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Relationship of plasma homocysteine with the severity of chronic heart failure.

Chronic heart failure (CHF) is a major public health problem causing considerable morbidity and mortality (1-3). Prevention of CHF by identifying risk factors is therefore a major issue. Previous studies found that hypertension, smoking, diabetes mellitus, obesity, and advancing age are the most important risk factors for CHF (4). Recently, plasma homocysteine (Hcy) has been suggested as a newly recognized risk factor (5,6). However, there are no data regarding the association between Hcy and various objective as well as subjective measures of CHF. The demonstration of such relationships would help to clarify the role of hyperhomocysteinemia in CHF. We hypothesized that plasma Hcy is associated with clinical and echocardiographic signs of CHF as well as with N-terminal pro-brain natriuretic peptide (NT-proBNP), suggesting a relationship between Hcy and the severity of CHF. Accordingly, we investigated the relationships of plasma Hcy with serum NT-proBNP and clinical and echocardiographic indices of CHF in patients and in controls.

For this study, 95 patients with systolic CHF and 12 healthy persons without cardiac diseases were interviewed and examined by the same 2 experienced cardiologists, who were blinded to the study. All participants had a medical history, physical examination, venous blood sampling, 6-min walking test (6-MWT), electrocardiography, and echocardiography. Eighty-two patients underwent a cardiac catheterization according to the American Heart Association guidelines (7). Additionally, 37 patients performed a symptom-limited bicycle exercise test (Ergoline cardio-systems) with gas-exchange analysis (MedGraphics CPX/D spiroergometry system; Medical Graphics Corporation) to determine maximum oxygen uptake ([Vo.sub.2max]). Informed consent was obtained from all participants, and the study protocol was approved by the Institutional Review Board.

Nonfasting venous blood samples (plasma and serum) were drawn during the office visits and centrifuged within 45 min. Total Hcy was measured in EDTA-plasma by an HPLC application (Immundiagnostik) according to the method of Araki and Sato (8). Inter-and intraassay CVs were <5.1%. Serum NT-proBNP and cardiac troponin T were measured with commercial chemiluminescence assays on an Elecsys 2010 analyzer (Roche Diagnostics). Intra-and interassay CVs were <2.7% and <3.2%, respectively, at concentrations [greater than or equal to]175 ng/L.

Anthropometric data are provided as the mean (SD) and were compared by a Student t-test. Because Hcy and NT-proBNP were not normally distributed, we performed a logarithmic transformation before further data exploration. We then performed a Pearson correlation analysis. Hcy and NT-proBNP are influenced by renal function and age; we therefore also calculated a partial correlation controlling for age and creatinine. Calculations were done with the software package SPSS 11.0 (SPSS Inc.).

Most of the patients investigated were classified as New York Heart Association (NYHA) classes II (n = 27) and III (n = 39; Table 1). The mean age increased (P = 0.03) with increasing NYHA class [controls, 44 (10) years; NYHA class I, 51 (16) years; NYHA class II, 53 (11) years; NYHA class III, 55 (12) years; NYHA class IV, 61 (15) years]. Weight and height did not differ among the NYHA classes. As expected, physical performance decreased with increasing NYHA classes. The 6-MWT decreased from 530 (70) m in controls to 26 (82) m in NYHA class IV patients (P < 0.001). Additionally, [Vo.sub.2max] decreased from 25 (13) mL*[min.sup.-1]*[(kg body weight).sup.-1] in NYHA class I patients to 16 (4) mL*[min.sup.-1]*[(kg body weight).sup.-1] in NYHA class III patients (P = 0.026). Because symptoms were present at rest, NYHA class IV patients were excluded from spiroergometry.

Serum Hcy was lowest in controls and increased with increasing NYHA class (P = 0.002; Fig. 1A). Median Hcy concentrations in NYHA class II-IV patients were [greater than or equal to]12 [micro]mol/L, which represents the recommended cutoff of the German, Austrian, and Swiss consensus conference (9). Moreover, we observed significant negative correlations between serum Hcy and the 6-MWT (r = -0.266; P = 0.014) and [Vo.sub.2max] (r = -0.528; P < 0.001).

In addition to the associations of Hcy with clinical measures, we also observed correlations between serum Hcy and echocardiographic measures of CHF (Fig. 1, C and D). As serum Hcy increased, left ventricular end diastolic diameter (LVDD) increased and ejection fraction decreased. Partial correlation analysis controlling for age and creatinine confirmed the relationship between Hcy and LVDD (P = 0.041).

NT-proBNP increased with increasing NYHA class (P <0.001). Correlation analysis revealed a significant relationship between Hcy and NT-proBNP (Fig. 1B). Partial correlation analysis controlling for age and creatinine confirmed this association (P = 0.002).

The main finding of this study is a consistent association of plasma Hcy with clinical and echocardiographic measures of CHF as well as with NT-proBNP, indicating a relationship between Hcy and the severity of CHF. Although NYHA classification, 6-MWT, and [Vo.sub.2max] describe different domains of clinical status and each of these tests has its limitations (10-18), the overall results suggest a relevant association between Hcy and clinical status in CHF patients. Our data show that this relationship can be observed even at moderately increased Hcy concentrations. Only controls and NYHA class I patients had a median Hcy below the 12 [micro]mol/L cutoff (9). These results are supported by the study by Vasan et al. (5), who reported an increased incidence of CHF in individuals with Hcy concentrations [greater than or equal to]11-12 [micro]mol/L. Both studies suggest that an Hcy concentration of 12 [micro]mol/L is a reliable cutoff for an increased risk of CHF.

NT-proBNP is known to have a high negative predictive value (19-21) and might be useful for differential diagnosis of dyspnea in CHF and pulmonary diseases (22,23). In the persons investigated, we found a positive association of Hcy and NT-proBNP. However, Hcy and NT-proBNP are influenced by age and renal function (9,24,25). We therefore performed a partial correlation analysis controlling for age and creatinine. This analysis confirmed the relationship between Hcy and NT-proBNP. Sex and body mass index are other potential confounders of NT-proBNP. However, because of the limited number of women among our participants, separate statistics for men and women were not appropriate. Additionally, we also observed a relationship between Hcy and LVDD, which remained significant after correction for age and creatinine. Animal studies support the existence of morphologic changes in the presence of increased Hcy. Joseph and coworkers observed ventricular hypertrophy (26) and adverse cardiac remodeling (27,28) in the presence of high Hcy concentrations. Because Hcy depends strongly from folate, vitamin [B.sub.6], and vitamin [B.sub.12] status, it would be of particular interest to consider these data in our statistics. Unfortunately, these data were not available for our patients. Therefore, future studies are needed to clarify the role of these vitamins in CHF.

Our data and the results from animal studies (26-29) suggest adverse effects of Hcy on the myocardium mediated by 2 potential mechanisms: direct actions of Hcy on cardiac myocytes or Hcy-derived vascular damage leading to reduced perfusion. Direct effects of Hcy on cardiac myocytes could be attributable to the diminished Hcy degradation capacity of these cells (30) and the oxidative capacity of Hcy (31,32). The vascular hypothesis is extended by data from Kennedy et al. (29), who reported a negative inotropic effect of Hcy that is mediated by a "coronary endothelium-derived agent". However, more data are needed to understand the mechanistic role of Hcy in CHF.


The clinical impact of our results is not fully clear at the moment. Further studies are needed to analyze whether increased Hcy concentrations in CHF patients are associated with faster progression of the disease and a worse clinical outcome. If Hcy is associated with outcome in CHF, Hcy-lowering therapy with folate, vitamin [B.sub.12], and vitamin [B.sub.6] supplementation might help to reduce progression of the disease and improve the clinical outcome. Because Hcy-lowering therapy has almost no side effects, it might be a promising basic therapy comparable to anticoagulants in thrombotic diseases. Data from intervention trials are not currently available, however; therefore, an evidence-based recommendation to supplement B vitamins in CHF patients is not justified at the moment.

Financial support was provided by the "Competence-Network Heart Failure" of the National Ministry of Education and Research.


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DOI : 10.1373/clinchem.2005.049841

Markus Herrmann, [1] Ingrid Kindermann, [2] Stephanie Muller, [1] Thomas Georg, [3] Michael Kindermann, [2] Michael Bohm, [2] and Wolfgang Herrmann [1] * ([1] Abteilung fur Klinische Chemie and Laboratoriumsmedizin/ Zentrallabor, [2] Klinik for Innere Medizin III, and [3] Institut for Medizinische Biometrie, Epidemiologie and Medizinische Informatik, Universitatsklinikum des Saarland, Homburg/Saar, Germany; * address correspondence to this author at: Abteilung fur Klinische Chemie and Laboratoriumsmedizin/Zentrallabor, Universitatsklinikum des Saarland, D-66421 Homburg/Saar, Germany; fax 49-6841-1630703, e-mail
Table 1. Characteristics of patients and controls.

 Patients Controls
 (n = 95) (n = 18)
Anthropometric data
 Mean (SD) age, years 54 (13) 44 (10)(a)
 Mean (SD) weight, kg 84 (20) 76 (11)
 Mean (SD) height, cm 173 (9) 177 (10)
M/F, n 74/21 12/6

NYHA classification, n
 I 16 0
 II 27 0
 III 39 0
 IV 13 0

Mean (SD) blood pressure,
 RRsysb 75 (13) 77 (5)
 RRdia 120 (20) 121 (9)


 EF, % 38 (20) 67 (8)(a)
 FS, % 19 (9) 37 (6)(a)
 LVDD, mm 64 (10) 50 (4)(a)
Mean (SD) laboratory
 Hcy, mol/L 17.1 (20) 9.6 (2.6)a
 NT-proBNP, ng/L 2630 (4290) 38 (38)a
 Troponin T, g/L 0.013 (0.009) <0.01 (0.00)
 Creatinine, mg/L 11 (3) 9.4 (1.2)
Cardiac risk factors, %
 nonsmoker 25/54/21 13/7/80
 Hypertension 62 0
 Coronary artery disease 35 0
 Myocardial infarction 17 0
 Stroke 5 0
 Diabetes mellitus 15 0
Medication, %
 Beta blockers 88 0
 Diuretics 51 0
 ACE inhibitors 81 0
 Digoxin/digitoxin 14 0
 Antiarrhythmics 18 0
 Aspirin 25 0
 Marcumar 32 0

(a) P<0.01 vs patients.
(b) RRsys, Riva-Rocci systolic; RRdia, Riva-Rocci diastolic; EF,
ejection fraction;
FS, fractional shortening; ACE, angiotensin I-converting enzyme.
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Title Annotation:Technical Briefs
Author:Herrmann, Markus; Kindermann, Ingrid; Muller, Stephanie; Georg, Thomas; Kindermann, Michael; Bohm, M
Publication:Clinical Chemistry
Date:Aug 1, 2005
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