclerosis . Local inflammatory responses can trigger events leading to plaque 19  instability and acute coronary syndromes -' . 19  20  C-reactive protein ( C R P ) is a pentameric, acute-phase protein that is substantially 21  increased as an inflammatory response to tissue injury or infection . It is primarily synthesized in the liver, and is released when stimulated by cytokines such as IL-6 and T N F - a . Research indicates that C R P may play a direct role in atherosclerosis by inducing secretion o f endothelin-1 22  and IL-6 . C-reactive protein may directly induce endothelial cell expression o f adhesion molecules, leading to recruitment o f monocytes to sites o f endothelial i n j u r y ' . Another role 23  24  may involve facilitating LDL-cholesterol uptake by macrophages . 25  A meta-analysis o f 14 prospective studies on the effect o f C R P on C V D mortality and myocardial infarctions reported that individuals with C R P at the top tertile have an odds ratio o f  9  1.9 (95% confidence interval: 1.5 - 2.3) as compared with those at the bottom tertile, after adjustment for factors such as age, sex, and smoking habits  . Furthermore, Ridker et al. have  suggested that even small increases in C R P are predictive o f future C V D events in apparently 27  healthy individuals and provides additive value to the Framingham risk score .  Measurement o f C-reactive protein has also been shown to be useful in those with established C V D . Studies have demonstrated that C R P levels provides additive value in predicting recurrent C V D events in patients with acute coronary syndrome, angina, and peripheral vascular disease  " .  The additive value o f C R P to traditional risk factors superceded the value o f other nontraditional measures, for instance, carotid intima media thickness, calcium score, and the presence o f the metabolic syndrome " .  Nevertheless, one limitation o f using C R P as part o f routine risk assessment is its nonspecificity for C V D events: C R P is also elevated in other inflammatory processes, including infections and in chronic diseases . Since a majority o f the studies comprise Caucasians, 35  whether the predictive value o f C R P is applicable to other ethnic populations is still questionable.  10  Lipoprotein(a)  L i k e C R P , lipoprotein(a) [Lp(a)] is an acute phase protein that is upregulated in response 36  to IL-6 and is synthesized in the liver . Lipoprotein(a) is similar to a L D L particle, except an apolipoprotein(a) [apo(a)] moiety is linked to apolipoprotein B through disulfide linkage . It is 37  a non-modifiable risk factor, as Lp(a) levels are not affected by diet or exercise . Conversely, 38  Lp(a) concentrations are genetically determined and vary depending on the size o f the apo(a) isoform . 38  The biological function o f Lp(a) is unclear. One atherogenic property o f Lp(a) may be to promote smooth muscle cell proliferation and chemotaxis o f monocytes by binding to endothelial 39  cells and macrophages  . However, the most important role o f Lp(a) in atherosclerosis may be to  prevent fibrinolysis . Lipoprotein(a) is a competitive inhibitor o f plasminogen, which binds to fibrinogen, plasminogen receptors, and  fibrin . 40  Epidemiological evidence has generally supported the idea that elevated levels o f Lp(a) are highly atherogenic, especially in the presence o f elevated L D L - C levels, low H D L - C levels, hypertension, diabetes, and hyperhomocysteinemia " . 41  45  Nevertheless, the additive value o f Lp(a) in global risk assessment is uncertain. First, there is no standardized measurement o f Lp(a); currently, the accuracy o f Lp(a) values are highly dependent on Apo(a) s i z e . Secondly, there are no published large clinical trials that have 46  demonstrated an association between lowering Lp(a) values and decreased C V D clinical events.  11  Homocysteine  Homocysteine is a sulfur-containing amino acid that is a by-product o f the methionine pathway . The enzymes along the pathway require B vitamins as cofactors, specifically folate, 47  pyridoxine (vitamin B^), and cobalamin (vitamin B12) . Excess homocysteine levels may be 47  atherogenic by promoting oxidative and endoplasmic reticulum stress, endothelial dysfunction, hypercoagulation, platelet activation, and vascular smooth muscle cell proliferation . 47  Gene mutation in the 5,70-methylenetetrahydrofolate  reductase (MTHFR) gene, which  encodes one o f the enzymes in homocysteine metabolism, can lead to moderate increases in AO  homocysteine levels (up to 25%)  . The mutation (677C —> T) is present in about 15% o f the  Caucasian population. Recent studies have shown that individuals (both with or without C V D ) who are homozygous for the mutant alleles (TT) have slight but significant increases in C V D risk as compared to wild-type carriers " . Findings were similar after adjusting for age and 48  50  ethnicity.  It is known that individuals with extremely high levels o f homocysteine are especially at risk o f developing premature atherosclerosis . However, even those with mildly elevated 47  homocysteine are at higher risk o f developing atherosclerosis than the general population. Early identification o f these individuals w i l l be beneficial, as the administration o f high doses o f B vitamins and folic acid may lower homocysteine to normal ranges . Whether the 51  supplementation o f B vitamins and folic acid to lower homocysteine w i l l actually prevent C V D  12  and whether homocysteine is a causal risk factor w i l l still need to be answered by ongoing, 52  randomized, controlled trials .  F a m i l y H i s t o r y of C a r d i o v a s c u l a r Disease  Genetics Versus  Environment  Large epidemiological studies have shown that a family history o f premature coronary heart disease ( C H D ) is an independent risk factor for cardiovascular disease " . The U . S . 53  57  National Cholesterol Education Program Third Adult Treatment Panel ( N C E P - A T P III) defined premature C H D as before 55 years in men and 65 years in w o m e n . In particular, having a 58  family history o f premature C H D is associated with 1.5- to 2-fold increase in risk o f developing cardiovascular disease ' . Furthermore, maternal family history o f C H D may even predict 59  60  future cardiovascular events more strongly than a paternal family history, and at older ages o f 2 3 61  disease onset ' '  . Recently, Nasir et al. suggest that sibling history o f premature C H D is more  strongly associated with subclinical C A D than parental history . A positive family history o f 62  premature C A D is also associated with impaired endothelium-dependent coronary blood flow regulation  6 3  .  The pathophysiology o f C H D is complex and involves an interaction o f genetic, lifestyle and environmental factors. Some C V D risk factors tend to be more prevalent within these families, including dyslipidemia, hypertension, diabetes, physical inactivity, high-fat dietary habits, smoking, excessive alcohol consumption, and obesity. For example, compared to the  13  general population, individuals with positive family history o f C H D had significantly higher levels o f lipids ( T C , L D L - C ) , glucose, and were overweight from a young age . There is also a 64  tendency for similar socioeconomic status within families . 65  Besides increased frequencies o f C V D risk factors, different studies have found familial clustering o f C H D in those with positive family history . A study involving twins has shown 66  that the odds ratio for risk o f death was over eight times higher i f one twin died from premature CHD . 6 7  A positive family history o f C H D may be considered to reflect genetic, biochemical and behavioural components that may predispose an individual to be at higher risk. Screening families with a history o f C H D may be a cost-effective method to identify individuals who w i l l benefit from more intensive prevention strategies directed at modifiable risk factors such as hypertension, hypercholesterolemia, smoking, or obesity . 66  14  INTERHEART  The I N T E R H E A R T study was a large, international, case-control study that examined the associations between various cardiac risk factors and the risk o f developing a first myocardial infarction. In total, about 30,000 participants were recruited from 52 countries i n all parts o f the world. Factors evaluated included demographics, lipids (apolipoprotein A l and apolipoprotein B), blood pressure, lifestyle factors, smoking, diabetes, weight, physical activity, and waist-tohip ratios. Results from I N T E R H E A R T demonstrated that 90% o f all the cardiovascular disease is accounted for by these modifiable risk factors, with the apolipoprotein B / A - I ratio and cigarette smoking being associated with the highest population attributable risks o f developing myocardial infarction . The associations were consistent across all regions and ethnicities. 68  A l s o , psychosocial factors such as depression may also place individuals at increased risk o f C H D . The study confirmed the idea that most cardiac events can be avoided by altering 6 9  modifiable risk factors, and stressed the importance o f implementing prevention strategies in the treatment o f cardiovascular disease w o r l d w i d e . 68  15  C H A P T E R II: M E T H O D S A N D P R O C E D U R E S  S u m m a r y of Research Project  The purpose o f the study was to examine the prevalence and severity o f traditional and non-traditional cardiovascular risk factors in first-degree relatives o f index patients (patients with premature atherosclerotic disease <50 years in men and <60 years in women) as compared to the general population. It was hypothesized that index patients and their F D R s would have similar cardiac risk factors; furthermore, F D R s would have higher prevalence and severity o f C V D risk factors than those found in the general population. Data for index patients and F D R s were collected through the Family Atherosclerosis Counseling and Testing Study ( F A C T S ) . Controls included participants in the Multicultural Community Health Assessment Trial ( M C H A T ) as well as results from the Canadian Community Health Survey. M - C H A T controls were matched to F D R s by ethnicity, sex, and body-mass-index ( B M I ) . W e also expected to observe differences between gender in terms o f C V D risk factors.  Research Design  Research for this thesis was part o f the ongoing Family Atherosclerosis Counseling and Testing Study ( F A C T S ) at the Healthy Heart Program, St. Paul's Hospital, Vancouver, British Columbia. This thesis is a cross-sectional, case-control study that describes the prevalence o f cardiovascular risk factors in individuals with a positive family history. This thesis also compared the differences in the prevalence o f traditional and non-traditional cardiac risk factors  16  between F D R s with a positive family history o f premature atherosclerotic disease ( F A C T S patients) to controls ( M - C H A T participants and results from the Canadian Community  Health  Survey). M y role in F A C T S include i) recruiting index patients, ii) recruiting F D R s and conducting initial F D R appointments, and iii) data entry and analyses.  F a m i l y Atherosclerosis Counseling and Testing Study ( F A C T S )  Background  A history o f premature atherosclerosis in a first-degree relative ( F D R ) is an independent risk factor for C H D . Compared to those with no family history, F D R s are up to 2.5 times more 70  likely to develop C H D  . Previous studies have shown a clustering o f risk factors within  families, implying that both genetic and environmental factors may be i n v o l v e d . Moreover, the 56  risk o f C H D in individuals with a family history o f C H D appears to be profoundly affected by 70  modifiable behaviours, for example, by diet, smoking, and exercise .  M a n y F D R s are unaware o f their risk; therefore, they do not recognize the need to modify their lifestyle or the importance o f adhering to treatment regimens (such as lifestyle modification), particularly when clinical disease is not evident.  17  Research Objectives  The purpose o f the ongoing F A C T study was to identify and phenotype younger patients with evidence o f premature atherosclerotic disease (cardiovascular disease, peripheral vascular disease or cerebrovascular disease) as well as their first-degree relatives and spouses. The F A C T S project was designed to test the hypothesis that these F D R s had more frequent and more severe risk factors for C V D than the general population. They were also more likely to adhere to lifestyle and treatment recommendations. The hypothesis was that F D R s who are provided intense lifestyle and treatment recommendations w i l l have decreased risk for C V D than F D R s in the usual care (control) group after one year.  This thesis included all F D R s recruited as o f M a y 2005, and only those index patients with at least one F D R i n the study. Information collected during baseline assessment was used for analyses.  Research Design  The Family Atherosclerosis Counseling and Testing Study was a prospective, cluster*  randomized , controlled trial with one year fixed follow-up. Family cohorts were randomized into either Usual Care (no specific recommendations) or Intervention (with routine lifestyle and treatment recommendations) group; cardiovascular risk was assessed at baseline and w i l l be reassessed after 12 months using anthropometric and biochemical measures, as well as the Framingham Risk Score. Cluster randomization: A l l F D R s from the same index patient were assigned to the same treatment. 18  Recruitment ofIndex Patients  Recruitment for the F A C T study commenced from M a y 2002. Index patients were recruited from St. Paul's Hospital, Vancouver, British Columbia (from the interventional catheterization laboratories, the Heart Function Clinic, the Heart Transplant Clinic, cardiac inpatient wards, as well as the Lipid Clinic and the Cardiovascular Rehabilitation Clinic in the Healthy Heart Program); index patients were also recruited from seven cardiologists' offices within the Greater Vancouver area. In September 2003, recruitment was expanded to include the outpatient Cardiac Rehabilitation and Prevention Program at Vancouver Hospital, Vancouver, British Columbia.  Every effort was made to ensure that sampling was unbiased. Therefore, records were kept for all patients screened, including reasons for each individual's ineligibility or refusal to participate in the study.  Throughout the week, the research assistants screened for eligible participants from the various locations. Only individuals who fit the inclusion criteria (Table 3.1) were approached for the study. Our definition o f premature C H D was more stringent than the N C E P - A T P III definitions to ensure that F D R s have strong family influences. Eligible patients in the cardiologists' offices were initially approached by the cardiologist, and only referred to F A C T S . research assistants i f they were interested in participating.  19  Inclusion Criteria  Exclusion Criteria  •  •  Age at onset o f premature atherosclerosis Male <50 years old  (as defined in the study)  •  Female <60 years old  •  Female > 65 years old  •  Female <65 years old  •  Have F D R s in the Greater Vancouver*  •  W i l l i n g to provide contact information of first-degree relatives  Age at time o f recruitment Male > 60 years old  Age at time o f recruitment Male <60 years old  Do not have premature atherosclerosis  Do not have F D R s in Greater Vancouver  •  Cannot provide contact information for FDRs  •  Premature atherosclerosis due to secondary causes (i.e. polycythemia, H I V medications, monogenic dyslipidaemia, rare autosomal recessive disorders)  • 3.1.  Cannot understand or read English  Only index patients who meet all the inclusion criteria were approached regarding the F A C T study. Addresses and phone numbers were obtained for potential F D R s who live in the Lower Mainland (*); contact information was also obtained for F D R s living in British Columbia. ' Table  Inclusion and Exclusion Criteria for Index Patient Recruitment.  If the eligible patient expressed an interest in participating in the F A C T study, the study coordinator or research assistant explained the study and obtained informed consent (Appendix A ) . Subsequently, the recruited index patients underwent a comprehensive risk factor  20  assessment (Appendix C ) , including obtaining a fasting blood sample, an evaluation o f all risk factors such as anthropometry (i.e. height, weight, waist circumference), diabetes, smoking, hypertension, and family history, as well as biochemical measures (i.e. total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, lipoprotein(a), homocysteine, C-reactive protein, glucose). Risk for future events was estimated according to the Framingham Risk Score. Participants were also asked to complete dietary (Willett), exercise (Modifiable Activity Questionnaire - Appendix D ) , and psychosocial questionnaires. Furthermore, mailing and contact information for-FDRs was obtained.  Recruitment of First-Degree Relatives  Recruitment o f F D R s commenced in M a y 2003. A l l F D R s over the age o f 16 years old were eligible for the study. First-degree relatives were initially contacted by mail with information regarding the study. Subsequently, usually about four to five days later, F D R s were contacted by phone and/or email. If a F D R agreed to participate, an arrangement was made for an initial assessment (similar to the risk assessment performed on the index patient) at St. Paul's Hospital (Appendices C and D). Also, prior to the initial appointment, participants were mailed and asked to complete dietary (Willett), exercise (Modifiable Activity Questionnaire) and psychosocial questionnaires. Spouses o f first-degree relatives (i.e. cohabiting for more than one year) were invited to participate.  21  Inclusion Criteria  Exclusion Criteria  •  •  A g e >16 years old at time o f recruitment  •  B e willing to come to St. Paul's Hospital for assessments and  A g e < 16 years old at time o f recruitment  •  Cannot come to St. Paul's for assessment and counseling  counseling ( i f in Intervention group)  Table 3.2. Inclusion and Exclusion Criteria of First-Degree Relatives. F D R s who did not live i n the Lower Mainland were still eligible for the study (*) i f they were w i l l i n g to come to St. Paul's Hospital for scheduled risk assessments and counseling (when applicable).  Initial Appointment for FDRs  First-degree relatives were contacted 1 -2 days prior to their appointment to confirm the meeting. They were also reminded to fast for 12 hours before the appointment, and to bring along their completed questionnaires and any relevant medical records (e.g. previous laboratory results).  22  Data  Collection  A comprehensive questionnaire was developed specifically for the F A C T study by experts in the field (Appendix C ) . Topics covered by the comprehensive questionnaire included:  •  Sociodemographic factors: Comprehensive survey questions were replicated from a larger research study within St. Paul's Hospital. Items included name, date o f birth, sex, ethnicity of the participant's parents and grandparents, and personal education history. 71  •  Risk perception : A n individual's interpretation and understanding o f the chance o f an adverse outcome.  •  Alcohol consumption: Average weekly consumption o f alcohol, classified as 'none', 'occasional' (less than 7 drinks), 'moderate' (7 to 14 drinks), or 'heavy' (greater than 14 drinks).  •  Smoking history: Items pertaining to tobacco use were taken from Health Canada's 77  Summary Report o f the Workshop for Monitoring Tobacco Use .  •  Menopausal history: Women completed five items related to menopausal history, use o f hormone replacement therapy, and use o f contraceptives.  •  Medical history: Questions were asked about medical history, including cardiovascular risk factors and any current medications. For index patients, the cardiovascular diagnoses were self-reported and confirmed by medical reports; for F D R s , current medical histories were self-reported and only confirmed when records were available. Recent history o f changes in exercise, eating habits, smoking, alcohol intake and weight was determined by rating it as decreased, the same or increased.  23  •  Family history: Data were collected on the participant's family history o f coronary artery disease, peripheral artery disease, cardiovascular disease or evidence o f diabetes, hypertension or dyslipidemia. A family tree was obtained from each index patient and copied for the first-degree relative's records.  •  Physical examination: Anthropometry: Participants were asked to remove their shoes and any items from their pockets before measuring their weight to the nearest 0.1 k g on a calibrated scale. Height was measured to the nearest 0.1 cm. Body mass index (BMI) was calculated by dividing weight (kg) by height squared (m ). Waist circumference was measured to the nearest 0.1 cm over the point o f maximal narrowing o f the trunk with the participant standing in an upright position and after expiration. B l o o d pressure: Blood pressure was measured in the left arm using an appropriately sized cuff, following 30 seconds o f seated rest. Absence/presence o f xanthelesmas, arcus, tendon and palmar xanthomas  •  Previous laboratory data: Pre-treatment laboratory results for participants who were currently on medications.  •  Laboratory data: Fasting-blood samples were obtained from all participants. A complete lipid profile (TG, T C , L D L - C , H D L - C , T C : H D L ) and glucose levels were measured at the St. Paul's Hospital laboratory by routine laboratory methods (all with coefficient o f variances of less than 5% except for C R P at 6%). Apolipoprotein A l , apolipoprotein B , C-reactive protein, lipoprotein(a), and homocysteine levels were analyzed at St. Paul's Hospital and Vancouver General Hospital (Vancouver, British Columbia) laboratories.  24  C R P was measured using a solid-phase, chemiluminescent immunometric assay with a functional sensitivity o f 0.2 m g / L ( I M M U N I T E 2000, D P C ) . Apolipoprotein A l and apolipoprotein B were both measured by rate nephelometry (measuring rate o f increase in light from antigen-antibody complexes suspended in solution)(Beckman C o u l t e r ) ' . 73  74  Lipoprotein(a) levels were quantified with Mercodia Apo(a) E L I S A , a solid phase twosite enzyme immunoassay. Homocysteine for M - C H A T participants were measured at St. Paul's Hospital by fluorescence immunoassay while F A C T S participants were measured at Vancouver General Hospital via solid-phase enzyme immunoassay; external quality controls showed that results from both labs have comparable accuracy and precision, with coefficient o f variation less than 5%.  •  Diet: A comprehensive dietary assessment was obtained using the Willett Questionnaire (1998 version). This is a validated questionnaire used extensively to provide essential nutrient data for research on the role o f diet in health and disease.  •  Physical activity: The Modifiable Activity Questionnaire ( M A Q ) was used to evaluate each participant's leisure and occupational physical activity within the last year . 75  Cardiovascular risk assessments for F A C T S participants also included the Framingham Risk Score, which utilizes the C o x regression algorithm to estimate 10-year total cardiovascular risk o f myocardial infarction or coronary d e a t h ' . The relationship between the index patient 76  77  and the family member was defined as a parent (mother or father), a sibling (brother or sister), or a child (daughter or son). For this thesis, only data collected for index patients and first-degree relatives at the baseline appointment o f F A C T S were used for analysis.  25  Multicultural Community Health Assessment Trial (M-CHAT)  Controls for this study were selected from the Multicultural Community Health Assessment Trial ( M - C H A T ) . The purpose o f M - C H A T was to understand the difference body fat distributions among four different ethnic populations: Europeans, South Asians, Chinese, and Aboriginals. In total, 200 participants (100 men and 100 women) were recruited for each ethnic group. F D R s were matched by ethnicity, sex, and body-mass-index (BMI) to participants in the M - C H A T study. Due to limited sample numbers, it was not possible to match all F D R s to controls by age as well.  Canadian Community Health Survey  F D R s and M - C H A T controls were compared to the general population using data from the Canadian Community Health Survey in 2000 . 7  Data Analysis  Before analyses, questionnaires were reviewed for completeness and legibility. Missing data were retrieved by contacting the participant or by locating the correct information. The data were then coded and entered into a spreadsheet. T o maintain data integrity, all information was entered twice, and verified by comparing the two sets o f data using queries in the Microsoft Office Access program. After the records were verified, data were coded and a codebook was  26  generated. Further statistical analyses were performed with SPSS Version 13.0. Preliminary data assessment involved the identification o f missing values. Subsequently, frequency distributions were used to check for outliers and any internal data discrepancies. Assessments o f assumptions for statistical tests were reviewed for any violations (for example, measures o f skewness and kurtosis to assess normality). Data were presented in mean ± standard error or median (25 - 7 5 percentile), as appropriate. In cases where differences in age was observed, th  th  data was analyzed using univariate A N O V A for continuous variables and logistic regression for categorical variables.  Research Questions  1. Are traditional and non-traditional cardiovascular risk factors similar in the index patien and theirfirst-degreerelatives?  The hypothesis was that index patients and their F D R s share the same C V D risk factors. For nominal variables, frequency distribution tables were used to assess normality. A s a further check, measures o f skewness and kurtosis (as well as their respective standard errors) were also used. Nominal data (such as B M I , waist circumference, and blood pressure) for both index patients and F D R s that meet the criteria for normality were compared using independent t-tests. Categorical data (such as smoking, alcohol consumption, and hypertension) were compared using chi-square tests. Statistically significant results were adjusted for age using univariate A N O V A for nominal variables and logistic regression for categorical variables.  27  2. Do FDRs have higher prevalence and severity of traditional and non-traditional cardiovascular risk factors as compared to a control (M-CHAT) population?  W e hypothesized that F D R s w i l l have increased prevalence and severity o f traditional and non-traditional cardiovascular risk factors compared to a control population.  A n objective risk assessment was done b y the Framingham risk score to estimate 10-year risk o f C V D - estimations are represented in both percentages and as categories (low risk = 0% to 10%; moderate risk = 1 1 % to 19%; high risk = greater than 20%).  Normality was assessed using frequency distribution tables, and also measures o f skewness and kurtosis. Nominal data (including biochemical measurements and anthropometry) for both F D R s and controls that meet the criteria for normality were compared using independent t-tests. Categorical data (such as smoking, alcohol consumption, and hypertension) were compared using chi-square tests.  3. Is there an impact of sex (men versus women) and type of relation (parent versus sibling history) on the prevalence and severity of either traditional or non-traditional cardiovascular risk factors?  Previous studies have shown differences in C V D risk between men and women; however, there is a lack o f information regarding the differences in the prevalence o f homocysteine, C-reactive protein, lipoprotein(a), and metabolic syndrome i n F D R s o f patients  28  with premature atherosclerosis. The first part o f the analysis involved the confirmation o f traditional C V D risk factor differences between men and women, using both F D R and control data. The prevalence o f elevated homocysteine (men >9.1 m M ; women >7.8 m M ) , hyperhomocysteinemia (>15 m M ) , high C R P (>3.0 mg/L), high lipoprotein(a) (>300 mg/L), and also the prevalence o f metabolic syndrome were compared between the sexes using chi-square tests o f association. Homocysteine, C R P , and lipoprotein(a) levels were assessed through . descriptive analysis o f the means and medians, using parametric and non-parametric tests, respectively.  Similarly, chi-square tests and independent t-tests were used to examine possible association between the non-traditional risk factors and the relation o f the F D R s to the index patient. It was hypothesized that siblings o f index patients w i l l exhibit the same prevalence and severity in C V D risk factors as the index patients themselves because o f shared genetics and environmental factors.  Ethical Considerations  Ethical approval was obtained through the University o f British Columbia, St. Paul's Hospital Research Ethics Board, and Vancouver General Hospital Research Ethics Board. Participants (both index patients and first degree relatives) were fully informed o f the purpose and obligations for participating in F A C T S . Patient records were kept anonymous through coding and strict protocols on data storage and input and sample analysis. Ethical issues were considered during all components o f the study.  29  CHAPTER IV: RESULTS Efficiency of Sampling  The total number o f index patients contacted for recruitment between M a y 2002 and February 2005 is presented in Table 3.3. A s a result o f the stringent age criteria (participants must have had premature C V D i.e. men <50 years; women <60 years within the last 10 years), the enrollment rate was extremely low at 1.1%. The gender distribution o f all subjects screened and ineligible subjects were similar. Over 7,200 patients were ineligible; primary reasons for ineligibility include age and geography (most were out o f town). A s o f M a y 2005, the total number o f index patients recruited for the F A C T study was 238.  Frequency (%) Subjects screened  12400  Women  3874(31.2)  Men  8526 (68.8)  Ineligible subjects  7257  Women  2017 (27.8)  Men  5240 (72.2)  Enrolled into F A C T S  238 (1.9)  Index patients with F D R s in F A C T S  92 (38.7*)  Table 3.3. Recruitment and Enrollment of Index Patients. The total number o f potential subjects screened, stratified by gender. Percentages are shown in brackets.  30  B y M a y 2005, ninety-two index patients who have at least one F D R participating in the F A C T study were recruited for the study; this represents 38.7% ofthe total number o f index patients currently enrolled in the F A C T study.  Recruitment o f F D R s began in M a y 2003. Potential subjects were initially mailed a letter of invitation to participate in the study; subsequently, subjects were contacted by phone about a week later. If F D R s still did not respond after two letters o f invitation and up to four phone calls, they were considered as refusing to participate in the study. Out o f 415 potential subjects, 71 male and 78 female F D R s were recruited for the study. Reasons for refusing to participate in the study, as well as information on refused subjects were not collected by research assistants.  Frequency (%) Potential subjects  415  Male  221 (53.3)  Female  194(46.7)  Enrolled Male  71 (47.7)  Female  78 (52.3)  Table 3.4. Recruitment and E n r o l l m e n t of First-Degree Relatives. The number o f potential F D R s and the number who enrolled into the F A C T study, stratified by gender. Percentages are shown in brackets.  31  Characteristics of the Index Patients  The ethnic distribution o f index patients is shown on Table 3.5. A majority o f the index patients recruited are Caucasian, while only 10.9% and 8.7% were South Asians and East Asians (predominantly Chinese), respectively. In the greater Vancouver, the ethnic distribution comprises 17.4% Chinese and 8.4% South Asians . 7  Male N (%)  Female N (%)  Total N (%)  Caucasian  44  (68.8)  23  (82.1)  67  (72.8)  South Asian  10  (15.6)  0  (0)  10  (10.9)  East Asian  7  (10.9)  1  (3.6)  8  (8.7)  Mid-Eastern  3  (4.7)  2  (7.1)  5  (5.4)  Black  0  (0)  1 (3.6)  1  (1.1)  First Nations  0  (0)  1 (3.6)  1  (1.1)  Table 3.5. Ethnicity of Index Patients. The ethnic distribution o f male and female index patients. Percentages are shown in brackets.  General characteristics o f the index patients, including age, anthropometric measurements, and systolic and diastolic blood pressure, are shown i n Table 3.6. A s expected, there were more male (n = 64) than female (n = 28) index patients with premature coronary heart disease. This group o f individuals with established C H D was relatively young, with mean ages o f 51 ± 1 years (median: 50 years old; 2 5 and 7 5 percentile: 45 to 56 years old) for the men th  th  and 54 ± 1 years (median: 54 years; 25 ' and 7 5 percentile from 50 - 60 years) for the'women. 1 1  th  32  Both the median systolic and diastolic blood pressures were within normal ranges (Table . 3.6). However, this could be due to the fact that 71.9% o f the male and 29.6% o f the female index patients were currently on blood pressure medications. In general, index patients had anthropometric measurements that placed them at increased risk: the mean waist circumference for the female index patients were elevated at 89.5 ± 2.6 cm. For men, their B M I s were relatively higher (mean 29.3 ± 0.5 kg/m ) than in the women (mean 27.3 ± 1 . 1 kg/m ). In both 2  2  sexes, the prevalence o f overweight index patients with B M I > 25 k g / m (78.1% o f men versus 2  67.9% o f women) was significantly higher than in the general population o f British Columbia (61.0% in men versus 33.4% in women).  N  M e n ( N = 64) Median (25th - 75th percentile)  N  Median (25th - 75th percentile)  64  50 (45 - 56)  28  54 (50 - 60)  Body mass index (kg/m )  62  28.3 (25.9 - 30.0)  28  25.6 (23.9- 31.3)  Waist circumference (cm)  61  97.0(90.2 - 102.0)  26  87.3 (80.8 - 92.8)  63  1 2 0 ( 1 1 0 - 130)  28  1 2 6 ( 1 1 0 - 130)  63  70 (67 - 80)  28  70 (61 - 79)  Age (yr)* 2  Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)  Women ( N = 28)  Table 3.6. General Baseline Characteristics of Index Patients. Median values o f age, body mass index, waist circumference, as well as systolic and diastolic blood pressures o f index patients. The 2 5 to 7 5 percentiles were shown in brackets. A g e represented the age o f index patients at time o f recruitment (inclusion criteria:< 60 years for men and < 65 years for women see Table 3.1). th  th  This group was moderately educated, with 60.9% o f the sample having at least some post-secondary education. In particular, over a quarter o f the male index patients have attained  33  at least a bachelor's degree. This trend was comparable to the general population where 54.0% had some post-secondary education (p = 0.186)..  The participants' smoking and alcohol consumption histories were self-reported, and the distributions were compared to the general population. About half o f the index patients were exsmokers (51.6% for men and 46.4% for women), while only a small proportion o f the index patients were current smokers (10.9% in men versus 21.4% in women), demonstrating possible lifestyle changes. The distribution o f non-smokers, ex-smokers, and current smokers was highly comparable between female index patients and females living in Vancouver, British Columbia (p = 0.945). However, there were significant differences among the men: there were fewer male index patients who were current smokers compared to males in Vancouver (p <0.001). About 33% o f the males and 21 % o f the female index patients were moderate or heavy drinkers (defined as greater than 7 drinks per week).  34  Characteristics of First-Degree Relatives  General baseline characteristics o f the 149 F D R s are outlined in Table 3.7. This was a relatively young cohort with the age average o f 40 years old. Waist circumference, systolic blood pressure, and diastolic blood pressure were within normal ranges. However, mean B M I s 2  2  for male and female F D R s was 26.9 ± 0.5 kg/m and 26.5 ± 0.6 kg/m respectively, indicating that alarge proportion o f this group was overweight or obese. British Columbian population data found that 48% o f the men and 63% o f the women have B M I s less than 25 k g / m ; this was a 2  significantly greater proportion than that o f the male (35%) and female (45%) F D R s in this study. However, the high proportion o f people with acceptable B M I s in British Columbia could be due to the higher numbers o f East Asians.  N  Male ( N = 71) Median (25 - 75th percentile)  N  Female ( N = 78) Median (25th - 75th percentile)  A g e (yr)  71  41 (28 -49)  78  40 (28 - 52)  Body mass index (kg/m )  71  25.9(24.1 -29.0)  77  25.6 (22.1 - 2 9 . 3 )  Waist circumference (cm)  68  91.5 (84.7 -99.1)  77  85.0(77.2-92.4)  Systolic blood pressure (mmHg)  71  1 2 0 ( 1 1 0 - 130)  77  1 1 0 ( 1 0 0 - 122)  Diastolic blood pressure (mmHg)  71  78 (72 - 86)  77  70 (65 - 78)  th  Table 3.7. General Baseline Characteristics of the First-Degree Relatives. Median values o f age, body mass index, waist circumference, as well as systolic and diastolic blood pressures o f F D R s . The 2 5 to 7 5 percentiles were shown in brackets. There were no age criteria for F D R recruitment. ,n  m  35  The F D R s in the study were highly educated, with 75.2% o f the group having at least some post-secondary education, and 36.9% having at least a bachelor's degree. This observation was significantly different than that found in the general population, where only 54.0% had some post-secondary education (p <0.001).  Surprisingly, most o f the F D R s have never smoked: there were more non-smokers (73.2% o f men; 60.3% o f women), fewer ex-smokers (11.3% o f men; 25.6% o f women), and similar number o f current smokers (15.5% o f men; 14.1% o f women) as in the general British Columbian population (p <0.001 for men; p = 0.027 for women). Twenty-five percent o f the male index patients consumed more than 7 alcoholic drinks per week, as opposed to 9.1% o f the females.  For F D R s , physical activity was assessed by calculating the number o f leisure metabolic minutes per week from the Modifiable Activity Questionnaire. Participants with less than 210 minutes per week were considered 'inactive'. Results were compared to self-reported responses from the general population in British Columbia. Compared to the general population, the F D R s in our study were less active: 59.2% o f the male and 61.5% o f the female F D R s were physically inactive, compared to 34.1% and 41.8% for men and women in the general population, respectively.  Laboratory data, including overall lipid profiles and other biochemical markers such as glucose, homocysteine, apolipoprotein B , apolipoprotein A , high density C-reactive protein  36  ( C R P ) , and lipoprotein(a), are shown in Table 3.8. A s expected for this young cohort, lipid profiles, including LDL-cholesterol and T C : H D L - C , were within normal ranges.  N  Male Median (25th - 75th percentile)  N  Female Median (25th - 75th percentile)  Total cholesterol ( m M )  71  5.20 (4.39 - 6.18)  78  5.24 (4.57 - 6.00)  LDL-cholesterol ( m M )  69  3.05 (2.60 - 3.97)  77  3.18(2.52 -3.81)  HDL-cholesterol ( m M )  71  1.22 (1.04- 1.47)  78  1.45 (1.25 - 1.76)  TC:HDL-C  71  4.14(3.27 - 5.30)  78  3.36(2.79-4.51)  Triglycerides ( m M )  71  1.14(0.79-2.12)  78  1.05 (0.64- 1.58)  Glucose ( m M )  71  5.1 (4.7 - 5.6)  78  4.9 (4.4 - 5.3)  Apolipoprotein A - I (g/L)  71  1.31 (1.19- 1.56)  78  1.51 (1.38 - 1.76)  Apolipoprotein B (g/L)  71  1.02 (0.78 - 1.27)  78  0.93 (0.77- 1.14)  apoB:apoA-I  71  0.72 (0.57 - 0.92)  78  0.58 (0.49 - 0.74)  Lipoprotein(a) - m g / L  66  105 (45 -238)  73  218 (63 -483)  Homocysteine (uM)  67  10.2 (9.3 - 12.1)  78  8.8 (7.6-9.7)  C-reactive protein (mg/L)  71  0.8 (0.6 - 2.4)  78  1.0(0.6-3.6)  T a b l e 3.8. B i o c h e m i c a l Measurements of First-Degree Relatives. Median values o f traditional and non-traditional cardiovascular risk factors for both male and female F D R s . The 2 5 to 7 5 percentiles are shown in brackets. A l l laboratory measurements were conducted at St. Paul's Hospital Laboratory, except for homocysteine (Vancouver General Hospital Laboratory). th  th  O f interest were the higher levels o f non-traditional risk factors - lipoprotein(a), C R P , and homocysteine. For women, mean lipoprotein(a) levels (313 ± 3 5 mg/L) were higher than the 8 0 percentile o f the population; median values were 105 m g / L (25 percentile = 45 m g / L ; 7 5 th  th  th  percentile 238 m g / L ) for male F D R s and 218 m g / L (25 percentile = 63 mg/L; 7 5 percentile = th  th  483 mg/L) for female F D R s . Mean concentrations o f C-reactive protein were also mildly  37  elevated in F D R s (1.8 ± 0.2 m g / L for men and 2.5 ± 0.3 m g / L for women). There was significantly higher mean homocysteine levels for both male and female F D R s : both male (10.9 + 0.5 pjvl) and female F D R s (9.0 ± 0.3 \xM) have homocysteine levels that were in the 7 5 7K 7Q  percentile o f the data from other studies (men >9.1 ( i M , women >7.8 [J.M) '  th  .  Characteristics of M - C H A T controls  In the previous section, we compared F D R characteristics to general population using data from the Canadian Community Health Survey conducted in 2000. Though the sample size was large, one caveat o f the survey was that most o f the data were self-reported and hence its reliability is questionable. Moreover, non-traditional risk factors such as homocysteine and C reactive protein were not included in the survey. Additionally, it is useful to compare F D R s with a healthy control population with the same traditional risk factors (e.g. similar B M I ) and determine i f the non-traditional cardiovascular risk factors are more prevalent in at-risk individuals with positive family history.  Therefore, participants from the Multicultural Community Health Assessment Trial ( M C H A T ) were used as controls. The M - C H A T participants were selected as controls because they lived in the same geographical area, had similar cardiovascular risk factor assessments, and the same non-traditional risk factors were measured as in the F D R s in this study. Controls were initially matched by ethnicity and gender, then by B M I and age. Because o f insufficient sample size in the European cohort, it was not possible to match all F D R s by age.  38  A s shown in Table 3.9, the controls are about 10 years older than the F D R s (Table 3.7). This could cause considerable bias in analyses, especially when calculating the age-dependent Framingham risk score (this w i l l be addressed subsequently). Though this was an older population, mean waist circumference was less than 102 cm for men and 88 cm for women, while mean blood pressures were less than 130/85 m m H g for both sexes. Because these F D R s were matched with the M - C H A T controls by B M I , the body-mass-index distribution o f the controls was also significantly different than the B . C . results from the Canadian Community Healthy Survey (p <0.001).  N  Male Median (25th - 75th percentile)  N  Female Median (25th - 75th percentile)  Age(yr)  73  52 (43 - 60)  79  50 (42 - 57)  Body mass index (kg/m )  73  26.6 (24.5 - 29.2)  79  25.7 (22.6- 30.1)  Waist circumference (cm)  73  90.4 ( 8 4 . 7 - 100.3)  79  82.0 (74.0 - 90.8)  71  1 2 0 ( 1 4 4 - 131)  79  119 (105 - 130)  71  77 (73 - 86)  79  77 ( 6 9 - 81)  Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)  Table 3.9. General Baseline Characteristics of Controls. Median values of age, body mass index, waist circumference, as well as systolic and diastolic blood pressures o f F D R s . The 25 to 7 5 percentiles were shown in brackets. Controls were matched to F D R s by ethnicity, sex, B M I , and age when possible.  tf  th  This cohort appeared to have fairly healthy lifestyles, with only 4% current smokers and over 50% non-drinkers. When compared to the general population, there appeared to be very few current smokers in control group but similar number o f ex-smokers (about 40%). Since  39  participants voluntarily signed up for the study, these may be 'healthy volunteers' and not necessarily representative o f the general population.  Physical activity o f the M - C H A T controls was also assessed using the Modifiable Activity Questionnaire. The level o f physical activity between M - C H A T controls and the general population was almost identical for both men and women, as seen in Table 3.10.  N Men  Controls (%)  British Columbia Exp. N (%) p value*  Vancouver/Richmond Exp. N (%) p value*  73  Active  48  (65.8)  48  (65.9)  Inactive  25  (34.2)  25  (34.1)  Women  0.979  48  (65.5)  25  (34.5)  47  (60.0)  32  (40.0)  0.479  79  Active  49  (62.0)  46  (58.2)  Inactive  30  (38.0)  33  (41.8)  0.491  0.492  *Compared to controls  Table 3.10. Comparison of Physical Activity Between Controls and the General Population in British Columbia. The level of physical inactivity was compared between controls and population data from the Canadian Community Health Survey. In controls, physical inactivity was defined as less than 210 leisure M E T minutes per week, as calculated using the Modifiable Activity Questionnaire. Population data was obtained by participants' self-reports.  Laboratory data for the M - C H A T controls are shown on Table 3.11. Overall, lipid profiles for both sexes were within normal ranges. Mean lipoprotein(a) levels were close to the 80 percentile (300 mg/L); in contrast, the median values were lower, at 192 m g / L (25 lh  percentile = 88 m g / L ; 7 5 percentile = 377 mg/L) for male controls and 177 m g / L (25 th  th  th  percentile = 96 m g / L ; 7 5 percentile = 270 m g / L ) for female controls. Homocysteine levels th  40  were borderline high with a mean o f 8.5 ± 0.2 \iM and 7.3 + 0.2 | i M for male and female controls, respectively.  N  Male Median (25th - 75th percentile)  N  Female Median (25th - 75th percentile)  Total cholesterol ( m M )  73  5.01 ( 4 . 5 6 - 5 . 4 7 )  79  5.25 ( 4 . 4 0 - 5 . 9 9 )  LDL-cholesterol ( m M )  73  3.14(2.76-3.64)  78  3.15 ( 2 . 5 3 - 3 . 8 6 )  HDL-cholesterol ( m M )  73  1.14(0.91 - 1.49)  79  1 . 3 9 ( 1 . 2 3 - 1.73)  TC:HDL-C  73  4.19 (3.53 - 5.51)  79  3.68 ( 3 . 0 8 - 4 . 5 1 )  Triglycerides ( m M )  73  1.13 (0.77 - 1.68)  79  1.13 ( 0 . 7 9 - 1.46)  Glucose (mM)  73  5.1 (4.9-5.5)  79  5.0(4.8 - 5.4)  Apolipoprotein B (g/L)  73  0.96 (0.81 - 1.09)  79  0.92 ( 0 . 7 8 - 1.06)  Lipoprotein(a) - m g / L  49  192 (88 - 377)  64  177 ( 9 6 - 2 7 0 )  Homocysteine (uM)  73  8.4 (7.4 - 9.5)  79  7.0(6.3-8.0)  C-reactive protein (mg/L)  68  0.9 (0.6 - 2.2)  76  1.2 ( 0 . 8 - 4 . 2 )  T a b l e 3.11. Biochemical Measurements of Controls. Median values o f traditional and nontraditional cardiovascular risk factors for both male and female M - C H A T controls. The 2 5 to 7 5 percentiles are shown in brackets. A l l laboratory measurements were conducted at St. Paul's Hospital Laboratory, including homocysteine. th  th  41  Comparison Of Index Patients With Their First-Degree Relatives  Continuous variables (age, B M I , waist circumference, systolic blood pressure, diastolic blood pressure, and leisure activity minutes) were tested for assumptions o f normality and equal variances. If the assumptions o f normality were valid, independent sample t tests were used to analyze differences between first-degree relatives and either controls or index patients; conversely, i f the assumptions o f normality were not met, the non-parametric Mann-Whitney U test was used to identify any differences. Categorical variables were tested using the Pearson chi-square test or Fisher exact test.  While a majority o f the index patients were men, the gender distribution o f F D R s was fairly equal (Table 3.12). There were 72 siblings and 71 children o f index patients recruited for the study; in contrast, only 6 parents were recruited and hence they were excluded from further analyses.  Since index patients have established C H D , we hypothesized that they have a higher number o f C V D risk factors, though many may have already undergone therapeutic lifestyle changes.  \  42  Frequency (%) n - 149 Sex o f first-degree relative Male  78 (52.3)  Female  71 (47.7)  Relationship to index patient Father  3 (2.0)  Mother  3 (2.0)  Brother  29(19.5)  . Sister  43 (28.9)  Son  39 (26.2)  Daughter  32(21.5)  Table 3.12. Gender and Relation of First-Degree Relatives to Index Patients. The gender distribution o f F D R s are shown. F D R s were classified as parents (fathers or mothers), siblings (brothers or sisters), as well as children (sons or daughters) o f index patients.  A s expected, index patients were significantly older than their F D R s . Because the age differences for both genders were statistically significant (p <0.001), age was adjusted using univariate A N O V A for nominal variables and logistic regression for binary variables. Male index patients were markedly different than male F D R s , with significantly higher median values o f B M I , waist circumference, and systolic blood pressure, as well as significantly lower median diastolic blood pressures (Table 3.13). Median body mass index values were highest in male index patients at 28.3 k g / m (25.9 - 30.0 kg/m ) compared to 25.9 k g / m (24.1 - 29.0 kg/m ) for 2  2  2  2  2  2  2  male F D R s , 25.6 kg/m (23.9 - 31.3 kg/m ) for female index patients, and 25.6 kg/m (22.1 2  '  29.3 kg/m ) for female F D R s (p = 0.002). However, the prevalence o f overweight individuals was not significantly different between male index patients and male F D R s , with 8 1 % o f the male index patients and 65% o f the F D R s being overweight (p = 0.373; Table 3.14). 43  Index Patients* Median (25th N - 75th percentile)  N  FDRs Median (25th - 75th percentile)  P value  41 (28 -49)  <0.001  Ageadjusted p value  MEN • A g e (yrs)  64  B o d y mass index (kg/m )  62  Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)  61 63  50(45 - 56) 28.3 (25.9 - 30.0) 97.0 (90.2 - 102.0) 120 ( 1 1 0 - 130)  71 71 68 71  25.9 (24.1 -29.0) 91.5 (84.7 -99.1) 120 (110-130)  63  70 (67 - 80)  71  78 (72 - 86)  59  207 (102-444)  63  105 (45 - 230)  Age (yrs)  28  54 (50 - 60)  78  40(28 - 52)  Body mass index (kg/m )  28  Lipoprotein(a) - m g / L  0.017  0.002  0.093  <0.001  0.085  0.026  <0.001  0.001  0.014  0.344  WOMEN  Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Lipoprotein(a) - m g / L  26 28  25.6 (23.9-31.3) 87.3 (80.8 - 92.8) 126  77 77 77  (110-130) 28 28  70(61 - 79) 366 (87 - 630)  25.6 (22.1 -29.3) 85.0 (77.2 - 92.4) 110 ( 1 0 0 - 122)  <0.001 0.482  0.811  0.372  0.444  0.010  <0.001  77  70(65 - 7 8 )  0.678  0.221  78  225 (65 - 502)  0.238  0.171  Table 3.13. Comparison of General Characteristics Between Index Patients and FirstDegree Relatives. Median values o f age, body mass index, waist circumference, as well as diastolic and systolic blood pressures were compared between index patients and F D R s . p values less than 0.050 were considered statistically significant and are shown in bold. It should be noted that 71.9% o f male and 29.6% o f female index patients were on blood pressure medications at the time o f recruitment (*).  In contrast, female index patients only differed from female F D R s in systolic blood pressures (p <0.001). In both sexes, there was no difference in the prevalence o f high blood pressure (> 140/90 m m H g ; Table 3.14). However, when the high blood pressure criterion was  44  lowered, considerably more male index patients (81.0%) than F D R s (35.2%) had blood pressure o f >130/85 m m H g (p = 0.001). Though the prevalence o f hypertension appeared to be higher in female index patients (82.1%) than female F D R s (22.1%), it did not reach statistical significance because o f the low number o f female index patients.  Female index patients were also the least educated, with only 46.4% having reached postsecondary education (compared to 79.5% in female F D R s , 67.2% in male index patients, and 70.4% in male F D R s ) . A higher proportion o f index patients than F D R s were ex-smokers (51.6% versus 11.3% in men,/? <0.001; 46.4% versus 25.6% in women,p = 0.036); this could signify lifestyle modifications in index patients.  The prevalence o f abdominal obesity was comparable according to the N C E P - A T P III guidelines (26.2% in male index patients versus 20.6% in F D R s ; p = 0.042). When a lower waist circumference cut-off according to IDF definition o f >94 cm was used, the prevalence o f abdominal obesity was 65.6% o f the male index patients versus 47.1% in F D R s - this was not statistically significant after adjusting for age (p = 0.648). There were no differences in the prevalence o f abdominal obesity between female index patients and female F D R s (p = 0.780).  For the non-traditional C V D risk factors, homocysteine and C R P values were not measured because a majority o f the index patients were already on lipid medications and folate therapy, which may influence results - instead, only lipoprotein(a) measurements were compared between index patients and F D R s . In general, women had increased lipoprotein(a) levels when contrasted to their male counterparts. M a l e index patients had higher median lipoprotein(a)  45  values at 207 mg/L (102 - 444 mg/L) than male F D R s at 105 m g / L (45 - 230 mg/L), with the same p value even after log-transformation (p = 0.014). The prevalence o f male index patients with elevated lipoprotein(a) values (greater than 300 m g / L ) was 36.4%, compared to 18.3% o f male F D R s (p = 0.089). Female index patients had similar median lipoprotein(a) values than female F D R s , at 366 mg/L (87 - 630 mg/L) and 225 m g / L (65 - 502 mg/L), respectively (p = 0.171). The prevalence o f elevated lipoprotein(a) was statistically higher in female index patients (55.0%) than female F D R s (35.9%), after adjusting for age (p = 0.045).  (Next page) Table 3.14. C o m p a r i s o n of Index Patients W i t h T h e i r First-Degree Relatives. Percentages are shown in brackets, p values less than 0.050 were considered statistically significant and are shown in bold.  46  Index Patients N  (%)  FDRs N  Agep value  (%)  adjusted p value  MEN Education  -  Post-secondary education  43  (67.2)  50  (70.4)  N o post-secondary education  21  (32.8)  21  (29.6)  Non-smoker  24  (37.5)  52  (73.2)  Ex-smoker  33  (51.6)  8  (11.3)  7  (10.9)  11  (15.5)  Never/Occasional  43  (67.2)  53  (74.6)  Moderate/Heavy  21  (32.8)  18  (25.4)  0.685  0.401  <0.001  <0.001  0.340  0.325  0.042  0.373  Smoking  Current smoker Alcohol  B o d y Mass Index Normal <25 k g / m  12  (19.4)  25  (35.2)  34  (54.8)  32  (45.1)  16  (25.8)  14  (19.7)  M e n > 102 cm ( N C E P - A T P III)  16  (26.2)  14  (20.6)  0.449  0.579  M e n >94 c m * (IDF Definition)  40  (65.6)  32  (47.1)  0.035  0.648  >130/85 m m H g  51  (81.0)  25  (35.2)  <0.001  0.001  >140/90 m m H g  10  (15.9)  13  (18.3)  0.709  0.585  Post-secondary education  13  (46.4)  62  (79.5)  <0.001  0.010  N o post-secondary education  15  (53.6)  16  (20.5)  9  (32.1)  47  (60.3)  0.036  0.386  13  (46.4)  20  (25.6)  6  (21.4)  11  (14.1)  22  (78.6)  70  (90.9).  0.090**  0.372  6  (21.4)  7  0.471  0.306  2  Borderline 25 - 26.9 k g / m Overweight >27 k g / m  2  2  Abdominal Obesity  Hypertension  WOMEN Education  Smoking Non-smoker Ex-smoker Current smoker Alcohol Never/Occasional Moderate/Heavy  (9.1)  B o d y Mass Index Normal <25 k g / m  9  (32.1)  35  (45.5)  12  (42.9)  26  (33.8)  7  (25.0)  16  (20.8)  >88 cm ( N C E P - A T P III)  13  (50.0)  .33  (42.9)  0.526  0.742  >80cm (IDF Definition)  21  (80.8)  54  (71.1)  0.332  0.780  >130/85 m m H g  23  (82.1)  17  (22:1)  O.001  0.106  > 140/90 m m H g  4  (14.3)  12  (15.6)  0.870  0.318  2  Borderline 25 - 26.9 k g / m Overweight >27 k g / m  2  2  Abdominal Obesity  Hypertension •  * >90 for East and South Asian men.** Fisher's exact test  A l s o , it was useful to compare C V D risk factors between index patients and their healthier siblings because they share both genetic information and environmental characteristics. Only those index patients with at least one sibling in the study were selected for analyses.  The median age o f index patients was 50 years (25 to 7 5 percentile: 45 - 53 years), th  th  which was comparable to the F D R siblings at 46.years (25 to 7 5 percentile: 42 - 53 years; p = th  ,h  0.130). Overall, F D R siblings o f index patients were more educated (Table 3.15); 80.6% o f the siblings had some post-secondary education, compared to 64.0% o f the index patients (p = 0.044).  A l s o , as mentioned previously, a higher proportion (46.0%) o f the index patients than  their siblings (26.9%) were ex-smokers. O n the other hand, while the percentage o f overweight siblings closely resembled those o f the index patients (64.2% and 69.3%, respectively; p = 0.680), more siblings than index patients were classified as having central obesity using the N C E P - A T P III guidelines (44.6% versus 29.8%), though median values were not statistically different (p = 0.111). Seventy-four percent o f the index patients had blood pressures o f >130/85 m m H g , compared to just 37.3% in their siblings (p <0.001).  Median lipoprotein(a) values were equivalent in both groups - index patients at 176 m g / L (102 - 476 mg/L) and siblings at 182 m g / L (59 - 474 mg/L; p = 0.516). The prevalence o f elevated lipoprotein(a) was also simil ar in the index patients (41.9%) as in their siblings (33.3%) that did not reach statistical significance (p = 0.367) Because lipoprotein(a) was positively skewed, log transformation was performed; however, normality assumptions were still not achieved, and non-parametric independent two-sample tests also showed no differences between index patients and their siblings (p = 0.458).  48  Index Patients N (%)  Siblings N (%)  50  67  Male  35(70.0)  28(41.8)  Female  15(30.0)  39(58.2)  Post-secondary education  32(64.0)  54(80.6)  N o post-secondary education  18(36.0)  13(19.4)  Non-smoker  20(40.0)  42(62.7)  Ex-smoker  23(46.0)  18(26.9)  7(14.0)  7(10.4)  Never/Occasional  36(72.0)  56(83.6)  Moderate/Heavy  14(28.0)  11(16.4)  Normal (less than 25 kg/m )  15(30.6)  24(35.8)  Borderline (25 to 26.9 kg/m )  23(46.9)  . 26(38.8)  Overweight (>26.9 kg/m )  11(22.4)  17(25.4)  14(29.8)  29(44.6)  32(68.1)  43(67.2)  >130/85 m m H g  37(74.0)  25(37.3)  > 140/90 m m H g  8(16.0)  13(19.4)  Gender  Pearson Chi-Square Test x2 df p value 9.168  1  0.002  4.050  1  0.044  Education  Smoking  Current smoker  6.074 2  0.048  2.286  1  0.131  0.772 2  0.680  2.536  1  0.111  0.010  1  0.920  15.470 1  <0.001  Alcohol  B o d y Mass Index 2  2  Abdominal Obesity M e n >102 cm; women >88 cm ( N C E P - A T P III) M e n >94 cm*; women >80cm (IDF Definition) Hypertension 0.225  1  0.635  * >90 cm for East and South Asian men. T a b l e 3.15. C o m p a r i s o n O f Index Patients W i t h T h e i r Siblings. Prevalence o f cardiovascular risk factors o f index patients with at least one F D R participating in the F A C T study. Percentages are shown in brackets! p values less than 0.050 were considered statistically significant and are shown in bold.  49  C o m p a r i s o n s O f First-Degree Relatives W i t h Controls  Findings in the F D R s were compared with participants in the Multicultural Community Health Assessment Trial ( M - C H A T ) . F D R s were matched to controls by ethnicity, sex, body mass index, and whenever possible, by age. The purpose was to compare the prevalence and severity o f traditional and non-traditional cardiovascular risk factors between F D R s and controls. It was hypothesized that F D R s w i l l have a higher prevalence o f risk factors than controls because of their positive family history.  A g e was significantly different between F D R s and controls in both genders (Table 3.16). Because F D R s were matched to controls by body mass indexes, both the median B M I and waist circumference distributions were very similar between the two groups. In men, median systolic and diastolic blood pressures were very similar between F D R s and controls (p = 0.902 for systolic blood pressure and p = 0.899 for diastolic blood pressure); unexpectedly, female controls had significantly higher median systolic and diastolic blood pressures (119 m m H g and 77 m m H g , respectively) than female F D R s (110 m H g and 70mmHg, respectively), though the prevalence o f hypertension was similar (Table 3.17).  Even though the controls were older on average, they were physically more active than the F D R s : the average amount o f time spent on leisure activities per week was 284 minutes for F D R s and 371 minutes for controls (p <0.001). Female F D R s (208 ± 28 min/wk) and female controls (342 ± 32 min/wk) were less active than their male counterparts (367 ± 104 min/wk for F D R s and 402 ± 42 min/wk for controls).  50  FDRs N  Median (25th 75th percentile)  Controls Median (25th N 75th percentile)  71  41 (28 - 49)  73  52 (43 - 60)  71  25.9 (24.1 -29.0)  73  26.6 (24.5 - 29.2)  0.519  68  91.5 (84.7 - 99.1)  73  90.4(84.7 - 100.3)  0.650  71  1 2 0 ( 1 1 0 - 130)  71  120(114-131)  0.902  71  78 (72 - 86)  71  77 (73 - 86)  0.899  71  120 ( 0 - 4 1 5 )  73  318 (162 - 594)  <0.001  78  40 (28 - 52)  79  50 (42 - 57)  <0.001  77 ' 25.6 (22.1 -29.3)  79  25.7 (22.6-30.1)  0.631  77  85.0 (77.2 -92.4)  79  82.0 (74.0 - 90.8)  0.100  77  1 1 0 ( 1 0 0 - 122)  79  119(105 - 130)  0.020  77  70 (65 - 78)  79  77 ( 6 9 - 81)  0.004  78  167 ( 0 - 2 7 7 )  79  303 (132 -492)  p value  MEN Age (yrs) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Leisure physical activity ( M E T min/wk)  <0.001  WOMEN Age (yrs) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Leisure physical activity ( M E T min/wk)  <0.001  Table 3.16. Comparison of General Characteristics Between First-Degree Relatives and Controls. Percentages are shown in brackets, p values less than 0.050 were considered statistically significant and are shown in bold. Age-adjusted p values were calculated using univariate A N O V A .  A s shown on Table 3.17, the number o f current smokers in the control group was very low. The prevalence o f ex-smokers and current smokers were almost identical between the  51  female groups. O n the other hand, 7 3 . 2 % o f the male F D R s have never smoked, which was much higher than 5 4 . 8 % in the control group (p <0.001).  F D R s also had a higher prevalence o f physical inactivity than controls: 5 9 . 2 % i n F D R s versus 3 4 . 2 % in controls for men (p = 0.012) and 6 1 . 5 % i n female F D R s versus 3 8 . 0 % in female controls (p = 0.006), after adjusting for age. Despite being matched by B M I s , a higher percentage o f female F D R s also had waist circumferences o f greater than 88 cm ( 4 2 . 9 % i n F D R s versus 2 6 . 6 % in controls; p = 0.055). When waist circumference cut-offs were lowered to IDF recommendations, 7 1 % o f the female F D R s and 5 8 % o f the female controls were abdominally obese (p = 0.051). There were no differences in the prevalence o f abdominal obesity between the male F D R s and controls (p = 0.847).  (Next page) Table 3.17. Categorical Comparisons Between First-Degree Relatives and Controls. Percentages are shown in brackets, p values less than 0.050 were considered statistically significant and are shown in bold.  52  FDRs N  (%)  Controls N  p value  Ageadjusted p value  (%)  MEN Positive history of C V D Smoking Non-smoker Ex-smoker Current smoker ' Alcohol Never/Occasional Moderate/Heavy Physical Activity Inactive (<210 M E T min/wk) Body Mass Index Normal (less than 25 kg/m ) Overweight (25 to 26.9 kg/m ) Obese (>26.9 kg/m )' Abdominal Obesity >102 cm (NCEP-ATP III) >94 cm* (IDF Definition) Hypertension 2  2  2  > 130/85 mmHg > 140/90 mmHg  71  (100)  43  (58.9)  62 8 11  (73.2) (11.3) (15.5)  40 30 3  (54.8) (41.1) (4.1)  <0.001  0.199  43 21  (67.2) (32.8)  53 18  (74.6) (25.4)  0.340  0.391  42  (59.2)  25  (34.2)  0.003  0.012  25 32 14  (35.2) (45.1) (19/7)  23 36 14  (31.5) (49.3) (19.2)  0.865  0.767  14 32  (20.6) (47.1)  16 30  (21.9) (41.1)  0.847 0.476  0.441 0.071  25 13  (35.2) (18.3)  19 17  (26.8) (23.9)  0.276 0.411  0.002  78  (100)  39  (49.4)  47 20 11  (60.3) (25.6) (14.1)  53 23 3  (67.1) (29.1) (3.8)  0.077  0.076  70 7  (90.9) (9.1)  71 8  (89.9) (10.1)  0.826  0.770  48  (61.5)  30  (38.0)  0.003  0.006  35 26 16  (45.5) (33.8) (20.8)  35 23 21  (44.3) (29.1) (26.6)  0.659  0.751  33 54  (42.9) (71.1)  21 46  (26.6) (58.2)  0.033  0.095  0.055 0.051  17 12  (22.1) (15.6)  20 14  (25.3) (17.7)  0.634 0.720  0.577 0.600  0.986  WOMEN Positive family history Smoking Non-smoker Ex-smoker Current smoker Alcohol Never/Occasional Moderate/Heavy Physical Activity Inactive (<210 M E T min/wk) Body Mass Index Normal (less than 25 kg/m ) Overweight (25 to 26.9 kg/m ) Obese (>26.9 kg/m ) Abdominal Obesity >88 cm (NCEP-ATP III) >80cm (IDF Definition) Hypertension >130/85 mmHg > 140/90 mmHg 2  2  2  * >90 cm for East and South Asian men.  Comparison o f traditional biochemical risk factors showed no differences between F D R s and controls (Table 3.18). Total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and glucose values were not significantly different between the F D R s and controls. A l s o , as shown in Table 3.19, though the mean values o f apolipoprotein B were similar in both men and women, the prevalence o f elevated apolipoprotein B was significantly higher in male F D R s (26.8% versus 8.2% in controls), after adjusting for age (p = 0.010). This suggests that male F D R s may have more (possibly smaller) L D L particles.  Median lipoprotein(a) values were comparable between female F D R s at 218 (63 - 483) m g / L and female controls at 177 (96 - 270) m g / L (p = 0.674). In contrast, male F D R s had significantly lower lipoprotein(a) than male controls at 105 (45 - 238) m g / L and 192 (88 - 377) mg/L respectively (p = 0.022). The prevalence o f elevated lipoprotein(a) (greater than 300 mg/L) was not significantly different between male F D R s and male controls (18.3% versus 21.9%;p = 0.589), but was significantly higher in female F D R s than female controls (35.9% versus 16.5%; p = 0.006). A l s o , mean serum homocysteine levels were higher than in both male and female F D R s at 10.9 ± 0.5 pJVl and 9.0 ± 0.3 p:M, compared to 8.5 ± 0.2 u M and 7.3 ± 0.2 p:M for male and female controls. Mean C-reactive protein values were 1.8 ± 0.2 m g / L in male and 2.5 ± 0.2 m g / L in female F D R s ; they did not differ significantly from the controls (1.7 ± 0.3 m g / L for men and 1.7 ± 0.3 m g / L for women).  54  N  FDRs Median (25th 75th percentile)  N  Controls Median (25th 75th percentile)  p value  Ageadjusted p value  MEN Total cholesterol (mM) 71  5.20 (4.39 -6.18)  73  5.01 (4.56-5.47)  0.289  0.093  LDL-cholesterol (mM)  69  3.05 (2.60 - 3.97)  73  3.14(2.76-3.64)  0.465  0.337  HDL-cholesterol (mM)  71  1.22(1.04- 1.47)  73  1.14(0.91 - 1.49).  0.101  0.149  T C : H D L - C (mM)  71  4.14(3.27 -5.30)  73  4.19(3.53-5.51)  0.404  0.277  Triglycerides (mM)  71  1.14(0.79-2.12)  73  1.13 (0.77 - 1.68)  0.846  0.890  Glucose (mM)  71  5.1 (4.7-5.6)  73  5.1 (4.9-5.5)  0.263  0.024  Apolipoprotein B (g/L)  71  1.02 (0.78 - 1.27)  73  0.96 (0.81 - 1.09)  0.198  0.11.8  Lipoprotein(a) - mg/L  66  105 (45 -238)  49  192 (88 - 377)  0.014  0.022  Homocysteine (uM)  67  10.2 (9.3 - 12.1)  73  8.4 (7.4-9.5)  O.001  C-reactive protein mg/L  71  0.8 (0.6-2.4)  68  0.9(0.6-2.2)  0.886  0.403  Total cholesterol (mM) 78  5.24 (4.57 - 6.00)  79  5.25 (4.40-5.99)  0.958  <0.001  LDL-cholesterol (mM)  77  3.18(2.52 - 3.81)  78  3.15 (2.53 - 3.86)  0.885  0.001  HDL-cholesterol (mM)  78  1.45 (1.25 - 1.76)  79  1.39 (1.23 - 1.73)  0.274  0.071  T C : H D L - C (mM)  78  3.36 (2.79 -4.51)  79  3.68 (3.08 -4.51)  0.970  0.310  Triglycerides (mM)  78  1.05 (0.64- 1.58)  79  1.13 (0.79- 1.46)  0.397  0.712  Glucose (mM)  78  4.9 (4.4 - 5.3)  79  5.0 (4.8 - 5.4)  0.063  0.001  Apolipoprotein B (g/L)  78  0.93 (0.77- 1.14)  79  0.92 (0.78 - 1.06)  0.735  0.035  Lipoprotein(a) - mg/L  73  218 (63 -483)  64  177 (96-270)  0.674  0.331  Homocysteine (uM)  78  8.8(7.6-9.7)  79  7.0 (6.3 - 8.0)  O.001  C-reactive protein mg/L  78  1.0 (0.6-3.6)  79  1.2 (0.8-4.2)  0.168  0.001  WOMEN  0.001 0.272  Table 3.18. Comparisons of Biochemical Measurements Between First-Degree Relatives and Controls. Percentages are shown in brackets, p values less than 0.050 were considered statistically significant and are shown in bold.  FDRs  Controls /? value  Ageadjusted p value  N  (%)  N  (%)  19  (26.8)  6  (8.2)  0.003  0.010  11  (14.1)  9  (11.4)  0.611  0.234  MEN High apoB (>1.25 g/L) WOMEN H i g h a p o B ( > 1 . 2 5 g/L)  Table 3.19. Prevalence of Elevated Apolipoprotein B in First-Degree Relatives and Controls. Percentages are shown in brackets, p values less than 0,050 were considered statistically significant and are shown in bold.  Besides having higher mean homocysteine values, there was also increased prevalence o f elevated homocysteine above the 8 0 percentile (Table 3.20). Seventy-three percent o f the th  F D R s had elevated homocysteine; in contrast, only 4 1 % o f the male and 33% o f the female controls had high homocysteine values (p <0.001). There were no differences in the prevalence o f increased lipoprotein(a) values. However, 34.6% o f the female F D R s compared to only 16.5% o f the female controls had lipoprotein(a) over 300 m g / L (p = 0.023). The prevalence o f low, moderate, and high C R P values in F D R s were not significantly different than controls, even after adjusting for age.  56  FDRs  Controls  N  (%)  N  (%)  Lipoprotein(a) >300mg/L  13  (18.3)  16  (21.9)  0.589  0.638  Elevated homocysteine (men >9.1uM; women >7.8uM)  52  (73.2)  30  (41.1)  <0.001  <0.001  L o w (< 1.0 mg/L)  38  (53.5)  42  (57.5)  0.877  0.591  Moderate (1.0 to 3.0 mg/L)  23  (32.4)  21  (28.8)  High (>3.0 mg/L)  10  (14.1)  10  (13.7)  27  (34.6)  13  (16.5)  0.009  0.023  ' 57  (73.1)  26  (32.9)  <0.001  <0.001  0.637  0.338  p value  Ageadjusted p value .  MEN  C-Reactive protein  WOMEN Lipoprotein(a) >300mg/L Elevated homocysteine (men >9.1uM; women >7.8uM)  -  C-Reactive protein L o w (<1.0 mg/L)  38  (48.7)  33  (41.8)  Moderate (1.0 to 3.0 mg/L)  19  (24.4)  20  (25.3)  High (>3.0 mg/L)  21  (26.9)  26  (32.9)  Table 3.20. Comparison of the Prevalence of Elevated Non-Traditional Risk Factors Between First-Degree Relatives and Controls. The frequencies and prevalence o f elevated lipoprotein(a), homocysteine, and C-reactive protein were compared between F D R s and controls, stratified by gender. Percentages are shown in brackets, p values less than 0.050 were considered statistically significant and are shown in bold.  The Framingham risk score was used to objectively predict 10-year cardiovascular risk for F D R s and controls in the study. Because our groups were relatively young, over 92% o f the female F D R s and 98% o f the female controls were classified as 'low-risk', even after multiplying by two for those with positive family history (Table 3.21). Most men in both groups were also at 'low-risk': for male F D R s , 72% were at low risk, 18% at moderate risk, and 10% at  57  high risk compared to 73% at low risk, 11% at moderate risk, and 16% at high risk for male controls.  Since the controls were about 10 years older than the F D R s , we re-calculated the Framingham risk scores for both groups assuming all individuals were 45 years o f age. Again, almost 99% o f the females were categorized as i o w - r i s k ' , while the proportion o f low-risk individuals in men was changed to 85% i n F D R s and 92% in controls.  FDRs  Controls  N  (%)  N  (%)  p value  L o w risk  51  (71.8)  53  (72.6)  0.284  Moderate risk  13  (18.3)  8  (11.0)  High risk  7  (9.9)  12  (16.4)  L o w risk  72  (92.3)  77  (98.7)  Moderate risk  4  (5.1)  1  (1.3)  High risk  2  (2.6)  0  (0.0)  L o w risk  60  (84.5)  67  (91.8)  Moderate risk  9  (12.7)  4  (5.5)  High risk  2  (2.8)  2  (2.7)  L o w risk  77  (98.7) ,  78  (98.7)  Moderate risk  1  (1.3)  1  (1.3)  High risk  0  Men  Women 0.138  M e n - normalized to 45 years 0.320  Women - normalized to 45 years 1.00  o  Table 3.21. Framingham Risk Scores for First-Degree Relatives and Controls After Adjusting for Positive Family History. Percentages are shown in brackets. Framingham risk scores were calculated according to N C E P - A T P III guidelines.  58  The Framingham risk score is a useful tool to assess C V D risk, though the risk algorithm places a strong emphasis on age, which is a traditional risk factor for C H D . To evaluate between the groups without the influence o f age, we calculated the number o f modifiable risk factors in index patients, F D R s , and controls, and compared results with findings from the Canadian  Community Health Survey. In the survey, self-reported modifiable risk factors included smoking, physical inactivity, overweight ( B M I >25 kg/m ), high blood pressure (>140/90 2  mmHg), as well as diabetes mellitus. The  Canadian Community Health Survey also included  'less than recommended consumption o f fruits and vegetables' as a modifiable risk factor, which was not included in our analysis. Overall, 86% o f the F D R s and 78% o f the controls had at least one modifiable risk factor - this was comparable to 80% o f the general population as found in the Canadian survey (Table 3.22).  59  FDRs  Controls  Canadian Community Health Survey 2000*  N  (%)  N  (%)  %  N o risk factors  21  (14.0)  33  (22.0)  (19.8)  1 risk factor  52  (35.0)  67  (44.0)  (39.1)  2 risk factors  49  (33.0)  38  (25.0)  (30.0)  3+ risk factors  27  (18.0)  14  (9.3)  (11.1)  128  (86.0)  119  (78.0)  (80.2)  N o risk factors  11  (16.0)  14  (19.0)  1 risk factor  19  (27.0)  33  (45.0)  2 risk factors  27  (38.0)  17  (23.0)  3+ risk factors  14  (20.0)  9  (12.0)  A t least 1 risk factor  60  (85.0)  59  (81.0)  N o risk factors  10  (13.0)  19  (24.0)  1 risk factor  33  (42.0)  34  (43.0)  2 risk factors  22  (28.0)  21  (27.0)  3+ risk factors  13  (17.0)  5  (6.3)  A t least 1 risk factor  68  (87.0)  60  (76.0)  TOTAL  A t least 1 risk factor MEN  WOMEN  -  * Source: Statistics Canada, Canadian C o m m u n i t y Health Survey. R i s k factors were self-reported. ** R i s k factors also included 'less than recommended consumption o f fruits and vegetables', w h i c h was not included in this analysis.  Table 3.22. Number of Major Modifiable Cardiovascular Risk Factors in First-Degree Relatives and Controls. Modifiable risk factors include i) current smoker, ii) physical inactivity, iii) being overweight ( B M I >=25 kg/m ), iv) hypertension (> 130/85 mmHg), or v) diabetes. 2  60  Next, we tabulated the number o f non-traditional risk factors in the groups (Table 3.23). In the control group, 41.4% did not have any non-traditional risk factors (including elevated lipoprotein(a), homocysteine, and C-reactive protein); among the F D R s , the percentage o f participants without any non-traditional C V D risk factors was only 13.4% (p <0.001). Although a majority o f the female F D R s were classified as Tow-risk' according to the Framingham risk score, 92% o f them had at least one elevated non-traditional risk factor (mostly elevated homocysteine).  FDRs  Controls  N  (%)  N  (%)  N o non-traditional risk factors  20  (13.4)  63  (41.4)  1 non-traditional risk factor  82  (55.0)  60  (39.5)  2 non-traditional risk factors  43  (28.9)  26  (17.1)  3 non-traditional risk factors  4  (2.7)  3  (2.0)  N o non-traditional risk factors  14  (19.7)  31  (42.5)  1 non-traditional risk factor  41  (57.7)  29  (39.7)  2 non-traditional risk factors  14  (19.7)  12  (16.4)  3 non-traditional risk factors  2  (2.8)  1  (1.4)  N o non-traditional risk factors  6  (7.7)  32  (40.5)  1 non-traditional risk factor  41  (52.6)  31  (39.2)  2 non-traditional risk factors  29  (37.2)  14  (17.7)  3 non-traditional risk factors  2  (2.6)  2  (2.5)  TOTAL  MEN  WOMEN  T a b l e 3.23.  N u m b e r of N o n - t r a d i t i o n a l R i s k Factors in First-Degree Relatives a n d C o n t r o l s . N o n -  traditional risk factors (*) included lipoprotein(a) >300 m g / L , elevated homocysteine (>7.8 p M in women and >9.1 p M i n men), as w e l l as C-reactive protein >3.0 m g / L . Homocysteine and C R P cutoffs are at 8 0 percentile while lipoprotein(a) is at 7 5 percentile. th  th  61  A s defined by the N C E P - A T P III guidelines, the metabolic syndrome represents a clustering o f three or more risk factors, including abdominal obesity (waist circumference >102 cm in men and >88 cm in women), high blood pressure (>130/85 mmHg), elevated triglycerides (>1.7 m M ) , fasting glucose (>6.2 m M ) , or low HDL-cholesterol (<1.0 m M for men; <1.3 m M for women). Prevalence rates were similar in females: 15.4% o f the F D R s and 16.5% o f the controls had the metabolic syndrome (p = 0.854). In men, there were also no significant differences (p = 0.392), with 12.7% o f the male F D R s and 17.8% o f the controls having the metabolic syndrome. Furthermore, when the prevalence o f metabolic syndrome was re-assessed using the I D F definitions (with a lower waist circumference cut-off as well as having central obesity as an essential criteria); results for both F D R s and controls were the same as when the N C E P - A T P III definitions were used.  62  C H A P T E R IV: DISCUSSION  Participants in F A C T S comprised 72.8% Caucasians, 15.9% South Asians, and 8.4% East Asians, which was relatively similar to the ethnic distribution in the Greater Vancouver (17.4% Chinese and 8.4% South Asians). The higher percentage o f South Asians is expected because this group is known to have higher C H D events.  Recruitment rates were very low, mostly as a result o f the lower age cut-offs in our definition o f premature C H D . A s seen in Figure 4.1, only 34% o f men and 29% o f women have C V D from ages 45 to 54 years when compared to over half the population in those over 55 years (note that the figure shows percentages o f C V D , while our study involved those with C H D ) . Only 28 female index patients participated in F A C T S , which influenced the power o f the study. Therefore, we did not compare results between the gender o f the index patient and their F D R s .  F i g u r e 4.1. Prevalence of C a r d i o v a s c u l a r Diseases i n A m e r i c a n s A g e 20 Years a n d O l d e r by A g e and Sex  20-24 25-34  35-44  45-54 55-64 65-74  75+  Ages Source: NHANES III (1988-94), CDCVNCHS.  63  Index Patients and F D R Siblings  Index, F D R s and controls had similar prevalence o f modifiable lifestyle risk factors - this suggests that environmental influences may be a stronger determinant than genetics. W e expected index patients to have a greater number o f modifiable risk factors. One possible reason as to why index patients had the same prevalence o f modifiable risk factors may be due to the fact that most o f the index patients had already undergone therapeutic lifestyle modification, as demonstrated by the large percentage o f ex-smokers. Male index patients did have the highest median B M I values than all the other groups. Because o f the small number o f female index patients recruited, any possible differences between female index patients and female F D R s may not be detected.  Siblings o f index patients had similar risk factors as index patients themselves, except more F D R siblings were non-smokers. However, there was a higher prevalence o f abdominal obesity in F D R siblings than the index patients - again suggesting that index patients had already undergone lifestyle modification.  A s expected, lipoprotein(a) values were higher in index  patients than their F D R s . Interestingly, lipoprotein(a) values for siblings were similar to index patients, and hence were higher than the F D R s overall (including children o f index patients).  64  First-Degree Relatives C o m p a r e d T o C o n t r o l s  A s opposed to the gender disparity in index patients, there were almost equal numbers o f male and female F D R s (53% and 47%, respectively). In general, F D R s were a relatively young cohort with the average age at 40 ± 2 years; because this group was quite young, almost all the siblings and children o f index patients did not have established C H D . A l s o , F D R s were more educated compared to the general population - this could be due to the fact that people OA  volunteering for studies have been shown to have higher educational levels .  Traditional cardiovascular risk factors  The prevalence o f traditional C V D risk factors was low, as most were within normal ranges. Compared to the general population, F D R s were more highly educated, and less likely to smoke. Total cholesterol-to-HDL-cholesterol and LDL-cholesterol levels were borderline high, even though the F D R s were asymptomatic and relatively younger.  One traditional risk factor that was significantly different was B M I . The median B M I s for both male and female F D R s were greater than 25 kg/m ; this half o f the F D R s were overweight. The high prevalence o f overweight F D R s is a concern, as high B M I contributed independently and significantly to incident C H D , beginning in the overweight range and was most notable for obese siblings with a high-risk F R S . Because B M I does not differentiate 8 1  between fat and muscle, it may not accurately predict increased risk, especially for younger  •  individuals (with higher muscle mass) and the elderly (who lose muscle mass).  65  However, the percentage o f F D R s with abdominal obesity was also elevated in this group. In female F D R s , 4 3 % were abdominally obese according to N C E P - A T P III guidelines; when I D F guidelines were used, 70% had waist circumference greater than 80 cm. In contrast, 2 1 % o f the male F D R s were abdominally obese. Moreover, most o f the F D R s were physically inactive. Using B M I is therefore a valid tool to identify these individuals with excess body fat, because even though the F D R s were younger and may possess greater muscle mass, they were also more physically inactive. Compared to results from the  Canadian Community Health  Survey, especially to the general population in British Columbia, F D R s were more likely to be overweight or obese.  Controls were selected from the M - C H A T study, and matched by ethnicity, gender, and B M I . Unfortunately, because our .study had a larger Caucasian population than the M - C H A T study, it was not possible to match F D R s in our study by age as well. Consequently, the average age o f controls was 10 years greater than the F D R s . This disparity confounds results, since age affects risk factors such as cholesterol, B M I , and C R P . 5 6  Though the B M I s were elevated for controls, they were as physically active as the general population. L i k e F D R s , there were also more controls that do not smoke, when compared to the general population.  When comparing differences between F D R s and controls, the frequency o f most traditional modifiable risk factors were similar, except for smoking, abdominal obesity, and  66  physical activity. In men, about 40% o f the controls were ex-smokers, while only 11 % o f male F D R s smoked. Also, almost twice the number o f female F D R s than controls was abdominally obese. For both sexes, the prevalence o f physical inactivity was greater in the F D R s than in controls.  Male F D R s had higher frequencies o f elevated apolipoprotein B , which may indicate an increase in atherogenic, small, dense L D L particles.  The percentage o f F D R s , index patients, and controls with at least one modifiable risk factor was comparable to the results from the  Canadian Community Health Survey. However,  because we did not include 'less than recommended daily consumption o f fruits and vegetables', the prevalence may actually be higher than the general population.  Almost all the F D R s and controls were at low-risk C H D according to the Framingham risk score, after adjusting for those with positive family history. This was unexpected, as there was a 10-year in difference in mean ages between F D R s and controls; as well, since we also doubled the calculated risk for controls with family history o f C V D (regardless o f whether it was premature), the risk for controls were actually over-estimated.  One possible explanation was  that the controls were very healthy for their ages, and hence their Framingham risk scores were comparable even with the strong influence o f age in the prediction equation. Conversely, the F D R s have a similar risk than the older controls, suggesting that these F D R s were less healthy than expected for their age and sex. A l s o , because F D R s were younger than controls, they would  67  probably have more severe risk factors in 10 years. For example, blood pressure and T C : H D L - C levels would most likely worsen.  Our results suggest that male F D R s were healthier than female F D R s . In general, male F D R s had significantly lower B M I , waist circumference, and blood pressures (systolic and diastolic) than male index patients. A l s o , male F D R s were comparable to M - C H A T controls and even had lower lipoprotein(a) values. In contrast, female F D R s had similar traditional risk factors as index patients. When matched with M - C H A T controls by B M I , female F D R s (who were younger than female controls) had greater prevalence o f abdominal obesity.  Non-traditional  cardiovascular  risk  factors  Because the selection o f comparison groups were not matched by age, comparability 82  between the comparison groups could potentialy be confounded  . Though F D R s and controls  had very similar prevalence and severity o f traditional C V D risk factors, some obvious differences were observed in the non-traditional risk factors. Despite all this, the younger F D R cohort still had higher frequency o f non-traditional risk factors.  27  Previous studies have shown C R P to provide additive value to global risk assessment ' 32  . W e found no significant differences in C-reactive protein between F D R s and controls: both the prevalence o f high C R P and median C R P levels were also very similar in both sexes. Since C R P is correlated to a variety o f risk factors including increased B M I , this could be the reason that no differences were observed. Regression analysis showed that C R P was dependent on B M I  68  (data not shown). Since half o f the controls also had family history o f C V D , it is possible that both groups have elevated C R P as compared to the general population. A s well, it has been postulated that C R P is not useful for individuals at low-risk, but provides value for moderate-tohigh risk patients.  Also, male F D R s had significantly lower lipoprotein(a) levels than the male controls, while median values for women did not vary. However, lipoprotein(a) levels greater than 300 mg/L were twice as frequent in female F D R s than in controls. Siblings o f index patients had higher frequency o f elevated lipoprotein(a) than children o f index patients. This is possibly due to genetics - since elevated lipoprotein(a) is a dominant-recessive trait, siblings o f F D R s could have both alleles while children may only have one.  In both sexes, homocysteine levels were significantly higher in the F D R s than controls; both male and female F D R s had median levels that were higher than the 7 5 percentile in the th  general population. Regression analysis showed that homocysteine levels were not affected by age (data not shown). Since gene mutation of MTHFR  is common in Caucasians, F D R s with  family history o f premature C H D may be more likely to have mutant (TT) alleles than controls: this w i l l need to be confirmed with future genetic studies.  Interestingly, 87% o f the F D R s had at least one non-traditional risk factor ( C R P , Lp(a), or homocysteine) compared to 59% o f the controls. O f those participants classified as i o w risk' according to the Framingham risk score, only 25.5% o f the male F D R s were without nontraditional risk factors, compared to 49.1% o f the male controls. In women, where over 90%  69  were at ' l o w risk', only 91.7% o f the female F D R s had at least one non-traditional risk factor (60% in female controls).  It would be worthwhile to compare lipid records, as well as homocysteine and C-reactive protein values o f the index patients with the F D R s and the controls. However, because drugs such as statins w i l l affect biochemical profiles, comparisons need to be made with pre-treatment records. A s found in our study, obtaining pre-treatment records from family physicians was difficult. Because records were incomplete, they were not analyzed in this study.  Risk assessments for FDRs - are they necessary?  The question remains as to whether F D R s with family history o f premature C V D should be routinely screen for non-traditional risk factors such as homocysteine, C R P , and lipoprotein(a). Primary health workers should still follow traditional C V D risk factor assessment, but non-traditional risk factors such as homocysteine may provide additive value for identifying at-risk individuals on a case-by-case basis. For example, i f a patient has undergone a complete traditional C V D risk assessment and is found to be at moderate risk, measuring nontraditional C V D risk factors may be used as additional information to determine where the patient stands in terms o f possible treatment and therapy. If the patient has elevated homocysteine, a rational approach would be to administer homocysteine-lowering therapy. It is important to remember that non-traditional C V D risk factors such as homocysteine should be interpreted as another C V D risk factor (i.e. provides additive value), but should not be seen as an indicator for medications or angiograms.  70  A t this time, measuring homocysteine for all F D R s is not necessary and not costeffective. Though plasma homocysteine can be effectively and easily lowered by folate therapy, there is currently a paucity o f research to show the effectiveness o f lowering plasma homocysteine in decreasing the number o f cardiovascular events. W e have to await results from a number o f randomized, double-blinded, multi-center, placebo-controlled trials.  The Vitamin Intervention for Stroke Prevention Trial (VISP) in the United States involved 3,680 patients with ischemic stroke (n = 1,827 on high-dose vitamins versus n = 1,853 on low-dose vitamins) who were followed for 2 years . Results showed that while modest 8 3  reductions in homocysteine were achieved in the high-dose group, there was no effect on the odds o f recurrent strokes, C V D , or mortality. There was an association between baseline homocysteine levels and vascular risk. However, further study is warranted because participants only have mildly elevated homocysteine at baseline. Other potential problems included only achieving modest reductions in homocysteine and a short follow-up period. A s well, foods in the United States are already fortified with folate, which could mask possible effects. Other ongoing clinical trials that w i l l address these issues include the Norwegian Vitamin Intervention Trial ( N O R V I T ) , Western Norway B - V i t a m i n Intervention Trial ( W E S B I T ) , Study o f Effectiveness o f Additional Reduction in Cholesterol and Homocysteine ( S E A R C H ) in the United Kingdom, as well as the Prevention with a Combined Inhibitor and Folate i n Coronary Heart Disease ( P A C I F I C ) in Australia.  71  Similarly, for C R P and lipoprotein(a), further research is necessary to determine i f elevated levels are indicative o f future C V D events. Until further evidence arises from clinical trials, it is not necessary to screen F D R s for non-traditional C V D risk factors, particularly our younger F D R s who were ' l o w risk' according to the Framingham risk score. In the case o f F D R s in the, F A C T study, participants should be consulted on potential weight loss i f their B M I was greater than 25 k g / m , and be informed o f the increased risks o f C V D associated with 2  abdominal obesity and physical inactivity.  A l s o , it is uncertain whether the differences observed between F D R s and controls were based on genetics or environmental factors. Data on the small number o f spouses o f F D R s (n = 19 for males and n = 14 for females) suggest that environmental factors may actually play a bigger role, as prevalence o f C V D risk factors were similar between spouses and F D R s (data not shown).  Limitations  There were several limitations to our study, including small sample size, possible selection bias for F D R s and controls, as well as the methodologies for measuring biochemical samples.  72  Sample size  One main limitation o f the study was the low recruitment rate for both index patients and their F D R s . The stricter age criteria (both the age o f premature C H D and the current age o f the index patient) and the requirement that F D R s must live in the Greater Vancouver, meant that a larger number o f participants had to be screened. In terms o f F D R s , many did not voluntarily respond to multiple letters o f invitation and/or phone calls. Unfortunately, information such as anthropometric measurements and reasons for ineligibility or refusal was not collected for both ineligible index patients and non-respondent F D R s .  Therefore, the current sample size may not be sufficient to power the study. If we increased both the number o f families and the number o f F D R s as well, we may find that some other traditional and non-traditional C V D risk factors actually differed between the F D R s and controls. In particular, more female index patients are needed to study whether gender o f index patients or F D R relation to index patients influences the prevalence and severity o f C V D risk factors. Moreover, with larger families (currently only about 1 - 2 F D R s per family), it w i l l be possible to study interactions within families.  In addition to a larger sample size, future recruitment strategies for F A C T S should attempt to include a more diverse range o f ethnicities, especially South Asians and Chinese.  In this study, another problem encountered, was that most F D R s were at low-risk as calculated by the Framingham risk scores, even after doubling C V D risk estimation for those  73  with positive family history. This made it difficult to observe any discrepancies between and within groups.  Selection of FDRs and controls  F D R s were matched to controls from the M - C H A T study by ethnicity, gender, and B M I ; because o f the larger than expected number o f Caucasian families, it was not possible to match by age as well. However, since age is an important non-modifiable risk factor, comparing F D R s with the selected controls confounded results, as increased age is associated C V D risk factors such as higher cholesterol levels, higher blood pressures, or increased waist circumference.  When F D R s were matched by age with B M I from the Canadian Community Health Survey, we found that there were significantly higher proportions o f overweight or obese individuals in our group than results found in the general population. Therefore, i f controls were selected by age, we may find that F D R s were apparently healthy because o f their younger age, but were actually at higher risk than people o f the same age and sex in the general population.  W e attempted to eliminate or minimize the influence o f age by: 1) normalizing F R S for F D R s and controls and 2) comparing the number o f modifiable risk factors between the two groups. Framingham risk scores for F D R s and controls were re-calculated after normalizing age to 4 5 years. Normalizing age showed no difference in risk - in fact, more male F D R s were reclassified into ' l o w risk'. A n additional method was to analyze or investigate modifiable C V D risk factors not considered in the Framingham calculation, including physical inactivity and  74  being overweight. Eighty-six percent o f the F D R s and 78% o f the controls had at least one modifiable risk factor (current smoker, physical inactivity, B M I > 25 k g / m , blood pressure 2  >140/90 m m H g , diabetes), which was analogous to 80% found in the general Canadian population.  Apart from an elevated B M I , F D R s and controls had comparable risk factors to the general population - was this a real effect? The low prevalence o f traditional C V D risk factors could indicate a 'healthy volunteer bias' - the screened group is healthier or more healthconscious than the general population. The bias may be particularly magnified in M - C H A T participants, who were recruited at various health fairs within the community. Studies have shown that those who voluntarily participate in epidemiological research typically report healthier lifestyle patterns than the general p o p u l a t i o n ' . Our findings also suggested that the 84  85  controls were healthier than expected for their age.  One possible explanation for why F D R s and controls have similar number o f modifiable lifestyle and traditional C V D risk factors could be due to the matched B M I . This study does not conclusively reveal whether F D R s o f patients with premature C H D have higher C V D risk than others o f the same age and sex in the general population.  A l s o , though the inclusion criteria for M - C H A T stipulated that participants must not have diagnosed C V D or be currently taking medications, half o f the controls had positive family history o f C V D , a higher reported prevalence o f positive history than other studies, though only took parental history into account  2,89  ; in the Physician's Health Study (PHS) and the Women's  75  Health Study ( W H S ) , about a quarter o f the participants reported parental history o f C V D . However, there could be potential recall bias, as family history was self-reported for M - C H A T • •  participants  90-92  Unfortunately, no information was collected as to whether the family history was in a first-degree relative, or i f the history was premature C V D . W e could only assume the percentage of premature C V D based on other studies: o f the participants with positive family history, 10% in the P H S and 40% in the W H S had history o f premature C V D . The frequency o f premature 2  C V D was even higher in the Framingham Offspring Study, at 50% o f those reporting positive family history  .  Selection bias  Selection bias occurs when the characteristics being studied differ between the comparison groups , and is a particular concern when dealing with low recruitment rates . It is 86  87  possible that the 'self-selection' o f volunteers for both F A C T S and M - C H A T led to a group that may not be representative o f other F D R s and controls respectively. Studies have found that nonresponders differ from participants in factors such as age, socioeconomic status, and ethnicity ; moreover, people with risk factors that are perceived as socially unacceptable - such as smoking and alcohol consumption - are less likely to voluntarily participate in studies . This 86  phenomenon was certainly observed in our study - compared to the general population, significantly lower percentages o f index patients, F D R s , and M - C H A T controls were nonsmokers, and larger percentages o f index patients and M - C H A T controls were ex-smokers.  76  Though attempts were made to minimize selection bias from the study, there were limitations in available methods to correct for the bias. First, since collecting information on all non-respondents was not economically feasible in F A C T S , we cannot determine whether the F D R s in the study had higher socioeconomic status than non-respondents. In M - C H A T , volunteers were from the general population, and only individuals with family history o f C V D may have been more motivated to participate. Therefore, because we could not completely correct for selection bias (including the age difference between F D R s and M - C H A T controls), this may affect the ability to detect differences between F D R s and controls, as well as influencing the strength o f the associations. However, we compared results to the general population to minimize the differences.  Other studies, such as the Oslo Health Study, found that response rates were positively associated with age, education and being female. However, the prevalence o f smoking and elevated B M I only differed slightly from expected frequencies. The study concluded that self88  selection by sociodemographic variables had little impact on prevalence estimates .  Comparing data with the Canadian population  W e attempted to compare some traditional C V D risk factors - education, smoking, B M I and physical inactivity - between F D R s and the general population, using data specifically for British Columbia.  However, our group may not necessarily be representative o f the ethnically  diverse population in British Columbia.  77  Moreover, apart from apolipoprotein A and B , there is no current Canadian data on 'normal' ranges o f non-traditional risk factors; clinical cut-offs for lipoprotein(a) and homocysteine are based on American percentiles, which may not accurately reflect the Canadian population.  Dietary and psychosocial information were collected for the study, but have not been analyzed at the time this thesis was written.  Family history  In our study, family history was treated as a binary variable: an individual either had or did not have a family history o f cardiovascular disease. However, this method did not consider the multivariate aspects o f family history with different influences on an individual's overall risk factor profile. Studies have shown that using more complex definitions for family history 93  improves overall cardiovascular risk prediction .  Biochemical measurements  A l l measurements o f biochemical markers (for example, lipids, C R P , lipoprotein(a)) for index patients, F D R s , and controls were performed at St. Paul's Hospital laboratory. However, homocysteine measurements for F A C T S were conducted at Vancouver General Hospital  78  laboratory while M - C H A T controls were performed at St. Paul's Hospital. However, results from both laboratories were comparable in accuracy and precision.  Summary  Despite the above limitations, F D R s are still different from the M - C H A T controls and population-based data from British Columbia.  •  More F D R s were overweight or obese as compared to the general population. A s most spouses o f F D R s were also overweight (data not shown), this suggests that environmental influences played a larger role than genetics. 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Immunology. 1971;20:1019-1040.  75. Ainsworth B E , Haskell W L , Leon A S , et al. Compendium o f physical activities: Classification o f energy costs o f human physical activities. Med Sci Sports Exerc. 1993;25:7180.  76. Kannel W B , Castelli W P , Gordon T. Cholesterol in the prediction o f atherosclerotic disease, new perspectives based on the framingham study. Ann Intern Med. 1979;90:85-91.  77. Kannel W B , Feinleib M , M c N a m a r a P M , Garrison R J , Castelli W P . A n investigation o f coronary heart disease in families, the framingham offspring study. Am J Epidemiol. 1979;110:281-290.  78. Homocysteine Studies Collaboration. Homocysteine and risk o f ischemic heart disease and stroke: A meta-analysis. JAMA.  2002;288:2015-2022.  89  79. Pahor M , Elam M B , Garrison R J , Kritchevsky S B , Applegate W B . Emerging noninvasive biochemical measures t o predict cardiovascular risk. Arch Intern Med. 1999;159:237-245.  80. Chase G A , Kwiterovich PO,Jr, Bachorik P S . The  Columbia  population study. III. volunteer  status, educational background, and plasma total cholesterol level in a prepaid health care program. Johns Hopkins Med J. 1981;148:191-195.  81. M o r a S, Yanek L R , M o y T F , Fallin M D , Becker L C , Becker D M . Interaction o f body mass index and framingham risk score in predicting incident coronary disease in families. Circulation. 2005;111:1871-1876.  82. Rochon P A , Gurwitz J H , Sykora K , et al. Reader's guide to critical appraisal o f cohort studies: 1. role and design. BMJ. 2005;330:895-897.  83. Toole JF, M a l i n o w M R , Chambless L E , et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: The vitamin intervention for stroke prevention (VISP) randomized controlled trial. JAMA. 2004;291:565-575.  84. Austin M A , Criqui M H , Barrett-Connor E , Holdbrook M J . The effect o f response bias on the odds ratio. Am J Epidemiol. 1981;114:137-143.  85. Lindsted K D , Fraser G E , Steinkohl M , Beeson W L . Healthy volunteer effect in a cohort study: Temporal resolution in the adventist health study. J Clin Epidemiol. 1996;49:783-790.  86. Last J M , ed. A Dictionary of Epidemiology. N e w Y o r k , N Y : Oxford University Press; 1995.  87. Morimoto L M , White E , Newcomb P A . Selection bias in the assessment o f geneenvironment interaction in case-control studies. Am J Epidemiol. 2003;158:259-263.  90  88. Sogaard A J , Selmer R, Bjertness E , Thelle D . The oslo health study: The impact o f selfselection in a large, population-based survey. Int J Equity Health. 2004;3:3.  89. Lloyd-Jones D M , N a m B H , D'Agostino R B S, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: A prospective study o f parents and offspring. JAMA. 2004;291:2204-2211.  90. Bensen JT, Liese A D , Rushing JT, et al. Accuracy o f proband reported family history: The N H L B I family heart study (FHS). Genet Epidemiol. 1999;17:141-150.  91. Kee F , Tiret L , Robo J Y , et al. Reliability o f reported family history o f myocardial infarction. BMJ. 1993;307:1528-1530.  92. Murabito J M , N a m B H , D'Agostino R B S, Lloyd-Jones D M , O'Donnell C J , Wilson P W . Accuracy o f offspring reports o f parental cardiovascular disease history: The framingham offspring study. Ann Intern Med. 2004;140:434-440.  93. Ciampi A , Courteau J, Niyonsenga T, Xhignesse M , Lussier-Cacan S, R o y M . Family history and the risk o f coronary heart disease: Comparing predictive models. Eur J Epidemiol. 2001;17:609-620.  91  Description of the research: If -you decide to participate in this study, we require your permission'and cooperation with our research staff concerning the study. Your participation in this study is entirely voluntary. You have the right to refuse to participate in this stud v. If von decide to participate, your' decision- is -not binding and von may choose to withdraw from the study at any time without any negative consequences to the medical care, education, or other services you or your family mav receive from this hospital. 1. . Interview: A trained interviewer will ask you questions concerning your family and personal medical history ot heart or blood vessel disease, high blood pressure, smoking, physical activity, stress, high blood sugar, high blood cholesterol, operations undergone and use of medications. Physical examination will be done including vour height, weight, waist circumference blood pressure and heart-rate. You will be asked to stretch out your hands for visualization of anv fat deposits. You will be examined for any visual fat deposition on around the eyes. This usually requires 20 minutes. 2.  3.  -I.  Fasting blood sample: "A venous blood sample will be taken once at the beginning of the. study and once at the end of the study (approximately I year). This will require us to put a needle m a vein in your arm and withdraw approximately "15ml (1.5 - tablespoons) of blood, faking this sample may cause minor discomfort and local bruising. We will be examining your blood for a variety of biochemical and lipid markers. Medical Chart review: Your past and future health records may be reviewed for medical history, laboratory"results, and radiology results and to follow vour progress. Pharmacare/Pharmanet search: Your Pharmanet records will be searched for your medication history. Pharmanet is a secure compurer network that links all British Columbia community pharmacies and many hospital pharmacies to a central database. Pharmanet: is designed ro prevent unauthorized access and protect the information i n the. databases. .All users are. required to sign a- confidentiality agreement.  5.  Contact your first-degree relatives (l-'DRs): We will ask your permission to contact bv mail or email your first-degree relatives for participation in the stuciv and we will ask you to provide us the mailing addresses of vour FDRs. We ask vour permission to inform your F D R s that they have a first-degree relative who has early heart and vascular disease, which puts them at higher risk for developing atherosclerosis.  ().  You will be asked to. fill in a dietary and exercise ami questionnaire -describing your food habits and physical activity level in the past 1 year. You will also be given an optional .psychosocial questionnaire, which assesses chronic level of stress. You' will be given the option of completing these questionnaires while you're, at the hospital or you can rake it home to complete. If you choose to fill out: the questionnaire at: home, you will be provided with written instructions and a stamped self addressed envelope. This will take approximately about 35 minutes ro complete. If you decide not to complete the. psychosocial questionnaire please print vour initials here  7.  If there is any missing information with regards to the questionnaire the study research coordinator will contact vou bv mail or by telephone.  F A C T study index patient consent form V 3 Mar 05 2004 Page. 2 of 4-  Informed Consent 1. acknowledge -mat. the study protocol lias been explained ro me and that I. have had my questions answered ro my-.satisfaction-to help me understand what my participation will involve. T have received a. copv o f this form. Ir has also been explained to.me that it I 'have any further questions about'any of these procedures J can' contact the PHndpal'invesrigator:at the telephone number s h o w n o n this torm. 1 recognize that it is my right, to .withdraw from, any o f these procedures at anv time without any. consequences to mv medical treatment and that: all o f the information obtained will be kept in a confidential tile. 1 consent to participate' for all the measurement" in the, study:  N a m e ot subject (Please print)  '.  Signature of'subject  Date  N a m e of witness (Please, print)  Signature ot witness  Date  N a m e ot person explaining the consent  ('Please print)  Signature ot person explaining the consent  Date  F A C T srudv index patient, consent form V 3 M a r 05 2004 Page 4 o f 4  negative consequences to the medical care, education, or other sen-ices you .dr.your family.may receive from this hospital. If you.decide "'intervention" ''intervention" treatment and "'intervention" team). -  to participate in this study, you will be randomized into either a "usual care'"' or group. 1 he "usual care", group will be called twice during 1 year penod and the group 3-4 rimes during the.] year period. W e would like to assess the response to counseling between the ''usual care" (rio treatment trom research team) and group (counseling & treatment where and when necessary from the I - A C T Study '.' '•  1.  Interview: A trained interviewer will ask von questions concerning your family and personal medical history of heart, or blood vessel disease, high blood pressure, smoking, physical activity, stress, high blood sugar, high blood cholesterol, operations undergone and use ot medications. Physical examination will be done including your height, weight, waist circutn terencc blood pressure and heart rale. Y o u will be asked to stretch out your hands lor visualization ot any tat deposits. Y o u will be examined tor any visual tat deposition on around the eyes. This usually requires 20 minutes. ,  2.  Fasting blood sample: A venous blood sample will be taken once at the beginning ot the study and oncciat the end Ot the study (approximately 1 year). 1 his will require us to put a needle, in a vein in voiir arm and withdraw approximately 15ml (1.5 tablespoons) ot blood, taking this sample may cause minor discomfort and local bruising. We. will lie examining your blood for a variety ot biochemical and lipid, markers.  3.  Y o u will be asked to till in a dietary and exercise and questionnaire describing your food.habits and physical activity level in the. past 1 vear. Y o u will also be. given an optional psychosocial questionnaire, which assesses chronic level of stress. Y o u will be given,the option of completing these questionnaires, while, you're at the hospital or you can fake it home to complete. If you choose to till out the questionnaire "at. home vou will be provided with written instructions, and a stamped self addressed envelope. This will take approximately about 35 minutes to complete. If vou decide nor ro complete the psychosocial questionnaire, please print your initials here  4.  Y o u will be asked lo come in for noninvasive measurements ot the intima and media ot the common and internal carotid an civ (the arteries in the. neck). This will be. made using highresolution ultrasonography and il takes approximately about 15 minutes. This will be repealed at the end ot 2 years.  5.  Medical Chart review: Y o u r past and future health records may be reviewed tor information on medical history, laboratory analysis, medication his torn .and radiology results and to follow your progress.  ()..  Pharmaeare./l'hannanei search: Y o u r l'hamianet: records will be searched tor your medication history. Pharmanct is a secure computer network that links all British Columbia communitypharmacies' and many hospital pharmacies to a central database. Pharmanct is designed to prevent unauthorized access and protect the information in the databases. A l l users are required to sign aeonlidentialifv agreement. '  F A C T •study - first degree relative/spouse consent form V4 |ul 19, 2004 Page 2 of 4  7.  If. you arc randomized ro the usual care group, vou will receive an initial assessment of risk factors" and will be asked to discuss this and your treatment options with your family 'physicians. N o individualized, counseling or treatment: will be provided to you from the P A C T Study team. However you may contact your family physician with the risk assessment summary: You will be reassessed at the end of 1 -year and will be asked to spend 30-45 minutes for repetition of risk factor profile.  8.  If you are selected to be in the intervention group, vou will receive a risk assessment summary after your initial visit. Based on the risk profile, recommendations for treatment, of modifiable risk factors to targets (l)lood pressure control, lipids, glucose, and smoking cessation) anil counseling will be. carried out. Wc will mail the risk assessment summary to.your family physician. Your family physician will be given an option to treat vou- or to refer you to the physicians at Wealthy Heart. Program, St. Paul's hospital. You may lie asked to come, al 3, fi, 'J months, for about: 30 minutes for counseling and vou will be reassessed at the end of 1 vear. We may contact: vou over the phone 2-3 times as a follow-up to our counseling.  9.  Contact The. first-degree relatives (l-DR) of your affected family member: We will ask vour permission to contact by mail or email additional fust-eiegrcc relatives of -the affected family member tor participation in the study anil we will ask you to provide us the mailing addresses of those relatives. We ask your permission ro inform FDRs o f the affected,member that they have a first-degree relative who has early heart or other vascular disease, which puts them at greater risk for develc jping atherosclerosis.  It). It there is any missing information with regards ro the questionnaire the study research coordinator will contact vou bv mail or bv telephone. Confidentiality: Your confidentiality will be respected. No information that discloses voiir identity will be released or published without your specific consent ro the disclosure. However, research records and medical records identifying you may be inspected m the presence of the Investigator or his or her designate by representatives of the sponsor of the study. Health Canada, and the U B C Research li'.ihics Board for the purpose of monitoring the research. However," no records, which identify.you by-name or initials; will be allowed ro leave the -Investigators' offices._A11 data will be kept m a secure database, where only authorized individuals involved in the study can access it. N o personal information such as your name or address will be included in the database; only a code will identity vou. The documents relating vour name and code will be kept m a separate location m a secure place. All resulting doeunienls and computer files will be identified bv this code number and will be •kept: in a secure collection m an access-controlled database. Risk assessment, summary, will be given to you and will be sent: ro your family doctor, f'.very effort will be made to keep vour records confidential and yOur information will only be used for. the. purposes described in this consent form. Costs and compensation: There is no cost, to vou for studv procedures however we will compensate you tor your parking expense oi ~5 dollars per visit. There is no monetary compensation for vour participation.. Signing this consent form in no wav limits your legal rights against: the sponsor, investigators, or anyone else. Potential risks and benefits: I he onlv risk to you in participating in this studv is that o f the .blood drawing mentioned earlier in this form. If vou are in the intervention group, we. will assess vour risk tor heart disease using Framingham risk score, and if you have a plaque or thickened intima media as  FACT suidv - firsi degree relative/spouse consent form V4 |ul 19. 2004 Pago 3 of 4  Appendix C: General  Questionnaire  Atherosclerosis cohort of gene environment Study questionnaire (v2) 1. Personal data:  (a) PH'N #  (b) Patient ID  (c) Visit Date •33  (cl) Name: Fasi  First  (e) Date o f Birth: I  I  mm (g)  I I I I I I I (f) Sex: Male - 0 •  ild  l'cmale-1  vv  Subjective risk:  What do you think is your risk o l having a heart: attack in the next. 10 years, compared with other people ol vour age and sex: 1- Low I | 2- Moderate • •  3- H i g h  (h)  Absolute risk:  What do you think ]s your risk of having a heart, attack in' the. next 10 years: Percentage:  P a j ^ I o f 7. f K M I I I I ; . ' I H - . I I T pi'd^niin/ATlH-ioscli'm.si.^  hibomrnrv/liMpntiv  •  (i)  Ethnicity:  •Caucasian  CZI Black  French- Canadians  CZICZICZ] CZ] CZICZI  F per P C M CZICZICZ] CZ]CZ] CZI  Non-abonginal-  CZICZICZ]  CZICZICZI  M  fuiropcair  MCF MI;M  .Australians . •  African  I  I—II—JI—I  M  Egyptian Iranian Lebanese Moroccan Atirhan  MCI M O M  CZICZICZ] CZICZICZ] CZICZICZI CZICZICZI  CZICZICZ] CZICZICZI  I  Haitian  I  II  II  I  I  l|  II  I  ||  ||  I  I  II  II I  African-American CZICZICZI  I  II  ll  M  Japanese Korean Filipino Oriental Indonesians Malayans  MCI M C M  CZICZICZ] CZICZICZI CZICZICZ] CZICZICZ) CZICZICZI CZICZICZI CZICZICZI  PCI P C M  CZICZICZ] CZICZICZ] CZICZICZ] CZICZICZ] CZICZICZ] CZICZICZ]  M  Polynesians Hawaiian* Maori  F per P C M N.A. .Indian • CZ1CZI Metis CZICZICZI Inuit CZICZICZ] CZI CZICZI Native Australian CZICZICZI CZICZICZ] CZICZICZI  Hispanic  Pakistani  CZICZICZI CZICZICZ]  Sri Lankan  czirzaczi  MCI M C M  CZICZICZ] CZICZICZI CZICZICZI  I  South Asian I I Fatst:' Indian  I I  CZPacific Islander  CZlAsian  (Chinese  P<;M  Jamaican  CZIMid-Eastern Armenian  per  M . ,YU;F M C M |—[|—||—|  CZICZICZI CZICZICZ] CZICZICZ]  i per P C M CZICZICZI CZICZICZ] CZICZICZI  lAborieinal  M . MCI M C M  czicziczi'  CZICZICZ] CZICZICZ] CZICZICZ]  I  PCI P C M  CZICZICZI CZICZICZI CZICZICZI CZICZICZ]  CZlLatino M  MCI' MCM  CZICZICZI  F  PCI P C M  CZICZICZI  AtllcroscicrtVi^ o>ht »rr of O c m - c n v n o n m c n r Sillily I D —  SnK.lv i:]iicsri(>nii;tiic v2 jiinnaiv 20O4  '-  2. P e r s o n a l history: Education: 0- H i g l i s c h o o l n o r c o m p l e t e d 1- H i g h s c h o o l c o m p l e t e d 2 - S.ome t r a d e / t e c h n i c a l / v o c a t i o n a l / b u s i n e s s 3 - D i p l o m a / c e n i t i c a f e in  trade/technical/vocational/business  4 - B a c h e l o r ' s degree (BA, B.Sc, I..I..B i-.it.) 5- M a s i . e r s degree ( M A , M . S c , M B A cic) 6- D e g r e e i n M e d i c i n e / v c t e r i n a n ' / O p t o m c r x y (MD, D'DS.DMD, D V M , O D ) 7- D o c t o r a t e (Ph.D.. D . S c , D.iul)  1). E x e r c i s e : Please sec " M o d i f i a b l e A c t i v i t y Q u e s t i o n n a i r e (c)  (MAQ)"  Diet:  Please sec " W i l l e t t " Q u e s t i o n n a i r e  (d)  Smoking:  Start  Stop  Type  Age  Age  (cig, pipe, cigar, marijuana)  Ui:ci:o: (e)  Yes •  No  #/.day  \~]  Alcohol:  W h a t category best, describes y o u r d r i n k i n g habits? • I r~1 I  O-Nevcr I 1 - O c c a s i o n a l (less titan 2-3 d r i n k / \ v k ) 2 - m o d e t a t c (7-14 d r i n k s / \ v k o r 1-2 d r i n k a day) I 3 - H e a v y (>14 d r i n k s / w k . o r >2-3  drinks a d a y ) '  Pa;;*: 2 o f 7. I li:allhv luuri iMii.^r.Mn/Alh'.'ru^cli.-riiyi.-; inbor.iloiv/latpmiv  Exposure (1" or-2")  Arhero^demMS coluiiT o f (.K-tic envu'<mmnil Snulv quesnnnnaue v2 |anuarv 2004 Sillily I D  (0  F o r w o m e n only:  H a v e y o u h a d any m e n s t r u a l p e r i o d d u r i n g d i e past 2 years? Y e s _ _ • frio-|~~| I f N o , (i)  -Have v o u reached m e n o p a u s e ?  1-Ycs  f__-lf >•«.<; what age?  2- N o 3- In m e n o p a u s e  L_l  4- S h o \ v i n g s v i n p t o m s (ii)  I f reached m e n o p a u s e , was it d u e t o l - N a r u r a l  I  I  3- Radial i o n  [  4- U n s u r c  __  |  I f reached m e n o p a u s e , arc y o u o n h o r m o n e r e p l a c e m e n t therapy? 1- Y. e.S  r__H*vcs. since when?_  2- N o  Years  •  3- U n k n o \ v n (iv)  CZI.  r__  2- Surgery  (iii)  Years  •  __  H a v e v o u ever taken b i r t h c o n t r o l pills? 1.Y C S  2- N o  |  [ It" ves, I low loniy  Years  •  3- M ' c n s t r u a l c y c l e - m e d i c a t i o n  |  |  Uailt: 3 u f 7. I K-alihy ht'ai't prut*rani/-AihiT<i.<rlc.'mi:i:; ial>i>r.iioiT/li-apnuv  103  'Arheri>?cicrosi? cohort of dene environment Srnch" i.|tiesrionmiire v2 |:inuarv 2004 .Srmlv ID——  3. R e c e n t h i s t o r y : In the past six months the following have changed: (a) ' E x e r c i s i n g  O - D c c r c ased 1 1  1-Same CD  . 3-Increased  (b) E a t i n g (c) S m o k i n g  O-Decreased' I  • 3-1 increased  O - D e c r e lsed  CD  1- Same CD 1- S a m e 1 1  (d) D r i n k i n g A l c o h o l  0-Dec re ised  [_•  1-Samc  3-Increased  (e) 'Weight.  0-Deere; seel  LZ3  1  r~l  1-^same i—i  3-1 increased 3-lncrcascd  •  •  n n  4. M e d i c a l history: 1-Ycs:  2-No  3-Svmtoms  (a) C A D :  •  (b) I>YD  CD  (cj'CVDp, .k ,-nA- } (d) Diabetes mcllirus. B  1  S  CZ1  (e) R e n a l insufficiency' ft)  Hypertension CZI  fg) O b e s i t y (IV) L ''rec|Lie'ni; C h r o n i c i n f e c t i o n :  ^pecifv.  5. F a m i l y H i s t o r y : (in.  . the pedigree)  1-Yes CD CD  2-No  C V D ( Stroke, T1AV)  3-Svmnr.oms  cn  a  CD  CD  CD  cn  CD  (d) Diabetes mellitus  CD  CD  CD  (c) H y p e r t e n s i o n  CD  CD  CD  CD  CD  CD  (a) C A D : (1>) 1 » \ D (c)  •(f) H i g h b l o o d cholesterol  H o w m a n v relatives?  c z n  A pedigree will he d r a w n t o r lamily m e m b e r s w i t h a n d without, the above illnesses. Age and cause ot death w i l l also 'be i n c l u d e d it applicable.  6. C u r r e n t M e c l i c a t i o n s : Yes  .Medication 1)  ASA  2)  A C E inhibitors  3)  Beta blockers  No  (ironi tiic chiin)  Name ot Medication  Dosai^c-  Freuticncv  '  Wi^s. 4 of 7. I k-;ilihv hi';irt pni^nini/Atht'iD.^Urrosis hbi-r.iioiv/lcipruiv  Concentration  Ariieri i^derosi:* a>h< »rr of (Jonc ravin ihtncitr SriidvA|ucsntinti-.i]rc, v2 |:inujrv 2004  4) 5)  Calcium Channel blockers Antioxidants '  6} Lipid. :< wring drugs 7) Insulin sensitizers . 8)  Oilier  7. A w a r e n e s s o f disease a n d c o r o n a r y heart r i s k factors p e r c e p t i o n : (a) H a v e y o u ever b e e n diagnosed or treated for any o f the following? (Juicn-iuw) Risk factors.  Yes  No  Currently Evaluating  Yes  No  Tested  Yes  No  Symptoms  Yes  No  T I A Positive  Yes  No  Symptoms  (i) High blood pressure (ii) 1 ligh blood cholesterol (in) Mich bl. II nl sugar (iv) Ml before, age 55 . (vj Did vou have an Ml  -  (vi) Stroke before age 6.5 (vii) I lea IT failure (viii) Decreased blood flow to the legs . . • • If answered yes for (i) and (ii), Value  Risk factors Highest blood pressure Highest cholesterol  (c)  Date of first diagnosis  /  H a v e y o u ever h a d heart or vascular surgery?  Yes 1 •  .  No -2  •  Pctgc 5 o f 7. \ k-nlthy h e . m | X u p ; f i n / A i h i T u ^ d v n i < i s h b n r . t i o n , 7 k \ i p n n v  Unsure  Alherosdemsis a>hoiT of (>i.i>^ environment Srndv i.|Uc*rionn:iite v2 |:inu:trv 20*14 SimlvlD-— --  (d)  If yes, w h i c h o f the following procedures have b e e n d o n e to.you? :l-Yes  2-No  3-Unkho\vn  I  CZ CZ]  CZ  Peripheral Vessel A n g i o p l a s t y E Z  CZ  CZ  Bvpass surgery Peripheral V a s c u l a r Surgery  cz n  (0  Angiography  I  (»).  Coronary Angioplasty  1 1  (iii)(iv) (v)  Procedure  1 1 1 1  P o s i t i v e NNegative  n  cz cz n Results  Date  (e).  A r e y o u o n any of the following medications?  (i)  Pligb b l o o d pressure  1=3  (ii) (iii)  H i g h b l o o d lipids  CZ  A n g i n a o r chest p a i n  CZ  (iv)  Blood thinning  •  I Yes  2 No  •  czicz] CZ  (V)  D i a b e t e s o r h i g h blot >d sugar 1 1  (vi)  Aspirin  CZ CZ  3-Unknown CZ CZ  cz cz cz cz  8. P h y s i c a l e x a m i n a t i o n : Kgs  AVcisrhf Waist  1 eight  circumference  Cms  B l o o d pressure (silting K arm) Xanrhclesnias |  [  M e a n rate ( H R )  ...ms  Arcus I  / nun  mmHg I  T e n d o n xanthomas |  | Palmar  Plij^c ti of 7. I le.ibliv heart pou'rain/Atherosclero^is laboi-atoi-v/leapmiv  I  I  Arh('rr>~dcro^i.s cohoiT i.f Gene enviiruiniem Srudy »|ue*rionil:iire v2 lanuarv 2004 Suuh- I!)  9. C u r r e n t A n g i o g r a p h y result: (a) H o w m a n y vessels affected? (b) % ( . ) f o b s t r u c t i o n  None I  <50' A,\~\ }  I  11  |  2 I  I  3 I  |  >50% | |  10.Current D i a g n o s i s : •  0 - .Angina  •  8 - P e r i p h e r a l vascular disease  CZI 1-Coi'Onarv artery disease  I  1.9-Hypertension  •  2- A c u t e c o r o n a r y s y n d r o m e  I  I 10-6iabcr.es mcllirus  •  3- Myocardial infarction  I  I 11-Mcrabolic syndrome  CZI 4-(Congestive heart: Inilure  I I 1 2 - L i v e i : disease  I  I 5-(Jarcliomvopathv  I  I 1 3 - R e n a l disease  •  6 - V a l v u l a r disease  I  I 1 4 - L u n g disease  O  7-Cet:cbrovascular disease  O t h e r _ '_  11. L a b D a t a : "PC  ApoB  TG  Apo A I  LO  -  I.P A I HDL  i < »< « M Ml i < „ ,  'IT  LIDL'LG  LDL  CRP  L a s t i n g glucose  Homocvsrinc  P:t;;e 7 nr 7. I lealthy he.m prnea-mv'-Allieinseuai^is lah'TamiY/lcapriiie  Appendix D: Modifiable Activity Questionnaire (MAQ)  Name  F A C T S ID  MODIFIABLE ACTIVITY QUESTIONNAIRE (MAQ) 1.  Please circle all activities listed below that you have done more than 10 times in the p a s t year:  Jogging (outdoor, treadmill) Swimming (laps, snorkeling) Bicycling (indoor, outdoor) Softball/Baseball Volleyball Bowling Basketball Skating (roller, ice, blading) Martial Arts (karate, judo) Tai Chi Calisthenics/Toning exercises . Wood Chopping Water/coal hauling Football/Soccer Racquetball/Handball/Squash Horseback riding Hunting Fishing Aerobic Dance/Step Aerobic Watet Aerobics Dancing (Square, Line, Balltoom) Activity  JA N  F E B  M A R  1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 A P R  M A Y  J U N  Gardening or Yardwork Badminton Strength/Weight training Rock climbing Scuba Diving . Stair Master Fencing Hiking Tennis Golf Canoeing/Rowing/Kayaking Water skiing Jumping rope Snow skiing (X country/Nordic track) (downhill) Snow shoeing Yoga Other Walking for exercise (outdoor, indoor at mall or fitness center, treadmill)  J U L  A U G  S E P  0 C T  N O V  D E C  Average # of Times Per Month  :  22 23 24 25 26 27 28 . 29 30 31 32 33 34 35 36 37 38 39 40  Average # of Minutes Each Time  -  2. In general, how many H O U R S per D A Y do you usually spend watching television?__  hrs  3. Over this past year, have you spent more than one week confined to a bed or chair as a result of an injury, illness or surgery? If yes,.how many weeks over this past year were you confined to a bed or chair?  no  yes  weeks  4. Do you have difficulty doing any of the following activities? a. getting in ot out of a bed or chair?  Yes  No  b. walking across a small room without resting?  Yes.  No  c-walking for 10 minutes without resting?  Yes  No  5. Did you ever compete in an individual or team sport (not including any time spent in sports performed during school physical education classes)? If yes, how many total years did you participate in competitive sports?  -  6. Have you had a job for more than one month over this past year, fromJast ?  •  Yes  to this No  List all J O B S that you have held over the past year for mote than one month. Account for all 12 months of the past year.  If unemployed/disabled/retired/homemaker/student during all of part of  the past year, list as such and probe for job activities of a noftnal 8 hour day, 5 day week. Job name  Job code  Walk or bicycle to/from work  AVERAGE JOB SCHEDULE  Out of the total # of 'Hrs/Day" the individual reported working at this "job", how much of this time was usually spent sitting? Enter this # in "Hrs Sittingcolumn, then place a check "\' ' in the category which best describes their job activities when they were not sitting. Hrs spent C h e c k the c a t e g o r y that b e s t d e s c r i b e s sitting at work j o b activities w h e n not sitting :  Min/Day Mos/Yr  Day/Wk  Hrs/Day  H r s sitting  Eg. Painter  B  30  Category A  Category B  Category C  (includes all sitting activities)  (includes most indoor activities)  (heavy industrial work, outdoor construction, farming)  Sitting Standing still w/o heavy lifting Light cleaning - ironing, cooking, washing, dusting Driving, a bus. taxi, tractor Jewelry making/weaving General office work Occasional/short distance walking  Carrying light loads Continuous walking Heavy cleaning - mopping, sweeping. . scrubbing, vacuuming Gardening - planting, weeding Painting/Plastering PlumbingA/Velding Electrical work Sheep herding JOB  Not e m p l o y e d o u t s i d e of the h o m e :  Student Home Maker Retired Disabled 5. U n e m p l o y e d  Carrying moderate to heavy loads Heavy construction Farming - hoeing, digging. mowing, raking Digging ditches, shoveling Chopping (ax), sawing wood Tree/pole climbing .Water/coal/wood hauling  CODES . E m p l o y e d (or v o l u n t e e r ) : 6. A r m e d S e r v i c e s 7. O f f i c e w o r k e r 8. N o n - o f f i c e W o r k e r  Appendix E: Framingham Risk Score  Table 1: Model for estimating the 10-year risk ol coronary artery disease in a patient wilhoul diabetes inellilus or clinically evident cardiovascular disease, using data from the Framingham Heart Study' MEN  WOMEN  Risk factor  Risk points  Risk factor  Risk points  Age group, yr  Age group, yr  20-54 55-39 40 .14 I.. 4''  40-44 45-40 50-54. 55 59 (10-04  50-54  00-04 '05-09-  Ii) I I  70-74 75-70  75—7't Total cholesterol level, mmol/L  < 4.14 I.:> • :  As» group, yr 20-!!!) • 0 •I  40-40 0 3  70-50 0 2  fiO-09 0 1 '  .••.20-7.20 > 7.21 Smoker No  Total cholesterol level, mmol/L  Ai;-; \;IOTI|), yr  39  40-49  50-5!)  00-0:  •1.15- 5.1'. 5.20-0. i > 7.2 I  0  0  0  0  Smoker No  Yes  Yi-s  HDL-C level, . mmob'L  HDL-C level, minol/L  > j 5.5 1.50-1.54 1.0-1 1.20 - < 1.04  : 1.55 1.30-1.54 1.04. 1.20 < 1.04 ' Systolic blood pressure, mm Hg  Systolic b l o o d pressure, mm Hg  . Inlrc-atcxl  < 120 •11'0-12'.I I 50-17.0 140-150 > I 00 Total risk points  to 12 14 10  Tu;ali;il  I 20-120 130-130 1-10-150 > 100 10-vear risk, %  Total risk points  I 0-year risk, '  <0 0-1  10 II 14  10 12 10  10-vear risk:  I I 14 17  Source/ Genest F o d o r J G , F r o h l i c h JJ, Genest JJ,Jr, M c P h e r s o n P R . Recommendations for the management and treatment o f d y s l i p i d e m i a . report o f the w o r k i n g group on hypercholesterolemia and other dyslipidemias. CMAJ. 2000;162:1441-1447.  

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