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Delayed protection against ventricular arrhythmias by cardiac pacing
  1. Department of Physiology and Pharmacology,
  2. University of Strathclyde,
  3. Royal College,
  4. Glasgow G1 1XW, UK
  5. Department of Pharmacology,
  6. Albert Szent-Gyorgyi Medical University,
  7. Szeged, Hungary

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Although heavy physical exercise, and psychological stress that produces similar physiological responses, may trigger a cardiac event in the immediate (within one hour) postexertion period,1 ,2 there is prospective evidence that the relative risk of sudden cardiac death and non-fatal myocardial infarction occurring during this period is reduced in individuals who exercise regularly.2 ,3 The intensity of the exercise required to induce this protection, as well as the time course of this protection, are subjects of ongoing debate3 ,4; the conclusion that “the protective effect of exercise requires continued exertion”3 implies that the duration of the protection is relatively short lived. The mechanisms of this risk reduction remain unclear but include an increase in baroreflex sensitivity (and increased vagal activity that is antifibrillatory5) and favourable effects on other risk factors.6

Both exercise training7 and right ventricular pacing8 ,9 confer significant protection against coronary artery occlusion induced ventricular fibrillation in conscious7 and anaesthetised8 ,9 dogs. Similar to the protection associated with ischaemic preconditioning (defined as the protective effect of brief coronary artery occlusions against the consequences of a subsequent more prolonged period of ischaemia), the protection is demonstrable immediately after, or even during,7 the pacing or exercise period but is lost shortly afterwards.9 Of potential clinical interest is the more recent finding that the protection associated with both ischaemic preconditioning and cardiac pacing, returns 20–24 hours after the initial stimulus, a phenomenon that has been described as the second window of protection10 or delayed myocardial protection.11 In pacing studies, protection is again lost 48 hours after the stimulus8 but can be regained if the pacing stimulus is repeated.12 Under these conditions, the protection now lasts for at least 48 hours (fig 1). Whether protection against ischaemia induced arrhythmias can be maintained indefinitely by repeated periods of pacing is presently being investigated.

Figure 1

The incidence of ventricular fibrillation (VF) during coronary artery occlusion and reperfusion, ventricular tachycardia (VT) on occlusion, and survival rate following a combined ischaemia–reperfusion insult in anaesthetised dogs subjected to occlusion of the left anterior descending coronary artery at various times after right ventricular pacing (4 × 5 min at 220 beat/min). The incidence of VF was significantly reduced (*p < 0.05) 24 hours after pacing compared with unpaced controls (C) but this protection was lost 48 hours after the initial pacing stimulus. However, if dogs were repaced at this time protection was still apparent a further 48 hours later (at 96 hours). Filled columns, incidence of VF and VT during occlusion; Open columns, incidence of VF during reperfusion following a 25 minute period of coronary artery occlusion.

A number of suggestions have been made10 to explain certain manifestations of the second window of protection of the heart, such as the reduction in the extent of myocardial necrosis. These include the induction of cytoprotective heat shock (stress) proteins, or of potentially protective enzymes such as nitric oxide synthase, and increased myocardial anti-oxidant status. There is evidence for the initial participation of endogenous myocardial protective substances13 such as adenosine as triggers for this protection, and for the involvement of signal transduction processes that include the early activation of tyrosine kinase and protein kinase C.10 It is not known whether pacing or exercise triggers similar mechanisms to those involved in ischaemic preconditioning and other possibilities have been suggested to explain the delayed antiarrhythmic effect of pacing and exercise. These include a change, as a result of the tachycardia, in cardiac autonomic balance producing an increase, or a relative dominance, of the vagal component.5 The release from coronary vascular endothelial cells of a variety of diffusible mediators, which include prostacyclin, bradykinin and, of especial importance, nitric oxide has also been suggested as important for this protection.14

Role of endothelium derived mediators in the antiarrhythmic effects of ischaemic preconditioning and cardiac pacing

The hypothesis that coronary vascular endothelial cells contribute to arrhythmia suppression through the increased generation of diffusible mediators is illustrated in fig 2. It implies that endothelial cells not only modulate platelet function (adhesion, aggregation) and vascular smooth muscle activity (vasodilatation, vasoconstriction) but communicate directly with cardiac myocytes through the release of the same or similar mediators. This regulation of myocyte function by endothelial cells takes two forms, modulation of contractility15 and protection of the myocyte against some of the consequences of ischaemia.14 Most of the evidence for this hypothesis comes from studies involving the effects of coronary vascular endothelial denudation16 and of ischaemic preconditioning. It includes the results from studies indicating the early release of bradykinin following occlusion and reperfusion in both experimental animals, as well as in patients following balloon inflation (angioplasty),17 and the abolition of the antiarrhythmic effects of ischaemic preconditioning (and of cardiac pacing18) by blockade of the relevant (B2) bradykinin receptor. Further, there is evidence for the cardiac generation of nitrosyl-haem products, implying a bradykinin mediated generation of nitric oxide. Nitric oxide involvement is also suggested by the attenuation of the antiarrhythmic effects of ischaemic preconditioning following inhibition of nitric oxide generation through the L-arginine pathway, and by inhibition of the nitric oxide target organ, soluble guanylyl cyclase.19

Figure 2

The role of endothelium derived endogenous protective mediators in ischaemic preconditioning and in cardiac pacing. Bradykinin is released, probably from endothelial cells (which have the mechanisms for generating and releasing kinins), which then acts on B2 receptors on the endothelial surface to increase the calcium transient within these cells and hence activate the L-arginine nitric oxide pathway. Nitric oxide then communicates with the cardiac myocyte, stimulates soluble guanylyl cyclase, and raises cGMP. This reduces cAMP and calcium entry through L-type calcium channels as well as suppressing myocardial oxygen consumption.


Figure 2 also illustrates how nitric oxide, generated in coronary vascular endothelial cells as a result of activation of the kallikrein–kinin pathway, might reduce arrhythmia severity. There is evidence that cGMP concentrations are raised following rapid cardiac pacing20 and this would lead to reduced calcium influx and increased cAMP breakdown through stimulation of a cGMP sensitive cAMP phosphodiesterase.19 Nitric oxide so generated might also reduce the oxygen deficit of myocytes during ischaemia, in part through its ability to reduce myocardial contractility. Indeed, nitric oxide has been described as an “endogenous suppressor of myocardial oxygen consumption”.21 There is experimental evidence that cell nitric oxide synthase (NOS) in cardiovascular endothelial cells is upregulated by exercise22 and by pacing, resulting in a nitric oxide mediated increase in the calibre of epicardial arteries.23 In dogs preconditioned by a single brief coronary artery occlusion there are increased coronary vascular responses to endothelium dependent vasodilators, such as bradykinin, and this is associated with increased (doubled) amounts of nitric oxide breakdown products such as nitrite and nitrate.24 Whether this is caused by upregulation of endothelial (constitutive NOS (NOS-3)) or to induction of iNOS (NOS-2) has not been clarified but the time course (a peak effect one to two days after ischaemia) suggests the latter. What triggers this increased ability of coronary vascular endothelial cells to generate nitric oxide is not known but may involve changes in shear stress resulting from increased coronary blood flow during tachycardia. How long this induction, or upregulation, lasts after cessation of the exercise or pacing stimulus is also not known, nor to what extent, if at all, it occurs in endothelial cells in atherosclerotic vessels.

Clinical implications

What are the implications of these findings? Presumably, under known conditions where endothelial dysfunction is evident (hypertension, atherosclerosis, hypercholesterolaemia) the ability to generate such endogenous myocardial protective substances may be impaired. This would lead to the attenuation of a major pathway for protection and may explain, in part, the increased susceptibility of such patients to the arrhythmic consequences of acute ischaemia. If bradykinin indeed proves to be an important trigger for this cardioprotective process then one might expect arrhythmias to be less severe in patients on angiotensin converting enzyme (ACE) inhibitors, as ACE is also one of a family of enzymes (kininases) destroying kinins. As has been recently reviewed in this journal,25there is some evidence that these drugs may offer protection against the important arrhythmias that complicate cardiac failure. Similarly, one might expect that inhibition of neutral endopeptidase (NEP), enzymes present in cardiac tissue, would also be cardioprotective. Inhibition of kinin metabolism using NEP inhibitors increases nitric oxide production from local coronary microvessels, suggesting that this enzyme also plays an important role in local kinin modulated vascular nitric oxide production.26 Another possible implication is that the beneficial effects of exercise may be partly explained by increased endothelial NOS gene expression leading to increased nitric oxide production, reduced platelet and leucocyte adherence to the vascular endothelium, inhibition of cardiac sympathetic transmission, and modulation of the cAMP:cGMP balance in cardiac myocytes.