Early Onset Ischemic Heart Disease Research Articles

Epistasis analysis of metabolic genes polymorphisms associated with ischemic heart disease in Yucatan

ObjectiveEpistasis is a type of genetic interaction that could explain much of the phenotypic variability of complex diseases. In this work, the effect of epistasis of metabolic genes and cardiovascular risk on the susceptibility to the development of ischaemic heart disease in Yucatan was determined. MethodsCase–control study in 79 Yucatecan patients with ischaemic heart disease and 101 healthy controls matched by age and origin with cases. The polymorphisms -108CT, Q192R, L55 M (paraoxonase 1; PON1), C677T, A1298C (5,10-methylenetetrahydrofolate reductase; MTHFR), and the presence/absence of the glutathione S-transferase T1 (GSTT1) gene were genotyped. Epistasis analysis was performed using the multifactorial dimensional reduction method. The best risk prediction model was selected based on precision (%), statistical significance (p<0.05) and cross-validation consistency. ResultsWe found an independent association of the null genotype GSTT1*0/0 (OR=3.39; CI: 1.29–8.87; p=0.017) and the null allele (OR=1.86; CI: 1.19–2.91; p=0.007) with ischaemic heart disease. The GSTT1*0 deletion and the 677TT genotype (MTHFR) were identified as being at a high cardiovascular risk, whereas the GSTT1*1 wild type genotype and the CC677 variant were at low risk. The gene–environment interaction identified the GSTT1 gene, C677T polymorphism (MTHFR) and hypertension as the factors that best explain ischaemic heart disease in the study population. ConclusionsThe interaction of the GSTT1 and MTHFR and hypertension may constitute a predictive model of risk for early onset ischaemic heart disease in the population of Yucatan.

Análisis de epistasia de polimorfismos de genes metabólicos asociados a cardiopatía isquémica en Yucatán

ObjectiveEpistasis is a type of genetic interaction that could explain much of the phenotypic variability of complex diseases. In this work, the effect of epistasis of metabolic genes and cardiovascular risk on the susceptibility to the development of ischemic heart disease in Yucatan was determined. MethodsCase-control study in 79 Yucatecan patients with ischemic heart disease and 101 healthy controls matched by age and origin with cases. The polymorphisms -108CT, Q192R, L55M (paraoxonase 1; PON1), C677T, A1298C (methylenetetrahydrofolate reductase; MTHFR), and the presence/absence of the glutathione S-transferase T1 (GSTT1) gene were genotyped. Epistasis analysis was performed using the multifactorial dimensional reduction method. The best risk prediction model was selected based on precision (%), statistical significance (P<0.05), and cross-validation consistency. ResultsWe found an independent association of the null genotype GSTT1*0/0 (OR=3.39, CI: 1.29-8.87, P=0.017) and the null allele (OR=1.86, CI: 1.19-2.91, P=0.007) with ischemic heart disease. The GSTT1*0 deletion and the 677TT genotype (MTHFR) were identified as being at a high cardiovascular risk, whereas the GSTT1*1 wild type genotype and the CC677 variant were at low risk. The gene-environment interaction identified the GSTT1 gene, C677T polymorphism (MTHFR), and hypertension as the factors that best explain ischemic heart disease in the study population. ConclusionsThe interaction of the MTHFR, GSTT1 and hypertension may constitute a predictive model of risk for early onset ischemic heart disease in the population of Yucatan.

Association of Hemostatic Gene Polymorphisms With Early-Onset Ischemic Heart Disease in Egyptian Patients.

The association between hereditary thrombophilia and venous thrombosis is well established but controversial data exist with respect to arterial thrombosis. We performed a pilot study on 31 patients with acute myocardial infarction (AMI), 21 patients with unstable angina (UA), and 20 healthy volunteers to investigate the role of various hemostatic gene polymorphisms in young Egyptian patients, who survived their first ischemic heart disease (IHD). Thrombophilic gene polymorphisms were tested using multiplex polymerase chain reaction and reverse-hybridization technique. We showed an increased risk of AMI with factor V (FV) Leiden and prothrombin G20210A heterozygosity. The increased risks of UA was associated with GA and A allele of fibrinogen β-455G→A polymorphism. Conversely, factor XIII (FXIII) Val34Leu GT and T allele were protective in the UA group. Nevertheless, the prevalence of FV H1299R, plasminogen activator inhibitor 1 4G/5G, glycoprotein IIIa C1565T, 5,10-methylenetetrahydrofolate reductase C677T, and A1298C mutations did not differ between patients with IHD and controls. The data have clinical implications regarding screening and thromboprophylaxis in high-risk individuals younger than 40 years.

Genetic score based on high-risk genetic polymorphisms and early onset of ischemic heart disease in an Italian cohort of ischemic patients

Several single-nucleotide polymorphisms (SNPs) have been recognized as associated with ischemic heart disease (IHD) although the optimal set of risk genotypes has not be identified. This study aimed to examine whether identified high-risk SNPs are associated with early onset of IHD. In the GENOCOR study, 44 high-risk SNPs were genotyped in 114 patients with early onset of IHD (46.2±5.1years) and 384 patients with late onset of IHD (60.7±5.9years). The associations between individual SNPs and early onset IHD were assessed. A multilocus genetic risk score (GRS) for each associated risk genetic markers was constructed by summing the number of risk alleles. The SNPs significantly associated with IHD were: -482C>T of Apolipoprotein C III gene (ApoC3, p=0.02); 1171 5A>6A of Matrix metalloproteinase 3 stromelisine I gene (p=0.01); G98T of Selectin E gene (p=0.05); C/G of 9p21.3 locus (p=0.01). Likelihood ratio test showed a strong interaction for increasing risk of early IHD between the presence of ApoC3 and 9p21.3 locus with hypertriglyceridemia (p=0.0008, 0.0011) as well as between 9p21.3 locus and smoking (p=0.0010) after correction for multiple testing. The OR for premature IHD for GRS unit was 1.3 (95% CI 1.1-1.6, p=0.001). Patients in the top tertile of GRS were estimated to have a 3.2-fold (95% CI 1.5-6.8; p=0.001) increased risk of early IHD compared with those in the bottom tertile. The results show that currently identified high-risk SNPs confer an additive biomarker for cardiovascular events. GRS may provide important incremental information on the genetic component of IHD.

Psychosocial factors as predictors of early onset ischemic heart disease in a sample of Pakistani women

Empirical research documents that in some cases psychosocial factors conquer greater if not equal risk of IHD. This study was conducted to infer the psychosocial factors associated with the risk of IHD in women. Case control study design was utilized to explore the association of psychosocial factors with the risk of IHD in women aged 35 to 55 years. A sample of 71 women cases diagnosed with IHD and 142 age and gender matched community controls were recruited for this purpose. Binary logistic regression analyses was conducted to ascertain the association of proposed psychosocial factors with the risk of IHD. The values of the coefficients revealed that a unit increase in score of trait anger is associated with increase in the odds of IHD by a factor of 1.21 (95 % CI 1.04 and 1.42). A unit increase in optimism score is associated with decrease in the odds of IHD by a factor of 0.67 (95% CI 0.53 and 0.83). The values of the coefficients reveal that each unit increase in score of social support is associated with decrease in odds of IHD by a factor of 0.91 (95% CI 0.89 and 0.95). The study highlights that women aged 35 to 55 years are protected against the risk of IHD, and trait anger is the only risk factor of IHD. Furthermore trait anger is modifiable and can lay directions for designing preventive cardiac interventions.

Dietary predictors of early-onset ischaemic heart disease in a sample drawn from a Pakistani population

ObjectiveA relationship between dietary pattern and ischaemic heart disease (IHD) has long been established through empirical research. It is well documented that an unhealthy diet—rich in animal products (eggs and...

Silent myocardial ischaemia and long-term coronary artery disease outcomes in apparently healthy people from families with early-onset ischaemic heart disease

A family history of premature coronary artery disease (CAD) in an apparently healthy individual conveys an increased risk of future CAD. The extent to which inducible myocardial ischaemia exists and is associated with long-term incident CAD in apparently healthy siblings of early-onset CAD patients is unknown. Asymptomatic siblings (n = 1287, aged 30-59 years) of patients with onset of CAD <60 years of age underwent risk factor screening and maximal graded treadmill testing with nuclear perfusion imaging, and were followed for incident CAD events for up to 25 years. Incident CAD occurred in 15.2% of siblings (68% acute coronary syndromes); mean time to first CAD event was 8.2 ± 5.2 years. Inducible ischaemia was highly prevalent in male siblings (26.9%), and was independently associated with incident CAD. Male siblings ≥ 40 years of age who were low or intermediate risk by traditional risk assessment, had a prevalence of inducible ischaemia and a 10-year risk of incident CAD that were near or ≥ 20%. In female siblings ≥ 40 years of age, the presence of inducible ischaemia was also independently associated with incident CAD, but the prevalence of inducible ischaemia was markedly lower, as was the risk of incident CAD. Inducible ischaemia is highly prevalent in male siblings, suggesting a previously unknown long quiescent period before the occurrence of a clinical event. While inducible ischaemia is associated with a worse prognosis, male siblings with negative tests still bear a high risk of incident disease, such that we propose that in male siblings over 40 years of age, aggressive primary prevention interventions be instituted without nuclear testing. For women, the prevalence of ischaemia was so low as to not warrant screening, but the incidence of CAD was high enough to at least warrant lifestyle interventions.

Fibrinogen Reference Range in Adolescents

Introduction: Elevated fibrinogen levels are well recognized as an independent risk factor for cardiovascular events in adults. Current research highlights the need to understand the mechanisms that influence fibrinogen levels in adolescents in order to elucidate its role in early onset ischaemic heart disease in young people. Depressed levels of fibrinogen are observed in a range of pathological conditions including acquired and congenital hypo- and afibrinogenaemias, consumptive coagulopathies, carcinoma and liver disease. Appropriate determination of the status of fibrinogen levels in patients is vital in identifying fibrinogen as a risk factor for cardiovascular events and in the investigation of coagulopathy. Ascertaining the meaningful status of the fibrinogen level in a patient relies on comparison with a reference range determined by the same methodology using an analogous population from which the patient originates. We present a reference range for Clauss fibrinogen determination in adolescents aged 12–14 years using the Sysmex CA-1500 coagulometer (Sysmex Corp., Kobe; Japan).Methodology: Blood samples for fibrinogen determination were collected from 240 adolescent schoolchildren aged between 12 and 14 years (M=119; F=121). All of the children were healthy with no apparent underlying pathology. Early morning samples were collected into siliconised glass BD Vacutainers containing tri-sodium citrate (Ref: 367691) and analysed within 4 hours of collection. Fibrinogen determination was performed using Dade-Behring thrombin and Owrens Veronal buffer reagents. Calibration of the Clauss fibrinogen assay was performed using NIBSC WHO International reference plasma for human fibrinogen (product number 98/612).Results: Fibrinogen results for males and females were examined for normality using Anderson-Darling and Kolmogorov-Smirnov tests. Results were found to be normally distributed and reference ranges constructed using the arithmetic mean +/− 1.96SDs. Male and female results were examined using the two-sample T- test for gender differences where p<0.05 indicates a statistically significant difference. Fibrinogen data from the adolescent group (Table) were compared with 209 healthy adults (F=151; M=58: aged 21–55 years for both gender) tested in the same way.NMean (g/l)SDRef Range (g/l)Two sample test for gender difference (p)AdolescentsMale1192.660.4641.76 – 3.580.76Female1212.670.4671.76 – 3.59Total sample2402.670.4651.76 – 3.58AdultsMale582.710.6721.37 – 4.05<0.05Female1512.990.6531.68 – 4.29Total sample2092.930.6631.60 – 4.30Conclusion: Reference ranges for Clauss fibrinogen for school children aged 12–14 years (1.8–3.6g/l) determined using the Sysmex CA-1500 coagulometer differ from the reference range for the healthy adult population (1.6–4.3g/l) determined using the same analyzer and methodology. No statistically significant difference was observed between adolescent male and female cohorts in contrast to significant gender differences observed within the healthy adult population. Reference ranges described in our study show the upper limit in adolescents to be lower than in the healthy adult population. The meaningful assessment of fibrinogen as a risk factor for cardiovascular events in young people should take cognizance of the age specific reference interval. The use of an appropriate, robust reference range for young people is essential in evaluating the influence of contributory risk factors for cardiovascular disease such as diet, body mass and exercise. Assessment of haemostatic function and investigations of coagulopathies in adolescents should be undertaken with reference to age specific ranges where available. This study was approved by the LREC and informed consent was obtained from parents/guardians.

Lack of MEF2A Delta7aa mutation in Irish families with early onset ischaemic heart disease, a family based study.

BackgroundIschaemic heart disease (IHD) is a complex disease due to the combination of environmental and genetic factors. Mutations in the MEF2A gene have recently been reported in patients with IHD. In particular, a 21 base pair deletion (Δ7aa) in the MEF2A gene was identified in a family with an autosomal dominant pattern of inheritance of IHD. We investigated this region of the MEF2A gene using an Irish family-based study, where affected individuals had early-onset IHD.MethodsA total of 1494 individuals from 580 families were included (800 discordant sib-pairs and 64 parent-child trios). The Δ7aa region of the MEF2A gene was investigated based on amplicon size.ResultsThe Δ7aa mutation was not detected in any individual. Variation in the number of CAG (glutamate) and CCG (proline) residues was detected in a nearby region. However, this was not found to be associated with IHD.ConclusionThe Δ7aa mutation was not detected in any individual within the study population and is unlikely to play a significant role in the development of IHD in Ireland. Using family-based tests of association the number of tri-nucleotide repeats in a nearby region of the MEF2A gene was not associated with IHD in our study group.

Long-Term Outcome after Ischaemic Stroke/Transient Ischaemic Attack

During the first 30 days after a stroke, the case fatality is about 25% and the major cause of death is the index stroke and its sequelae. The most consistent predictor of 30-day mortality after stroke is stroke severity. Other predictors include increasing age, a history of previous stroke, cardiac failure, and a high blood glucose concentration and white blood cell count. Other less common, but important, causes of early mortality are recurrent ischaemic stroke and a coronary event. The risk of a recurrent cerebrovascular event is highest in the first month (4%) and year (12%) after a stroke and transient ischaemic attack (TIA), probably reflecting the presence of active, unstable atherosclerotic plaque. Thereafter, the risk of a recurrent cerebrovascular event falls to about 5% per year, similar to the risk of a coronary event. During years 1–5 after a TIA and ischaemic stroke, cardiovascular disease increasingly becomes the major cause of death, reflecting the generalized nature of atherothrombosis, the most common cause of the index stroke. The most robust predictor of death within 1–5 years after stroke is increasing age, closely followed by cardiac failure. Additional baseline predictors of longer-term mortality include a history of previous symptomatic atherothrombosis (TIA, ischaemic stroke, peripheral arterial disease, and early-onset ischaemic heart disease), risk factors for atherothrombosis (smoking), other heart diseases (cardiac failure, atrial fibrillation) and increasing stroke severity. Lacunar syndromes can be predictive of relative longevity. At 5 years after stroke, survival is about 40%, and about half of survivors are disabled and dependent. The most robust predictors of disability at 5 years after stroke are increasing age, stroke severity, and recurrent stroke. The most powerful predictor of early recurrent stroke (within 30 days after stroke) is an atherosclerotic ischaemic stroke caused by large-artery atherosclerosis with >50% stenosis, whereas the strongest predictor of stroke recurrence over 5 years is diabetes. Other predictors of recurrent stroke include increasing age, previous TIA, atrial fibrillation, high alcohol consumption, haemorrhagic index stroke, and hypertension at discharge. The clinical implication of these findings is that strategies for optimizing long-term outcome after TIA and stroke should be directed toward reducing the high risk of recurrent stroke and coronary events by removing/recanalizing the symptomatic atherosclerotic plaque, controlling the underlying causal vascular risk factors, and administering long-term, effective antiplatelet therapy.

Predictors of postprandial triacylglycerol response in children: the Columbia University Biomarkers Study

Predictors of postprandial lipemia have not been explored in children. Our objective was to determine whether the postprandial triacylglycerol response is associated with low HDL-cholesterol and high fasting triacylglycerol concentrations and family history of early-onset ischemic heart disease (IHD) in children. We administered a standardized fat load (52.5 g fat/m(2)) to 60 children (mean age: 14.0 y), 20 with and 40 without a family history of early-onset IHD, and to 29 mothers, all recruited from families enrolled in the Columbia University Biomarkers Study. Plasma lipid and retinyl palmitate concentrations were measured in the fasting state and 3, 6, and 8 h after the oral fat load. In children, postprandial lipemia, as indicated by the incremental area under the triacylglycerol response curve, was associated with elevated fasting triacylglycerol concentrations (>/=1.13 mmol/L; P: < 0.01), with low fasting HDL-cholesterol concentrations (</=0.91 mmol/L; P: < 0.01), and with the combination of low HDL-cholesterol and high triacylglycerol concentrations (P: < 0.05). Family history of IHD, baseline LDL-cholesterol concentration, and apolipoprotein E genotype were not associated with the postprandial triacylglycerol or retinyl palmitate response. The mothers had fasting triacylglycerol concentrations similar to those of their children but a more prolonged response with higher triacylglycerol concentrations at 6 and 8 h (P: < 0.01 and P: < 0.05, respectively). In children, a delayed postprandial triacylglycerol response to a fat load is associated with the combination of high fasting triacylglycerol and low HDL-cholesterol concentrations. Predictors of postprandial triacylglycerol concentrations may be similar in children and adults.

Association of genetic polymorphisms in the ACE, ApoE, and TGF beta genes with early onset ischemic heart disease.

The genetic factors that contribute to ischemic heart disease (IHD) are poorly understood, and it is likely that multiple genes acting independently or synergistically contribute to the risk of IHD and outcome. The genes for angiotensin-converting enzyme (ACE) and apolipoprotein E (ApoE) have been implicated independently in the risk of IHD. This study examined whether genetic polymorphisms in the ACE and ApoE genes are associated with early onset IHD. Polymorphisms in a third gene, transforming growth factor beta 2 (TGF beta 2), with a known role in wound repair and cardiac development, are also examined with respect to early onset IHD. In all, 101 patients with IHD and onset of disease before 55 years for men and 60 years for women, and 100 controls with angiographically confirmed normal coronary arteries were recruited for this study. The ACE, ApoE, and TGF beta 2 genotypes were determined by polymerase chain reaction amplification or Southern blotting and were compared with the patient's clinical and family histories. The frequency of the ACE D allele was significantly lower in the patient group (0.475) than in the control group (0.59, p = 0.03), which was attributed to a reduction in the number of patients with the DD genotype (patients: 24% DD, controls: 33% DD). Sudden cardiac death was also associated with the DD genotype. These data are consistent with the ACE D allele contributing to a fatal outcome. No association between the DD genotype and risk of myocardial infarction, presenting age, extent of vessel disease, family history, hypertension, or hypercholesterolemia was seen. Analysis of the ApoE genotype showed no association with early onset IHD. There was no evidence for a synergistic effect between the ACE and ApoE genotypes on the risk of early onset IHD. A polymorphism in the TGF beta 2 gene was rare and not associated with early onset IHD.

Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus

Objectives: To determine the prevalence of abnormalities in myocardial perfusion or function in children with systemic lupus erythematosus (SLE), and describe potential factors that may predict their development. Study design: Patients ( n = 40; 30 female) were enrolled through the Lupus Clinic at The Hospital for Sick Children between 1990 and 1992. Resting and exercise thallium myocardial perfusion scans, radionuclide angiography with multiple gated acquisition (MUGA), and resting M–mode and two–dimensional echocardiography were performed. Results: All patients were free of symptoms, and none had a history of ischemic heart disease. Their median age was 15.9 years (range 10.5 to 19.8 years) at enrollment. Abnormalities of coronary perfusion were found in 5 (16%) of 31 patients (95% confidence interval: 3%, 29%) and included a large fixed perfusion defect in 1; 5 of 27 MUGA scans showed marginally low left ventricular ejection fractions at rest, whereas all had normal exercise responses. In the group with abnormal thallium scans, three of five patients had antiphospholipid antibodies detected, and two of four had an abnormal plasma lipid profile. This group tended to have a shorter disease duration and had received a lower cumulative dose of corticosteroids; these differences were not statistically significant compared with the group with normal scans. Conclusion: Asymptomatic abnormalities of myocardial perfusion occur in children with SLE and are more common than previously suspected. Patients with these abnormalities of myocardial perfusion may be predisposed to the previously recognized early–onset ischemic heart disease seen in adults with SLE. (J Pediatr 1998;132:109–16)

Limited discriminant value of lipoprotein AI, lipoprotein Lp(a) and other lipoprotein particles in patients with and without early onset ischaemic heart disease.

To assess whether the ability of lipoprotein related variables to discriminate between individuals with or without premature clinical ischaemic heart disease (IHD) was improved using data on high density lipoprotein-lipoprotein AI (HDL-LpAI) fractions, alone or in combination with data on Lp(a). Lipid and apolipoprotein concentrations were measured in 26 middle-aged men (mean age 50.3 years) with early onset IHD and coronary artery bypass grafting prior to sampling, and in 26 matched lipaemic and 26 normolipaemic asymptomatic controls. Triglyceride and Lp(a) concentrations were higher, while HDL cholesterol and apolipoprotein A-I (apoA-I) concentrations were lower in patients than in controls. LpAI concentrations were also lower in IHD patients and were correlated with HDL and apoA-I in both IHD and control groups. Lp(a) was not correlated with any other lipid or apolipoprotein measured in either patients or controls. Univariate discriminant function analysis showed that the proportion correctly classified as patients or controls was marginally greater using LpAI concentrations as the discriminator, which was not increased in combination with Lp(a). Serum triglycerides, HDL cholesterol, apoA-I and Lp(a) alone all had similar, but weaker, discriminant power, which increased in various combinations with LpAI. LpAI particle measurement may be useful in research to define mechanisms of cardiovascular protection by HDL but the discriminating power for IHD was only marginally superior to measuring total apoA-I or Lp(a) concentrations. Little further advantage arose through combining LpAI data with other variables.

Angiographic and risk factor characteristics of subjects with early onset ischaemic heart disease.

Sixty-six consecutive patients less than 40 years of age with angiographically documented coronary artery disease and coronary heart disease took part in a study aimed at (1) identifying the presence of factors which might explain the premature onset of ischaemic heart disease, and (2) assessing the distribution and severity of the coronary artery lesions. For comparisons we have used a study of risk factors in 1832 men defined as "normals" according to a recent comprehensive examination. The findings show that the typical early onset coronary heart disease case is an overweight, heavily smoking male "blue collar" worker, with high serum levels, a marginally raised blood pressure, and a high prevalence of coronary heart disease among first degree relatives. Coronary angiography showed a preponderance of one vessel disease. In particular, left anterior descending artery lesions were common, which might have contributed to the early manifestation of disease.