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Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial

^a Department of Endocrinology, Aalborg Hospital, Denmark, ^b Department of Cardiology, Aalborg Hospital, Denmark, ^c MediLab A/S, Copenhagen, Denmark

Correspondence to: Dr Jeppe Hagstrup Christensen, Department of Endocrinology, Aalborg Hospital, Reberbansgade, PO Box 561, 9100 Aalborg, Denmark.

Marine n-3 polyunsaturated fatty acids may protect against ischaemic heart disease.¹ In the diet and reinfarction trial patients with an acute myocardial infarction advised to eat fish rich in n-3 polyunsaturated fatty acids had a 29% reduction in two year all cause mortality compared with controls.² The authors hypothesised that dietary n-3 polyunsaturated fatty acids might reduce malignant ventricular arrhythmias and sudden cardiac death, as reported in animals.³ We investigated a possible antiarrhythmic effect of dietary n-3 polyunsaturated fatty acids in survivors of myocardial infarction.

Patients, methods, and results

Patients were eligible for study if they had been discharged from the department of cardiology at Aalborg Hospital between November 1991 and August 1993 after a myocardial infarction and had a ventricular ejection fraction below 0.40. We excluded patients aged over 75, patients with pacemakers or permanent tachyarrhythmias, and those with serious non-cardiac disease. Eighty one patients fulfilled the inclusion criteria and 55 gave informed consent to a double blind placebo controlled trial.

Patients were randomly allocated to receive either 5.2 g of n-3 polyunsaturated fatty acids daily (as 4.3 g eicosapentaenoic acid and docosahexaenoic acid, equal to eight capsules of Pikasol, a re-esterified triglyceride (EPAX 5500; Pronova Biocare A/S, Norway)) or olive oil for 12 weeks. Treatment began at the time of allocation. Patients were randomised in blocks of 10 and numbered consecutively. Patients drew treatment A or B from a sealed envelope and were given capsules packed in boxes correspondingly marked A or B.

Diet and medicines were kept constant during the trial. Compliance was monitored by measuring the incorporation of eicosapentaenoic acid and docosahexaenoic acid into platelets. The trial protocol was approved by the regional ethics committee.

A 24 hour Holter recording was obtained at baseline and at the end of the study. A two channel tape recorder (Tracker Reynolds; Reynolds Medical, Hertford, United Kingdom) was used. All tapes were processed without knowledge of the randomisation code. The end point was heart rate variability. A Reynolds Pathfinder 700 system (Reynolds Medical) was used to analyse the time domain heart rate variability measures mean RR (mean of all normal RR intervals during the 24 hour recording) and standard deviation of all normal RR intervals in the entire 24 hour recording. QRS complexes with abnormal morphology were excluded from analysis.

A paired t test was used to compare any heart rate variability differences within the fish oil and control groups, and the groups were compared by non-paired t test. The mean RR variable was used to calculate the required sample size. With an estimated standard deviation of 80 ms and type I and type II errors accepted at the 5% level the total sample size should be 52, provided that the smallest difference between the means not to be overlooked was 10%.

During the trial one patient from the control group died, one patient from each group withdrew for personal reasons, two controls were excluded (one developed a ventricular aneurism, one atrial flutter), and one patient in the fish oil group was excluded because of a technically insufficient Holter recording.

The remaining 26 patients in the fish oil group and 23 controls were comparable in age, sex, ejection fraction, qualifying myocardial infarction (size, location, thrombolytic therapy), smoking, hypertension, plasma cholesterol concentrations, and cardiovascular drugs.

Compliance was confirmed by an increase in eicosapentaenoic acid and docosahexaenoic acid in platelets in all patients in the fish oil group whereas no changes occurred among controls (data not shown). The standard deviation of all normal RR intervals in the entire 24 hour recording increased significantly in the fish oil group compared with baseline and control values. The 95% confidence interval of the difference in mean differences in standard deviation of all normal RR intervals in the entire 24 hour recording (with the two groups compared) was -34 to -2 ms. Table 1 summarises the results.

Table 1--Heart rate variability in the two groups
---------------------------------------------------------------------------------------------
                                           Mean (SD)   Mean (SD)      Mean difference
Treatment group                             before      after      (95% confidence interval)
---------------------------------------------------------------------------------------------
Standard deviation of all normal RR intervals in 24 hour Holter recording (ms)
 n-3 Polyunsaturated fatty acids            115 (39)    124 (30)+       -8.3 (-16 to -1)++
 Control                                    115 (45)    105 (36)         9.4 (-2 to 20)
Mean RR interval (ms)
 n-3 Polyunsaturated fatty acids            807 (104)   825 (95)       -18.4 (-39 to 3)
 Control                                    823 (187)   827 (175)       -3.4 (-39 to 32)
---------------------------------------------------------------------------------------------
+P=0.04 v baseline.
++P=0.01 v control.

Comment

These findings indicate that n-3 polyunsaturated fatty acids may increase heart rate variability in survivors of myocardial infarction. This may be of clinical importance because an increased parasympathetic cardiac tone reflected by an increased heart rate variability or standard deviation of all normal RR intervals in a 24 hour recording increases the ventricular fibrillation threshold and protects the myocardium against ventricular arrhythmias.⁴ In accordance with this a decreased heart rate variability is strongly associated with increased mortality in postmyocardial infarction patients.⁵ Furthermore, it is notable that improved long term survival occurs in high risk patients given ß blockers or angiotensin converting enzyme inhibitors, both of which increase heart rate variability.⁵

Our study supports the hypothesis that n-3 polyunsaturated fatty acids may have an antiarrhythmic effect in humans, which could in part explain the reduced mortality reported in postmyocardial infarction patients given these acids.² Further studies are needed.

The trial capsules were provided by Lube A/S, Denmark.

Funding: Medical Research Foundation of the County of Northern Jutland. Conflict of interest: None.

1. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis. Lancet 1978;ii:117-9.
2. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial infarction: evidence from the diet and reinfarction trial (DART). Lancet 1989;ii:757-61.
3. Charnock JS. Lipids and cardiac arrhythmias. Prog Lipid Res 1994;4:355-85.
4. van Ravenswaaij-Arts CMA, Kollee LAA, Hopman JCW, Stoelinga GBA, van Geijn HP. Heart rate variability. Ann Intern Med 1993;118:436-47. [Medline]
5. Stein PK, Bosner MS, Kleiger RE, Conger BM. Heart rate variability: a measure of cardiac autonomic tone. Am Heart J 1994;127:1376-81.

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