Homozygosity of the TT methylenetetrahydrofolate reductase C677T genotype is an independent long-term predictor of cardiac death in patients with premature myocardial infarction.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is the main genetic modulator of homocysteine. Data suggest a potential association of homozygosity for the TT MTHFR genotype with premature myocardial infarction (MI). We explored whether TT homozygosity is associated with long-term prognosis in patients with premature ST-segment elevation MI (STEMI). METHODS: A total of 265 consecutive patients who had survived their first STEMI ≤35 years of age were followed for a median of 8 years (5-12). Primary endpoints were cardiac death and secondary endpoints were hospitalizations for acute coronary syndrome, myocardial revascularization, arrhythmic event or ischemic stroke. Serum lipids, homocysteine, folate levels were measured at baseline and all patients were also tested for the MTHFR C677T polymorphism. RESULTS: During follow-up 14 patients died (cardiac death) [5.3%] while 84 (31.7%) met the secondary endpoints. In univariate Cox regression analysis TT homozygosity predicted the occurrence of cardiac death (Hazard ratio (HR): 4.071; 95% confidence interval (CI): 1.404-11.809, p = .010) but not the occurrence of secondary endpoints (HR: 0.877; 95% CI: 0.479-1.605, p = .669). TT homozygosity remained an independent predictor of cardiac death after adjustment for conventional risk factors (i.e., sex, diabetes mellitus, hypertension, family history of premature coronary artery disease [CAD]) [HR: 4.350; 95% CI: 1.472-12.856, p = .008]. The association also remained after adjustment for left ventricular ejection fraction or the presence of significant CAD. CONCLUSIONS: Homozygosity for the TT MTHFR is an independent long-term predictor of cardiac death in patients with premature STEMI.

Prevalence of heterozygous familial hypercholesterolemia and combined hyperlipidemia phenotype in very young survivors of myocardial infarction and their association with the severity of atheromatous burden.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) and combined hyperlipidemia (CHL) phenotype are associated with premature myocardial infarction (MI). OBJECTIVE: To assess the prevalence of HeFH and CHL phenotype among young survivors of MI and compare patients' characteristics with these 2 lipid disorders. METHODS: We recruited 382 young survivors of MI (≤40 years). Fasting lipids, lipoprotein(a) [Lp(a)], apolipoprotein A-1, and apolipoprotein B (apoB) levels were determined. Using the Dutch Lipid Clinic Network (DLCN) algorithm, patients having definite or probable HeFH were identified. Patients with apoB levels >120 mg/dL and triglyceride levels >170 mg/dL (1.92 mmol/L) [>90th percentile of 326 age and sex-matched healthy controls] were classified as having CHL phenotype. Common carotid artery intima-media thickness (CCA-IMT) was measured by B-mode ultrasonography. RESULTS: Eighty-one patients (21.2%) had definite/probable HeFH and 62 (16.2%) had CHL phenotype. Twenty-three patients fulfilled the criteria for both HeFH and CHL phenotype and were removed from further comparisons. Patients with HeFH (n = 58) had higher levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, Lp(a), and apoB, whereas patients with CHL phenotype (n = 39) had higher levels of triglycerides and lower high-density lipoprotein (HDL)-cholesterol levels. The prevalence of metabolic syndrome was higher in patients with CHL phenotype compared to those with HeFH (67.0% vs 16.4%, P < .001). Patients with HeFH had more extensive coronary artery disease (3-vessel disease: 36.2% vs 12.8%, P = .011) and greater right CCA-IMT (0.67 ± 0.11 mm vs 0.56 ± 0.09 mm, P < .001) and left CCA-IMT (0.68 ± 0.10 mm vs 0.56 ± 0.08 mm, P < .001) compared to CHL phenotype patients. CONCLUSIONS: Both HeFH and CHL phenotype are common among patients with premature MI. CHL phenotype compared to HeFH is associated with less atheromatous burden in coronary and carotid arteries at the time of first MI.

Prothrombotic genetic risk factors in patients with very early ST-segment elevation myocardial infarction.

The contribution of prothrombotic genetic risk factors in the pathogenesis of premature acute myocardial infarction (MI) is controversial. We examined the prevalence of prothrombotic polymorphisms (G1691A of factor V gene [FV Leiden] and G20210A of prothrombin [FII] gene), deficiencies of natural anticoagulants (protein C, protein S and antithrombin III) and antiphospholipid syndrome (APS) in patients with early ST-segment elevation MI (STEMI). We recruited 255 consecutive patients who had survived a STEMI ≤ 35 years of age (224 men). The control group consisted of 400 healthy individuals matched with cases for age and sex. G20210A polymorphism of FII gene was more frequent in young patients than in controls (7.4 vs. 3.5%, p = 0.023). The odds ratio (OR) for STEMI for carriers versus non-carriers was 2.239 (95% CI 1.102-4.250). The adjusted OR for major cardiovascular risk factors was 2.569 (95% CI 1.086-6.074). The risk was increased by 22-fold (95% CI 9.192-66.517) when G20210A polymorphism was present in combination with smoking. There was no difference in the prevalence of FV Leiden between patients and controls (7.8 vs. 6.5%, p = 0.512). There was only one patient (0.4%) with protein C deficiency and one with APS (0.4%). G20210A polymorphism of FII gene may be associated with increased risk of premature STEMI and the risk increases substantially when smoking is present. The contribution of other prothrombotic disorders such as deficiencies of protein C, protein S and antithrombin III and APS was minimal in this cohort.

Prevalence of heterozygous familial hypercholesterolaemia and its impact on long-term prognosis in patients with very early ST-segment elevation myocardial infarction in the era of statins.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an important cause of early onset coronary artery disease. We assessed the prevalence of clinical heterozygous FH (HeFH) among patients with very early ST-segment elevation myocardial infarction (STEMI), its management and its impact on long-term prognosis in the era of widespread utilization of statins. METHODS: We recruited prospectively 320 consecutive patients who had survived their first STEMI ≤35 years of age. Using the Dutch Lipid Clinic Network algorithm patients having HeFH (possible, probable or definite) were identified. RESULTS: Sixty-five patients (20.3%) had definite/probable HeFH and 163 patients (50.9%) had possible FH. Two years after discharge among 51 patients with definite/probable HeFH and available lipid levels, 43 (84.3%) were taking statins of whom 10 (23.3%) were on high-intensity statin therapy but only 1 (2.3%) of the statin-treated patients had LDL cholesterol levels <1.8 mmol/L (70 mg/dL). After a median follow-up of 9.1 years, major adverse coronary events (MACE) occurred in 99 (38.8%) of 255 patients with available follow-up information. Definite/probable HeFH was associated with an excess risk for recurrence of MACE independently of statin use, continuation of smoking after the STEMI, hypertension, diabetes mellitus, and sex (hazard ratio = 1.615, 95% confidence interval, 1.038 to 2.512, p = 0.03). CONCLUSIONS: One out of five patients who develop STEMI ≤35 years of age has definite/probable HeFH and despite the use of statins there is a therapeutic gap and a high recurrence rate of cardiac events during long-term follow-up.

Circadian pattern of symptoms onset in patients ≤35 years presenting with ST-segment elevation acute myocardial infarction.

BACKGROUND: There are scarce data regarding the circadian pattern of symptoms onset in young patients presenting with acute myocardial infarction (AMI). We explored whether young patients with ST-segment elevation AMI exhibit a circadian variation in symptoms onset. METHODS: We recruited prospectively 256 consecutive patients who had survived their first ST-segment elevation AMI ≤35 years of age. Patients were categorized into 4 groups by 6-h intervals over 24 h. RESULTS: In 49 patients (19.1%) the clinical presentation of AMI was atypical. The symptoms onset was as follows: 00:01 to 06:00, 19.1%, 06:01 to 12:00, 32.4%; 12:01 to 18:00, 28.1%; and 18:01 to 24:00, 20.3%. There was a significant association between the time of day and the likelihood of symptoms onset (Rayleigh test, p<0.001). Between 00:01 and 06:00 the incidence of AMI onset was lower than expected and between 06:01 and 12:00 was higher (p=0.034 and p=0.011, respectively), whereas in the other 6-h period groups no difference was found between expected and observed AMI incidence (p=0.280 and p=0.131). No significant differences were found regarding clinical characteristics, i.e. traditional risk factors, reperfusion treatment of AMI, ejection fraction of left ventricle, time interval from pain onset to hospital arrival, dietary habits and physical activity, among the 6-h period groups. CONCLUSIONS: ST-segment elevation AMI in individuals ≤35 years of age follows a circadian pattern with a morning peak. This information might be useful for the prompt diagnosis and treatment of AMI in very young patients which occurs rarely and frequently with atypical clinical presentation.