Skip Navigation


European Heart Journal Advance Access first published online on August 31, 2007
This version published online on September 11, 2007
European Heart Journal, doi:10.1093/eurheartj/ehm343
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
28/22/2763    most recent
ehm343v2
ehm343v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Pilz, S.
Right arrow Articles by März, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pilz, S.
Right arrow Articles by März, W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Elevated plasma free fatty acids predict sudden cardiac death: a 6.85-year follow-up of 3315 patients after coronary angiography

Stefan Pilz1,2, Hubert Scharnagl2, Beate Tiran2, Britta Wellnitz3, Ursula Seelhorst3, Bernhard O. Boehm4 and Winfried März5,*

1 Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Austria
2 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
3 LURIC Study Nonprofit LLC, Freiburg, Germany
4 Division of Endocrinology and Diabetes, Graduate School of Molecular Diabetology and Endocrinology, Ulm University, Germany
5 Synlab Center of Laboratory Diagnostics, 69031 Heidelberg, Germany

Received 21 March 2007; revised 2 July 2007; accepted 17 July 2007.

* Corresponding author. Tel: +49 6221 7930; fax: +49 6221 793 111. E-mail address: maerz{at}synlab.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims: Sudden cardiac death (SCD) is the most common fatal cardiovascular event. Free fatty acids (FFAs) exert several harmful effects on the myocardium and may therefore contribute to SCD. We examined whether fasting FFA predict SCD in patients who had undergone coronary angiography.

Methods and results: FFAs were measured at baseline (1997–2000) in 3315 patients scheduled for coronary angiography. Angiographic coronary artery disease was found in 2231 study participants. After a median time of follow-up of 6.85 years, 165 SCD occurred in the entire study population. In a Cox proportional hazards model, the unadjusted hazard ratio (HR) for SCD in the fourth when compared with the first FFA quartile was 2.95 (95% CI 1.84–4.73; P < 0.001). After adjustment for common and emerging cardiovascular risk factors, the HR remained significant at 1.76 (1.03–3.00; P = 0.038). High FFA levels were also significantly associated with all-cause and cardiovascular mortality, even after exclusion of patients with SCD.

Conclusion: Our study shows that elevated plasma FFAs are an independent risk factor for future SCD in patients referred to coronary angiography. These results may suggest that modulation of myocardial fatty acid uptake and/or metabolism are a possible target of treatment, but it still remains to be clarified whether high FFA levels are a cause or a consequence of pathological processes that underlie the association between FFA and SCD.

Key Words: Free fatty acids • NEFA • Sudden cardiac death • Epidemiology • Mortality


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Sudden cardiac death (SCD) accounts for ~50% of all fatal coronary heart disease events.1 Patients die unexpectedly and shortly after the onset of a change in clinical status that usually begins with an abrupt loss of consciousness.1 Ventricular tachyarrhythmias are most often recorded in subjects with SCD but the underlying pathological processes that lead to an electrically unstable myocardium remain to be further clarified.1 Hence, there is still a great need to identify risk factors for SCD so that preventive strategies may be applied to this significant public health problem. Epidemiological studies have shown that the incidence of SCD is highest in patients already afflicted with coronary artery disease (CAD) but every second SCD occurs in persons of relatively low cardiovascular risk.1 This suggests that apart from common cardiovascular risk factors, other aetiological factors may exist in the pathogenesis of SCD. There is growing evidence that free fatty acids (FFAs), also named non-esterified fatty acids (NEFAs), contribute to SCD.2

Circulating FFAs are mainly released from triglyceride stores of the adipose tissue and serve as physiologically important energy substrates. An excess of FFA has been implicated in insulin resistance and hepatic steatosis.3,4 Furthermore, elevated FFAs are associated with atherosclerosis5 and hypertension.6 Fatty acid oxidation supplies the heart with ~70% of its energy but an overwhelming delivery of plasma FFA to the heart, as it is observed in acute coronary syndromes (ACS) and heart failure, may contribute to myocardial dysfunction.2,7,8 High FFA and subsequent increased utilization of fatty acids for energy generation in the ischaemic myocardium may cause a ‘metabolic crisis’ in patients with CAD because fatty acid oxidation requires more oxygen when compared with the use of glucose.2,7 Apart from this, high concentrations of FFA have been shown to exert pro-arrhythmic actions.2,9,10 The population-based Paris Prospective study has already shown that elevated levels of FFA are predictive for SCD but not for overall cardiovascular mortality or fatal myocardial infarction, suggesting that FFAs are specifically related to SCD.11,12 We have previously demonstrated in the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study that FFA predict all-cause and even more pronounced cardiovascular mortality in patients scheduled for coronary angiography.13 In the present work, we report about data from an extended follow-up examination of LURIC. We aimed to address the role of FFA as an independent risk factor for SCD.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Study population
The LURIC study is a prospective cohort study that is designed to investigate cardiovascular risk factors.14 Between July 1997 and January 2000, baseline measurements were performed in 3316 Caucasians who were scheduled for coronary angiography at the Herzzentrum Ludwigshafen in South-West Germany. Inclusion criteria were German ancestry and clinical stability with the exception of ACS. Patients with any acute illness other than ACS, any non-cardiac chronic disease, or a history of malignancy within the past 5 years were excluded. Written informed consent was obtained from all the participants and the Institutional Review Board at the Ärztekammer Rheinland-Pfalz approved the study.

Our study cohort comprises patients in whom coronary angiography was clinically indicated which was most commonly the case in patients with chest pain or results of non-invasive tests in which myocardial ischaemia was suspected. CAD was defined as the occurrence of one stenosis of 50% or more in at least one of 15 coronary segments by using the maximal luminal narrowing. In 3194 study probands, left ventricular (LV) function had been graded semiquantitively by contrast ventriculography into normal, minimally, moderately, or severely impaired. LV ejection fraction, calculated from the right anterior oblique was available in 1360 of these patients and correlated highly significantly with the semiquantitatively assessed LV function (Spearman's correlation coefficient=–0.84; P < 0.001) suggesting that the semiquantitative grading provides a reliable estimate of LV function.

Patients with a fasting plasma glucose level >1.25 g/L or with a 2 h value greater than 2.00 g/L in an oral glucose tolerance test were classified as having type 2 diabetes as well as patients who were already treated with oral antidiabetics or insulin. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated as the product of the fasting insulin value (in µU/mL) and the fasting glucose value (in mmol/L) divided by 22.5.15 Hypertension was diagnosed if the systolic and/or diastolic blood pressure exceeded 140 and/or 90 mmHg or if there was a clinically significant history of hypertension.

Laboratory analysis
Baseline laboratory measurements in LURIC have been described previously.14 Blood collection was done after an overnight fast, in the morning before coronary angiography and samples were snap frozen and stored at –80°C until analysis. FFAs were measured enzymatically (ACS-ACOD method) with an NEFA C kit (Wako Chemicals GmbH, Neuss, Germany) on a Wako 30R analyzer. Inter- and intra-assay coefficients of variations for the FFA assay were 3.0 and 1.6%, respectively. N-terminal pro-B type natriuretic peptide (NT-pro-BNP) was measured by electrochemiluminescence on an Elecsys 2010 (Roche Diagnostics, Mannheim, Germany). Noradrenaline was determined by HPLC (electrochemical detection) with a Chromsystem HPLC Noradrenaline kit (Chromsystems Instruments and Chemical GmbH, Martinsried, Germany).

Follow-up
Information on vital status was obtained from local person registries. Medical records of local hospitals, death certificates, and autopsy data were used for the classification of the causes of death. The descendents were classified into those who died from cardiovascular and non-cardiovascular causes. Death from cardiovascular causes was further subdivided into SCD, fatal myocardial infarction, death due to congestive heart failure, death immediately after intervention to treat CAD, fatal stroke, and other deaths due to cardiac causes. SCD was defined as sudden unexpected death either within 1 h of symptom onset or within 24 h of having been observed alive and symptom free.16 Patients who suffered from any non-cardiac chronic and terminal disease (e.g. cancer) so that their death was not unexpected and persons whose sudden death was most likely attributed to a non-cardiac cause were not coded as an SCD. Three experienced clinicians who were blinded to any data of the study patients independently classified the causes of death. In cases of a disagreement or uncertainty concerning the coding of a specific cause of death, classification was based on majority opinion.

Statistical analysis
We established quartiles of FFA from the values of all study participants. Distributions of continuous variables were examined for skewness and kurtosis and were logarithmically transformed, where appropriate. Baseline characteristics according to quartiles of FFA are presented as percentages for categorical data and as means±standard deviations or as medians with inter-quartile range for continuous data depending on whether or not their distribution was Gaussian. Comparisons between groups were performed with {chi}2 test for categorical data and with analysis of variance (ANOVA) for continuous variables. Kruskal–Wallis test was applied for group comparisons of continuous variables that followed a skewed distribution even after being logarithmically transformed and that violated the ANOVA assumption of equality of error variances. Differences in survival without SCD between the quartiles of FFA were analysed using the Kaplan–Meier method followed by a log-rank test. To further examine the impact of FFA on mortality, we calculated hazard ratios (HRs) and 95% CI using the Cox proportional hazards model. HRs are presented for FFA quartiles using the first quartile as the reference and are also shown per increase of one FFA quartile with multivariate adjustments as indicated. Backward stepwise LR selection method was used and the results of the final step are shown. We tested for plausible interactions between the covariates by adding product terms to our models and we also tested for collinearity. The assumptions underlying the proportional-hazards model were further evaluated with log-minus-log survival and partial (Schönfeld) residuals vs. survival time plots and found valid. All statistical tests were two-sided and a P < 0.05 was considered statistically significant. The SPSS 14.0 statistical package (SPSS Inc., Chicago, IL, USA) was used.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Baseline FFA concentrations were measured in 3315 (99.97%) of our study patients. Angiographic CAD was found in 2231 of the study participants and was ruled out in 1035 participants, whereas the information about angiography was not available in 49 cases. Baseline characteristics of our study participants according to FFA quartiles are shown in Table 1. High levels of FFA levels were significantly associated with age, body mass index, HOMA-IR, triglycerides, systolic and diastolic blood pressure, homocysteine, C-reactive protein, creatinine, NT-pro-BNP, and noradrenaline concentrations. Type 2 diabetes, female gender, systemic hypertension, reduced LV function, and bundle branch block were associated with increased and smoking with decreased FFA concentrations.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline characteristics of the study population stratified by free fatty acid quartiles

 
During a median follow-up time of 6.85 years, 639 persons (19% of the study population) have died, including 416 (12.5%) cardiovascular deaths. SCD, as defined, occurred in 165 of these persons accounting for every fourth (25.8%) case of death. Information about causes of death were not available for 49 deceased persons, whose dates of death were classified as censoring dates. The Kaplan–Meier curves of SCD-free survival according to quartiles of FFA are depicted in Figure 1. The log-rank test showed that the risk for SCD significantly increases across the FFA quartiles (P < 0.001). The Unadjusted HR (and 95% CI) for SCD in the fourth when compared with the first FFA quartile was 2.95 (1.84–4.73; P < 0.001) (Table 2). This HR remained significant after adjustments for several cardiovascular risk factors and the use of medication. In detail, we adjusted for age, sex, body mass index, systolic and diastolic blood pressure, hypertension, HOMA-IR, type 2 diabetes, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol, homocysteine, creatinine, smoking status (current and active smoker: yes/no), CAD, left bundle branch block, C-reactive protein, use of beta-blockers, ACE-inhibitors and statins, NT-pro-BNP, noradrenaline, and LV function. In patients with significant CAD, unadjusted and fully adjusted HRs (according to model 5 in Table 2) for SCD were 3.25 (1.84–5.67; P < 0.001) and 1.72 (0.92–3.22; P = 0.088), and the unadjusted and fully adjusted HRs for SCD per increase of one FFA quartile were 1.48 (1.26–1.75; P < 0.001) and 1.24 (1.02–1.50; P = 0.028), respectively. FFA were also significantly predictive for all-cause and overall cardiovascular mortality. Unadjusted and fully adjusted HRs for all-cause mortality in the fourth when compared with the first FFA quartile were 2.70 (2.14–3.39; P < 0.001) and 1.54 (1.19–2.00; P = 0.001). Unadjusted and fully adjusted HRs for cardiovascular mortality were 3.09 (2.29–4.19; P < 0.001) and 1.61 (1.14–2.26; P = 0.007). After exclusion of patients with SCD, unadjusted and fully adjusted HRs for cardiovascular death were 3.28 (2.22–4.85; P < 0.001) and 1.78 (1.14–2.78; P = 0.011). Unadjusted and fully adjusted HRs for all deaths other than SCD were 2.68 (2.06–3.49; P < 0.001) and 1.58 (1.17–2.13; P = 0.003). There was no significant collinearity or interaction in the Cox proportional hazards models.


Figure 1
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 The Kaplan–Meier curve for sudden cardiac death according to free fatty acid quartiles in the whole study population.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Hazard ratios and 95% confidence intervals for sudden cardiac death according to free fatty acid quartiles with the first quartile as the reference and per increase of 1 SD of logarithmically transformed free fatty acid values

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
Our study shows that high concentrations of fasting blood FFA are an independent risk factor for SCD in patients scheduled for coronary angiography. Furthermore, after exclusion of patients with SCD, high FFA levels remained predictive for all-cause and cardiovascular mortality. These results highlight elevated FFA as a marker for the identification of subjects at high risk for SCD and other fatal cardiovascular events. However, it remains to be determined whether high FFAs are a causal factor in the pathogenesis of these diseases or whether they are elevated in response to other pathological processes that contribute to fatal cardiovascular events.

Several studies support the hypothesis that FFA increase cardiac sympathetic activity and are related to ventricular tachyarrhythmias that are the final common event in SCD.1,2,17–21 FFAs correlate with the frequency of ventricular premature complexes,9 a risk factor for SCD, and are associated with ventricular fibrillation in subjects with myocardial infarction.2,10 Pro-arrhythmic features of FFA that may explain their close association with SCD involve damaging of membranes, increases in reactive oxygen species (ROS), and disturbances of ion channels with subsequent instability of the membrane potential of the cardiomyozytes.2,22,23

A causal role of FFA in the pathogenesis of SCD is further supported by the fact that FFAs are associated with heart failure that is a significant risk factor for SCD.1,7 FFA concentrations are elevated in patients with heart failure because lipolysis is stimulated by high levels of catecholamines in these patients.2,7 Natriuretic peptides (e.g. NT-pro-BNP), which are closely related to heart failure, were also recently shown to exert lipolytic activities.24,25 Furthermore, it was demonstrated that high concentrations of FFA worsen ventricular function, partially mediated through an increase in mitochondrial uncoupling proteins that impair mitochondrial energy production.7 In addition, intralipid/heparin infusions that increase FFA concentrations are associated with raised catecholamine levels and enhanced adrenoreceptor reactivity, therefore suggesting a stimulatory effect of FFA on the sympathetic nervous system.6,17–20 Thus, the hypothesis has been raised of a vicious metabolic cycle, in which catecholamines and natriuretic peptides stimulate an increase in FFA that causes myocardial dysfunction and elevation of lipolytic substances.7 This relationship between high concentrations of FFA and heart failure may partially explain the increased risk for SCD in patients with reduced LV function.1 Trimetazidine, a drug that inhibits beta-oxidation of fatty acids, was shown to reduce ROS generation in the myocardium and improved LV function in patients with heart failure.23,26,27 It remains to be clarified whether the inhibition of fatty acid oxidation with drugs such as trimetazidine could also reduce the incidence of SCD. Considering the significant association between high FFA and SCD in our study, it may be speculated that the protective effect of beta-blockers on SCD may in part be mediated by their ability to reduce FFA levels.1,2

Common cardiovascular risk factors that contribute to the development of CAD are associated with an increased risk for SCD.1 FFAs were also shown to contribute to insulin resistance and hypertension.3,4,6 This relationship between FFA and cardiovascular risk factors (Table 1) may in part explain the link between FFA and SCD but FFA remained a significant predictor for SCD even after adjustments for several cardiovascular risk factors including measures of insulin resistance (HOMA-IR), LV function, or emerging cardiovascular risk factors such as NT-pro-BNP that was also associated with SCD in our study (data not shown).

Interestingly, the risk for SCD and the risk for non-SCD cardiovascular mortality associated with high FFA were very similar suggesting that FFAs are not specifically related to SCD. Hence, high FFA may also be associated with other fatal cardiovascular diseases such as heart failure or myocardial infarction, which were not separately analysed in this work because of insufficient numbers of precisely classified events.5,7,8 However, FFA may be directly involved in the development of atherosclerosis because it was reported that FFAs are associated with endothelial dysfunction and induce endothelial apoptosis and the expression of endothelial adhesion molecules.5,28,29 Further, pro-atherosclerotic features of FFA involve their contribution to macrophage to foam cell formation and their pro-inflammatory effects.5,30 Thus, FFA may not only serve as a risk factor for SCD, but also as a general cardiovascular risk factor.

We want to point out that our results do not prove causality for the association between high FFA concentrations and fatal cardiovascular events. FFA levels are associated with several cardiovascular risk factors but it remains largely unclear whether high FFA levels are mainly a cause or a consequence of these risk factors that are well known to be causally involved in the pathogenesis of cardiovascular diseases including SCD. The established knowledge about the increased lipolysis associated with heart failure, ACS, and other conditions associated with increased sympathetic nervous system activity as well as the impaired ability of insulin to suppress lipolysis in patients with insulin resistance may favour the hypothesis that high FFAs are merely a consequence of other metabolic and cardiovascular disease entities.2,3,7,24 Taking into account that FFA remained a significant predictor for SCD even after adjustments for these cardiovascular risk factors, it could be speculated that FFA reflect certain aspects of metabolic or cardiovascular pathologies that are crucial for the pathogenesis of SCD but are not adequately considered by the risk factors included in our analysis.

Our results may be limited because FFA levels have a relatively high day-to-day variability that is likely to be non-differential and might bias our results toward the null. Furthermore, fasting FFA may not adequately reflect circadian variations of FFA. FFA concentrations strongly depend on the nutritional state with commonly lower FFA levels in the post-prandial period due to insulin-mediated suppression of lipolysis.31 Considering that FFAs are raised in subjects with ACS and are associated with severe arrhythmias and increased mortality risk in these patients,2,13 it might be a promising diagnostic approach to identify those patients who show a strong increase in FFA in response to a catecholamine stimulus. In this context, it should be mentioned that the incidence of SCD is also significantly increased during physical activity and is related to social stress.1 Both conditions are associated with a hyperadrenergic state and subsequently increased FFA levels. A ‘FFA tolerance test’ with a lipolytic agent such as, for example, the adrenergic agonist isoproterenol might therefore identify subjects who are prone to an excessive raise of FFA in ACS, but also in daily stress situations or during physical activity. There is bound to be some apprehension in patients scheduled for coronary angiography and those who over-react at this time are likely to do so when an ACS develops. Blood collection in LURIC was done in the morning before coronary angiography and it is therefore conceivable that levels of FFA were particularly high in those patients with a hyperadrenergic response to the stress situation of a coronary angiography.

It should be noted that our results from a study population at intermediate to high risk for cardiovascular disease fit well with the results from the Paris Prospective study that showed an independent association between high FFA and SCD in men free of known ischaemic cardiac disease at baseline.11 Our results provide important additional information because we are the first to show the association between FFA and SCD in high-risk patients for SCD. In addition, we were able to show that this association remained statistically significant even after multivariable adjustments including several important risk factors for SCD (e.g. LV function) that were not all considered in the Paris Prospective study.

Nevertheless, our results are limited by relatively high CIs (Table 2) warranting confirmation of our findings in further studies with more cases of SCD. Furthermore, we did not ban smoking before blood sampling, which may limit our results in view of data showing an acute increase of FFA after smoking.32

In summary, our study shows that elevated plasma FFA are an independent risk factor for SCD in patients referred to coronary angiography. These results point to the need for future investigations that further address the question whether the association between high FFA and future SCD is causal and might therefore provide an epidemiological background for therapeutic approaches aiming to modulate FFA metabolism in the prevention of SCD.33,34


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
The authors extend their appreciation to the participants of the LURIC study because without their collaboration this article would not have been written. We thank the LURIC study team either temporarily or permanently involved in patient recruitment and sample and data handling and the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg, Ulm, and Graz and the German registration offices and local public health departments for their assistance. We are grateful to Professor Emeritus MF Oliver (London) for advice and for reading this manuscript. B.O.B. was supported by the Deutsche Forschungsgemeinschaft, GRK 1041 and SFB 518.

Conflict of interest: none declared.


   Footnotes
 
The originally published version of this paper was incorrect. On page 5, footnote ‘b’ to Table 2 contained some errors. This has now been corrected.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association the Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death—executive summary: A report of the American College of cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J (2006) 27:2099–2140.[Free Full Text]
  2. Oliver MF. Sudden cardiac death: the lost fatty acid hypothesis. QJM (2006) 99:701–709.[Abstract/Free Full Text]
  3. Blaak EE. Fatty acid metabolism in obesity and type 2 diabetes mellitus. Proc Nutr Soc (2003) 62:753–760.[CrossRef][Web of Science][Medline]
  4. Roden M. Mechanisms of disease: hepatic steatosis in type 2 diabetes: pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab (2006) 2:335–348.[CrossRef][Web of Science][Medline]
  5. Oram JF, Bornfeldt KE. Direct effects of long-chain non-esterified fatty acids on vascular cells and their relevance to macrovascular complications of diabetes. Front Biosci (2004) 9:1240–1253.[Web of Science][Medline]
  6. Sarafidis PA, Bakris GL. Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance? J Hum Hypertens (2007) 21:12–19.[CrossRef][Web of Science][Medline]
  7. Opie LH. The metabolic vicious cycle in heart failure. Lancet (2004) 364:1733–1734.[CrossRef][Web of Science][Medline]
  8. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev (2005) 85:1093–1129.[Abstract/Free Full Text]
  9. Paolisso G, Gualdiero P, Manzella D, Rizzo MR, Tagliamonte MR, Gambardella A, Verza M, Gentile S, Varricchio M, D'Onofrio F. Asociations of fasting plasma free fatty acid concentration and frequency of ventricular premature complexes in nonischemic non-insulin-dependent diabetic patients. Am J Cardiol (1997) 80:932–937.[CrossRef][Web of Science][Medline]
  10. Azzazy HM, Pelsers MM, Christenson RH. Unbound free fatty acids and heart-type fatty acid-binding protein: diagnostic assays and clinical applications. Clin Chem (2006) 52:19–29.[Abstract/Free Full Text]
  11. Jouven X, Charles MA, Desnos M, Duciemetiere P. Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation (2001) 104:756–761.[Abstract/Free Full Text]
  12. Charles MA, Fontbonne A, Thibult N, Claude JR, Warnet JM, Rosselin G, Ducimetiere P, Eschwege E. High plasma nonesterified fatty acids are predictive of cancer mortality but not of coronary heart disease mortality: results from the Paris Prospective Study. Am J Epidemiol (2001) 153:292–298.[Abstract/Free Full Text]
  13. Pilz S, Scharnagl H, Tiran B, Seelhorst U, Wellnitz B, Boehm BO, Schaefer JR, März W. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease. J Clin Endocrinol Metab (2006) 91:2542–2547.[Abstract/Free Full Text]
  14. Winkelmann BR, März W, Boehm BO, Zotz R, Hager J, Hellstern P, Senges J, LURIC Study Group (LUdwigshafen RIsk and Cardiovascular Health). Rationale and design of the LURIC study: a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics (2001) 2:1–73.[Medline]
  15. Matthews DR, Hosker JR, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia (1985) 28:412–419.[CrossRef][Web of Science][Medline]
  16. Chugh SS, Jui J, Gunson K, Stecker EC, John BT, Thompson B, Ilias N, Vickers C, Dogra V, Daya M, Kron J, Zheng ZJ, Mensah G, McAnulty J. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol (2004) 44:1268–1275.[Abstract/Free Full Text]
  17. Stepniakowski KT, Goodfried TL, Egan BM. Fatty acids enhance vascular {alpha}-adrenergic sensitivity. Hypertension (1995) 25:774–778.[Abstract/Free Full Text]
  18. Grekin RJ, Vollmer AP, Sider RS. Pressor effects of portal venous oleate infusion. Hypertension (1995) 26:193–198.[Abstract/Free Full Text]
  19. Paolisso G, Manzella D, Rizzo MR, Ragno E, Barbieri M, Varricchio G, Varricchio M. Elevated plasma fatty acid concentrations stimulate the cardiac autonomic nervous system in healthy subjects. Am J Clin Nutr (2000) 72:723–730.[Abstract/Free Full Text]
  20. Manzella D, Barbieri M, Rizzo MR, Ragno E, Passariello N, Gambardella A, Marfella R, Giugliano D, Paolisso G. Role of free fatty acids on cardiac autonomic nervous system in noninsulin-dependent diabetic patients: effects of metabolic control. J Clin Endocrinol Metab (2001) 86:2769–2774.[Abstract/Free Full Text]
  21. Oliver MF, Kurien VA, Greenwood TW. The relation between serum free fatty acids and arrhythmias and death after acute myocardial infarction. Lancet (1968) 1:710–715.[Web of Science][Medline]
  22. Oliver MF, Opie LH. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet (1994) 343:155–158.[CrossRef][Web of Science][Medline]
  23. Gambert S, Vergely C, Filomenko R, Moreau D, Bettaieb A, Opie LH, Rochette L. Adverse effects of free fatty acid associated with increased oxidative stress in postischemic isolated rat hearts. Mol Cell Biochem (2006) 283:147–152.[CrossRef][Web of Science][Medline]
  24. Birkenfeld AL, Boschmann M, Moro C, Adams F, Heusser K, Franke G, Berlan M, Luft FC, Lafontan M, Jordan J. Lipid mobilization with physiological atrial natriuretic peptide concentrations in humans. J Clin Endocrinol Metab (2005) 90:3622–3628.[Abstract/Free Full Text]
  25. Goetze JP, Mogelvang R, Maage L, Scharling H, Schnohr P, Sogaard P, Rehfeld JF, Jensen JS. Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction. Eur Heart J (2006) 27:3004–3010.[Abstract/Free Full Text]
  26. Fragasso G, Perseghin G, De Cobelli F, Esposito A, Palloshi A, Lattuada G, Scifo P, Calori G, Del Maschio A, Margonato A. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatinine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J (2006) 27:942–948.[Abstract/Free Full Text]
  27. Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol (2006) 48:992–998.[Abstract/Free Full Text]
  28. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest (1997) 100:1230–1239.[Web of Science][Medline]
  29. Hufnagel B, Dworak M, Soufi M, Mester Z, Zhu Y, Schaefer JR, Klumpp S, Krieglstein J. Unsaturated fatty acids from human lipoproteins activate protein phosphatase type 2Cß and induce apoptosis in endothelial cells. Atherosclerosis (2005) 180:245–254.[CrossRef][Web of Science][Medline]
  30. Lloyd EE, Gaubatz JW, Burns AR, Pownall HJ. Sustained elevations in NEFA induce cyclooxygenase-2 activity and potentiate THP-1 macrophage to foam cell formation. Atherosclerosis. Published online ahead of print 2006.
  31. Frayn KN. Plasma non-esterified fatty acids: why are we not measuring them routinely? Ann Clin Biochem (2005) 42:413–414.[CrossRef][Web of Science][Medline]
  32. Kershbaum A, Bellet S, Dickstein ER, Feinberg LJ. Effect of cigarette smoking and nicotine on serum free fatty acids: Based on a study in human subjects and the experimental animal. Circ Res (1961) 9:631–638.[Abstract/Free Full Text]
  33. Folmes CD, Clanachan AS, Lopaschuk GD. Fatty acid oxidation inhibitors in the management of chronic complications of atherosclerosis. Curr Atheroscler Rep (2005) 7:63–70.[CrossRef][Medline]
  34. Frayn KN, Fielding BA, Karpe F. Adipose tissue fatty acid metabolism and cardiovascular disease. Curr Opin Lipidol (2005) 16:409–415.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
D. J. Chess and W. C. Stanley
Role of diet and fuel overabundance in the development and progression of heart failure
Cardiovasc Res, July 15, 2008; 79(2): 269 - 278.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
D. Mozaffarian
Free fatty acids, cardiovascular mortality, and cardiometabolic stress
Eur. Heart J., November 2, 2007; 28(22): 2699 - 2700.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
28/22/2763    most recent
ehm343v2
ehm343v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Pilz, S.
Right arrow Articles by März, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pilz, S.
Right arrow Articles by März, W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?