Autonomic dysfunction and phase 2 ventricular fibrillation post myocardial infarction.

Dr Charles Murimi Mugera                                                                  MSc Pharmacology  
Introduction  
The majority of the approximately 100,000 sudden cardiac deaths each year in the UK 
are caused by ventricular fibrillation related to ischaemia and infarction (Clements-
Jewery et al., 2005; Wannamethee et al., 1995). 
Despite rapid advancements in the diagnosis and management of acute  myocardial 
  
infarction (MI), an estimated 50% of patients die suddenly in the first hours before 
receiving medical attention (Lowel et al., 1993). 
 
Clinical studies  indicate that the risk of sudden cardiac death is highest during the first 24 
 
hours  after an MI and diminishes thereafter (Zehender et al., 1991).The majority of these
 
early deaths are caused by VF. Surprisingly little is known, however, about the exact time 
course of VF and even less about their underlying mechanisms in man.  
 
Ventricular arrhythmias post myocardial ischaemia and infarction have been extensively 
 
evaluated using animal models, and have been shown to occur in 2 distinct phases, phase 
1 and phase 2 (Ravingerova et al., 1995; Clements-Jewery et al., 2005; Johnston et al., 
nd
1983). Animal studies have shown the 2  phase to be the more malignant 
 
arrhythmogenic period accounting for 87% of the arrhythmic deaths (Opitz et al., 1995). 
 The relative importance of the phases of VF  have not been elucidated   in man and the 
spatial and temporal patterns  of VF in man are difficult to acertain .However, the phases 
of VF in animal models have shown incredible similarity  that cuts across  all species 
from  rodents to primates with little species variation (Curtis et al., 1987) . This evidence 
puts forward the elegant hypothesis that man exhibits the same biphasic susceptibility to 
VF (Clements-Jewery et al., 2005).   
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 Cardiovascular Division King's College London the Rayne Institute St. Thomas' Hospital
Dr Charles Murimi Mugera                                                                  MSc Pharmacology  
If the mechanisms of VF in man are phase-dependent, like they are in animal models, 
then the effects of drugs on VF will be phase-dependent and this implies that drugs that 
target the early phase of VF may not be effective in the late phase. In addition  
  drugs that target  one phase of VF may exacerbate another phase of VF as was seen in 
the SWORD & CAST  trials  (Greenberg et al., 1995; Hallstrom et al., 1995; Cobbe, 
1996; Pratt et al., 1998; Goldstein et al., 1995).  
Various clinical studies point to a bimodal pattern of Ventricular tachyarrhythmia in man 
(O'Doherty et al., 1983; Pantridge et al., 1981). The incidence of VT, which is often the 
precursor to VF,  followed a bimodal time course with an early phase and a delayed 
phase between 7 and 14 hours with a quiescent period in between .Interestingly, these 
studies showed a monophasic pattern of VF ,with an early peak and then a steady decline 
(O'Doherty et al., 1983; Pantridge et al., 1981; Meinertz et al., 1991; Gressin et al., 1992; 
Gressin et al., 1992) . 
 
These clinical trials, unfortunately, excluded the large proportion of patients (50% to 
80%) who die before ever receiving medical attention (Gilman & Naccarelli, 1997). The 
studies also failed to assess the detailed time course of VT and VF during the first hours 
of acute MI (Opitz et al., 1995). 
All animal models examined to date demonstrate two phases of VF (Clements-Jewery et 
al., 2002; Clements-Jewery et al., 2005). Phase 1 VF occurs roughly 2–30 minutes 
 
following coronary artery occlusion when changes are still reversible in the event of 
reperfusion. In the canine model, phase 1 VF demonstrates a bimodal distribution with 
phases 1a and 1b. Phase 1a arrhythmias occur between 2–10 minutes. The 
 
pathophysiology is thought to be related to alterations in cellular electrophysiology and 
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 Cardiovascular Division King's College London the Rayne Institute St. Thomas' Hospital
Dr Charles Murimi Mugera                                                                  MSc Pharmacology  
  
re-entrant mechanisms. Phase 1b arrhythmias, which occur 10–30 minutes after acute 
coronary occlusion, may be related to local accumulation of catecholamine associated 
with non-exocytotic release of NE and increased automaticity (Clements-Jewery & 
Curtis, 2001). It should be noted, however, that phase 1 is not bimodal in most animal 
models that have sparse collateral formation e.g. the rat.  
Phase 2 or sub acute phase of VF coincides with the onset of irreversible injury, 
whereupon reperfusion becomes incapable of salvaging the tissue. This  sets in after 
about  60 minutes (Garcia-Dorado et al., 1987) to 90 minutes (Hochman & Choo, 1987)  
 
of continuous ischaemia and occurs any were up to 72 hours after coronary artery 
 
occlusion, with a peak incidence between 12–24 h (Clements-Jewery et al., 2005; Opitz 
et al., 1995; Patterson et al., 1986; Harris, 1950). These arrhythmias are triggered by 
abnormal automaticity; delayed afterdepolarisations related triggered activity within 
damaged but surviving Purkinje fibres or from the epicardial border zone overlying the 
infarct in canine models (Curtis et al., 1993; Janse et al., 1986; Janse & Wit, 1989). 
  
Chronic phase arrhythmias developing after 72 h are usually due to re-entry mechanisms 
(Kleber, 1991). 
 
Knowledge of autonomic nervous system activity in the pathophysiology of VF, post 
 
acute myocardial ischaemia and infarction, is far from complete. During the early minutes 
   
of acute coronary occlusion, intense local adrenergic activation of the ischaemic 
myocardium, along with other numerous metabolic and neurohumeral  factors, contribute 
 
to VF, which may contribute to the evolution of abnormal cellular electrical behaviour 
 
and, ultimately, result in lethal phase 1 (VF) (Curtis et al., 1993). However, in the later 
phase 2 VF the exact role of the autonomic nervous system is unclear.   
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 Cardiovascular Division King's College London the Rayne Institute St. Thomas' Hospital
Dr Charles Murimi Mugera                                                                  MSc Pharmacology  
There is an ever-growing body of evidence suggesting that heightened sympathetic 
activity contributes to fatal arrhythmias, both in the acute, sub acute, and chronic phases 
 
of ischaemia and infarction (Pozzati et al., 1996). Sympathetic hyperactivity favours the 
 
genesis of life-threatening ventricular tachyarrhythmia’s, whereas vagal activation exerts 
both a direct  anti-fibrillatory effect ,via post synaptic M receptor activation,  as well as 
2
an  anti-adrenergic effect, via presynaptic inhibition of NE release,  as well as promoting 
an anti-ischaemic effect via  vasodilatation (Pozzati et al., 1996).  
Anti-adrenergic therapy is known to prevent sudden cardiac death both in the acute phase 
(Smith et al., 2005) and late phases. In canine in vivo models left stellectomy abolished 
the phase 2 VF (Schwartz & Stone, 1980; Nelson et al., 1989). 
In vivo the rat, heart readily demonstrates both phases of VF whereas in vitro the 
denervated isolated heart does not exhibit phase 2 VF (Clements-Jewery et al., 2002). 
This suggests that excessive adrenergic activity, diminished parasympathetic activity, or 
both, may be the pathophysiological mechanisms underlying the onset of phase 2 VF. 
. 
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 Cardiovascular Division King's College London the Rayne Institute St. Thomas' Hospital
Dr Charles Murimi Mugera                                                                  MSc Pharmacology  
Chapter 2: Over view of the autonomic control of the heart.   
The autonomic nervous system consists of a central component and peripheral 
component (Cheng et al., 2004). The peripheral component consists of the sensory 
afferent neurons and motor efferent neurons that run between the central component 
(cortex, hypothalamus and medulla oblongata) and various internal organs such as the 
heart, lungs & viscera (Kalia & Mesulam, 1980; Kalia & Mesulam, 1980). It is 
responsible for maintaining homeostasis in the internal environment  which involves 
monitoring conditions (afferent component)  and bringing about appropriate changes in 
them ( Motor component). 
 
 
 2.1. The Central autonomic network and autonomic control of cardiac function   
The central nervous system (CNS) controls the heart from multiple nuclei in the cortex 
(insular cortex), diencephalons (hypothalamus) and brainstem (Zahner & Pan, 2005). 
Afferents fibres transmit information to the CNS from the periphery e.g. from the arterial 
baroreceptors and chemoreceptors, as well as cardiopulmonary mechano- and 
chemoreceptors. These fibres terminate in the nucleus tractus solitaires (NTS) (Jordan, 
2005). Fibres from the NTS then run to the dorsal motor root of the vagus (DMV) nerve, 
were the preganglionic parasympathetic (PNS) nerve fibres for the respiratory and 
gastrointestinal tract originate, and to the nucleus ambigus (NA) which is the major 
source of preganglionic parasympathetic fibres that project to the heart. The NTS and NA 
fibres project via the rostral and caudal ventral lateral medulla (RVLM & CVLM) to the 
spinal cord were they terminate in the intermedialateral column (IML), between the first 
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 Cardiovascular Division King's College London the Rayne Institute St. Thomas' Hospital
Dr Charles Murimi Mugera                                                                  MSc Pharmacology  
thoracic spine (T1) and upper lumber spine (L1). The preganglionic SNS fibres originate 
from the IML and project to the stellate ganglion   which is the source of the post 
ganglionic sympathetic nervous fibres to the heart (Talman & Kelkar, 1993).  
Figure 2.1 shows the main neural components participating in the SNS control of the 
heart rate.  
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 Cardiovascular Division King's College London the Rayne Institute St. Thomas' Hospital