Abstract

Aims

This study investigated the potential association between homocysteine levels and cardiovascular events or atrial fibrillation (AF) recurrence following radiofrequency catheter ablation (RFCA) in patients with AF.

Methods and results

Blood samples were obtained prior to the RFCA procedure. Levels of homocysteine and carboxy-terminal telopeptide of collagen type I (CITP), a collagen type I degradation marker, were measured in 96 patients receiving RFCA; 62 paroxysmal or persistent AF patients and 34 paroxysmal supra-ventricular tachycardia patients. Patients were followed up for 2.1 ± 1.5 years. Plasma homocysteine levels were significantly higher in patients with persistent AF ( P < 0.05) compared with levels in paroxysmal AF and control patients. Homocysteine levels also positively correlated with left atrial dimension (LAD) ( P < 0.01) and CITP levels ( P < 0.001). While no significant correlation was found between basal homocysteine levels and recurrent AF after RFCA in AF patients, patients in the high homocysteine group exhibited a significantly higher rate of cardiovascular events without AF recurrence compared with those in the low homocysteine group ( P < 0.05).

Conclusion

High homocysteine levels are associated with the presence of persistent AF, which is accompanied by increased CITP levels and LAD. Also confirmed is the role of homocysteine as a risk factor for the pathogenesis of cardiovascular events after RFCA in AF patients. Measurement of homocysteine level may provide useful information for the managing cardiovascular risk in patients with AF.

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. Radiofrequency catheter ablation (RFCA) recently has been established as a curative therapy for paroxysmal or persistent AF. However, reports indicate that 15–40% of patients receiving RFCA later experienced recurrent AF in spite of successful RFCA, 1–3 which might lead to cardiovascular events such as heart failure and ischaemic stroke. 4 , 5 Therefore, it is clinically valuable to discover a useful marker to determine the pathogenesis of cardiovascular events after successful RFCA in patients with AF.

Homocysteine, a type of amino acid present in the human body, is produced during the metabolism of methionine. Several epidemiological studies demonstrated that elevated homocysteine levels have been related to increased risk of the development of cardiovascular diseases 6 such as coronary artery diseases, 7 , 8 heart failure, 9–11 and ischaemic stroke. 12–14 With regard to AF, plasma homocysteine levels are upregulated in patients with chronic AF. 13 A relationship between hyperhomocysteinemia and the occurrence of cerebro-vascular ischaemic events has been suggested by previous reports. 12–14 Here we investigated the association between plasma homocysteine levels and the pathogenesis of cardiovascular event after RFCA in patients with AF.

Methods

Study population

We recruited 96 consecutive patients with paroxysmal, persistent AF, and paroxysmal supra-ventricular tachycardia (PSVT) without AF and atrial tachycardia (AT) history [atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT)] admitted for scheduled RFCA at Nagoya University Hospital between April 2004 and March 2005. Patients with valvular heart diseases, haemodialysis or unsuccessful RFCA were excluded. At the time of the RFCA treatment, all patients had received appropriate therapy with antiarrythmic drugs, β-blockers, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, and aldosterone antagonist. Each patient’s pattern of AF (paroxysmal or persistent) was determined on the episodes of AF as follows: 15 , 16 (i) Paroxysmal AF was defined as a history of one or more episodes of medically or self-terminated AF within 7 days. (ii) Patients with a history of one or more episodes of AF >7 days who underwent pharmacological cardioversion or who received electrical cardioversion to establish normal sinus rhythm were defined as persistent AF. Etiologies were paroxysmal AF in 43 patients and persistent AF in 19 patients. In addition, we assessed 34 patients with PSVT (26 AVNRT and 8 AVRT) and no previous record of AF or AT, who were considered to represent a control group. There were no permanent AF patients in this study. This study was approved by the ethics committee of the Nagoya University School of Medicine, and all patients enrolled in this study provided written informed consent.

Biomarker analysis

In every patient, blood samples were obtained at the time RFCA. After 10 min of rest in the supine position, vital signs were recorded and 35 mL blood was collected from the antecubital vein. Plasma levels of homocysteine and carboxy-terminal telopeptide of collagen type I (CITP) were measured by commercial laboratories (Mitsubishi Chemical Medience Corp.).

Echocardiography

Two-dimensional and Doppler echocardiography were performed by an experienced sonographer using a Vivid4 System (GE Healthcare). The images were recorded on videotape and analysed offline. Left ventricular (LV) end-diastolic diameter (LVEDD) and left atrial dimension (LAD) were measured from standard M-mode measurements as recommended by the American Society of Echocardiography. Left ventricular ejection fraction (LVEF) was calculated using a modified Simpson’s rule.

Radiofrequency catheter ablation to atrial fibrillation

All catheter ablations were performed by the same experienced operators. A multipolar electrode catheter was introduced in the coronary sinus (CS) through the left subclavian vein to record left atrial activity, and thereafter the pulmonary veins (PVs) were mapped after transseptal catheterization with three catheters: two circular mapping catheters (Lasso, Biosense Webster Inc.) to record electrical activity of myocardial extensions connecting the LA with a PV and an ablation catheter (Brazer, Boston Scientific). The Lasso catheters were situated as proximal as possible inside the PV, whereas the ablations catheter was positioned at the ostium to segmentally isolate the PV. RF (radiofrequency) energy was applied at ostial sites with the earliest PV activation guided by the circular catheter. The RF energy was delivered from an RF generator (EPT-1000, Boston Scientific) in temperature-controlled mode. The RF power output was limited to 30 W, with a maximal target temperature of 55°C and a preset duration of 30 s. The procedure endpoint was complete elimination of electrical conduction into the PV. After 20 min following the final RF application, we confirmed PV isolation by recording no potentials by the Lasso catheter and no induced AF by CS burst pacing.

Post-ablation follow-up

Patients were discharged 3 days after the ablation procedure unless complications occurred. Follow-up was obtained by outpatient clinical visits or telephone interviews. Arrhythmia events within the first month following the ablation were not included in the final results. All antiarrhythmic medication was stopped at 1 month after the ablation. However, in the case of symptomatic recurrent AF, the patients were offered resumption of antiarrhythmic drug therapy. Cases of second ablation were excluded. Patients were routinely monitored by clinical examination and Holter ECG on an outpatient basis after 1, 3, 6, 12, 18, 24, 30, 36, 42, and 48 months. The clinical outcome was classified as complete success if the patient was without any documented arrhythmias and was free of antiarrhythmic medication. And partial success was defined by an absence of clinical symptoms while the patient was still taking antiarrhythmic drugs. These two groups comprised patients with no recurrent AF. The recurrent AF group was classified as the remaining patients who showed no benefit while usually still on medication. Cardiovascular events were a composite of myocardial infarction, ischaemic stroke, cerebro-vascular haemorrhage, heart failure, and sudden death attributed to coronary heart disease, but not included recurrent AF.

Statistical analysis

Box plots in Figures  1 , 3 B and C represent median levels with 25th and 75th percentiles of observed data, with whiskers representing the 5th and 95th percentiles in each group. The other data are expressed as mean ± standard deviation (SD). Statistical significance was assessed with one-way ANOVA with Bonferroni’s correction. The correlations between homocysteine levels and LAD, or CITP levels were examined by univariate analysis. Freedom from cardiovascular events was determined by Kaplan–Meier analysis with the log-rank test. A level of P < 0.05 indicated statistical significance. All analyses were performed using Stat View-J (version 5.0; SAS Institute Inc.).

Figure 1

Box plots represent median levels with 25th and 75th percentiles of homocysteine (Hc) levels; whiskers represent the 5th and 95th percentiles in each group.

Figure 1

Box plots represent median levels with 25th and 75th percentiles of homocysteine (Hc) levels; whiskers represent the 5th and 95th percentiles in each group.

Results

Baseline characteristics

Baseline characteristics are shown in Table  1 . A total of 96 subjects comprising patients with paroxysmal AF, patients with persistent AF, and the control group were enrolled in this study. No significant differences were observed in the etiology of AF and accompanying diseases among three groups. Mean age was significantly lower in the control patients than in the AF patients. The percentage of males was higher in the paroxysmal and persistent AF group than in the control patients.

Table 1

Patients characteristics

  Control ( n = 34)   Paroxysmal AF ( n = 43)   Persistent AF ( n = 19)  
Age (years) 49.5 ± 19.1 58.6 ± 10.2** 60.7 ± 13.3** 
Male 16 (47.1%) 34 (79.1%)* 14 (73.7%)* 
BMI (kg/m 2 )  21.5 ± 3.1 23.4 ± 3.0* 23.2 ± 3.8 
Etiology of AF 
 Coronary artery disease 2 (5.9%) 5 (11.6%) 1 (5.3%) 
 Hypertension 7 (20.6%) 9 (20.9%) 4 (21.1%) 
Duration of symptoms (year) 5.0 ± 9.5 4.3 ± 4.2 6.0 ± 5.9 
Accompanied disease 
 Diabetes mellitus 2 (5.9%) 8 (18.6%) 2 (10.5%) 
 Hyperlipidaemia 5 (14.7%) 12 (27.9%) 7 (36.8%) 
Medication 
 Anti-arrhythmic agents 6 (17.6%) 32 (74.4%)** 12 (63.2%)** 
 Angiotensin converting enzyme inhibitor 0 (0%) 3 (7.0%) 2 (10.5%) 
 Angiotensin receptor blocker 4 (11.8%) 11 (25.6%) 3 (15.8%) 
 Aldosterone antagonist 0 (0%) 2 (4.7%)  4 (21.1%)*  
 Digitalis 0 (0%) 6 (14.0%)* 2 (10.5%) 
 β-blocker 3 (8.8%) 6 (14.0%) 6 (31.6%)* 
 Calcium channel blocker 9 (26.5%) 9 (20.9%) 3 (15.8%) 
 Statin 1 (2.9%) 4 (9.3%) 2 (10.5%) 
 Anticoagulant 0 (0%) 43 (100%)** 19 (100%)** 
Echocardiography 
 Left atrial dimension (mm) 30.5 ± 7.6 38.8 ± 7.2** 41.7 ± 9.5** 
 Left ventricular end-diastolic diameter (mm) 48.6 ± 7.8 50.1 ± 6.6 53.1 ± 9.3* 
 Left ventricular ejection fraction (%) 67.9 ± 5.3 65.1 ± 6.2  57.0 ± 14.9** †† 
Biochemistry 
 Fasting blood sugar (mg/dL) 93.8 ± 18.0 97.8 ± 27.0 97.9 ± 29.4 
 HbA1c (%) 5.1 ± 0.4 5.4 ± 0.7 5.4 ± 0.7 
 Ccr (creatinine clearance) (mL/min) 103.0 ± 29.6 93.9 ± 29.9 89.4 ± 35.1 
 LDL cholesterol (mg/dL) 112.9 ± 32.6 119.5 ± 24.5 115.4 ± 33.0 
 HDL cholesterol (mg/dL) 58.8 ± 11.5 52.5 ± 13.2* 49.2 ± 11.1* 
 TG (mg/dL) 91.0 ± 46.7 126.6 ± 58.8** 128.3 ± 74.2** 
 FFA (mmol/L) 0.48 ± 0.30 0.46 ± 0.28 0.46 ± 0.33 
  Control ( n = 34)   Paroxysmal AF ( n = 43)   Persistent AF ( n = 19)  
Age (years) 49.5 ± 19.1 58.6 ± 10.2** 60.7 ± 13.3** 
Male 16 (47.1%) 34 (79.1%)* 14 (73.7%)* 
BMI (kg/m 2 )  21.5 ± 3.1 23.4 ± 3.0* 23.2 ± 3.8 
Etiology of AF 
 Coronary artery disease 2 (5.9%) 5 (11.6%) 1 (5.3%) 
 Hypertension 7 (20.6%) 9 (20.9%) 4 (21.1%) 
Duration of symptoms (year) 5.0 ± 9.5 4.3 ± 4.2 6.0 ± 5.9 
Accompanied disease 
 Diabetes mellitus 2 (5.9%) 8 (18.6%) 2 (10.5%) 
 Hyperlipidaemia 5 (14.7%) 12 (27.9%) 7 (36.8%) 
Medication 
 Anti-arrhythmic agents 6 (17.6%) 32 (74.4%)** 12 (63.2%)** 
 Angiotensin converting enzyme inhibitor 0 (0%) 3 (7.0%) 2 (10.5%) 
 Angiotensin receptor blocker 4 (11.8%) 11 (25.6%) 3 (15.8%) 
 Aldosterone antagonist 0 (0%) 2 (4.7%)  4 (21.1%)*  
 Digitalis 0 (0%) 6 (14.0%)* 2 (10.5%) 
 β-blocker 3 (8.8%) 6 (14.0%) 6 (31.6%)* 
 Calcium channel blocker 9 (26.5%) 9 (20.9%) 3 (15.8%) 
 Statin 1 (2.9%) 4 (9.3%) 2 (10.5%) 
 Anticoagulant 0 (0%) 43 (100%)** 19 (100%)** 
Echocardiography 
 Left atrial dimension (mm) 30.5 ± 7.6 38.8 ± 7.2** 41.7 ± 9.5** 
 Left ventricular end-diastolic diameter (mm) 48.6 ± 7.8 50.1 ± 6.6 53.1 ± 9.3* 
 Left ventricular ejection fraction (%) 67.9 ± 5.3 65.1 ± 6.2  57.0 ± 14.9** †† 
Biochemistry 
 Fasting blood sugar (mg/dL) 93.8 ± 18.0 97.8 ± 27.0 97.9 ± 29.4 
 HbA1c (%) 5.1 ± 0.4 5.4 ± 0.7 5.4 ± 0.7 
 Ccr (creatinine clearance) (mL/min) 103.0 ± 29.6 93.9 ± 29.9 89.4 ± 35.1 
 LDL cholesterol (mg/dL) 112.9 ± 32.6 119.5 ± 24.5 115.4 ± 33.0 
 HDL cholesterol (mg/dL) 58.8 ± 11.5 52.5 ± 13.2* 49.2 ± 11.1* 
 TG (mg/dL) 91.0 ± 46.7 126.6 ± 58.8** 128.3 ± 74.2** 
 FFA (mmol/L) 0.48 ± 0.30 0.46 ± 0.28 0.46 ± 0.33 

Values are mean ± SD.

* P < 0.05, ** P < 0.01 vs. control, P < 0.05, ††P < 0.01 vs. paroxysmal atrial fibrillation (AF).

All patients were maintained on standard therapy for PSVT or AF. Medications taken, including antiarrhythmic agents and anticoagulants, differed for the control group and patients with the two types of AF. However, the medications taken by the paroxysmal AF and persistent AF groups were nearly identical.

Echocardiographic analysis indicated LAD was significantly larger in patients with the two types of AF in comparison with the control patients. LVEF in patients with persistent AF was significantly lower than in the control and paroxysmal AF patients. Additionally, the largest LVEDD among the three groups was exhibited by the persistent AF patients.

No significant differences were observed in the three groups’ blood glucose, haemoglobin A1c, creatinine clearance, LDL-cholesterol, and free fatty acid (FFA) levels. HDL-cholesterol and triglyceride were significantly higher in the two types of AF patients than in the control patients.

Influence of atrial fibrillation on homocysteine levels

Plasma homocysteine levels were significantly higher in persistent AF patients (12.7 ± 4.3 µmol/L, P < 0.05) as compared with levels among the paroxysmal AF patients (10.4 ± 3.6 µmol/L) and control patients (9.6 ± 3.6 µmol/L) ( Figure  1 ). No statistically significant differences in homocysteine levels were found between the paroxysmal AF and control patients ( P = 0.26).

Correlation of homocysteine levels to cardiac parameters and collagen metabolism markers

LAD and circulating CITP levels as the index of collagen type I degradation are believed to contribute to atrial remodelling. 17 , 18 Therefore, we examined the association between plasma homocysteine levels and cardiac and collagen metabolism markers. Plasma homocysteine levels were significantly correlated with LAD ( r = 0.30, P < 0.01, Figure  2 A ). Plasma homocysteine levels were also positively correlated with plasma CITP levels ( r = 0.36, P < 0.001, Figure  2 B ) but not with levels for type III procollagen-N-peptide (PIIINP), a marker of collagen type III synthesis (data not shown).

Figure 2

Scatter plots of the correlations between ( A ) plasma concentrations of homocysteine (Hc) and left atrial dimension (LAD), and ( B ) plasma concentrations of Hc and carboxy-terminal telopeptide of collagen type I (CITP).

Figure 2

Scatter plots of the correlations between ( A ) plasma concentrations of homocysteine (Hc) and left atrial dimension (LAD), and ( B ) plasma concentrations of Hc and carboxy-terminal telopeptide of collagen type I (CITP).

Homocysteine and cardiovascular events after successful radiofrequency catheter ablation in patients with atrial fibrillation

After successful RFCA, 47 patients remained free of symptoms of AF, and 15 patients had recurrent AF during a mean follow-up period 2.1 ± 1.5 years. Nine of 43 paroxysmal AF patients and 6 of 19 persistent AF patients had recurrence of AF ( Figure  3 A ). There were no significant differences between patients with and without recurrent AF in basal homocysteine levels after RFCA (11.8 ± 6.2 vs. 10.8 ± 3.9 µmol/L, N.S., Figure  3 B ). During the follow-up period, 56 patients remained free from cardiovascular events, while six patients (two paroxysmal AF and four persistent AF) experienced cardiovascular events ( Figure  3 A ). Basal homocysteine levels were significantly higher in patients who experienced cardiovascular events than in patients who did not (16.9 ± 8.9 vs. 10.4 ± 3.5 µmol/L, P < 0.001, Figure  3 C ). A basal homocysteine value of 13 µmol/L (the threshold for the upper quartile in this population), as previous reports described, 19 , 20 was used to divide the population into two groups: 15 patients with high homocysteine levels (>13 µmol/L) and 47 patients with low homocysteine levels (≤13 µmol/L). Patients in the high homocysteine group exhibited a significantly higher incidence of cardiovascular events, as compared with those in the low homocysteine group ( P < 0.05, Figure  3 D ). Plasma atrial natriuretic peptide and brain natriuretic peptide levels were not associated with recurrent AF and cardiovascular events in this population (data not shown).

Figure 3

( A ) Flow chart of atrial fibrillation (AF) patients through the trials. CV event indicates cardiovascular event. The relationship between the circulating levels of homocysteine (Hc) and ( B ) recurrent AF, ( C ) cardiovascular events. Kaplan–Meier estimates of ( D ) the cardiovascular event-free rate after radiofrequency catheter ablation (RFCA).

Figure 3

( A ) Flow chart of atrial fibrillation (AF) patients through the trials. CV event indicates cardiovascular event. The relationship between the circulating levels of homocysteine (Hc) and ( B ) recurrent AF, ( C ) cardiovascular events. Kaplan–Meier estimates of ( D ) the cardiovascular event-free rate after radiofrequency catheter ablation (RFCA).

Discussion

Hyperhomocysteinemia has been shown to be associated with an increased risk of mortality and morbidity in patients with chronic heart failure, 9–11 hypertension, 19 and coronary artery diseases, 7 , 8 conditions which could be linked to the development and prevalence of AF. 21 In agreement with these observations, homocysteine levels were markedly increased in the patients with persistent AF as compared with levels in patients with paroxysmal AF and the control patients. These results are consistent with a recent study by Marcucci et al . 13 showing that a significant association between elevated homocysteine levels and the presence of AF. Homocysteine levels also positively correlated with CITP levels and LAD, which are believed to contribute to atrial remodelling. Measurement of plasma homocysteine level could provide useful information in the assessment of AF.

The occurrence and development of AF are associated with changes in electrical properties and cardiac structure, known as electrical and structural atrial remodelling. 21–24 Atrial structural remodelling is a complex process, involving, among other things, the activation of fibroblasts and elaboration of extracellular type I collagen. This contributes to heterogeneity of electrical conduction. Structural remodelling has been associated with the activation of matrix metalloproteinase-9 (MMP-9) 25 , 26 and extracellular signal regulated kinase (ERK). 27 Reports have described hyperhomocysteinaemia-caused extracellular matrix (ECM) remodelling by the activation of ERK-MMP-9 signalling axis in various cell types. 28 Among ECM proteins, collagen type I and type III are major components in the atrial interstitium. 29 , 30 Collagen type I, but not type III, is upregulated in the atrium of patients with sustained AF. 31 Serum levels of CITP, a marker of collagen type I degradation, are associated with the occurrence and maintenance of AF. 17 The present study demonstrated that homocysteine levels are positively correlated with CITP levels. Consistent with this notion, in vitro experiments indicate that homocysteine leads to ECM remodelling by altering collagen type I synthesis through the ERK pathway. 32 In addition, it has been reported that hyperhomocysteinaemia inhibited potassium channels in atrial myocytes, 33 which are associated with atrial electrical remodelling. 23 , 34 Therefore, homocysteine may influence the extent of pathological atrial remodelling accompanied by AF. However, our observation found that homocysteine levels did not predict the recurrence of AF after RFCA. It is possible that technical factors associated with isolating PV ectopy affect the recurrence of AF after RFCA because isolation triggered PV potential from left atrium is the preventing factor of the AF occurrence. 1 , 2 , 35 Further studies will be required to better understand the role of homocysteine in AF.

To the best of our knowledge, the present study is the first to examine the association between basal homocysteine levels and cardiovascular events after successful RFCA in patients with AF. In this study, basal homocysteine levels could be predictive of the pathogenesis of cardiovascular events after successful RFCA in AF. As shown in Figure  3 A , there were no differences in the incidence of cardiovascular events between with and without the recurrence of AF. These findings would probably show us that RFCA does not influence the incidence of cardiovascular events and the levels of homocysteine after ablation procedure. The reduction of homocysteine levels by means of vitamin supplementation decrease exacerbated LV diastolic dysfunction 36 but not attenuate cardiovascular disease in the VISP (vitamin intervention for stroke prevention) study, 37 Norwegian Vitamin trial (NORVIT) trial 38 and Heart Outcomes Prevention Evaluation (HOPE) 2 trial. 39 However, Herrmann et al . 40 reviewed re-analysis of the VISP study 37 and HOPE 2 trial 39 after excluding renal failure and vitamin B12 status tampering factors and detected an ∼20% decrease in the risk of ischaemic stroke. This suggests that elevated homocysteine levels may easily be reduced by vitamin supplementation; this approach might be helpful in preventing future cardiovascular events.

The present study, however, has several limitations. First, the sample size is relatively small, thus additional prospective studies in a large population are necessary. Secondly, we did not assess homocysteine levels in patients with permanent AF because they were not enrolled to RFCA in this period. In addition, we did not also evaluate the change in homocysteine levels before and after ablation therapy. Thirdly, we observed a negative association between AF status and HDL levels in this study. Low HDL levels, which are associated with antioxidant activity, 41 , 42 might affect on the risk of cardiovascular events during follow up. Finally, reduced LVEF and increased LVEDD in patients with persistent AF may influence the serum markers.

Taken together, our observations demonstrate that, in the clinical setting, circulating homocysteine levels are associated with the presence of AF, which are accompanied by pathological atrial remodelling. It was additionally suggested that elevated basal homocysteine levels could be one risk factor in the pathogenesis of cardiovascular events following successful RFCA in patients with AF. Measurement of homocysteine levels may provide useful information for managing cardiovascular risk in AF patients.

Funding

This work was supported by grant from the Japanese Ministry of Education, the Nakashima foundation and the Aichi D.R.G foundation to R.S.

Acknowledgements

We gratefully acknowledge the technical assistance of Megumi Kondo and Rie Miura.

Conflict of interest: none declared.

References

1
Haissaguerre
M
Jais
P
Shah
DC
Takahashi
A
Hocini
M
Quiniou
G
, et al.  . 
Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins
N Engl J Med
 , 
1998
, vol. 
339
 (pg. 
659
-
66
)
2
Haissaguerre
M
Jais
P
Shah
DC
Garrigue
S
Takahashi
A
Lavergne
T
, et al.  . 
Electrophysiological end point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci
Circulation
 , 
2000
, vol. 
101
 (pg. 
1409
-
17
)
3
O’Neill
MD
Jais
P
Hocini
M
Sacher
F
Klein
GJ
Clementy
J
, et al.  . 
Catheter ablation for atrial fibrillation
Circulation
 , 
2007
, vol. 
116
 (pg. 
1515
-
23
)
4
Grogan
M
Smith
HC
Gersh
BJ
Wood
DL
Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy
Am J Cardiol
 , 
1992
, vol. 
69
 (pg. 
1570
-
3
)
5
Hsu
LF
Jais
P
Sanders
P
Garrigue
S
Hocini
M
Sacher
F
, et al.  . 
Catheter ablation for atrial fibrillation in congestive heart failure
N Engl J Med
 , 
2004
, vol. 
351
 (pg. 
2373
-
83
)
6
Wang
TJ
Gona
P
Larson
MG
Tofler
GH
Levy
D
Newton-Cheh
C
, et al.  . 
Multiple biomarkers for the prediction of first major cardiovascular events and death
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2631
-
9
)
7
Whincup
PH
Refsum
H
Perry
IJ
Morris
R
Walker
M
Lennon
L
, et al.  . 
Serum total homocysteine and coronary heart disease: prospective study in middle aged men
Heart
 , 
1999
, vol. 
82
 (pg. 
448
-
54
)
8
Fallon
UB
Ben-Shlomo
Y
Elwood
P
Ubbink
JB
Smith
GD
Homocysteine and coronary heart disease in the Caerphilly cohort: a 10 year follow up
Heart
 , 
2001
, vol. 
85
 (pg. 
153
-
8
)
9
Vasan
RS
Beiser
A
D’Agostino
RB
Levy
D
Selhub
J
Jacques
PF
, et al.  . 
Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction
JAMA
 , 
2003
, vol. 
289
 (pg. 
1251
-
7
)
10
Herrmann
M
Taban-Shoma
O
Hubner
U
Pexa
A
Kilter
H
Umanskaya
N
, et al.  . 
Hyperhomocysteinemia and myocardial expression of brain natriuretic peptide in rats
Clin Chem
 , 
2007
, vol. 
53
 (pg. 
773
-
80
)
11
May
HT
Alharethi
R
Anderson
JL
Muhlestein
JB
Reyna
SP
Bair
TL
, et al.  . 
Homocysteine levels are associated with increased risk of congestive heart failure in patients with and without coronary artery disease
Cardiology
 , 
2007
, vol. 
107
 (pg. 
178
-
84
)
12
Boysen
G
Brander
T
Christensen
H
Gideon
R
Truelsen
T
Homocysteine and risk of recurrent stroke
Stroke
 , 
2003
, vol. 
34
 (pg. 
1258
-
61
)
13
Marcucci
R
Betti
I
Cecchi
E
Poli
D
Giusti
B
Fedi
S
, et al.  . 
Hyperhomocysteinemia and vitamin B6 deficiency: new risk markers for nonvalvular atrial fibrillation?
Am Heart J
 , 
2004
, vol. 
148
 (pg. 
456
-
61
)
14
Loffredo
L
Violi
F
Fimognari
FL
Cangemi
R
Sbrighi
PS
Sampietro
F
, et al.  . 
The association between hyperhomocysteinemia and ischemic stroke in patients with non-valvular atrial fibrillation
Haematologica
 , 
2005
, vol. 
90
 (pg. 
1205
-
11
)
15
Fuster
V
Ryden
LE
Asinger
RW
Cannom
DS
Crijns
HJ
Frye
RL
, et al.  . 
ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology
Circulation
 , 
2001
, vol. 
104
 (pg. 
2118
-
50
)
16
McNamara
RL
Brass
LM
Drozda
JP
Jr
Go
AS
Halperin
JL
Kerr
CR
, et al.  . 
ACC/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Commitee to Develop Data Standards on Atrial Fibrillation)
J Am Coll Cardiol
 , 
2004
, vol. 
44
 (pg. 
475
-
95
)
17
Tziakas
DN
Chalikias
GK
Papanas
N
Stakos
DA
Chatzikyriakou
SV
Maltezos
E
Circulating levels of collagen type I degradation marker depend on the type of atrial fibrillation
Europace
 , 
2007
, vol. 
9
 (pg. 
589
-
96
)
18
Takahashi
N
Imataka
K
Seki
A
Fujii
J
Left atrial enlargement in patients with paroxysmal atrial fibrillation
Jpn Heart J
 , 
1982
, vol. 
23
 (pg. 
677
-
83
)
19
Sundstrom
J
Sullivan
L
D’Agostino
RB
Jacques
PF
Selhub
J
Rosenberg
IH
, et al.  . 
Plasma homocysteine, hypertension incidence, and blood pressure tracking: the Framingham Heart Study
Hypertension
 , 
2003
, vol. 
42
 (pg. 
1100
-
5
)
20
May
HT
Alharethi
R
Anderson
JL
Muhlestein
JB
Reyna
SP
Bair
TL
, et al.  . 
Homocysteine levels are associated with increased risk of congestive heart failure in patients with and without coronary artery disease
Cardiology
 , 
2007
, vol. 
107
 (pg. 
178
-
84
)
21
Nattel
S
New ideas about atrial fibrillation 50 years on
Nature
 , 
2002
, vol. 
415
 (pg. 
219
-
26
)
22
Wijffels
MC
Kirchhof
CJ
Dorland
R
Allessie
MA
Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats
Circulation
 , 
1995
, vol. 
92
 (pg. 
1954
-
68
)
23
Li
D
Fareh
S
Leung
TK
Nattel
S
Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort
Circulation
 , 
1999
, vol. 
100
 (pg. 
87
-
95
)
24
Anne
W
Willems
R
Holemans
P
Beckers
F
Roskams
T
Lenaerts
I
, et al.  . 
Self-terminating AF depends on electrical remodeling while persistent AF depends on additional structural changes in a rapid atrially paced sheep model
J Mol Cell Cardiol
 , 
2007
, vol. 
43
 (pg. 
148
-
58
)
25
Nakano
Y
Niida
S
Dote
K
Takenaka
S
Hirao
H
Miura
F
, et al.  . 
Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation
J Am Coll Cardiol
 , 
2004
, vol. 
43
 (pg. 
818
-
25
)
26
Laurent
G
Moe
G
Hu
X
Holub
B
Leong-Poi
H
Trogadis
J
, et al.  . 
Long chain n-3 polyunsaturated fatty acids reduce atrial vulnerability in a novel canine pacing model
Cardiovasc Res
 , 
2008
, vol. 
67
 (pg. 
705
-
13
)
27
Li
D
Shinagawa
K
Pang
L
Leung
TK
Cardin
S
Wang
Z
, et al.  . 
Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure
Circulation
 , 
2001
, vol. 
104
 (pg. 
2608
-
14
)
28
Moshal
KS
Singh
M
Sen
U
Rosenberger
DS
Henderson
B
Tyagi
N
, et al.  . 
Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC
Am J Physiol Heart Circ Physiol
 , 
2006
, vol. 
291
 (pg. 
H2825
-
H2835
)
29
Weber
KT
Cardiac interstitium in health and disease: the fibrillar collagen network
J Am Coll Cardiol
 , 
1989
, vol. 
13
 (pg. 
1637
-
52
)
30
Swynghedauw
B
Molecular mechanisms of myocardial remodeling
Physiol Rev
 , 
1999
, vol. 
79
 (pg. 
215
-
62
)
31
Xu
J
Cui
G
Esmailian
F
Plunkett
M
Marelli
D
Ardehali
A
, et al.  . 
Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation
Circulation
 , 
2004
, vol. 
109
 (pg. 
363
-
8
)
32
Sen
U
Moshal
KS
Tyagi
N
Kartha
GK
Tyagi
SC
Homocysteine-induced myofibroblast differentiation in mouse aortic endothelial cells
J Cell Physiol
 , 
2006
, vol. 
209
 (pg. 
767
-
74
)
33
Cai
BZ
Gong
DM
Liu
Y
Pan
ZW
Xu
CQ
Bai
YL
, et al.  . 
Homocysteine inhibits potassium channels in human atrial myocytes
Clin Exp Pharmacol Physiol
 , 
2007
, vol. 
34
 (pg. 
851
-
5
)
34
Fareh
S
Benardeau
A
Thibault
B
Nattel
S
The T-type Ca(2+) channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs
Circulation
 , 
1999
, vol. 
100
 (pg. 
2191
-
7
)
35
Haissaguerre
M
Shah
DC
Jais
P
Hocini
M
Yamane
T
Deisenhofer
I
, et al.  . 
Electrophysiological breakthroughs from the left atrium to the pulmonary veins
Circulation
 , 
2000
, vol. 
102
 (pg. 
2463
-
5
)
36
Miller
A
Mujumdar
V
Palmer
L
Bower
JD
Tyagi
SC
Reversal of endocardial endothelial dysfunction by folic acid in homocysteinemic hypertensive rats
Am J Hypertens
 , 
2002
, vol. 
15
 (pg. 
157
-
63
)
37
Toole
JF
Malinow
MR
Chambless
LE
Spence
JD
Pettigrew
LC
Howard
VJ
, et al.  . 
Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the vitamin intervention for stroke prevention (VISP) randomized controlled trial
JAMA
 , 
2004
, vol. 
291
 (pg. 
565
-
75
)
38
Bonaa
KH
Njolstad
I
Ueland
PM
Schirmer
H
Tverdal
A
Steigen
T
, et al.  . 
Homocysteine lowering and cardiovascular events after acute myocardial infarction
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
1578
-
88
)
39
Lonn
E
Yusuf
S
Arnold
MJ
Sheridan
P
Pogue
J
Micks
M
, et al.  . 
Homocysteine lowering with folic acid and B vitamins in vascular disease
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
1567
-
77
)
40
Herrmann
W
Herrmann
M
Obeid
R
Hyperhomocysteinaemia: a critical review of old and new aspects
Curr Drug Metab
 , 
2007
, vol. 
8
 (pg. 
17
-
31
)
41
Annoura
M
Ogawa
M
Kumagai
K
Zhang
B
Saku
K
Arakawa
K
Cholesterol paradox in patients with paroxysmal atrial fibrillation
Cardiology
 , 
1999
, vol. 
92
 (pg. 
21
-
7
)
42
Bhattacharyya
T
Nicholls
SJ
Topol
EJ
Zhang
R
Yang
X
Schmitt
D
, et al.  . 
Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk
JAMA
 , 
2008
, vol. 
299
 (pg. 
1265
-
76
)