Evaluation of the prevalence of severe hyperhomocysteinemia in adult patients with thrombosis who underwent screening for thrombophilia.

INTRODUCTION: Treatment with B-vitamins and betaine reduces the high risk of thrombosis in patients with homocystinuria, a metabolic syndrome that is characterized by severe hyperhomocysteinemia (HHcy). In contrast, there is no clear demonstration that B-vitamins reduce the risk of thrombosis in patients with mild HHcy: for this reason, many question the clinical utility of measuring total Hcy (tHcy) in patients with thrombosis. However, thrombosis may be the first clinical manifestation of homocystinuria in patients reaching adulthood without signs and symptoms of the syndrome. AIM: 1) to measure the prevalence of severe, previously undiagnosed, HHcy among patients with thrombosis 2) to profile these patients on the basis of their characteristics. METHODS: Six Italian Thrombosis Centers completed a first questionnaire, reporting tHcy levels in patients with thrombosis who underwent thrombophilia screening, and a second questionnaire, reporting the characteristics of patients with severe HHcy (tHcy>100µmol/L). RESULTS: Of 19,678 cross-sectionally collected patients with thrombosis who underwent thrombophilia screening in the last 12.5years (median value, range 6-17), 38 had severe HHcy (0.2%). Their median age at diagnosis was 47years (range 19-83) and the median level of tHcy was 130µmol/L (range 101-262). Venous thromboembolism (71%) was more frequent than arterial thromboembolism (26%); recurrent thrombosis occurred in 42% of cases. CONCLUSIONS: Measurement of tHcy in adult patients with thrombosis may reveal the presence of severe HHcy. Since treatment of patients with severe HHcy decreases the risk of thrombosis, measurement of tHcy in patients with thrombosis may prove clinically useful.

Genotype-independent in vivo oxidative stress following a methionine loading test: maximal platelet activation in subjects with early-onset thrombosis.

BACKGROUND: Methionine ingestion (100mg/kg) identifies subjects in whom fasting total homocysteine (tHcy) may be normal but the post-methionine load (PML) tHcy is abnormally high. METHODS: In 96 subjects [54 M/42 F, 40.4 ± 12.3 yrs old; 28 with the 68 bp844 ins of the cystathionine-ß-synthase gene (CBSins+); 20 homozygotes for the C677T mutation of the methylene-tetrahydrofolate reductase gene (MTHFR++); 13 with the combination of the two, and 35 without any of them], we have evaluated in vivo oxidative stress and platelet activation, as reflected by urinary excretions of 8-iso-PGF(2α) and of 11-dehydro-TXB(2) respectively, before and after a methionine load test (PML). A history of early-onset thrombosis (18 arterial, 32 venous, 2 both) was present in 52/96 of them. RESULTS: Baseline; tHcy was highest in MTHFR++ carriers (p < 0,05); 8-iso-PGF(2α) and 11-dehydro-TXB(2) levels were independent of sex, MTHFR++ and/or CBSins + (p > 0.05). PML; The ~3-fold increase (p < 0.01 vs baseline) in tHcy reached a plateau within 6-8 hrs. Mean PML tHcy was maximal in MTHFR++ carriers (p = 0.000). 8-iso-PGF(2α) and 11-dehydro-TXB(2) increase reached a maximum within 4 hrs. 11-dehydro-TXB(2) increase was highest (p = 0.023 vs baseline) in subjects with a history of thrombosis. Baseline 11-dehydro-TXB(2) and a history of thrombosis independently predicted PML 11-dehydro-TXB(2) (ß = 0.287, p = 0.000 and ß = 0.308, p = 0.026, respectively).The PML increase in 8-iso-PGF(2α) or in 11-dehydro-TXB(2) were comparable in the different genotypes (p > 0.05). CONCLUSION: Regardless genotypes associated with moderate hyperhomocysteinemia, following a methionine loading test, in vivo oxidative stress and platelet activation occur, being the latter maximal in subjects with a history of early-onset thrombosis.

Telomere length in peripheral blood mononuclear cells is associated with folate status in men.

Human chromosomes are capped by telomeres, which consist of tandem repeats of DNA and associated proteins. The length of the telomeres is reduced with increasing cell divisions except when the enzyme telomerase is active, as in stem cells and germ cells. Telomere dysfunction has been associated with development of age-related pathologies, including cancer, cardiovascular disease, Alzheimer's disease, and Parkinson's disease. DNA damage in the telomeric region causes attrition of telomeres. Because folate provides precursors for nucleotide synthesis and thus affects the integrity of DNA, including that of the telomeric region, folate status has the potential to influence telomere length. Telomere length is epigenetically regulated by DNA methylation, which in turn could be modulated by folate status. In this study, we determined whether folate status and the 677C > T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene are associated with the telomere length of peripheral blood mononuclear cells in healthy men. The results of our study showed that plasma concentration of folate was associated with telomere length of peripheral blood mononuclear cells in a nonlinear manner. When plasma folate concentration was above the median, there was a positive relationship between folate and telomere length. In contrast, there was an inverse relationship between folate and telomere length when plasma folate concentration was below the median. The MTHFR 677C > T polymorphism was weakly associated (P = 0.065) with increased telomere length at below-median folate status. We propose that folate status influences telomere length by affecting DNA integrity and the epigenetic regulation of telomere length through DNA methylation.

Lipoprotein(a), fibrinogen and vascular mortality in an elderly northern Italian population.

BACKGROUND AND OBJECTIVES: High lipoprotein a [Lp(a)] and fibrinogen levels are suggested risk factors for coronary heart disease (CHD) and stroke morbidity and mortality. Experimental data strongly suggest that the mechanisms of atherothrombosis include an interaction between fibrinogen and Lp(a), but little clinical evidence of a synergism between these two parameters has been reported. DESIGN AND METHODS: Within the frame of a prospective population study conducted in the area of Cremona (Lombardy, Italy), 343 women and 216 men aged > or =65 years were evaluated for clinical and biochemical cardiovascular risk factors. Lp(a) levels > or =30 mg/dL were observed in 22.7% and 23.9% of men and women, respectively. Fibrinogen levels were higher in women (p<0.0001). After a median follow-up of 6.3 years 107 deaths were recorded, of which 33 were due to CHD or ischemic stroke. RESULTS: The combined incidence rate of CHD and stroke mortality increased from 10.8 (per 1000 person-years) for subjects with either Lp(a) > or =30 mg/dL or fibrinogen within the 5th quintile of the gender-specific distribution to 38.4 for subjects with both Lp(a) > or =30 mg/dL and fibrinogen within the 5th quintile. Age (p<0.0001), insulin (p<0.0002) and the combination of high Lp(a) and fibrinogen (hazard ratio=3.11, p=0.014), but not fibrinogen or Lp(a) levels in isolation, were independent predictors of CHD and stroke mortality. In a subgroup of 447 subjects in whom C-reactive protein (CRP) was measured, CRP levels were not predictive of combined CHD and stroke mortality. INTERPRETATIONS AND CONCLUSIONS: Based on these results obtained in a relatively small population of elderly subjects, the association of high Lp(a) and fibrinogen levels appears to carry an increased risk of pooled CHD and stroke mortality.

Moderate hyperhomocysteinemia and early-onset central retinal vein occlusion.

PURPOSE: To evaluate the prevalence of moderate fasting hyperhomocysteinemia (HHcy) and postmethionine load (PML) HHcy among patients with early-onset central retinal vein occlusion (CRVO). METHODS: The prevalence of fasting HHcy and that of PML HHcy were evaluated in a consecutive series of 58 patients with CRVO who were younger than 56 years of age (mean age, 40.3 years) and in 103 controls (mean age, 39.6 years). Plasma folate, vitamin B12, and pyridoxal-5'-phosphate (PLP) levels were measured in 42 patients and 67 controls. RESULTS: Mantel-Haenszel odds ratios for CRVO patients were 3.00 (95% confidence interval [CI], 0.83-10.8) for fasting HHcy, 3.50 (95% CI, 1.07-11.4) for PML HHcy, and 3.00 (1.18-7.6) for fasting HHcy and PML HHcy in subjects with normal fasting total homocysteine (tHcy) levels. Moderate HHcy was associated with reduced plasma levels of folate and PLP (P < or = 0.04). There was no significant dependence of fasting and PML tHcy levels on any traditional risk factor evaluated. CONCLUSIONS: Moderate HHcy is an independent risk factor for early-onset CRVO.

The association between hyperhomocysteinemia and ischemic stroke in patients with non-valvular atrial fibrillation.

BACKGROUND AND OBJECTIVES: Atrial fibrillation is complicated by a high rate of ischemic stroke. Previous studies have shown that an increased level of circulating total plasma homocysteine (tHcy) is an independent predictor of stroke, but it is unclear whether it is also predictive of stroke in patients with atrial fibrillation. The objective of this study was to evaluate whether increased tHcy is an independent predictor of cardio-embolic stroke in patients with non-valvular atrial fibrillation. DESIGN AND METHODS: We studied 163 consecutive patients (77 males and 86 females; mean age 72.3+/-8.8 years) with permanent (n=118) or paroxysmal (n=45) atrial fibrillation of non-valvular origin hospitalized for cardiac reasons. Ischemic stroke, documented by nuclear magnetic resonance or computerized tomography imaging, had occurred at an average of 2 years before hospitalization in 40 patients (16 males and 24 females, mean age 74.8+/-8.8 years). Fasting tHcy levels were determined by high performance liquid chromatography. RESULTS: Multivariate analysis adjusting for traditional cardiovascular risk factors, thromboembolic risk factors and predictors of tHcy (glomerular filtration rate, uric acid, gender) and fibrinogen levels (age, alcohol intake) showed that total homocysteine (OR: 1.056; for each 1 micromol/L increase, 95% C.I.: 1.00-1.12; p=0.042) and fibrinogen (OR: 1.008 for each 1 mg/dL increase; 95% C.I.: 1.00-1.014; p=0.016) were independently associated with ischemic stroke. With respect to patients in the first quartile of the tHcy distribution (4.6-7.5 micromol/L), patients in the fourth quartile of the tHcy distribution (18.7-67.1 micromol/L) had a 2.73-fold increased probability of ischemic stroke INTERPRETATION AND CONCLUSIONS: In patients with non-valvular atrial fibrillation hospitalized for cardiac reasons, increased fasting tHcy levels are independently associated with a history of ischemic stroke.