AJCN North Carolina Research Campus
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
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 Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marfella, R.
Right arrow Articles by Giugliano, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marfella, R.
Right arrow Articles by Giugliano, D.
Agricola
Right arrow Articles by Marfella, R.
Right arrow Articles by Giugliano, D.
American Journal of Clinical Nutrition, Vol. 73, No. 1, 27-30, January 2001
© 2001 American Society for Clinical Nutrition

Original Research Communication

Elevated plasma fatty acid concentrations prolong cardiac repolarization in healthy subjects1,2

Raffaele Marfella, Lorenita De Angelis, Francesco Nappo, Daniela Manzella, Mario Siniscalchi, Giuseppe Paolisso and Dario Giugliano

1 From the Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples.

2 Reprints not available. Address correspondence to R Marfella, via Emilio Scaglione, 141 I-80145 Naples, Italy. E-mail: dario.giugliano{at}unina2.it.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: High fatty acid concentrations have been shown to stimulate sympathetic nervous system activity, which may modify ventricular repolarization and thus the Q-T interval on electrocardiogram recordings.

Objective: The aim of this study was to investigate whether acute elevations of plasma fatty acid concentrations influence the corrected Q-T interval (Q-Tc), Q-Tc dispersion, and sympathetic nervous system activity in healthy nonobese subjects.

Design: Thirty-two healthy subjects ( ± SD: 48 ± 7 y of age) received an infusion of 10% triacylglycerol emulsion plus heparin (a bolus of 200 U followed by 0.2 Umin-1•kg body wt-1 for 180 min); on another occasion and in random order, the same subjects received a saline infusion.

Results: Compared with the saline infusion, infusion of 10% triacylglycerol emulsion increased plasma fatty acids (P < 0.001) and was associated with an increase in mean blood pressure (P < 0.05), heart rate (P < 0.05), Q-Tc (P < 0.01), Q-Tc dispersion (P < 0.01), and plasma epinephrine (P < 0.005). Furthermore, individual changes in plasma epinephrine correlated with changes in Q-Tc (r = 0.60, P < 0.001) and Q-Tc dispersion (r = 0.53, P < 0.02) even after adjustment for age, sex, and body mass index (P < 0.03 for all correlations). Only changes in plasma fatty acids (P = 0.04) and plasma epinephrine (P = 0.006) concentrations were significantly and independently associated with the lengthening of the Q-T interval.

Conclusion: Our study showed that elevated plasma fatty acid concentrations might affect cardiac repolarization, at least in part because of an increase in plasma catecholamines.

Key Words: Fatty acids • Q-T interval • Q-Tc dispersion • catecholamines • cardiac repolarization


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Elevated plasma fatty acid concentrations have been associated with an increased number of ventricular premature complexes and sudden death in nondiabetic subjects (1) and in nonischemic diabetic patients (2). High fatty acid concentrations have been shown to stimulate sympathetic nervous system (SNS) activity in rats (3) and to activate calcium channels in ventricular myocytes (4). Both fatty acid–related SNS overactivity and detergent effects of fatty acid on plasma membrane composition (5) might explain the occurrence of arrhythmia and sudden death in obese subjects (6), in whom elevated fatty acid concentrations is a common finding (7).

It is widely accepted that the SNS may influence ventricular electrical activity by modifying ventricular repolarization and thus the Q-T interval on electrocardiogram recordings (8). A prolonged heart rate–adjusted Q-T interval (corrected Q-T interval; Q-Tc) is a risk factor for sudden death in patients with the long-Q-T interval syndrome and in myocardial infarction patients (9). Interestingly, obesity (10) is associated with a rise in plasma fatty acid concentrations and a lengthening of the Q-T interval, whereas the opposite occurs in patients after weight loss (11). Because changes in plasma fatty acid concentrations may exert a stimulatory effect on sympathetic activity (6), one cannot exclude that a rise in fatty acid plasma concentrations might be responsible for the prolongation of the Q-T interval. The aim of this study was to investigate the effect of acute elevations in plasma fatty acids on the Q-Tc, Q-Tc dispersion, and sympathetic activity in healthy, nonobese subjects.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experimental design
Thirty-two healthy subjects volunteered for the study after a clear explanation of its experimental nature. All subjects had normal blood pressure, had no diabetes or hyperlipidemia, had no family history of premature vascular disease, and were nonsmokers. All subjects were following a weight-maintaining diet providing 250 g carbohydrate/d and had no recent change in body weight or intercurrent illness (Table 1Go). All subjects gave informed consent to participate in the study, which was approved by the ethical committee of our institution.


View this table:
[in this window]
[in a new window]
  		TABLE 1.. Characteristics of the study group1
 
After an overnight fast, all subjects received an infusion of 10% triacylglycerol emulsion (Intralipid; Pharmacia, Uppsala, Sweden) plus heparin (a bolus of 200 U followed by 0.2 U•min-1•kg body wt-1) for 180 min. On another occasion, and in random order, the same subjects received a control infusion of saline solution (0.9% NaCl) that was matched to the overall volume and duration of the 10% triacylglycerol emulsion infusion. No more than 1 wk elapsed between the 2 studies in the same subject. A subset of 6 subjects also received an infusion of propranolol (100 µg/kg over 10 min followed by 1 mg•kg-1•min-1; Inderal Zeneca, Milan, Italy), followed 10 min later by an infusion of 10% triacylglycerol emulsion plus heparin. Heart activity was recorded with a standard resting 12-lead electrocardiogram at 50 mm/s in the basal state and at the end of the infusions. A cardiologist who was blinded to other information conducted the Q-T interval analysis. Q-T intervals were corrected with Bazett's formula (Q-Tc = Q-T/{surd}R-R) (12); Q-Tc dispersion was calculated as the interlead variability in the Q-Tc (Q-Tc dispersion = Q-Tc maximum - Q-Tc minimum). Blood pressure and heart rate at baseline and during and at the end of the infusion were monitored in real time by using a Finapres apparatus (Ohmeda, Englewood, CO) (13).

Analytic methods
Plasma glucose was determined with the glucose oxidase method (Autoanalyzer; Beckman, Fullerton, CA). Blood samples for insulin determination were collected into heparin-containing tubes. After centrifugation (2500 x g, 5 min, 15°C), serum insulin was determined by using a commercially available radioimmunoassay kit (Sorin Biomedical, Milan, Italy; CV: 3.2 ± 0.3%). Plasma fatty acids were determined according to the method of Dole and Meinertz (14). Plasma epinephrine and norepinephrine were determined by HPLC.

Calculation and statistical analyses
Mean blood pressure was calculated as diastolic blood pressure plus one-third of pulse pressure. Individual changes in plasma hormone concentrations were calculated as the difference between the values found at 180 min and baseline values. To approximate normal distribution, insulin concentrations were log-transformed and then back-transformed for final presentation in standard units. Changes over time between treatments were assessed by analysis of covariance with the time 0 values as the covariate. Pearson's product-moment correlation coefficients were used. Partial correlation allowed us to test the relation between 2 variables independent of a covariate. Multivariate analysis allowed an evaluation of the independent role of age, body mass index (BMI), and change in fatty acid concentrations on the lengthening of the Q-T interval. A P value of 0.05 was chosen as the level of significance. SPSS (version 10.0; SPSS Inc, Chicago) was used for the analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The infusion of the 10% triacylglycerol emulsion was associated with a significant rise in plasma fatty acid, triacylglycerol, epinephrine, and norepinephrine concentrations, whereas there were no significant changes in plasma glucose and insulin concentrations (Table 2Go).


View this table:
[in this window]
[in a new window]
  		TABLE 2.. Changes in plasma metabolic indexes occurring during the control and 10% triacylglycerol emulsion infusions1
 
The infusion of 10% triacylglycerol emulsion was also associated with a rise in mean blood pressure (from 85.1 ± 2.2 to 88.9 ± 2.4 mm Hg; P < 0.05). Changes in heart rate, Q-Tc, and Q-Tc dispersion during infusion of the 10% triacylglycerol emulsion and saline solution are reported in Figure 1Go. The infusion of 10% triacylglycerol emulsion produced a significant increase in heart rate and Q-Tc dispersion. Intravenous propranolol was associated with no significant changes in basal Q-Tc values and did not significantly influence the increase in the Q-Tc seen during triacylglycerol infusion. In fact, the Q-Tc increased from 359.2 ± 18 ms at 0 min to 385.3 ± 27 ms at 180 min (P < 0.01) during combined infusion of propranolol and triacylglycerol.



View larger version (13K):
[in this window]
[in a new window]
  		FIGURE 1. . Effects of the control saline infusion and the 10% triacylglycerol emulsion infusion on the heart rate, the corrected Q-T interval (Q-Tc), and Q-Tc dispersion in 32 healthy subjects. *,**,***Significantly different from the control infusion: *P < 0.05, **P < 0.01, ***P< 0.01.

 
No significant change in any of the variables considered was seen during the saline infusion (Figure 1Go and Table 2Go). In particular, mean blood pressure values were 86.2 ± 4.2 mm Hg at baseline and 85.9 ± 3.9, 86.7 ± 5.1, and 84.9 ± 4.6 mm Hg at 60, 120, and 180 min, respectively.

Individual changes in plasma fatty acid concentrations correlated with changes in the Q-Tc (r = 0.63, P < 0.001), Q-Tc dispersion (r = 0.54, P < 0.02), and plasma epinephrine concentrations (r = 0.69, P < 0.005). Furthermore, individual changes in plasma epinephrine also correlated with changes in the Q-Tc (r = 0.60, P < 0.01) and Q-Tc dispersion (r = 0.53, P < 0.02). All such changes were still significant after adjustment for age, sex, and BMI (P < 0.03 for all correlations). In the stepwise multivariate analysis, the independent role of age, BMI, waist-to-hip ratio, and change in plasma fatty acid concentrations on lengthening of the Q-T interval was investigated. The whole model explained 47% of the variability in the lengthening of the Q-T interval with BMI (P < 0.05), and changes in plasma fatty acid concentrations (P < 0.001) were significantly and independently associated with the dependent variable. Addition of changes in plasma epinephrine concentrations among the independent variables increased the significance of the model, allowing it to explain 63% of the variability of the lengthening of the Q-T interval. Nevertheless, in such a model, only changes in plasma fatty acid (P = 0.04) and plasma epinephrine (P = 0.006) concentrations were significantly and independently associated with the lengthening of the Q-T interval.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study showed that acute increases in plasma fatty acid concentrations produce a lengthening of both the Q-Tc and Q-Tc dispersion in healthy subjects. The length of the Q-T interval, which is easily obtained from the use of a standard resting electrocardiogram, represents the time interval between the start of activation of the ventricle and the completion of its repolarization. The Q-T interval is influenced by the autonomic tone and represents an index of myocardial refractoriness and electrical stability; this is a critical determinant of ventricular fibrillation and sudden death (15). An association between a prolonged Q-T interval and sudden cardiac death was found in patients with coronary artery disease, congestive heart failure, and obesity (16, 17). Dispersion of repolarization is a consequence of the predominance of SNS activity and might be responsible for a high risk of ventricular fibrillation (18). Sympathetic stimulation unopposed by vagal activity might induce ventricular electrical instability, resulting in risk of arrhythmia and sudden death (19).

Fatty acid concentrations might affect Q-Tc and Q-Tc dispersion through a stimulation of SNS activity. In our study, acute elevations in fatty acid concentrations were associated with a rise in sympathetic activity, as evidenced by increased plasma catecholamine concentrations. The increased heart rate and the partial inhibition of the Q-Tc during the propranolol infusion also suggests an effect of fatty acid concentrations on cardiac repolarization mediated, at least in part, by an increase in plasma catecholamines. The link between plasma fatty acid concentrations and cardiac repolarization is also strengthened by the correlation between individual changes in plasma epinephrine concentrations and the Q-Tc or Q-Tc dispersion, a relation that is associated with changes in plasma fatty acid concentrations. Furthermore, in the multivariate analysis, changes in plasma fatty acids were independently associated with the lengthening of the Q-T interval. Whether the effect of fatty acid concentrations on the Q-Tc is mediated by the increase in plasma catecholamines or is also due to an effect on the central nervous system is unknown. Notwithstanding, the multivariate analysis encompassing age, BMI, waist-to-hip ratio, and both changes in plasma fatty acid and epinephrine concentrations showed that both plasma fatty acid and epinephrine concentrations remained statistically significant. Thus, plasma fatty acid concentrations, at least in part, are responsible for a direct effect on the lengthening of the Q-T interval. The latter possibility is also strengthened by evidence that prolongation of the Q-T interval might also result from a disturbed myocardial membrane function that, in turn, might be responsible for electrical instability (20). Indeed, it was shown previously that elevated fatty acid concentrations may inhibit Na+/K+-exchanging ATPase (21), resulting in disturbed myocardial membrane function. Nevertheless, only future studies specifically designed to assess such a possibility will clarify such a possible pathophysiologic relation.

A significant correlation between postprandial lipemia and common carotid intima media thickness was found previously in healthy middle-aged men (22). Similarly, there is a relation between cardiovascular mortality and postprandial hyperlipemia (23). Because the elevations in triacylglycerol concentrations obtained in our artificial model were similar to those observed during the postprandial phase, it is possible that modifications in the Q-T interval may occur during this phase. To our knowledge, this topic has never been addressed.

In conclusion, our study showed that elevated plasma fatty acid concentrations might affect cardiac repolarization. Such an effect seems partially mediated by an increase in plasma catecholamine concentrations. Our results may offer a novel mechanism for explaining the relation between increased visceral fat and elevated cardiovascular risk.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Paolisso G, Gualdiero P, Manzella D, et al. Hyperinsulinemia is associated with ventricular premature complexes. Metabolism 1996;45:1248–53.[Medline]
  2. Paolisso G, Gualdiero P, Manzella D, et al. Association of fasting plasma FFA concentration and frequency of ventricular premature complexes in non-ischemic non-insulin dependent diabetic patients. Am J Cardiol 1997;80:932–7.[Medline]
  3. Grekin RJ, Vollmer AP, Sider RS. Pressor effect of portal venous oleate infusion. A proposed mechanism for obesity hypertension. Hypertension 1995;26:195–8.
  4. Huang JMC, Xian X, Becaner M. Long-chain fatty acids activate calcium channels in ventricular myocytes. Proc Natl Acad Sci U S A 1992;89:6452–6.[Abstract/Free Full Text]
  5. Kuriem VA, Olivier MF. A metabolic cause of arrhythmias. Lancet 1970;1:813–5.[Medline]
  6. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J 1984;289:1257–61.
  7. De Fronzo RA, Ferranini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 1991;14: 173–94.[Abstract]
  8. Schwartz PJ, Priori SG. Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP, Jalife J, eds. Cardiac electrophysiology: from cell to bedside. Philadelphia: WB Saunders, 1990:330–43.
  9. Peters RW, Byington RP, Barker A, Yusuf S. BHAT Study Group. Prognostic value of prolonged ventricular repolarization following myocardial infarction: The BHAT experience. J Clin Epidemiol 1990;43:167–72.[Medline]
  10. Park JJ, Swan PD. Effect of obesity and regional adiposity on the QTc interval in women. Int J Obes Relat Metab Disord 1997;21:1104–10.[Medline]
  11. Pidlich J, Pfeffel F, Zwiauer K, Schneider B, Schmidinger H. The effect of weight reduction on the surface electrocardiogram: a prospective trial in obese children and adolescents. Int J Obes Relat Metab Disord 1997;21:1018–23.[Medline]
  12. Bazett HC. An analysis of time relations of the electrocardiogram. Heart 1920;7:353–70.
  13. Parati G, Casadei R, Groppelli A, Di Rienzo M, Mancia G. Comparison of finger and intra-arterial blood pressure monitoring at rest and during laboratory testing. Hypertension 1989;13:647–55.[Abstract/Free Full Text]
  14. Dole VP, Meinertz H. Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem 1960;235:2595–9.[Free Full Text]
  15. Ahnve S, Vallin H. Influence of heart rate and inhibition of autonomic tone on the QT interval. Circulation 1982;65:435–9.[Abstract/Free Full Text]
  16. Barr CS, Nans A, Freeman M, Lang C, Struthers AD. QT dispersion and sudden unexpected death in chronic heart failure. Lancet 1994; 343:327–9.[Medline]
  17. Vlay SC, Mallis GL, Brown EJ, Cohon PF. Documented sudden cardiac death in prolonged QT syndrome. Arch Intern Med 1984;144: 833–4.[Abstract]
  18. Watanabe T, Ashikaga T, Nishizaki M, Yamawake N, Arita M. Association of insulin with QTc dispersion. Lancet 1997;350:1821–2.[Medline]
  19. Zipes DP. The long QT interval syndrome: a Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 1991;84: 1414–9.[Free Full Text]
  20. Ben-David J, Zipes DP. Differential response to right and left ansae subclaviae stimulation of early after depolarizations and ventricular tachycardia induced by cesium in dogs. Circulation 1988;78:1241–50.[Abstract/Free Full Text]
  21. Kelly RA, O'Hara DS, Mitch WE, Smith TW. Identification of NaK-ATPase inhibitors in human plasma as nonesterified fatty acids and lysophospholipids. J Biol Chem 1986;261:11704–11.[Abstract/Free Full Text]
  22. Boquist S, Ruotolo G, Tang R, et al. Alimentary lipemia, postprandial triglyceride-rich lipoproteins and common carotid intima-media thickness in healthy, middle-aged men. Circulation 1999; 100:723–8.[Abstract/Free Full Text]
  23. Patsch JR, Miesenbock G, Hopferwieser T, et al. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb 1992;12:1336–45.[Abstract/Free Full Text]
Received for publication September 16, 1999. Accepted for publication April 20, 2000.




This article has been cited by other articles:


Home page
 CirculationHome page
P. Poirier, T. D. Giles, G. A. Bray, Y. Hong, J. S. Stern, F. X. Pi-Sunyer, and R. H. Eckel
Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss: An Update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease From the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism
Circulation, February 14, 2006; 113(6): 898 - 918.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. M. Corbi, S. Carbone, P. Ziccardi, G. Giugliano, R. Marfella, F. Nappo, G. Paolisso, K. Esposito, and D. Giugliano
FFAs and QT Intervals in Obese Women with Visceral Adiposity: Effects of Sustained Weight Loss Over 1 Year
J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2080 - 2083.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
M. R Goldstein
Fat emulsion infusions and prolongation of the Q-T interval
Am. J. Clinical Nutrition, August 1, 2001; 74(2): 272 - 272.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
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 Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marfella, R.
Right arrow Articles by Giugliano, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marfella, R.
Right arrow Articles by Giugliano, D.
Agricola
Right arrow Articles by Marfella, R.
Right arrow Articles by Giugliano, D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS