Multimarker approach predicts adverse cardiovascular events in women evaluated for suspected ischemia: results from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND: Inflammatory marker and hemoglobin levels (eg biomarkers) considered separately, predict adverse events in selected populations. HYPOTHESIS: A multiple biomarker approach predicts adverse events in women referred for evaluation of ischemia. METHODS: We investigated associations between biomarkers (high sensitivity C-reactive protein, interleukin-6, serum amyloid-A, and hemoglobin levels) with adverse outcomes in women referred for coronary angiography for suspected ischemia in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE). RESULTS: Among 595 women (mean age 58 years, ejection fraction [EF] 65%, majority without coronary stenosis >or= 50%) followed for 3.6 +/- 1.8 years (mean +/- SD), those without abnormal markers had fewer events (11.6%) compared to those with 1 (18.4%), 2 (20.9%), or 3 (37%) abnormal markers (p < 0.001 for trend). Women without abnormal markers had fewer deaths (1.6%) than women with 1 (6.1%), 2 (9.1%), or 3 (17%) abnormal markers (p < 0.001 for trend). Adding low hemoglobin was associated with higher adverse event and all-cause mortality rates. In multivariate analysis, as the number of abnormal biomarkers increased risk increased. Women with 3 or 4 abnormal biomarkers were approximately 10-20 times more likely to die (p < 0.05). Biomarkers added to the predictive information provided by the Framingham Risk Score. CONCLUSIONS: Among women undergoing coronary angiography for suspected ischemia, a multibiomarker approach predicted adverse events. Biomarkers added prognostic information beyond that obtained from traditional risk factors.

Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Altered coronary reactivity is frequent in women with findings of myocardial ischemia without significant obstructive disease. This suggests a defect in coronary microvascular function. The adenosine-related component of this altered reactivity has been described in male and mixed gender populations, while the factors influencing this component of coronary reactivity in symptomatic women have received limited attention. Accordingly, the relationship between adenosine-related microvascular coronary reactivity and risk factors in symptomatic women evaluated for suspected ischemia remains uncertain. HYPOTHESIS: Abnormal coronary microvascular reactivity to adenosine is predicted by atherosclerosis risk factors in women. METHODS: As part of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated the relationship between risk factors and coronary microvascular reactivity as flow velocity reserve to intracoronary adenosine (CFVR(Ado)) in 210 women referred for angiography to evaluate suspected ischemia. RESULTS: Univariate analyses identified associations between CFVR(Ado) and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVR(Ado) yielded an R2 of only 0.18. CONCLUSIONS: Among women with suspected ischemia, risk factors account for <20% of observed variability in CFVR(Ado). Therefore, other as yet unidentified factors must primarily account for coronary microvascular reactivity to adenosine.

Complementary and alternative medicine use among individuals participating in research: implications for research and practice.

STUDY OBJECTIVES: To determine the frequency and type of complementary and alternative medicine (CAM) use among healthy volunteers participating in research, and to investigate the potential for interactions between commonly used CAM modalities and various drugs. DESIGN: Prospective evaluation. SETTING: University general clinical research center. SUBJECTS: Sixty healthy adults participating in an ongoing drug study. MEASUREMENTS AND MAIN RESULTS: The clinical study database was queried to determine the use and type of existing and newly started CAM throughout the study period. Baseline characteristics were compared between users and nonusers of CAM to identify differences between them. Potential CAM-drug interactions were classified based on curated databases and primary literature sources. Of the 60 subjects enrolled, 30 (50%) used CAM during the study. Of these, 26 (87%) were using CAM at study entry. Baseline CAM users were on average 7 years older than nonusers (p=0.03) and had high-density lipoprotein cholesterol concentrations 10 mg/dl higher than those of nonusers (p=0.04). The group using CAM had more women and nonsmokers than the other group. Several potential CAM-drug interactions were identified. CONCLUSION: Because of high rates of CAM use (50% of the subjects were using biologically based CAM) and the many potential CAM-drug interactions, CAM use should be rigorously addressed in clinical practice and research. Failure to capture this information may have clinical repercussions through pharmacokinetic and pharmacodynamic interference of clinical response and clinical trial results. Clinicians and researchers may be able to identify those most likely to use CAM by their baseline characteristics; this would help target those patients and research subjects for more thorough assessment and follow-up.

Atorvastatin effect on circulating and leukocyte-produced CD40 ligand concentrations in people with normal cholesterol levels: a pilot study.

STUDY OBJECTIVES: To investigate whether atorvastatin decreases serum or leukocyte-produced CD40 ligand (CD40L) levels and whether these effects are dependent on reduction in low-density lipoprotein cholesterol (LDL) levels in people without overt dyslipidemia. DESIGN: Prospective pilot study. SETTING: University research center. SUBJECTS: Twenty-five normocholesterolemic volunteers (mean age 32 +/- 11 yrs; 15 women, 10 men) without cardiovascular disease. INTERVENTION: After a 2-week drug-free run-in period, subjects received atorvastatin 80 mg/day orally for 16 weeks. MEASUREMENTS AND MAIN RESULTS: All lipoprotein level measurements were performed with the subject in the fasting state. The CD40L concentrations were measured by immunofluorescence detection in serum and leukocyte culture supernates after 24-hour incubation, and treatment effect was analyzed. Baseline mean +/- SD total cholesterol, LDL, high-density lipoprotein cholesterol, and triglyceride levels were 179 +/- 33, 97 +/- 29, 62 +/- 20, and 102 +/- 69 mg/dl, respectively. Mean changes in each of these levels, respectively, after 16 weeks of atorvastatin were -34%, -59%, +3%, and -23%. The median serum CD40L level was lower at 16 weeks (2.3 ng/ml, interquartile range [IQR] 1.2-5.0 ng/ml) than at baseline (3.0 ng/ml, IQR 2.1-3.7 ng/ml), but the change was not significant (p=0.24). However, atorvastatin significantly lowered CD40L produced from leukocytes by 57% (21 pg/mg of protein [IQR 10-38 pg/mg] vs 49 pg/mg [IQR 21-149 pg/mg], p=0.045). Effects were independent of reduction in cholesterol levels. CONCLUSION: Although atorvastatin did not significantly lower serum CD40L levels, significant reduction in leukocyte production was seen independent of degree of LDL reduction. These pilot data suggest a potential benefit in normocholesterolemic individuals that should be further investigated, and that leukocyte CD40L concentrations should be considered in the drug response.

CXCL5 gene polymorphisms are related to systemic concentrations and leukocyte production of epithelial neutrophil-activating peptide (ENA-78).

Data exist linking elevated epithelial neutrophil activating peptide (ENA-78) concentrations with myriad inflammatory conditions. ENA-78 is encoded by the CXCL5 gene which has recently been shown to be polymorphic in nature (rs352046 and rs425535). No functional data on these polymorphisms exist. We investigated whether CXCL5 polymorphisms are associated with differences in plasma ENA-78 concentrations or leukocyte production of ENA-78 from cultured leukocytes in relatively healthy adults. We genotyped 114 adults for the above polymorphisms. Variant alleles at both loci were highly linked (D'=1, r2=0.94). The rs352046 variant allele was associated with significantly higher ENA-78 plasma concentrations. A genotype effect was also demonstrated for this polymorphism and leukocyte production of ENA-78. Both polymorphisms were predicted to have functional consequences by in silico analyses, with the rs352046 polymorphism found to occur at a transcription factor binding site for myeloid zinc finger proteins and the rs425535 polymorphism found to be located in an exon splicing enhancer site. Our findings add to the strength of CXCL5 as candidate gene in future disease-gene and pharmacogenetic association studies.

Modulatory effects of atorvastatin on endothelial cell-derived chemokines, cytokines, and angiogenic factors.

STUDY OBJECTIVE: To investigate the immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) by determining whether atorvastatin alters the production of specific endothelium-derived immunoactive proteins and whether its treatment effects depend on its concentration and/or inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. DESIGN: In vitro study using a multiplexing method for protein measurement. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Human umbilical vein endothelial cells were cultured to approximately 80% confluence and treated with atorvastatin 1-50 microM alone or with mevalonate for 24 hours. Untreated cells served as controls. Culture-conditioned media were removed and multiplex assayed for protein content of epithelial neutrophil-activating peptide-78, interleukin-8, monocyte chemotactic protein-1, interleukin-6, interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. Atorvastatin significantly reduced the production of epithelial neutrophil-activating peptide-78, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (p<0.001 to p<0.05) in a concentration-dependent manner without affecting basal production of interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. The treatment effects of atorvastatin were reversed with concurrent mevalonate therapy. CONCLUSION: By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, atorvastatin lowered concentrations of several inflammatory molecules derived from basal-state endothelial cells in a concentration-dependent manner. The in vivo importance of these immunomodulatory effects needs further investigation.

The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: Our objective was to determine the prognostic value of estimated metabolic equivalents (METs) based on self-reported functional capacity by the Duke Activity Status Index (DASI) in symptomatic women. BACKGROUND: Functional capacity is an important component affecting the predictive value of exercise testing, yet current guidelines offer limited assistance regarding identification of functional impairment and choice of pharmacologic stress testing. METHODS: A total of 914 women underwent clinically indicated coronary angiography and completed the 12-item DASI questionnaire; a subgroup of 251 women also underwent exercise testing. Cox proportional hazards modeling was used to estimate five-year death or myocardial infarction by DASI scores. In a secondary analysis, additional events included unstable angina, heart failure, or stroke at five years. RESULTS: Average DASI-estimated functional capacity was 5.7 +/- 4.2 METs and, for exercising women, 6.0 +/- 2.6 METs. In the 914 women, event-free survival ranged from 83% to 95% in subgroups with < or =4.7 to >9.9 METs (p = 0.009); 67% of the events occurred in women scoring < or =4.7 METs (p = 0.003). Event rates were similar by exercise and DASI MET values. In women with DASI-estimated METs < or =4.7 (n = 75), ischemia occurred less (39% vs. 64%, p < 0.0001), and exercise testing results were more often indeterminate (<85% predicted maximum heart rate = 37% vs. 6%, p = 0.001) as compared to women achieving >4.7 METs. CONCLUSIONS: Among women with suspected myocardial ischemia, functional impairment estimated by the DASI correlates with indeterminate exercise test results and is associated with an adverse prognosis. Use of the DASI before exercise testing can risk stratify symptomatic women and may improve the identification of higher-risk, functionally impaired subjects that would benefit from pharmacologic stress imaging and targeted risk management.

Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.

Despite a dramatic decline in mortality over the past three decades, coronary heart disease is the leading cause of death and disability in the U.S. Importantly, recent advances in the field of cardiovascular medicine have not led to significant declines in case fatality rates for women when compared to the dramatic declines realized for men. The current review highlights gender-specific issues in ischemic heart disease presentation, evaluation, and outcomes with a special focus on the results published from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. We will present recent evidence on traditional and novel risk markers (e.g., high sensitivity C-reactive protein) as well as gender-specific differences in symptoms and diagnostic approaches. An overview of currently available diagnostic test evidence (including exercise electrocardiography and stress echocardiography and single-photon emission computed tomographic imaging) in symptomatic women will be presented as well as data using innovative imaging techniques such as magnetic resonance subendocardial perfusion, and spectroscopic imaging will also be discussed.

Impaired coronary vascular reactivity and functional capacity in women: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: We investigated the relationship between coronary vascular reactivity and functional capacity as assessed from the Duke Activity Status Index (DASI) in a cohort of women evaluated for suspected ischemia. BACKGROUND: Reduced functional capacity and impaired vascular reactivity are associated with poor prognosis, but an association between vascular reactivity and functional capacity is unknown. METHODS: A total of 190 women enrolled in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE) study had baseline clinical assessment and coronary artery flow velocity response to adenosine (CFVR(ado)). We compared these results with self-reported DASI metabolic equivalents (METs). RESULTS: Mean age was 55 +/- 11 years (range 21 to 83 years), and only 18% had coronary stenosis > or =50%. Women with a CFVR(ado) <2.5 (n = 98) had mean DASI of 15.1 +/- 13.6, compared to women (n = 92) with CFVR(ado) > or =2.5, whose mean DASI was 21.0 +/- 15.2 (p = 0.004). This relationship was maintained after adjusting for age and presence of coronary artery disease. CFVR(ado) of > or =2.5 was associated with a DASI of >20 (odds ratio 3.03, 95% confidence interval 1.56 to 5.90, p = 0.001). CONCLUSIONS: Women with reduced CFVR(ado) were significantly more likely to have reduced functional capacity. Impairment in coronary vascular function and reduced levels of activity may both play a role in the poorer prognosis observed in the WISE study women; however, the relationship between the two is still unclear.

Global inflammation predicts cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study.

BACKGROUND: Measurement of C-reactive protein (CRP), a marker of inflammation, is recommended to improve cardiovascular disease (CVD) risk stratification. However, no studies have collectively evaluated how inflammatory markers cluster empirically and relate to angiographic coronary artery disease and CVD events. METHODS: From the WISE study, 580 women with fasting plasma samples of inflammatory markers (interleukin [IL]-6, IL-18, tumor necrosis factor alpha, transforming growth factor beta, CRP, serum amyloid A [SAA], and intercellular adhesion molecules) were analyzed over a median of 4.7 years follow-up. All women were referred for coronary angiography (1996-2000) to evaluate suspected myocardial ischemia. RESULTS: In factor analysis, a "proinflammation" factor (cluster) loaded on IL-6, CRP, and SAA (r = 0.63-0.87); a "proinflammation and anti-inflammation" cluster loaded on IL-18 and tumor necrosis factor alpha (r = 0.72, 0.77); and an "immunosuppressive" factor loaded singly on transforming growth factor beta (r = 0.96). No cluster was independently associated with angiographic coronary artery disease. However, quartile increases of the "proinflammation" cluster (IL-6, CRP, and SAA) yielded death rates of 2.6%, 7.2%, 13.1%, 26.6%, respectively (P < .0001). Women with > or = 2 of 3 proinflammation markers in the upper quartile had an adjusted relative risk of death of 4.21 (95% CI 1.91-9.25), a higher conferred risk than any single marker alone, all of which were roughly equally predictive. CONCLUSIONS: Although IL-6, CRP, and SAA all predict CVD risk in women, development of global measures of inflammation and simply counting the number of markers with high levels improve CVD risk stratification. In addition, results indicate that the adverse impact of inflammation may be largely through other mechanisms than promotion of atherogenesis (ie, destabilization of vulnerable plaques).

Global differences in blood pressure control and clinical outcomes in the INternational VErapamil SR-Trandolapril STudy (INVEST).

BACKGROUND: The INternational VErapamil SR-Trandolapril Study (INVEST), a prospective, randomized, antihypertensive trial, found that two different medication regimens produced similar blood pressure (BP) control with equivalent cardiovascular (CV) outcomes (death from any cause, nonfatal myocardial infarction [MI], or nonfatal stroke). HYPOTHESIS: The study was undertaken to investigate whether differences exist by global regions in demographics, treatment, and outcomes in the INVEST trial. METHODS: Data were analyzed for 22,576 patients with stable coronary artery disease (CAD) enrolled in INVEST. We investigated differences in patient characteristics, treatment approaches, BP control, and clinical outcomes by creating three global regions based on geographical location: Northern Americas (NA), Caribbean (CA), and Eurasia (EA). RESULTS: We observed significant regional differences in patient characteristics, treatment patterns, BP control, and CV outcomes. At baseline, patients from NA were older and had greater body mass index, higher rates of diabetes, peripheral vascular disease, and coronary revascularization, but lower rates of MI or left ventricular hypertrophy than patients in CA and EA. At 24 months, there were regional differences in both study and nonstudy antihypertensive drug use. Despite having higher mean baseline BP, patients from CA and EA achieved lower mean systolic BP throughout study follow-up. Furthermore, patients from both CA and EA had lower rates of all-cause mortality, fatal or nonfatal MI, fatal or nonfatal stroke, and newly diagnosed diabetes than patients from NA. CONCLUSIONS: In INVEST, regional differences in medication utilization, BP control, and CV outcomes were identified. These disparities warrant further investigation to define appropriate care for patients with hypertension and stable CAD from an international public health perspective.

Relationship of physical fitness vs body mass index with coronary artery disease and cardiovascular events in women.

CONTEXT: Individual contributions of obesity and physical fitness (physical activity and functional capacity) to risk of coronary heart disease in women remain unclear. OBJECTIVE: To investigate the relationships of measures of obesity (body mass index [BMI], waist circumference, waist-hip ratio, and waist-height ratio) and physical fitness (self-reported Duke Activity Status Index [DASI] and Postmenopausal Estrogen-Progestin Intervention questionnaire [PEPI-Q] scores) with coronary artery disease (CAD) risk factors, angiographic CAD, and adverse cardiovascular (CV) events in women evaluated for suspected myocardial ischemia. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) is a multicenter prospective cohort study. From 1996-2000, 936 women were enrolled at 4 US academic medical centers at the time of clinically indicated coronary angiography and then assessed (mean follow-up, 3.9 [SD, 1.8] years) for adverse outcomes. MAIN OUTCOME MEASURES: Prevalence of obstructive CAD (any angiographic stenosis >or=50%) and incidence of adverse CV events (all-cause death or hospitalization for nonfatal myocardial infarction, stroke, congestive heart failure, unstable angina, or other vascular events) during follow-up. RESULTS: Of 906 women (mean age, 58 [SD, 12] years) with complete data, 19% were of nonwhite race, 76% were overweight (BMI >or=25), 70% had low functional capacity (DASI scores <25, equivalent to

Hemoglobin level is an independent predictor for adverse cardiovascular outcomes in women undergoing evaluation for chest pain: results from the National Heart, Lung, and Blood Institute Women's Ischemia Syndrome Evaluation Study.

OBJECTIVES: This study was designed to investigate the relationship between hemoglobin level (Hgb) and adverse cardiovascular outcomes in women with suspected ischemia. BACKGROUND: Low Hgb levels correlate with increased cardiovascular morbidity and mortality in patients presenting with acute myocardial infarction (MI) or congestive heart failure (CHF). However, the prognostic significance of Hgb in women with suspected ischemia is unclear. METHODS: As part of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE), we prospectively studied 936 women referred for coronary angiography to evaluate suspected ischemia. We compared Hgb levels with cardiovascular risk factors, core lab interpreted angiograms, inflammatory markers, and adverse cardiovascular outcomes. RESULTS: Of women enrolled, 864 (mean age 58.4 +/-11.6 years) had complete Hgb, angiogram, and follow-up (mean 3.3 +/- 1.7 years) data. The mean Hgb was 12.9 g/dl (range 7.7 to 16.4 g/dl) and 184 women (21%) were anemic (Hgb <12 g/dl). Anemic women had higher creatinine and were more likely to be nonwhite and have a history of diabetes, hypertension, and CHF (p < 0.05). However, we found no difference in EF or severity of coronary artery disease. Anemic women had a higher risk of death from any cause (10.3% vs. 5.4%; p = 0.02) and total adverse outcomes (26% vs. 16%, p < 0.01). In a multivariable model, decreasing Hgb was associated with significantly higher risk of adverse outcomes (hazard ratio = 1.20, p = 0.002). Also, anemic women had shorter survival time free of adverse outcome (p < 0.001). CONCLUSIONS: Our findings extend previous reports, linking lower hemoglobin levels with higher risk for adverse cardiovascular outcomes, to women evaluated for suspected ischemia in the absence of acute MI or CHF.

Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Coronary vascular dysfunction has been linked to atherosclerosis and adverse cardiovascular outcomes in men, but these relationships have not been firmly established in women. METHODS AND RESULTS: As part of the Women's Ischemia Syndrome Evaluation (WISE) sponsored by the National Heart, Lung, and Blood Institute, 163 women referred for clinically indicated coronary angiography underwent coronary reactivity assessment with quantitative coronary angiography and intracoronary Doppler flow before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin and were then followed up for clinical outcomes. History of hypertension was present in 61%, dyslipidemia in 54%, diabetes in 26%, and current tobacco use in 21% of women enrolled. Seventy-five percent had no or only mild epicardial coronary artery disease (CAD). Over a median follow-up of 48 months, events occurred in 58 women. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area (DeltaCSA) in response to acetylcholine (P=0.0006) and nitroglycerin (P=0.04). In addition, women with abnormal coronary dilator response to acetylcholine had less time free from cardiovascular events (P=0.004). In multivariable analysis, after controlling for age, hypertension, diabetes, dyslipidemia, tobacco use, and CAD severity, %DeltaCSA with acetylcholine (P=0.001) independently predicted events. When the outcome was restricted to only death, myocardial infarction, congestive heart failure, and stroke, %DeltaCSA with acetylcholine remained a significant predictor (P=0.006). CONCLUSIONS: In women in this study, impaired coronary vasomotor response to acetylcholine was independently linked to adverse cardiovascular outcomes regardless of CAD severity.

Hyperhomocysteinemia in patients with heart failure referred for cardiac transplantation: preliminary observations.

BACKGROUND: Hyperhomocysteinemia is becoming recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with heart failure. HYPOTHESIS: The purpose of this study was to examine the prevalence of hyperhomocysteinemia in patients with severe heart failure and to correlate serum homocysteine levels with factors that may affect homocysteine metabolism. METHODS: Serum homocysteine levels were measured at the time of cardiac transplant evaluation in 89 consecutive patients with severe heart failure. Homocysteine levels for patients with ischemic cardiomyopathy (ICM) were compared with levels obtained in patients with nonischemic cardiomyopathy (NICM), and homocysteine levels were correlated with demographic and hemodynamic parameters as well as functional status. RESULTS: The mean plasma homocysteine level was increased (14.3 +/- 5.3 micromol/l, normal <9.0 micromol/l) and was equivalent between patients with ICM versus NICM (14.7 +/- 5.8 micromol/l vs. 13.8 +/- 4.5 micromol/l, p = 0.44). Elevated homocysteine levels were seen in a large proportion (89%) of patients and were equally common to patients with NICM (94%) and ICM (85%). Serum homocysteine levels correlated with serum creatinine (r = 0.51, p < 0.001), with a history of diabetes (p = 0.028), and with a history of peripheral vascular disease (p = 0.045). Only 6% of patients were receiving folic acid therapy at the time of transplant referral. CONCLUSION: Hyperhomocysteinemia is common in patients with severe heart failure, and plasma homocysteine levels are uniformly elevated regardless of the etiology of heart failure. Elevated plasma homocysteine levels are likely a consequence of heart failure-related renal insufficiency.