3ouml of Molecular
and Cellular
Cardiology
Are Free Fatty
(1975)
Acids
7, 155-159
Arrhythmogenic?
The letter by Dr E. Wasilewska-Dziubinska [19] raises new aspects concerning the contentious question of the effects of free fatty acids (FFA) on the rhythm of the heart. Evidence concerning the possible arrhythmogenicity of FFA stems from observations on the hearts of small animals (rats and guinea-pigs), large animals (dogs) and man.
1. Small
animals
Dr Wasilewska-Dziubiriska states that sodium palm&ate could profoundly change the epicardial action potential of the guinea-pig heart. Such data are of great interest because of the possibility that glycolytically produced ATP may be of special importance in the maintenance of the action potential duration [I, 61; hence palmitate as sole exogenous fuel could be expected to reduce duration of the action potential. Dr Wasilewska-Dziubiriska also reports that the changes in the action potential ‘rusually” led to spontaneous or electrically provoked fibrillation. Detailed analysis of this interesting finding must await publication of the definitive article which is still in press [20]. Nevertheless, it is surprising that physiological concentrations of palmitate (0.5 mM) bound to physiological concentrations of albumin (4g/lOO ml) with an FFA: albumin molar ratio of about 1: 1 should have produced fibrillation even in the presence of glucose, because a considerably higher FFA: albumin molar ratio (6:l) was required consistently to produce fibrillation in the isolated rat heart study of Willebrands et al. [21]. Evans et al. [3] perfused rat hearts with FFA: albumin molar ratios of 12 : 1 without noting ventricular fibrillation. Several possible explanations of the work of Wasilewska-Dziubinska [19] must be considered. First, the guinea-pig heart might be exceptionally prone to arrhythmias. Secondly, there might be technical factors promoting arrhythmias in the perfusion system, but such considerations must await the full publication. Possibly the insertion of the microelectrode could act as an irritable focus. It would be important to know the heart rates and coronary flow rates throughout the perfusion period, so as to ensure that the isolated heart was not hypoxic. Thirdly, there could be problems in the preparation of the FFA : albumin complex. Albumin is known to have various effects on the heart and some preparations are toxic even after exhaustive dialysis. Other batches can be used without dialysis [IO].
156
L.
H.
OPIE
AND
W.
F.
LUBBE
For the above reasons the data of Wasilewska-Dziubinska [19] do not necessarily give conclusive support to the concept that FFA are arrhythmogenic. 2. Large
animals
In dogs there appears to be conflicting evidence. Oliver and co-workers have produced convincing experimental data suggesting a close association between abrupt elevation of plasma free fatty acid values and the occurrence of arrhythmias following balloon distention of the circumflex coronary artery [S]. On the other hand, our co-workers [I31 failed to reproduce these results in an open-chest greyhound preparation with acute coronary artery ligation; Mjos [7] apparently confirmed these negative results. As it has been suggested that the closed-chest model is a better reflection of events in man than is an open-chest model [Z] we decided to re-examine the question in a closed-chest dog with experimental coronary thrombosis. Under morphine sedation the left coronary artery of the conscious sedated dog was catheterised and a thrombus electrolytically induced in the anterior descending or circumflex branch of the left coronary artery by passage of a current of 300 PA for 1 h, using a modified method of Salazar [IS]. After approximately 2 to 4 h, blood free fatty acids were abruptly elevated by the rapid intravenous infusion of at least 50 ml 10% Intralipid together with heparin (12 500 units/50 ml). Arterial blood samples were taken throughout the procedure from a femoral artery catheter. A total of 27 dogs were studied. Seven dogs developed early ventricular fibrillation during the cautery procedure due to left main coronary artery obstruction and these dogs were eliminated from further evaluation. Of the remaining animals, 8 served as controls. They were given 50 cc of 0.5~ saline (0.45 g/100 ml) and 3 of the 8 developed an increased incidence of ectopic beats in the hour after injection. By 4 to 8 h post-cautery, all animals developed virtually continuous ventricular tachycardia which lasted for about 2 days and then passed over spontaneously. The ventricular ectopic beats were frequently multiform in nature, but the rate of ventricular tachycardia was relatively slow at 150 to 190 beats/min. The R-on-T phenomenon was frequently observed in the late phase arrhythmias, but did not appear to have prognostic significance for the onset of ventricular fibrillation. Twelve other dogs were given Intralipid-heparin l-2 hours after the end of cautery raising the arterial FFA concentration to over 3000 pEq/l, and in 6 there were apparently positive effects in increasing the rate of ectopic beats; one of these animals developed ventricular fibrillation. The average serum albumin of the dogs was 1.5 g/ 100 ml, hence the peak FFA : albumin molar ratio was over 13 : 1. When 6 animals had reached the stage of totally irregular rhythm (Harris phase III) further injections of Intralipid-heparin did not precipitate ventricular fibrillation. These results are summarised in Table 1. Both in this work in the closed-chest animal with electrolytically induced coronary
LETTERS
TABLE
TO
1. Results of Intralipid-heparin coronary thrombosis
THE
157
EDITOR
infusion on heart rhythm of dogs with closed-chest
Positive effects after Intralipid-heparin A. Administration on 1st day Effects
within
Positive effects after control injections
of Intralipid-heparin 1 hour
Increased incidence of ectopic beats, including ventricular fibrillation in one
6112
case
50%
318 41%
B. Late administration of Intralipid-heparin During phase of total irregularity (2-3 days post-thrombosis) Effect in precipitating ventricular fibrillation
thrombosis, and in previous work with coronary artery ligation in an open-chest greyhound [13] it was not possible persistently to precipitate serious arrhythmias by Intralipid-heparin (as a means of elevating free fatty acids). A larger series is needed to test whether there might be an arrhythmogenic effect of infused FFA (in the form of triglyceride-heparin) in our dogs on the first day of coronary thrombosis but in the present series no consistent trends were found. In the late phase arrhythmias, triglyceride-heparin clearly failed to provoke ventricular fibrillation, which is of importance because Smith and Duce [18] recently reported a reduction in the late phase arrhythmias in dogs after the use of an anti-lipolytic nicotinic acid analogue. We believe that these late phase arrhythmias do not have prognostic importance for the development of ventricular fibrillation, as evidenced by their spontaneous disappearance in spite of the frequent occurrence of the R-on-T phenomenon. The resemblance to rhythm disturbances after human myocardial infarction seems remote. In our previous study, elevation of free fatty acids by Intralipid-heparin was shown to be arrhythmogenic in the presence of adrenaline infusion, raising the possibility that FFA and catecholamines could act together to promote arrhythmias [13]. Nevertheless, it should be noted that FFA uptake by the heart can be elevated by suppressor doses of noradrenaline with an apparent decrease in the incidence of arrhythmias [14].
3. Patients
with
acute
myocardial
In patients with acute myocardial infarction, correspondence columns of The Lancet [9,18].
infarction
the situation has been debated in the It could be argued that the evidence
158
L. H. OPIE
AND
YV. F. LUBBE
both for and against FFA being arrhythmogenic in clinically relevant concentrations is in the balance. The scales are likely to be tipped in favour of an arrhythmogenic role for FFA by the recent data of Rowe and Oliver [15] who administered an anti-lipolytic agent to patients with myocardial infarction within the first few hours of onset and found a decreased incidence of serious ventricular arrhythmias. However, studies with anti-lipolytic agents may need somewhat guarded interpretation because there are direct depressant effects of nicotinic acid (2 to 10 mM) or of P-pyridylcarbinol (1 to 5 mu) on the contraction force, frequency and efficiency of contraction of isolated beating guinea-pig atria [17]. These may well not be clinically relevant concentrations, but the possibility is raised that this category of compounds might have some direct action on the heart. The effects of antilipolytic agents on coronary blood flow, as adequately measured by techniques such as the administration of microspheres to dogs with coronary artery occlusion, also need consideration and have apparently not been reported. Thus, in the action of anti-lipolytic agents on arrhythmias in patients with acute myocardial infarction, it is at least conceivable that such agents may act in ways other than depression of circulating FFA. It would be of undoubted interest if other clinical situations, in which FFA could be arrhythmogenic, were also investigated e.g. asthmatics taking sympathomimetic drugs and at risk of ventricular fibrillation, and diabetics out of control with high circulating FFA values. It should be noted that the above comments relate solely to the question of the effect of FFA on arrhythmias. The possible effects ofcirculating FFA on contractility or infarct size are not presently under discussion. In summary, the important question of the arrhythmogenicity of FFA in clinical and experimental situations remains one for continued intensive investigation. Widely different experimental results still need explanation. It would be important to have a better understanding of which combination of experimental or clinical factors could allow otherwise “non-toxic” concentrations of FFA to become arrhythmogenic. The Ischaemic Heart Disease Laboratory is supported by the Medical Research Council of South Africa and the Chris Barnard Fund. L. H. OPIE Ischaemic Heart Disease Laborutoy, W. F. LUBBE Department of Medicine, University of Cape Town, South Africa REFERENCES 1.
CHANEVAL,
Metabolism, 2. 3.
Physiologie EDITORIAL,
J.-P., HYDE, A., BLONDEL, B. & GIRADIER, L. Heart cells in culture. action potential and transmembrane ionic movements. 3ournal de 64, 413-430
(1972).
Free fatty acids and heart attacks. Lancet 1, 843-844 (197 1). EVANS, J. R., OPIE, L. H. & SHIPP, J. C. Metabolism of palmitic acid in perfused rat heart. American Journal of PhysioloD 205, 766-770 (1963).
LETTERS
4.
5.
6. 7. 8.
9. 10.
11. 12. 13.
14.
15.
16. 17.
18.
19.
20.
21.
TO THE
EDITOR
159
GUPTA, D. K., YOUNG, R., JEWITT, D. E., HARTOG, M. & OPIE, L. H. Increased plasma-free-fatty-acid concentrations and their significance in patients with acute myocardial infarction. Lancet 2, 1209-1213 (1969). KURIEN, A., YATES, P. A. & OLIVER, M. F. The role offree fatty acids in the production of ventricular arrhythmias after acute coronary artery occlusion. European Journal of Clinical Investigation 1, 225-241 (197 1). MCDONALD, T. F. & MACLEOD, D. P. Metabolism and the electrical activity of anoxic ventricular muscle. Journal of Physiology 229, 559-582 (1973). MJ~s, 0. In Effect of Acute Ischaemia on Myocardial Function, M. F. Oliver, D. G. Julian, and K. W. Donald, Eds. p. 197. Edinburgh: Churchill, Livingstone. OLIVER, M. F., KURIEN, V. A. & GREENWOOD, T. W. Relation between serum free fatty acids and arrhythmias and death after acute myocardial infarction. Lancet 1, 710-715 (1968). OLIVER, M. F., MJC~S, 0. D., & ROWE, M. J. FFA, lipolysis and myocardial infarction (L). Lancet 1, 816 (1974). OPIE, L. H. Coronary flow rate and perfusion pressure as determinants of mechanical function and oxidative metabolism of isolated perfused rat heart. Journal of Physiology 180, 529-541 (1965) OPIE, L. H. Metabolic response during impending myocardial infarction. 1. Relevance of studies of glucose and fatty acid metabolism in animals. Circulation 45,483-490 (1972). OPIE, L. H. FFA, lipolysis and acute myocardial infarction (L). Lancet 1, 621 (1974). OPIE, L. H., NORRIS, R. N., THOMAS, M., HOLLAND, A. J., OWEN, P. & VAN NOORDEN, S. Failure of high concentrations of circulating free fatty acids to provoke arrhythmias in experimental myocardial infarction. Lancet 1, 818-822 (197 1). REGAN, T. J., MARKOV, A., OLDEM~LIRTEL, H. A. & BURKE, W. M. Myocardialmetabolism and function during ischaemia: response to L-noradrenaline. Cardiovascular Research 4, 334~342 (1970). Rowe, M. J. & OLIVER, M. F. Effect of a nicotinic acid analogue on plasma free fatty acids and ventricular arrhythmias after acute myocardial infarction [Abstract]. European Journal of Clinical Investigation 4,35 1 ( 1974). SALAZAR, A. E. Experimental myocardial infarction. Induction of coronary thrombosis in the intact closed-chest dog. Circulation Research 9, 1351-1356 (1961). SIESS, M. Effects ofnicotinic acid and some derivatives on performance and metabolism of spontaneously beating isolated atria. In Metabolic Effects of Nicotinic Acid and its Derivatives, K. F. Gey, and L. A. Carbon, Eds. p. 819. Bern: Hans Huber (1971). SMITH, E. R. & DUCE, B. R. Anti-arrhythmic and serum free fatty acid lowering effects of 5-fluoro-nicotinyl alcohol following experimentally induced myocardial infarction in the dog. Cardiovascular Research 8, 550-56 1 (1974). WASILEWSKA-DZIUB&SKA, E. Are free fatty acids arrhythmogenic? Effects of cellular cardiac action potentials (L). J ournal of Molecular and Cellular Cardiology 7, 153-154 (1975). WASILEWSKA-DZI~BI~~SKA, E., CZAMECKA, M., BERESEWCZ, A. & LEWARTOSKI, B. Influence of sodium palmitate on the cellular action potentials of the left ventricle of isolated perfused guinea-pig heart. Acta Physiologica Polonica 26, 1, (In press) (1975). WILLEB~NDS, A. F., TER WELLE, H. F. & TASSERON, S. J. A. The effect of a high molar FFA/albumin ratio in the perfusion medium on rhythm and contractility of the isolated rat heart. Journal of Molecular and Cellular Cardiology 5, 259-273 (1973).
and Cellular
Cardiology
Are Free Fatty
(1975)
Acids
7, 155-159
Arrhythmogenic?
The letter by Dr E. Wasilewska-Dziubinska [19] raises new aspects concerning the contentious question of the effects of free fatty acids (FFA) on the rhythm of the heart. Evidence concerning the possible arrhythmogenicity of FFA stems from observations on the hearts of small animals (rats and guinea-pigs), large animals (dogs) and man.
1. Small
animals
Dr Wasilewska-Dziubiriska states that sodium palm&ate could profoundly change the epicardial action potential of the guinea-pig heart. Such data are of great interest because of the possibility that glycolytically produced ATP may be of special importance in the maintenance of the action potential duration [I, 61; hence palmitate as sole exogenous fuel could be expected to reduce duration of the action potential. Dr Wasilewska-Dziubiriska also reports that the changes in the action potential ‘rusually” led to spontaneous or electrically provoked fibrillation. Detailed analysis of this interesting finding must await publication of the definitive article which is still in press [20]. Nevertheless, it is surprising that physiological concentrations of palmitate (0.5 mM) bound to physiological concentrations of albumin (4g/lOO ml) with an FFA: albumin molar ratio of about 1: 1 should have produced fibrillation even in the presence of glucose, because a considerably higher FFA: albumin molar ratio (6:l) was required consistently to produce fibrillation in the isolated rat heart study of Willebrands et al. [21]. Evans et al. [3] perfused rat hearts with FFA: albumin molar ratios of 12 : 1 without noting ventricular fibrillation. Several possible explanations of the work of Wasilewska-Dziubinska [19] must be considered. First, the guinea-pig heart might be exceptionally prone to arrhythmias. Secondly, there might be technical factors promoting arrhythmias in the perfusion system, but such considerations must await the full publication. Possibly the insertion of the microelectrode could act as an irritable focus. It would be important to know the heart rates and coronary flow rates throughout the perfusion period, so as to ensure that the isolated heart was not hypoxic. Thirdly, there could be problems in the preparation of the FFA : albumin complex. Albumin is known to have various effects on the heart and some preparations are toxic even after exhaustive dialysis. Other batches can be used without dialysis [IO].
156
L.
H.
OPIE
AND
W.
F.
LUBBE
For the above reasons the data of Wasilewska-Dziubinska [19] do not necessarily give conclusive support to the concept that FFA are arrhythmogenic. 2. Large
animals
In dogs there appears to be conflicting evidence. Oliver and co-workers have produced convincing experimental data suggesting a close association between abrupt elevation of plasma free fatty acid values and the occurrence of arrhythmias following balloon distention of the circumflex coronary artery [S]. On the other hand, our co-workers [I31 failed to reproduce these results in an open-chest greyhound preparation with acute coronary artery ligation; Mjos [7] apparently confirmed these negative results. As it has been suggested that the closed-chest model is a better reflection of events in man than is an open-chest model [Z] we decided to re-examine the question in a closed-chest dog with experimental coronary thrombosis. Under morphine sedation the left coronary artery of the conscious sedated dog was catheterised and a thrombus electrolytically induced in the anterior descending or circumflex branch of the left coronary artery by passage of a current of 300 PA for 1 h, using a modified method of Salazar [IS]. After approximately 2 to 4 h, blood free fatty acids were abruptly elevated by the rapid intravenous infusion of at least 50 ml 10% Intralipid together with heparin (12 500 units/50 ml). Arterial blood samples were taken throughout the procedure from a femoral artery catheter. A total of 27 dogs were studied. Seven dogs developed early ventricular fibrillation during the cautery procedure due to left main coronary artery obstruction and these dogs were eliminated from further evaluation. Of the remaining animals, 8 served as controls. They were given 50 cc of 0.5~ saline (0.45 g/100 ml) and 3 of the 8 developed an increased incidence of ectopic beats in the hour after injection. By 4 to 8 h post-cautery, all animals developed virtually continuous ventricular tachycardia which lasted for about 2 days and then passed over spontaneously. The ventricular ectopic beats were frequently multiform in nature, but the rate of ventricular tachycardia was relatively slow at 150 to 190 beats/min. The R-on-T phenomenon was frequently observed in the late phase arrhythmias, but did not appear to have prognostic significance for the onset of ventricular fibrillation. Twelve other dogs were given Intralipid-heparin l-2 hours after the end of cautery raising the arterial FFA concentration to over 3000 pEq/l, and in 6 there were apparently positive effects in increasing the rate of ectopic beats; one of these animals developed ventricular fibrillation. The average serum albumin of the dogs was 1.5 g/ 100 ml, hence the peak FFA : albumin molar ratio was over 13 : 1. When 6 animals had reached the stage of totally irregular rhythm (Harris phase III) further injections of Intralipid-heparin did not precipitate ventricular fibrillation. These results are summarised in Table 1. Both in this work in the closed-chest animal with electrolytically induced coronary
LETTERS
TABLE
TO
1. Results of Intralipid-heparin coronary thrombosis
THE
157
EDITOR
infusion on heart rhythm of dogs with closed-chest
Positive effects after Intralipid-heparin A. Administration on 1st day Effects
within
Positive effects after control injections
of Intralipid-heparin 1 hour
Increased incidence of ectopic beats, including ventricular fibrillation in one
6112
case
50%
318 41%
B. Late administration of Intralipid-heparin During phase of total irregularity (2-3 days post-thrombosis) Effect in precipitating ventricular fibrillation
thrombosis, and in previous work with coronary artery ligation in an open-chest greyhound [13] it was not possible persistently to precipitate serious arrhythmias by Intralipid-heparin (as a means of elevating free fatty acids). A larger series is needed to test whether there might be an arrhythmogenic effect of infused FFA (in the form of triglyceride-heparin) in our dogs on the first day of coronary thrombosis but in the present series no consistent trends were found. In the late phase arrhythmias, triglyceride-heparin clearly failed to provoke ventricular fibrillation, which is of importance because Smith and Duce [18] recently reported a reduction in the late phase arrhythmias in dogs after the use of an anti-lipolytic nicotinic acid analogue. We believe that these late phase arrhythmias do not have prognostic importance for the development of ventricular fibrillation, as evidenced by their spontaneous disappearance in spite of the frequent occurrence of the R-on-T phenomenon. The resemblance to rhythm disturbances after human myocardial infarction seems remote. In our previous study, elevation of free fatty acids by Intralipid-heparin was shown to be arrhythmogenic in the presence of adrenaline infusion, raising the possibility that FFA and catecholamines could act together to promote arrhythmias [13]. Nevertheless, it should be noted that FFA uptake by the heart can be elevated by suppressor doses of noradrenaline with an apparent decrease in the incidence of arrhythmias [14].
3. Patients
with
acute
myocardial
In patients with acute myocardial infarction, correspondence columns of The Lancet [9,18].
infarction
the situation has been debated in the It could be argued that the evidence
158
L. H. OPIE
AND
YV. F. LUBBE
both for and against FFA being arrhythmogenic in clinically relevant concentrations is in the balance. The scales are likely to be tipped in favour of an arrhythmogenic role for FFA by the recent data of Rowe and Oliver [15] who administered an anti-lipolytic agent to patients with myocardial infarction within the first few hours of onset and found a decreased incidence of serious ventricular arrhythmias. However, studies with anti-lipolytic agents may need somewhat guarded interpretation because there are direct depressant effects of nicotinic acid (2 to 10 mM) or of P-pyridylcarbinol (1 to 5 mu) on the contraction force, frequency and efficiency of contraction of isolated beating guinea-pig atria [17]. These may well not be clinically relevant concentrations, but the possibility is raised that this category of compounds might have some direct action on the heart. The effects of antilipolytic agents on coronary blood flow, as adequately measured by techniques such as the administration of microspheres to dogs with coronary artery occlusion, also need consideration and have apparently not been reported. Thus, in the action of anti-lipolytic agents on arrhythmias in patients with acute myocardial infarction, it is at least conceivable that such agents may act in ways other than depression of circulating FFA. It would be of undoubted interest if other clinical situations, in which FFA could be arrhythmogenic, were also investigated e.g. asthmatics taking sympathomimetic drugs and at risk of ventricular fibrillation, and diabetics out of control with high circulating FFA values. It should be noted that the above comments relate solely to the question of the effect of FFA on arrhythmias. The possible effects ofcirculating FFA on contractility or infarct size are not presently under discussion. In summary, the important question of the arrhythmogenicity of FFA in clinical and experimental situations remains one for continued intensive investigation. Widely different experimental results still need explanation. It would be important to have a better understanding of which combination of experimental or clinical factors could allow otherwise “non-toxic” concentrations of FFA to become arrhythmogenic. The Ischaemic Heart Disease Laboratory is supported by the Medical Research Council of South Africa and the Chris Barnard Fund. L. H. OPIE Ischaemic Heart Disease Laborutoy, W. F. LUBBE Department of Medicine, University of Cape Town, South Africa REFERENCES 1.
CHANEVAL,
Metabolism, 2. 3.
Physiologie EDITORIAL,
J.-P., HYDE, A., BLONDEL, B. & GIRADIER, L. Heart cells in culture. action potential and transmembrane ionic movements. 3ournal de 64, 413-430
(1972).
Free fatty acids and heart attacks. Lancet 1, 843-844 (197 1). EVANS, J. R., OPIE, L. H. & SHIPP, J. C. Metabolism of palmitic acid in perfused rat heart. American Journal of PhysioloD 205, 766-770 (1963).
LETTERS
4.
5.
6. 7. 8.
9. 10.
11. 12. 13.
14.
15.
16. 17.
18.
19.
20.
21.
TO THE
EDITOR
159
GUPTA, D. K., YOUNG, R., JEWITT, D. E., HARTOG, M. & OPIE, L. H. Increased plasma-free-fatty-acid concentrations and their significance in patients with acute myocardial infarction. Lancet 2, 1209-1213 (1969). KURIEN, A., YATES, P. A. & OLIVER, M. F. The role offree fatty acids in the production of ventricular arrhythmias after acute coronary artery occlusion. European Journal of Clinical Investigation 1, 225-241 (197 1). MCDONALD, T. F. & MACLEOD, D. P. Metabolism and the electrical activity of anoxic ventricular muscle. Journal of Physiology 229, 559-582 (1973). MJ~s, 0. In Effect of Acute Ischaemia on Myocardial Function, M. F. Oliver, D. G. Julian, and K. W. Donald, Eds. p. 197. Edinburgh: Churchill, Livingstone. OLIVER, M. F., KURIEN, V. A. & GREENWOOD, T. W. Relation between serum free fatty acids and arrhythmias and death after acute myocardial infarction. Lancet 1, 710-715 (1968). OLIVER, M. F., MJC~S, 0. D., & ROWE, M. J. FFA, lipolysis and myocardial infarction (L). Lancet 1, 816 (1974). OPIE, L. H. Coronary flow rate and perfusion pressure as determinants of mechanical function and oxidative metabolism of isolated perfused rat heart. Journal of Physiology 180, 529-541 (1965) OPIE, L. H. Metabolic response during impending myocardial infarction. 1. Relevance of studies of glucose and fatty acid metabolism in animals. Circulation 45,483-490 (1972). OPIE, L. H. FFA, lipolysis and acute myocardial infarction (L). Lancet 1, 621 (1974). OPIE, L. H., NORRIS, R. N., THOMAS, M., HOLLAND, A. J., OWEN, P. & VAN NOORDEN, S. Failure of high concentrations of circulating free fatty acids to provoke arrhythmias in experimental myocardial infarction. Lancet 1, 818-822 (197 1). REGAN, T. J., MARKOV, A., OLDEM~LIRTEL, H. A. & BURKE, W. M. Myocardialmetabolism and function during ischaemia: response to L-noradrenaline. Cardiovascular Research 4, 334~342 (1970). Rowe, M. J. & OLIVER, M. F. Effect of a nicotinic acid analogue on plasma free fatty acids and ventricular arrhythmias after acute myocardial infarction [Abstract]. European Journal of Clinical Investigation 4,35 1 ( 1974). SALAZAR, A. E. Experimental myocardial infarction. Induction of coronary thrombosis in the intact closed-chest dog. Circulation Research 9, 1351-1356 (1961). SIESS, M. Effects ofnicotinic acid and some derivatives on performance and metabolism of spontaneously beating isolated atria. In Metabolic Effects of Nicotinic Acid and its Derivatives, K. F. Gey, and L. A. Carbon, Eds. p. 819. Bern: Hans Huber (1971). SMITH, E. R. & DUCE, B. R. Anti-arrhythmic and serum free fatty acid lowering effects of 5-fluoro-nicotinyl alcohol following experimentally induced myocardial infarction in the dog. Cardiovascular Research 8, 550-56 1 (1974). WASILEWSKA-DZIUB&SKA, E. Are free fatty acids arrhythmogenic? Effects of cellular cardiac action potentials (L). J ournal of Molecular and Cellular Cardiology 7, 153-154 (1975). WASILEWSKA-DZI~BI~~SKA, E., CZAMECKA, M., BERESEWCZ, A. & LEWARTOSKI, B. Influence of sodium palmitate on the cellular action potentials of the left ventricle of isolated perfused guinea-pig heart. Acta Physiologica Polonica 26, 1, (In press) (1975). WILLEB~NDS, A. F., TER WELLE, H. F. & TASSERON, S. J. A. The effect of a high molar FFA/albumin ratio in the perfusion medium on rhythm and contractility of the isolated rat heart. Journal of Molecular and Cellular Cardiology 5, 259-273 (1973).
