Homocysteine and the Mortality of Critically Ill Patients: A Meta-Analysis.

Prevalence of hyperhomocysteinemia (HHcy) is high in critically ill patients. However, the association between serum homocysteine level and outcomes of the critically ill patients remains unknown. We performed a meta-analysis of cohort studies to comprehensively evaluate the above association. Relevant cohort studies were identified by search of electronic databases including PubMed, Embase, Web of Science, Wanfang, and CNKI from the inception of the databases to February 5, 2022. A randomized-effect model incorporating the possible between-study heterogeneity was used to pool the results. Overall, 16 cohorts with 1663 critically ill patients who were admitted to the intensive care unit (ICU) were involved in the meta-analysis. Pooled results showed that compared to non-survivors of the critical illnesses, survivors had significantly lower serum level of Hcy at ICU admission [mean difference (MD): -3.42 µmol/l, 95% confidence interval (CI): -5.89 to 0.94, p=0.007; I2=86%]. Subgroup analysis showed that the difference of Hcy between survivors and non-survivors was significant in Asian patients (MD: -8.17 µmol/l, p<0.001), but not in non-Asians (MD: 0.30 µmol/l, p=0.62; p for subgroup difference<0.001). Moreover, meta-analysis with seven cohorts, all including Chinese patients, showed that HHcy at ICU admission was independently associated with a higher risk of all-cause mortality in critically ill patients (odds ratio: 2.99, 95% CI: 2.26 to 3.97, p<0.001; I2=69%). A higher serum level of Hcy at ICU admission may be associated with an increased risk of all-cause mortality in critically ill patients, particularly in the Chinese population.

The outcomes of acute myocardial infarction patients comorbidity with hypertension and hyperhomocysteinemia.

This study investigated the outcomes and major adverse cardiovascular events (MACEs) incurred by acute myocardial infarction (AMI) patients comorbiding with hypertension and hyperhomocysteinemia (HHcy) during hospitalization and 1-year follow-up. 648 consecutive AMI patients were divided into four categories: (1) hypertension with Hcy ≥ 15 µmol/L; (2) hypertension with Hcy < 15 µmol/L; (3) no-hypertension with Hcy ≥ 15 µmol/L; (4) no-hypertension with Hcy < 15 µmol/L. Information taken from these case files included gender, past medical history, vital signs, laboratory examination, electrocardiogram, coronary angiography, cardiac ultrasound, and medicine treatment. The primary endpoints were duration of coronary care units (CCU) stay, duration of in-hospital stay, and MACEs during follow-up. Our data show that hypertension and HHcy have a synergistic effect in AMI patients, AMI comorbiding with hypertension and HHcy patients had more severe multi-coronary artery disease and more frequent non-culprit coronary lesions complete clogging, had a higher prevalence of pro-brain natriuretic peptide, and significant decreases in the left ventricular ejection fraction. These patients had significant increases in the duration of CCU stay and in-hospital stay, had significant increase in the rate of MACEs, had significant decreases in the survival rate during follow-up.

Association of Elevated Plasma Homocysteine Level with Restenosis and Clinical Outcomes After Percutaneous Coronary Interventions: a Systemic Review and Meta-analysis.

PURPOSE: We conducted this systemic review and meta-analysis to investigate the association between elevated plasma homocysteine (Hcy) levels and recurrent restenosis and clinical outcomes after percutaneous coronary intervention (PCI). METHODS: PubMed, EMBASE, and Web of Science were systematically searched prior to May 2018. Studies evaluating the association between plasma Hcy levels and the occurrence of restenosis, major adverse cardiac events (MACE), all-cause mortality, cardiac death, non-fatal myocardial infarction (MI), and target lesion revascularization were identified. RESULTS: A total of 19 articles with 4340 participants were identified. Higher Hcy levels were not associated with an increased risk of restenosis (relative risk (RR) = 1.10, 95% CI 0.90-1.33). Hcy levels in the restenosis group were not significantly higher than in the non-restenosis group (weighted mean difference = 0.70, 95% CI - 0.23-1.63). Subgroup analysis revealed that higher Hcy levels were not associated with restenosis after stenting but appeared to increase the risk of restenosis after angioplasty. Elevated Hcy levels increased the risk of all-cause mortality by an average of 3.19-fold (RR = 3.19, 95% CI 1.90-5.34, P = 0.000), the risk of MACE by 1.51-fold (RR = 1.51, 95% CI 1.23-1.85, P = 0.000), and the risk of cardiac death by 2.76-fold (RR = 2.76, 95% CI 1.44-5.32, P = 0.000) but appeared not to increase the risk of non-fatal MI (RR = 1.36, 95% CI 0.89-2.09). CONCLUSIONS: Our meta-analysis suggests that although there is no clear association between higher Hcy levels and restenosis following stent implantation, higher Hcy levels appeared to increase the risk of restenosis after coronary angioplasty and also increased the risk of all-cause mortality, MACE, and cardiac death after PCI. REGISTRATION DETAILS: The protocol of this meta-analysis was registered on PROSPERO (CRD42018096466). ( http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018096466 ).

Dietary diversity no longer offsets the mortality risk of hyperhomocysteinaemia in older adults with diabetes: a prospective cohort study.

BACKGROUND AND OBJECTIVE: The increased mortality risk of hyperhomocysteinaemia in diabetes may be mitigated by dietary quality. METHODS AND STUDY DESIGN: The Nutrition and Health Survey in Taiwan of 1999-2000 for elders formed this prospective cohort. Baseline health status, diet and anthropometry were documented and plasma homocysteine and biomarkers for B vitamins measured. Participants without diabetes (n=985) were referent for those who had diabetes or developed diabetes until 2006 (n=427). The effect of homocysteine on mortality risk during 1999-2008 was evaluated. RESULTS: Men, smokers and those with poorer physical function had higher homocysteine, but less so with diabetes. Diabetes incidence was unrelated to homocysteine. In hyperhomocysteinaemia (>=15 vs <15 µmol/L), those with diabetes had an adjusted hazard ratio (HR) (95% CI) for mortality of 1.71 (1.18-2.46); p for interaction between homocysteine and diabetes was 0.005. Without diabetes, but with hyperhomocysteinaemia and a low dietary diversity score (DDS <=4 of 6), where the joint mortality hazard for the greater DDS, (>4) and lower homocysteine (<15) was referent, the HR was 1.80 (1.27-2.54) with significant interaction (p=0.008); by contrast, there was no joint effect with diabetes. The contribution of DDS to mortality mitigation in hyperhomocysteinaemia could not be explained by B group vitamins, even though plasma folate was low in hyperhomocysteinaemic participants. With hyperhomocysteinaemia, heart failure was a major cause of death. CONCLUSIONS: In non-diabetic hyperhomocysteinaemia, a more diverse diet increases survival prospects independent of B group vitamins, but not in hyperhomocysteinaemic diabetes where the cardiomyopathy may be less responsive.

Homocysteinemia and early outcome of acute ischemic stroke in elderly patients.

OBJECTIVES: Plasma total homocysteine (tHcy) is a risk factor for ischemic stroke (IS) but its relationship with IS outcome is uncertain. Moreover, previous studies underrepresented older IS patients, although risk of both hyperhomocysteinemia and IS increases with age. We investigated whether, in elderly patients with acute IS, tHcy measured on admission to the Stroke Unit (SU) is an independent predictor of SU discharge outcomes. MATERIALS AND METHODS: Data are for 644 consecutive patients aged 80.3 ± 8.7 years, admitted to an Italian SU with diagnosis of acute IS. Plasma tHcy was measured on SU admission. Investigated outcomes included mortality during SU stay and poor functional status (modified Rankin Scale score ≥3) at SU discharge for survivors. The association of plasma tHcy with the study outcomes was assessed using Odds Ratios (OR) and their corresponding 95% confidence intervals (95%CI) from logistic regression models adjusted for demographics, pre-stroke features, IS severity, and laboratory data on SU admission (serum C-reactive protein, serum albumin, and renal function). RESULTS: Median plasma tHcy was 16.7 µmol/L (interquartile range, 13.0-23.3 µmol/L). Outcome incidence was 5.3% for mortality and 49.7% for poor functional status. Plasma tHcy was unrelated to mortality in both univariate and multivariable-adjusted analyses. Conversely, plasma tHcy was associated with poor functional status of survivors in univariate analyses (P = 0.014). Multivariable-adjusted analyses showed that, compared to normal homocysteinemia (tHcy <16 µmol/L), risk of being discharged with poor functional status significantly increased for moderate (tHcy ≥30 mol/L) but not mild (16.0-29.9 µmol/L) hyperhomocysteinemia. CONCLUSIONS: In elderly patients with acute IS, high admission plasma tHcy is unrelated to mortality during SU stay but is an independent predictor of poor functional status at SU discharge in survivors. The association, however, is limited to patients with moderate hyperhomocysteinemia.

Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial.

INTRODUCTION: Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old, and is associated with elevated arterial stiffness in this age group. Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes, we aimed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients. METHODS: The B-PROOF study is a double-blind, randomized controlled trial, including 2919 elderly aged at least 65 years, with hyperhomocysteinemia (12-50  µmol/l), treated with B-vitamins (500  µg vitamin B12 and 400  µg folic acid) or placebo for 2 years. In a subgroup (n = 569), the effect of B-vitamins on pulse wave velocity (PWV) was investigated as a measurement of arterial stiffness. To measure atherosclerosis, carotid intima-media thickness (IMT) measures had been used. Incidents of cardiovascular and cerebrovascular events were determined via structured questionnaires, and blood pressure was also measured. RESULTS: Compared to placebo, B-vitamin supplementation lowered serum homocysteine by 3.6  µmol/l (P < 0.001). Analysis of covariance showed no effect of supplementation on PWV levels, and this was not different for patients without increased arterial stiffness at baseline. Furthermore, no effect on carotid IMT was observed. DISCUSSION: Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT. Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes.

Homocysteine, frailty, and all-cause mortality in older men: the health in men study.

BACKGROUND: Frailty and hyperhomocysteinemia are common in the older population. The researchers' objectives were to determine whether elevated homocysteine (tHcy) is associated with frailty and mortality. METHODS: The researchers conducted a prospective cohort study. tHcy was measured by immunoassay in 4,248 community-dwelling men aged 70-88 years. Frailty was assessed with the Fatigue, Resistance, Ambulation, Illness and Loss of weight (FRAIL) scale. Mortality was determined from the death registry. RESULTS: At baseline, 1,117 men (26.3%) had high tHcy (≥15 µmol/L) and 685 (16.2%) were frail (ie, having three or more deficits in the FRAIL scale). There were 749 deaths during a follow-up duration of 5.1±1.3 years. In cross-sectional analysis, high tHcy was associated with increased prevalent frailty (odds ratio 1.49, 95% CI 1.22-1.81) after adjusting for confounding factors. After a period of 5.3±0.8 years, the longitudinal relationship between high tHcy and frailty was weakened in multivariate analysis (hazards ratio 1.25, 95% CI 0.95-1.65). When assessing the relationship between tHcy and incident frailty, the odds of being frail at follow-up for men with high tHcy and having zero deficit at baseline (ie, FRAIL scale = 0) were 1.59 (95% CI 0.88-2.89) in adjusted analysis. High tHcy also predicted all-cause mortality (hazards ratio 1.25, 95% CI 1.06-1.48) after adjusting for frailty and other covariates. CONCLUSIONS: Hyperhomocysteinemia is associated with the prevalence of frailty. It is also predictive of all-cause mortality, independent of frailty. The results suggest that the association between tHcy and mortality is largely not mediated through the occurrence of frailty.

The influence of thrombophilia on the long-term survival of patients with a history of venous thromboembolism.

Data on the long-term survival following venous thromboembolism (VTE) are rare, and the influence of thrombophilia has not been evaluated thus far. Our aim was to assess thrombophilia-parameters as predictors for long-term survival of patients with VTE. Overall, 1,905 out-patients (99 with antithrombin-, protein C or protein S deficiency, 517 with factor V Leiden, 381 with elevated factor VIII and 160 with elevated homocysteine levels, of these 202 had a combination and 961 had none of these risk factors) were included in the study between September 1, 1994 and December 31, 2007. Retrospective survival analysis showed that a total of 78 patients (4.1%) had died during the analysis period, among those four of definite or possible pulmonary embolism and four of bleeding. In multivariable analysis including age and sex an association with increased mortality was found for hyperhomocysteinemia (hazard ratio 2.0 [1.1.-3.5]) whereas this was not the case for all other investigated parameters. We conclude that the classical hereditary thrombophilia risk factors did not have an impact on the long-term survival of patients with a history of VTE. Thus our study supports the current concept that thrombophilia should not be a determinant for decision on long term anticoagulation. However, hyperhomocysteinaemia, known as a risk factor for recurrent VTE and arterial disease, might impact survival.

The effects of normalizing hyperhomocysteinemia on clinical and operative outcomes in patients with critical limb ischemia.

PURPOSE: To assess the outcome of patients with medically treated hyperhomocysteinemia (HHC) requiring intervention for critical limb ischemia (CLI). METHODS: A parallel observational study was conducted to compare the clinical and revascularization outcomes of CLI patients who received standardized treatment for HHC preoperatively (folic acid and vitamin B12) vs. contemporaneous patients with normal homocysteine levels. The threshold for HHC diagnosis was 13.0 µmol/L. From 2009 to 2011, 169 patients underwent revascularization procedures for CLI. Of these, all 66 patients (40 men; mean age 69.6 ± 11.2 years) with HHC (mean 17.3 µmol/L, range 13.5-34.9) were treated to normalize the homocysteine level prior to lower limb revascularization. The remaining 103 patients (58 men; mean age 72.7±8.1 years) had normal homocysteine levels (8.2 µmol/L, range 5-12.3) before revascularization. The primary endpoint was symptomatic and hemodynamic improvement in the treated HHC group. The secondary endpoints were all-cause survival, binary restenosis, reintervention, amputation-free survival, and major adverse events. The treated HHC cohort was compared to an age/sex-matched historical group of patients with untreated HHC from 2002 to 2006 before HHC pretreatment became routine. All interventions (endovascular, hybrid, and open) were performed by the same surgeon, and the groups were evenly matched. RESULTS: Patients with HHC were treated for a mean 12.2 days, which significantly reduced their mean homocysteine level after 3 weeks to 10.1 µmol/L (range 6.2-14.4, p<0.05). After revascularization, immediate clinical improvement was similar between normal homocysteine and medically corrected HHC groups. There was no significant difference in time to binary restenosis (p=0.822). Secondary endpoints and all-cause mortality were similar. Multivariate logistic regression showed that untreated HHC was a significant factor for graft occlusion and limb loss (p<0.0001), but medically corrected HHC was no longer predictive of adverse operative outcome. CONCLUSION: Patients with medically corrected HHC have similar outcomes compared to those with normal homocysteine levels. Thus, aggressively treating HHC with folic acid and vitamin B12 may help enhance the clinical outcome of CLI patients undergoing revascularization.

Low and high homocysteine are associated with mortality independent of B group vitamins but interactive with cognitive status in a free-living elderly cohort.

Hyperhomocysteinemia and cognitive impairment both predict mortality and partly because of dietary associations. We have hypothesized that for, nutritional reasons, homocysteine and cognition may act jointly to determine elder survival. In a Nutrition and Health Survey in Taiwan (1999-2000), some 1412 representative elderly were followed up for mortality up to 10 years. Cognition was assessed by the Short Portable Mental Status Questionnaire. Food and B vitamin intakes with their biomarkers, and plasma homocysteine, were measured at baseline. The possible effects of cognition on homocysteine-associated mortality were ascertained with Cox proportional-hazards models. Homocysteine was higher in those who were older, male, and single, consumed less fish and tea, and with alcohol and smoking. In models adjusted for these variables, when homocysteine exceeded 14.5 µmol/L, mortality was 1.80-fold more than when <9.3 µmol/L (hazard ratio [HR], 1.80; 95% confidence interval [95% CI], 1.20-2.71). P for trend was 0.002 and interactive with sex (P < .002). However, these homocysteine-mortality associations were dependent on cognition (P = .03); adjustment for food intake or nutrient status made little difference. Homocysteine did not predict cognitive impairment (adjusted OR, 1.40; 95% CI = 0.50-3.93). Vitamins B(1), B(2), and B(6) accounted somewhat for cognitive impairment. Cognition predicted mortality, fully adjusted for available covariates and also for homocysteine (HR, 3.66; 95% CI, 1.64-8.20) but interactively with homocysteine. Thus, the B-group vitamin insufficiency and cognitive impairment associations with premature mortality are confirmed. Yet cognition is inter-related with homocysteine in its association with survival in ways not detectably altered by foods or food-derived vitamins.

Homocysteine concentration and the risk of death in the adult Polish population.

BACKGROUND: Although there is a considerable epidemiologic evidence for a relation between homocysteine (Hcy) level and cardiovascular disease (CVD). The role of Hcy as a causal risk factor remains controversial. AIM: To determine associations between Hcy level and all-cause and cardiovascular mortality in general population of Poland. METHODS: Within the frame of the National Multicenter Health Survey (WOBASZ), a representative sample of whole Polish population aged 20-74 was screened in years 2003-2005 and prospectively followed up until 2009. Baseline determinations, among other classical risk factors, included Hcy level in 7165 responders, performed by an immunoenzymatic method using IMMULITE 1 analyser and DPC reagents. Survival rates were followed up until 2009 and average follow up time was 5.4 years. RESULTS: During the 38,818.9 person-years of follow-up there were 270 deaths including 108 due to CVD, 37 due to coronary heart disease and 21 due to stroke. The relative risk of all-cause and CVD mortality was significantly higher in the highest (> 10.51 µmol/L) compared to the lowest (< 8.20 µmol/L) Hcy tercile in crude and multivariable proportional hazards models adjusted for sex, age, smoking status, hypertension, body mass index, total cholesterol, glucose and high sensitivity-C-reactive protein. Hazards ratios (95% confidence intervals) were as follows: all-cause mortality HR (95% CI): crude = 4.528 (2.947-6.154), multivariable-adjusted = 1.766 (1.197-2.605), CVD mortality crude = 4.322 (2.426-7.700), multivariable- -adjusted = 1.937 (1.051-3.569). CONCLUSIONS: In Polish adult population Hcy concentration is independently associated with all-cause and CVD mortality.

Relative importance of risk factors for coronary heart disease--the Hordaland Homocysteine study.

OBJECTIVES: The aim was to rank coronary heart disease (CHD) risk factors according to their importance in predicting CHD morbidity and mortality using a scale-independent statistical approach. DESIGN: We studied 15 515 community-dwelling adults in a population-based cohort established during 1992-93 in Western Norway. Participants were 40-42 and 65-67 years old at baseline and were followed through 2006. Endpoints were non-fatal/fatal acute myocardial infarction (AMI) and CHD death. Each factor was rank transformed and scaled to the range 0-5 before estimation of Cox models. Hazard ratios (HR) may thus be interpreted as HR per quintile increment for each factor, and the magnitude of the HR was used to rank the risk factors according to strength. RESULTS: Total cholesterol and triglycerides were important risk factors for both CHD death and non-fatal/fatal AMI only in the middle-aged group. Risk factors were generally stronger in the middle-aged, except total homocysteine which was significantly associated with CHD death in the oldest group only. The only significant difference between men and women was found for single living which was an important risk factor for non-fatal/fatal AMI in middle-aged women but not in middle-aged men. CONCLUSIONS: We have demonstrated a simple method for direct and scale-independent comparison of the strength of both categorical and continuous risk factors. The importance of individual risk factors differed substantially between the two age groups.

Serum homocysteine and folate but not vitamin B12 are predictors of CHD mortality in older adults.

AIMS: The associations of serum levels of homocysteine (tHcy), vitamin B(12), and folate with risk of all-cause and coronary heat disease (CHD) mortality is controversial, and the evidence in older adults is limited. The aim of this study was to examine whether serum folate, vitamin B(12), and tHcy independently predict risk of CHD-related and all-cause mortality in older adults. METHODS AND RESULTS: Serum concentrations of folate, vitamin B(12), and tHcy were determined from blood samples obtained from 3010 Blue Mountains Eye Study participants (1997-99), aged ≥55 years. CHD and all-cause mortality was confirmed using the Australian National Death Index. RESULTS: Persons in the highest quartile of serum tHcy had increased risk of CHD mortality compared to those in the lowest quartile (multivariable-adjusted hazard ratio, HR, 2.45, 95% CI 1.30-4.62). A significant continuous association was observed between serum tHcy and CHD mortality (HR per SD ( = 4.8 µmol/l) increase in serum tHcy 1.25, 95% CI 1.08-1.45), after multivariable-adjustment. A significant association between folate deficiency and CHD-mortality was found (multivariable-adjusted HR 1.53, 95% CI 1.01-2.29). Hyperhomocysteinaemia (>15 µmol/l) was a significant predictor of all-cause mortality (multivariable-adjusted HR 1.47, 95% CI 1.18-1.83). A significant interaction was observed between hyperhomocysteinaemia and folate deficiency for all-cause and CHD mortality (p for interaction = 0.03 and p for interaction = 0.05, respectively). CONCLUSION: Serum tHcy and folate were independent predictors of CHD and all-cause mortality, while vitamin B(12) was not associated. As raised tHcy levels and folate deficiency are associated with poorer lifestyle, changes to a more healthful lifestyle among older adults may minimize the adverse vascular effects of elevated tHcy.

Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial.

BACKGROUND: Kidney transplant recipients, like other patients with chronic kidney disease, experience excess risk of cardiovascular disease and elevated total homocysteine concentrations. Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease. The impact of lowering total homocysteine levels in kidney transplant recipients is unknown. METHODS AND RESULTS: In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome (myocardial infarction, stroke, cardiovascular disease death, resuscitated sudden death, coronary artery or renal artery revascularization, lower-extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n=547 total events; hazards ratio [95 confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin. CONCLUSIONS: Treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level.

Effect of anemia and hyperhomocysteinemia on mortality of patients on hemodialysis.

INTRODUCTION: Anemia and hyperhomocysteinemia are risk factor of mortality of patients on dialysis. This study was conducted to assess the relationship of hemoglobin and homocysteine levels and mortality of patients on hemodialysis. MATERIALS AND METHODS: Fifty patients on hemodialysis and 20 healthy individuals were enrolled in the study. Blood samples were drawn for measurement of hematological parameters, serum iron, serum ferritin, transferrin saturation, and homocysteine levels. The patients were followed up for 1 year to determine the mortality rate and evaluate its association with anemia and hyperhomocysteinemia. RESULTS: The majority the patients (54%) were not on erythropoietin therapy. Forty-three patients (86%) were anemic (hemoglobin < 11 g/dL). Serum ferritin was high (> 500 ng/mL) in 33 patients (66%). Mortality was 28% in 1 year (33% in anemic patients versus no death among patients with a hemoglobin level greater than 11 g/dL). The relative risk of mortality was increased by 1.58 with every 1 g/dL decrease in hemoglobin level. All of the patients had a high homocysteine level, and a significant difference was observed between the homocysteine levels of the patients on hemodialysis and the control group (P < .001). Hyperhomocysteinemia did not affect mortality. In multivariate Cox regression analysis, only hemoglobin level was associated with mortality. CONCLUSIONS: Almost all of our patients on hemodialysis were anemic and this condition was a risk factor of mortality. Iron stores, however, were adequate in more than half of the patients. The reason of anemia could be untreated erythropoietin deficiency. Hyperhomocysteinemia was present in the majority of the patients, but it did not independently affect mortality.

Retinal vein occlusion: evaluation of "classic" and "emerging" risk factors and treatment.

Retinal vein occlusion (RVO) is the second most common retinal vein disease and an important cause of blindness and visual morbidity. Systemic risk factors are commonly associated with RVO, while unclear it is the role of the thrombophilic and coagulation disorders. To evaluate "classic" and "emerging" risk factors, and to establish a good treatment for RVO. Fifty patients, 31 males and 19 females, with RVO were selected for our study. RVO patients were divided into two groups: those with central retinal vein occlusion (CRVO) and those with branch retinal vein occlusion (BRVO). All patients were subjected to an anamnestic investigation and were tested for thrombophilia, coagulation disorders and hyperlipidemia. Treatment and prophylaxis were evaluated. We have named "classic" the systemic risk factors associated with RVO and "emerging" those risk factors, haemostasis related, not clearly associated with RVO. RVO occurs more commonly in patients aged over 50. "Emerging" risk factors were more frequent in CRVO, "classic" in BRVO. Hyperhomocysteinemia is the most common "emerging" risk factor related to RVO. 71.4% of tested patients had hypercholesterolemia. Treatment with LMWH would appear to be safe and effective, but the small number of patients considered not allow us a definitive evaluation of its efficacy. Although our study has shown the correlation between RVO and the "emerging" risk factors, more studies are necessary to better know the real role of thrombophilic and coagulation disorders in this disease and to determine a specific protocol for the treatment and prophylaxis of RVO.

Pre-operative homocysteine levels and morbidity and mortality following cardiac surgery.

AIMS: Elevated homocysteinaemia is associated not only with an increased risk for cardiovascular disease but also for increased morbidity and mortality in patients with established coronary artery or cerebrovascular disease. Whether elevated homocysteine further increases the morbidity and mortality in patients undergoing cardiac surgery on cardiopulmonary bypass (CPB) (a prothrombotic state itself) remains less known. METHODS AND RESULTS: Accordingly, we conducted a prospective observational study with pre-operative measurement of plasma homocysteine levels in 531 consecutive patients undergoing cardiac operations on CPB. The association of pre-operative plasma homocysteine levels with post-operative morbidity and hospital mortality was evaluated. Elevated homocysteine levels (>15 micromol/L) were observed in 209 patients (39.4%), and homocysteinaemia was associated with a higher mortality and perioperative morbidity (major morbidity, low cardiac output, acute renal failure, mesenteric infarction, and thrombo-embolic events). Even after accounting for the differences in baseline clinical features, EuroSCORE, and CPB time, pre-operative homocysteine levels remained independently associated with hospital mortality [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.03-1.11], major morbidity (OR 1.04, 95% CI 1.01-1.07), low cardiac output (OR 1.04, 95% CI 1.02-1.08), mesenteric infarction (OR 1.06, 95% CI 1.01-1.11), and thrombo-embolic events (OR 1.09, 95% CI 1.04-1.13). This association of homocysteine with increased risk of morbidity and mortality was observed particularly in CABG patients. CONCLUSION: Elevated pre-operative homocysteine level is independently associated with increased morbidity and mortality, particularly in patients undergoing CABG. Specific post-operative antithrombotic strategies may be advisable in hyperhomocysteinaemic patients.

Methionine loading does not enhance the predictive value of homocysteine serum testing for all-cause mortality or major adverse cardiac events.

BACKGROUND: Hyperhomocysteinaemia is independently associated with atherosclerotic disease. Methionine loading could improve the predictive value of hyperhomocysteinaemia by detecting mild disturbances in enzyme activity. The aims of this study were to determine the beneficial effect of methionine loading on the predictive value of homocysteine testing for long-term mortality and major adverse cardiac events (MACE). METHODS: In an observational study, 1122 patients with suspected or known vascular disease, underwent homocysteine testing, which was measured fasting and again 6 h after methionine loading. Hyperhomocysteinaemia was defined as a fasting level > or =15 micromol/L and post-methionine loading level > or =45 micromol/L or an increase of > or =30 micromol/L above fasting levels. Primary end-points were death and MACE. Multivariate Cox regression analysis was used, adjusting for all cardiac risk factors. RESULTS: During follow up (mean 8.9 +/- 3.4 years), 98 patients died (8.7%), 86 had a MACE (7.7%), 579 patients had normal tests, 134 patients had only fasting hyperhomocysteinaemia, 226 only post-methionine hyperhomocysteinaemia and 183 patients had both. In multivariate analysis, overall survival and MACE-free survival were significantly worse for those with fasting hyperhomocysteinaemia, with hazard ratios of 1.86 (95% confidence interval (CI) 1.20-2.87) and 2.24 (95%CI 1.41-3.53), respectively. The addition of hyperhomocysteinaemia after methionine loading did not significantly increase the risk of death or MACE, with hazard ratios of 0.97 (95%CI 0.52-1.81) and 0.89 (95%CI 0.47-1.69), respectively. CONCLUSION: The presence of post-methionine hyperhomocysteinaemia did not significantly alter risk of death or MACE in patients with normal or increased fasting homocysteine levels, respectively. In conclusion, methionine loading does not improve the predictive value of homocysteine testing with regard to long-term mortality or MACE.

Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events.

Homocysteine is a risk factor for atherosclerosis in the general population, and serum homocysteine levels are almost universally elevated in chronic renal failure patients. When such patients are treated with dialysis, cardiovascular disease accounts for more than 50% of their mortality, which, in some proportion, may be pathophysiologically related to the elevated serum homocysteine levels. From April 2003 to March 2005, we conducted a 2-year, double-blind, randomized, placebo-controlled trial of 186 patients with end-stage kidney disease due to any cause, who were older than 18 years and stable on hemodialysis. Patients were assigned to receive either oral folic acid 10 mg 3 times a week immediately after every dialysis session under nurse supervision or an identical-appearing placebo for the entire study. On admission, plasma total homocysteine (tHcy) levels were above 13.9 micromol/L in 96.7% of patients (median 25.0 micromol/L, range 9.3-104.0 micromol/L). In the placebo group, tHcy levels remained elevated at 6, 12, and 24 months, while oral folate significantly decreased tHcy to a median value of 10.5 (2.8-20.3) micromol/L, (p<0.01). During the study, 38 patients (folic acid group 17 vs. placebo group 21; p=0.47) died from cardiovascular disease. Kaplan-Meier life table analysis dealing with the incidence of cardiovascular events, both fatal and nonfatal (myocardial infarction, arrhythmias, angina, heart failure, cerebrovascular accident), showed that 2 years of folic acid treatment and the lowering of the homocysteine blood levels had no effect on cardiovascular events (p=0.41; hazard ratio 1.24, 95% CI 0.74-2.10). However, the carotid artery intima-media wall thickness measured in a blinded fashion decreased from 1.94 +/- 0.59 mm to 1.67 +/- 0.38 mm (p<0.01) after 2 years of folate therapy. In this short-term study of uremic patients, 2 years of folic acid supplementation normalized the tHcy blood levels in 92.3% of patients but did not change the incidence of cardiovascular events compared with the control group. However, ultrasonography of the common carotid arteries performed at entry and 24 months later showed a significant decrease in intima-media thickness with folate supplementation. This suggests that early folate supplementation may benefit patients with chronic renal failure by preventing cardiovascular deterioration.