Prevention of ventricular fibrillation by betablockers- possible mode of action.

        Lecture for 700  cardiologists in Birmingham 1996, content still relevant, will be extended with recent findings. Figures will be included shortly.

First slide. I will begin with a case report published by Olsson and Rehnqvist in Stockholm.A Holter ECG recording from a 70-year old man, who had recovered well after two myocardial infarctions. Here at 11 pm he is sitting with his wife in his home, relaxed, heart rate 70 beats/ minute. At 11:24 pm he notices that his wallet containg some important documents is missing. He gets worried, the heart rate goes up from 70 to 105, ventricular extrasystoli appear. Sixteen minutes later, next slide, in a period of regular sinus rythm, there occurs a premature ventricular contraction. This initiates ventricular tachycardia, which rapidly degenerates into ventricular fibrillation. Sudden cardiac death has occurred. The mechanisms involved are complex and
largely unknown. This case report shows some features, next slide, which often characterize sudden death victims. 1) Death occurred unexpectedly and outside hospital. 2) Death was due to ventricular fibrillation preceded by ventricular tachycardia. 3) The patient had coronary atherosclerosis. 4) TheVF attack was preceded by increased heart rate. 5) The VF attack was preceded by emotional stress.
As regards  prevention of sudden death, betablockers still are the drugs of choice. Next slide. The sudden death preventive effect of betablockers was well established in large long term clinical trials in the 1980´s, mainly with three drugs: metoprolol, propranolol and timolol. All these are lipophilic and elicit betablockade in the brain as well as in the heart. The two hydrophilic betablockers atenolol and sotalol which are less extensively distributed to brain, have never been shown to prevent arrhythmic sudden death. It has been suggested, that this apparent difference might imply that sudden death prevention requires beta blockade not only in the heart but also in the brain.

This thought was supported, next slide, by studies in conscious pigs, by Skinner and coworkers. If they brought conscious pigs directly to the frustrating environment in the laboratory,coronary artery occlusion led to ventricular fibrillation within 20 minutes in all pigs. Next slide, Ventricular fibrillation could be prevented or greatly delayed by three measures. One was adaptation to the stress, by making the pig accustomed to the laboratory procedures for one week. In these adapted pigs coronary occlusion did not result in ventricular fibrillation. Fibrillation could also be prevented by cryogenic blockade of central pathways involved in the stress response. The third preventive measure was an injection of a low dose of propranolol into a cerebral ventricle. This result suggests that beta-blocker induced prevention of ventricular fibrillation may involve not only cardiac beta-blockade but also beta-blockade in the central nervous system.

Next slide shows the most common response pattern to emotional stress, the so called defence reaction , studied extensively by Folkow, Hilton and others. Stressful stimuli elicit in the limbic system a complex effect pattern, including an increased heart rate, which depends in part on increased sympathetic tone, in part on a decrease of vagal tone.

This differential nerve discharge pattern may be ominous , because, next slide, together with myocardial ischemia, high cardiac sympathetic tone and low cardiac vagal tone are important factors predisposing to V.F. High cardiac sympathetic tone may well be the most important factor, because after complete surgical or chemical cardiac sympathectomy, dogs never develop VF after coronary occlusion.

How do beta-blockers influence these factors? We have studied this in an animal stress model with acute myocardial ischemia. Next slide, We used three groups of rabbits, which for three weeks were given either metoprolol, atenolol or vehicle control by subcutaneous osmotic minipumps. The doses chosen gave therapeutic plasma levels of the two beta -blockers.
These two blockers exert the same degree of beta 1-selectivity, but differ as regards lipophilicity, so that atenolol is less extensively distributed to brain. In the terminal experiment the rabbit was anaesthetised with chloralose. Rabbits exposed to this anaesthetic develop a defence reaction like autonomic outflow pattern with high sympathetic and low vagal tone to the heart. We occluded the coronary circumflex artery branch perfusing the free left ventricular wall . At the end we determined area at risk, that is the portion of left ventricle excluded from perfusion by the coronary occlusion.

Next slide, From one animal, computer averaged ECG lead V3, recordings before and 5 minutes after coronary occlusion. The occlusion caused ST elevation. The sinus rhythm was maintained. In the next 10 minutes many animals died due to V.F with disappearing pressure pulse.
Next slide shows that after coronary occlusion, almost all control and atenolol animals died in VF. In the metoprolol group there were significantly fewer VF attacks and most metoprolol rabbits survived. Why was only the lipophilic betablocker effective? Next slide shows the heart rate recorded just before the occlusion. The control rabbits had a high heart rate, which indicates an intense sympathetic activation in our animal model.

Metoprolol and atenolol produced similar reductions, not only of the heart rate, as shown here, but also of arterial pressure , and of the acute myocardial
ischemia. The two beta- blockers differed, however , when we studied cardiac vagal tone. Here one index of vagal tone, respiratory sinus arrhythmia, measuredas standard deviation of the R-R intervals.This index suggests that the metoprolol rabbits had significantly higher cardiac vagal tone than tha atenolol animals or controls.
This conclusion is supported by other findings summarized in next slide. In the high sympathetic stress model we found a higher vagal activation after metoprolol than after atenolol, as indicated not only by higher respiratory sinus arrhythmia but also by more pronounced tachycardic response to maximal muscarinic blockade and by higher baroreflex sensitivity, measured by means of i.v. phenylephrine injections as done in patints.
Next slide. So these results suggest that the prevention of VF caused by metoprolol in this animal model was due to a combination of reduced myocardial ischemia, reduced cardiac sympathetic activation and better maintained cardiac vagal tone in the stress situation studied, and this effect was probably due to an action in CNS, since the hydrophilic atenolol was ineffective.

Because of these findings we wanted to study a conscious stress model, next slide, and I will show some results from a free-moving pig, who has implanted radiotransmitters, so that we can record telemetric ECG and arterial pressure. Next slide.

Every Tuesday morning we let one alien pig visit the radiopig for three minutes and they fight for social dominance mainly by using their jaws. The radiopig usually develops a beautiful defence reaction. While this is the most common social interaction, next slide shows, that some pigs prefer love to fight in their first encounter. In these pigs the sympathetic activation is much weaker than in fighting pigs. Back to fighting pigs. Next slide shows that the three-minute fight caused the heart rate to increase from 100 to 250 beats/ minute. The tachycardia was rather transient, however.After 15-20 minutes the pig had calmed down and the heart rate had almost returned to the prefight level. Here we estimate the cardiac vagal tone by means of power spectral analysis of the R-R interval.. We believe we know how to translate the heart rate variability data into cardiac vagal tone. I will go directly to next slide, which shows the magnitude of cardiac vagal tone in 6 pigs, studied in a relaxed state and after fight. Week 1and 4 control, week 2 and 3 randomized treatment with metoprolol or atenolol for one week. In the low stress state the vagal tone was high and about the same in the metoprolol period as on atenolol or control. After stress vagal tone was reduced in all groups, but in the metoprolol period the vagal tone was maintained at a significantly higher level than in the atenolol or control periods. This finding corresponds to that we found in the rabbit stress model.

How does a brief sympathetic stress elicit this rather prolonged decrease of cardiac vagal tone? Next slide outlines one possible concept, which we are exploring with the NPY tycoon Jan Lundberg in Stockholm.

In brief, a short intense sympathetic activation, like the pig fight, results in release of noradrenaline giving beta-receptor mediated increase of the heart rate. This effect is short lasting, about 10 minutes. But, the sympathetic nerve activation also releases the cotransmittor neuropeptide Y, NPY, which elicits vasoconstriction but also, and I will focus on that now, NPY reduces cardiac vagal tone by decreasing neural release of acetylcholine. The effects of NPY are long-lasting, up to one hour, in part because NPY is
eliminated much more slowly than noradrenaline.

Next slide shows plasma NPY levels recorded at basal state and 30 minutes after confrontation. The NPY levels were increased in all groups after the fight, but the levels were significantly lower in the metoprolol week than in the atenolol week Our interpretation is that metoprolol, by betablockade in the brain, reduced the sympathetic neural release of NPY. This could contribute to explain the better maintained cardiac vagal tone in metoprolol treated animals exposed to stress, which should reduce the risk for VF.
SUMMARY. Prevention of ventricular fibrillation by betablockers may involve
Betablockade in the heart leading to reduced cardiac sympathetic tone and reduced myocardial ischemia
Betablockade in CNS, for one thing leading to better maintained cardiac vagal tone in psycosocial stress.