OBJECTIVES:CX3CR1 is a monocyte chemokine receptor and adhesion molecule. Two CX3CR1 mutations, V249I and T280M, reportedly decrease coronary artery disease (CAD) risk independent of established risk factors. An I249 protective effect is attributed to reducing CX3CR1 binding to fractalkine, its ligand. MATERIAL AND METHODS:We examined the frequencies of V249I and T280M among early-onset CAD patients (G1; n = 149; <50 years), late-onset CAD patients (G2; n = 150; >65 years) and healthy controls (HC; n = 149, 47-93 years) without known CAD risk factors. We compared plasma total cholesterol (TC)/high density lipoprotein-C (HDL-C) and apolipoprotein B (APOB)/apolipoprotein AI (APOAI) ratios among the groups and mutation carriers and non-carriers, and the prevalence of the mutations in G1 and G2 patients with multiple coronary vessel disease (MVD) and myocardial infarction (MI). RESULTS:G1 patients had non-significantly lower frequencies of I249 versus (vs.) G2 or controls (G1; 51 %, G2: 61 %, controls: 58 %, p = 0.19), with no difference in T280M (p = 0.8). TC/HDL-C and APOB/APOAI ratios were significantly higher in G1 patients vs. G2 and controls (p<0.0001) independently of either mutation. More G2 patients had MVD than younger ones (p<0.0001); however, more G1 patients were homozygous for V249 compared to G2 patients, who more often had the I249 allele (p<0.02). There was no such association with T280M (p = 0.38). Although more G1 patients had MI, this was not mutation related. CONCLUSIONS:There were significantly higher lipid ratios in G1 compared to G2 and HC (G1>G2>HC), but not in mutation prevalence. I249 mutation was associated with MVD in older patients, while V249 homozygosity was associated with the early-onset CAD. Neither allele affected MI or lipid levels.

BACKGROUND: It has previously been shown that the increased use of therapeutic intervention may not reduce patient fatality if there is a simultaneous increase in case severity. The present Study was designed to extend the relationship between case severity and therapeutic interventions to long-term survival in the same study population.OBJECTIVE: To compare five-year Survival of patients discharged after acute myocardial infarction from 1984 to 1988 and from 1989 to 1993, and to evaluate possible reasons for survival differences.METHODS: The present Study was population-based. Survival time was determined by record linkage into the Canadian Mortality Database. Association of five-year survival with patient characteristics, in-hospital treatment and discharge medications was assessed by logistical regression analysis. Case severity was calculated as the probability of death within five years, given the patient profile and excluding any interventions.RESULTS: Between the two Study periods, most patient characteristics and treatment intensity changed, but case severity for the study population remained constant. Five-year survival improved from 74.8% to 79.2% (P-chi 2=0.001). The improvement was adequately described by the combination of changes in patient profile and treatment without residual period effect (Pgoodness-of-fit = 0.752). The treatments significantly associated with five-year survival were coronary artery bypass graft surgery (OR 2.74; 95% Cl 1.86 to 4.05), percutaneous coronary intervention (OR 2.63; 95% Cl 1.67 to 4.14) and thrombolysis (OR 1.98; 95% Cl 1.50 to 2.62) during admission, as well as acetylsalicylic acid (OR 1.39; 95% Cl 1.15 to 1.68) or beta-blocker (OR 1.60; 95% Cl 1.34 to 1.92) prescription at discharge.CONCLUSIONS: Changes in patient profile did not affect long-term prognosis; instead, treatment modalities accounted for the observed improvement in five-year Survival.

OBJECTIVES:Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD [apolipoprotein E (APOE) epsilon4, butyrylcholinesterase (BChE) K, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala and endothelial nitric oxide synthase (ENOS) T-786C]. DESIGN AND METHODS:We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD (n = 150; <50 years), late-onset CAD (n = 150; >65 years) and healthy controls (n = 150, age range 47-93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes. RESULTS:Early-onset CAD patients had increased, but non-significant, frequencies of PPARgamma2 Pro12/Pro12 (P = 0.39) and ENOS T-786C (P = 0.72), while BChE-K was only significantly higher in early-onset CAD patients compared to controls (P = 0.03). There were significantly more APOE epsilon4 alleles alone (P = 0.02) or in combination with BChE-K (P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%, P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for PPARgamma2 to 1.70 for APOE epsilon4). This increased to 2.78 (1.44-5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%. CONCLUSIONS:While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.

Between 1984 and 1993, prevalence and case fatality of hospitalized acute myocardial infarction (AMI) had declined in the population of Halifax County. We aimed to determine whether these trends continued into the 21st century by investigating patient characteristics, treatment methods, and fatality for hospital admissions of residents of Halifax County, aged 25-74, during 1984-1989 (period 1), 1990-1993 (period 2), and 1998-2001 (period 3) and diagnosed as AMI that were extracted from databases for the Halifax County MONICA and ICONS (Improving Cardiovascular Outcomes in Nova Scotia) Studies. Trends in patient characteristics and treatment methods were assessed by chi2 statistics. Their association with 28-day fatality was determined by logistic regression. Event rate declined during 1984-1993 but not into 1998-2001 (p = 0.206). Compared with 1990-1993, fewer AMI patients during 1998-2001 were > or = 55 years (73.3% vs. 69.9%), cigarette smokers (49.8% vs. 42.9%), had a history of myocardial infarction (28.9% vs. 24.9%), and had an admission heart rate >100 (34.8% vs. 17.4%). Additionally, more patients had a history of diabetes (22.5% vs. 28.1%). Case fatality declined progressively over the 3 study time periods (16.6%, 13.1%, and 9.4%, respectively). Changes also occurred in prevalence of Killip class 4 status during admission (20.2%, 10.3%, and 13.3%, respectively), use of thrombolysis (9.0%, 30.9, and 32.6%, respectively), and percutaneous coronary intervention (PCI) (4.3%, 11.2%, and 22.4%, respectively) in the different periods. Significant associations were found between case fatality and patient history of diabetes, history of MI, age, elevated admission heart rate, Killip class 4 impairment, thrombolysis, and PCI. The ICONS registry of hospitalized acute myocardial infarctions was used to compare case fatality during 1998-2001 with that reported by the Halifax County MONICA Project for 1984-1993. Whereas the population rate of myocardial infarctions had declined between 1984-1993 but not subsequently, case fatality declined significantly throughout the study period. The continued decline in case fatality is likely explained by changes in patient profile on presentation and medical therapies, including the increased use of thrombolysis and PCI.

BACKGROUND:The Glu298Asp polymorphism of endothelial nitric oxide synthase (eNOS) gene has been associated with coronary artery disease (CAD) in some but not all studies. To determine the impact of the mutant Asp298 eNOS allele on the development of premature CAD, we examined the prevalence of this mutation in patients with early-onset CAD compared with those manifesting CAD later in life. If this mutation confers an increased risk of premature CAD, we hypothesized that the frequency of the homozygous mutation (Asp298Asp298) would be greater among the younger patient group.METHODS:A total of 299 patients with a history of myocardial infarction (MI) or angina pectoris plus angiographically documented CAD were studied. Patients were divided into 2 groups: group 1 (149 patients) included patients with CAD before the age of 50 years and group 2 (150 patients) included patients with a first presentation of CAD at >65 years old. Prevalence of eNOS Glu298 and Asp298 alleles was assessed by molecular analysis and compared for the 2 groups.RESULTS:There was no significant difference in the frequency of the mutant Asp298 allele between the 2 groups (G1: 42% vs G2: 42.7%, P =.79). The frequencies of the Glu298Glu298, Glu298Asp298, and Asp298Asp298 genotypes were similar in both groups (34.9%, 46.3%, and 18.8% for G1 and 29.3%, 56%, and 14.7% for G2, respectively, P =.29).CONCLUSIONS:Our study does not support the conclusion that the eNOS Asp298 allele contributes to the development of premature CAD.

BACKGROUND:The Halifax County MONItoring of trends and determinants in CArdiovascular disease (MONICA) Project found that between 1984 and 1988, the proportion of myocardial infarctions (MIs) that were fatal within 28 days remained constant, but declined between 1989 and 1993. The objective was to investigate association among case fatality, treatment and case severity of MI in hospitalized patients.PATIENTS AND METHODS:The MONICA MI register contains data on demographics, health history, in-hospital investigations, interventions and treatment, and vital status at 28 days after onset of symptoms for all MIs occurring in residents of Halifax County, aged 25 to 74 years. Logistic regression analysis was used to estimate trends in the use of cardioactive drugs and revascularization procedures. A case severity score was developed from patient characteristics at time of admission. Case fatality was calculated as the proportion of MIs that were fatal within 28 days.RESULTS:Between 1984 and 1988, a large increase (OR 1.3) occurred in the use of angiotensin-converting enzyme (ACE) inhibitors, acetylsalicylic acid (ASA), thrombolysis and percutaneous transluminal coronary angioplasty (PTCA); a minor increase occurred in use of calcium channel blockers (OR=1.29, 99% CI 1.19 to 1.40); beta-blocker use decreased; case fatality remained constant and case severity score increased. From 1989 to 1993, ACE inhibitor use increased (OR=1.4, 99% CI 1.27 to 1.55); minor increases occurred in use of ASA and beta-blockers, and in PTCA and coronary artery bypass grafting; case severity did not change and case fatality decreased.CONCLUSIONS:While use of beneficial treatment increased between 1984 and 1988, MI case fatality did not decrease, probably because case severity increased. Between 1989 and 1993, case severity remained constant, and the further increase in the use of beneficial therapy was associated with a decline in case fatality.

BACKGROUND According to vital statistics data for Halifax County, between 1984 and 1993 the annual mortality rate decreased for ischemic heart disease and myocardial infarction (MI). OBJECTIVES To estimate the change in MI mortality, applying standardized diagnostic criteria; to determine whether decreased case fatality or decreased MI event rate, or both, caused decreased mortality; and to determine the contribution of MI incidence rate to altered event rate. PATIENTS AND METHODS All persons in the study area aged 25 to 74 years and admitted to hospital or dying outside hospital with suspected acute coronary syndromes were registered prospectively. Demographic, health history and clinical data were extracted from medical records or collected from medical examiner reports, next-of-kin interviews or family physicians. Definite or possible MI was diagnosed according to World Health Organization MONItoring of trends and determinants in CArdiovascular disease (MONICA) criteria. Trends in age- and sex-standardized rates were estimated by using log-linear regression analysis. RESULTS Of 4283 patients admitted to hospital for MI, 23.9% died within 28 days; 1401 patients who had suffered an MI died before admission to hospital. MI mortality decreased annually by 3.9% (95% CI 1.9 to 5.8); two-thirds of the decline was due to MI event rates (2.6%; CI 1.3 to 3.8) and one-third to a decrease in 28-day case fatality (1.3%; CI 0.2 to 2. 3). A decrease in MI incidence rate (3.2%; CI 1.7 to 4.8), rather than a decline in MI recurrence rate (1.4%; CI 0.7 to -3.5), was the major reason for the declining event rate. CONCLUSIONS A decrease in the incidence of MI, possibly due to primary prevention, had a major impact on the declining MI mortality. Decreased in-hospital MI fatality, possibly due to improved treatment, was responsible for the decline in case fatality.

BACKGROUND:The objective of this study was to document changes in the prevalence and treatment of hypertension in Halifax County from 1985 to 1995 in an effort to observe, at the population level, the consequences of the availability of new antihypertensive medications.METHODS:The study population comprised a random sample of Halifax County residents, aged 25-64 years, who responded to the 1985 and 1995 surveys of the Halifax County MONICA Project and residents who responded to the Nova Scotia Health Survey conducted in 1995. Data from the two 1995 surveys were pooled. Information on hypertension awareness and use of medication were obtained through questionnaires, and blood pressure was measured according to a standard protocol, using phase I and V of Korotkoff sounds as respective markers for systolic and diastolic pressures. Uncontrolled hypertension was defined as a systolic pressure of 140 mm Hg or greater and a diastolic pressure of 90 mm Hg or greater. Changes in the prevalence of hypertension, prescribing trends and medication costs were examined, and the association between the type of antihypertensive treatment and characteristics of the respondents with self-reported hypertension was investigated by multivariate logistic regression.RESULTS:Of the 917 people interviewed in 1985 and the 1338 in 1995, 274 (29.9%) and 356 (26.6%), respectively, reported a history of hypertension. When age was controlled for, the proportion of respondents reporting hypertension did not differ between survey years or between men and women. The proportion of treated respondents who had uncontrolled hypertension increased between 1985 and 1995, from 32.6% to 57.4% among men and from 38.0% to 42.6% among women. An increase was seen in the use of calcium-channel blockers (from 2.1% to 19.7%) and angiotensin-converting-enzyme inhibitors (from 5.2% to 25.4%); the proportion of patients receiving combination therapy or diuretics decreased (from 39.6% to 15.6% and from 31.3% to 17.2% respectively). These changes were associated with an increase in the average daily cost of medication from $0.48 to $0.85 per patient.INTERPRETATION:The shift to new antihypertensive drugs was not associated with improved blood pressure control, but it was associated with an increase in average medication costs per patient. Uncontrolled hypertension remains a public health problem.

Objective: Apolipoprotein E (APOE) E4, apolipoprotein B-100 (APOB) Q3611 allele, the angiotensin converting enzyme (ACE) deletion (D) allele and glycoprotein IIIa (GP3A) P33 mutant allele are reported to predispose to early-onset coronary heart disease (CHD). These associations were not all confirmed in more recent studies. To determine the impact of these alleles on CHD, we examined the prevalence of these mutations in patients presenting with early-onset CHD and compared them to those manifesting CHD later in life. The delayed-onset was considered a sign of longevity and would serve as a comparative group to assess prevalence of the biochemical and genetic risk factors.Methods: 300 patients with a history of myocardial infarction or angina pectoris and angiographically documented CHD were studied. Patients were divided into two groups: group 1 (G1 = 150 patients) presenting with these findings under the age of 50 years; while group 2 (G2 = 150 patients) were patients presenting for the first time over the age of 65 years. Prevalence of the alleles of APOE, APOB, ACE and GP3A was assessed by molecular analysis. An association of any of these genotypes with early onset CHD could lead to a higher prevalence in the younger age group.Results and Conclusions: None of the suspected alleles namely APOB Q3611 [G1: 10.7% vs. G2: 9.0%, p = 0.57], ACE D (G1: 52.0% vs. G2: 49.7%, p = 0.57), or the GP3A P33 (G1: 17.3% vs. G2: 15.7%; p = 0.58) showed any significant difference between the two groups. Subjects with APOE E4 were more frequent in the younger age group (G1: 18.3% vs. G2: 13.7%; p = 0.047), while APOE E2 was more frequent in G2 (G2: 10.0% vs. G1: 2.7%; p = 0.0002). Multivariate analysis showed an odds ratio of APOE E2 allele in G1 of 0.27 with a confidence interval of 0.10–0.73.

OBJECTIVE: To investigate trends in heart disease risk factors (RFs) in the general population of Halifax County, Nova Scotia during a 10-year period. DESIGN: Two independent random samples of the population of Halifax County were surveyed in 1985 and 1995; age ranges were 25-64 years and 25-74 years. Blood pressure, cholesterol and body weight were measured. Smoking and health history were obtained by questionnaire. MAIN RESULTS: Participation rate was 66.3% in 1985 and 1995. All RFs were negatively correlated with education attainment. RF changes from 1985 to 1995 were related to education level, Among survey participants, mean body mass index increased from 26.7 kg/m(2) to 27.6 kg/m(2) (P=0.005) for men, and from 25.5 kg/m(2) to 27.3 kg/m(2) (P<0.00001) for women. Average smoking rate increased from 32.0% to 34.6% (not significant) in men and from 27.7% to 29.1% (not signficant) in women. Age-specific smoking rate increased by 13% (P=0.14) in younger women and decreased by 10% in older women (P=0.09). Mean levels of blood cholesterol decreased by 0.2 mmol/L (P=0.002) in men and 0.1 mmol/L (P=0.20) in women. Systolic blood pressure increased by 6.3 mmHg (P<0.0001) in men and by 7.9 mmHg (P<0.0001) in women, being steepest in the lowest education group. Mortality predicted from RFs declined between the survey years, but less than the observed mortality. This discrepancy may result from the effect of medical care or the delayed effect of RF changes. CONCLUSIONS: Some risk factors show a disturbing trend, indicating that an increased effort or a change in strategy is needed to combat: the risk of ischemic heart disease.

OBJECTIVE To determine the impact of mutations in the HFE gene (human leukocyte antigen H) on predisposition to coronary artery disease (CAD) in patients not diagnosed with hereditary hemochromatosis. BACKGROUND Elevated iron stores can predispose to acute myocardial infarction. Two mutations (C282Y and H63D) in the novel major histocompatibility complex (MHC) class 1 gene HFE were found in most patients with hereditary hemochromatosis causing high iron stores. The effect of these mutations on predisposition to CAD has not been investigated previously. METHODS Three hundred patients with a history of myocardial infarction or angina pectoris and angiographically documented CAD were studied. Patients were divided into two groups: group 1 (150 patients), manifesting early onset CAD and presenting with these findings under age 50 years; and group 2 (150 patients), presenting for the first time over age 65 years. Prevalence of the C282Y and H63D mutations was assessed by molecular analysis, and plasma ferritin was measured immunochemically. RESULTS There was no difference in the prevalence of homozygous, heterozygous or compound heterozygous (C282Y/H63D) states between the groups. Males in group 1 had higher plasma ferritin than those in group 2 (234 +/- 174 micrograms/L versus 136 +/- 103 micrograms/L, P < 0.0001), but this was not significantly different in females (75 +/- 54 micrograms/L versus 92 +/- 73 micrograms/L, P = 0.26). Ferritin remained higher in group 1 than in group 2 males after exclusion of mutation carriers (195 +/- 121 micrograms/L versus 109 +/- 76 micrograms/L, respectively, P < 0.0001), but did not change in females. CONCLUSIONS Higher iron stores were found in males with early onset CAD. This association was not related to the C282Y or H63D mutation in HFE. It is suggested that association of the MHC locus with delayed onset CAD is probably unrelated to HFE in these patients, and that HFE mutations are not a major risk factor in the development of high iron stores in early onset CAD.