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EDITORIAL FOCUS
1Section of Cardiology, Department of Lung, Blood, and Heart, University of Pavia and 2Department of Cardiology and 3Molecular Cardiology Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Policlinico S. Matteo, Pavia and 4Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico, Milan, Italy; 5Department of Medicine, University of Stellenbosch, Stellenbosch and 6Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, Cape Town, South Africa; and 7Department of Cardiology, Policlinico di Monza, Monza, Italy
THE DAUNTING PROBLEM of sudden cardiac death has many facets. One of these has revolved around the triggering role of sympathetic activation on one hand and around the seemingly protective effect of exercise training on the other. In their recent article in the American Journal of Physiology-Heart and Circulatory Physiology, Holycross et al. (9) add an important and novel piece of information that contributes to approach the solution of the puzzle.
A quantum leap for the understanding of sudden arrhythmic death during acute myocardial ischemia was provided in a previous issue of the Journal in 1969, when—by using the technique of single-fiber recording—Malliani et al. (13) demonstrated that myocardial ischemia elicits within seconds an excitatory cardio-cardiac sympathetic reflex. This reflex is independent of blood pressure changes and of baroreceptive reflexes, because it is present also at the spinal level, and is directly associated with the onset of ventricular tachyarrythmias as demonstrated by their disappearance following dorsal root section, a beautifully selective intervention that eliminates the sensory traffic from the heart while leaving intact the efferent cardiac-bound sympathetic activity (19). The consequent abrupt release of norepinephrine in the ischemic myocardium obviously provides an important arrhythmogenic milieu. Indeed, when the physiological sympathetic reflex was mimicked by direct electrical stimulation of the left stellate ganglion, either after a coronary artery occlusion or during a transient myocardial ischemia, it led to the frequent occurrence of ventricular fibrillation (VF) (7, 23). These findings and the related concept did contribute to the initial and successful use of 
-blockers for the reduction of sudden death among patients surviving a myocardial infarction (MI) (2) and explain the impressive and significant reduction in sudden death (from 21% to 3.5%) produced by left cardiac sympathetic denervation in a high-risk subgroup of post-MI patients (20).
Despite the numerous limitations inherent in clinical studies based on exercise training, in which randomization and adherence to therapeutic protocols are especially difficult to implement and monitor, there has been multiple and growing evidence indicating that—among post-MI patients—exercise training is associated with decreases in cardiac mortality and in sudden cardiac death (16). A wealth of hypotheses have been proposed to explain this beneficial effect, but the underlying mechanisms are not yet fully elucidated. It is nonetheless fair to say that significant evidence points to an important role for exercise training-induced modulation of the neural control of the heart. The aspect initially considered had stemmed from the well-known association between exercise and increases in vagal activity. Using a valid methodology for a reliable quantification of autonomic reflexes, predominantly vagal, as that known as baroreflex sensitivity (BRS) (12, 25), Billman et al. (3) provided the first evidence that exercise training can improve a depressed BRS present in high-risk post-MI dogs and at the same time reduce the probability of VF during a transient myocardial ischemia occurring during submaximal exercise, used as a means to physiologically increase sympathetic activity. This animal model for sudden cardiac death (18) is the same as that used by Holycross et al. in the study under discussion (9).
Multiple findings have pointed to vagal activation being a major player in the antifibrillatory protective effect of exercise training. Numerous experiments in anesthetized preparations (for a review, see Ref. 6) and clear evidence in the same postinfarction conscious dog model (28) have demonstrated that vagal stimulation at the onset of acute myocardial ischemia can effectively prevent VF. These experimental findings have been successfully translated to the clinical level. La Rovere et al. (11) have done—with the appropriate differences—in post-MI patients something very similar to what Billman et al. (3) had done in their dogs. They identified 95 patients with a first and recent MI and, after careful matching for several variables (including age, sex, site of MI, left ventricular ejection fraction, extent of coronary artery disease, and BRS) they were randomized to either 30 days of exercise training or 30 days of rest. BRS increased significantly in the exercise group and remained unchanged in the other group (11). The focus of the analysis was on those patients who had shown an increase in BRS 
3 ms/mmHg, regarded as a sign of adequate increase in reflex vagal activity. At 10-yr follow-up there was a striking difference in mortality (23% vs. 0; P < 0.04) patients with insufficient increase in BRS (including also several of those randomized to exercise) to those with clear-cut BRS increases. This study showed that exercise training per se is not sufficient for a statistically significant reduction in cardiac mortality, which also requires a meaningful shift in autonomic balance. This finding dovetails perfectly with the report by Holycross et al. (9).
Indeed, in the article under discussion (9), Billman and associates have continued in their tireless exploration of the underlying mechanisms that may shed light on the protective effect of exercise training. Using the animal model described together with Schwartz in 1984 (18), they have investigated the effects of endurance exercise on the expression of 1- and 2-adrenergic receptors in dogs known to be at high risk for VF (the so-called "susceptible" dogs). The main findings of the study were that 1) the high-risk dogs show a decrease in 1-adrenergic receptors, thus creating an imbalance with relative dominance of 2-adrenergic receptors; 2) exercise training restores the 1-adrenergic receptors in these animals; 3) there was no difference in 2-adrenergic receptors between high- and low-risk animals; and, finally, 4) among the low-risk dogs the 2-adrenergic receptors appear to reside in the caveolae, where they are less exposed to activation by catecholamines, whereas the opposite seems to be true in high-risk animals.
These data, as carefully discussed in the article, are consistent with the hypothesis that 2-adrenergic receptor activation could play a particularly important role in the onset of VF during acute myocardial ischemia. This intriguing concept has been recently supported by an important genetic finding. Sotoodehnia et al. (26) have investigated a possible relationship between specific polymorphisms of the 2-adrenergic receptor gene and occurrence of sudden cardiac death in a large population (26). They found that individuals homozygous for Gln27Glu had a significantly higher risk for sudden cardiac death (hazard ratio 1.56; 95% confidence interval 1.17–2.09) and concluded that their results demonstrate an association between functionally significant genetic variants and sudden cardiac death. In turn, this finding is supported by—and supports—the previous observation by Altschuld and Billman (1) that selective blockade of the 2-adrenergic receptors prevents VF in the canine model for sudden death.
Do these data translate into the results of clinical trials? To a certain extent, yes. Trials with metoprolol (8, 27) and with atenolol (10), both 1-adrenergic receptor blockers, have failed to reduce the incidence of VF despite reductions in total mortality, whereas propranolol and carvedilol have reduced both total mortality and sudden deaths (14, 24). This picture is somewhat more blurred in heart failure, another condition in which there is a downregulation of 1-adrenergic receptors (4), where clinical trials showed that the prevention of sudden death is similar when using selective (metoprolol and bisoprolol) and nonselective (carvedilol) -blockers (5, 15, 17). But sudden death after MI and in heart failure are different cups of tea.
The finding by Holycross et al. (9) that among dogs at high risk for VF the expression and protein content of 1-adrenergic receptors are decreased and that endurance exercise training restores the original ratio between 1- and 2-adrenergic receptors is important. When coupled with the previous evidence that these high-risk dogs show signs of impaired ability to reflexly increase cardiac vagal activity (22), the picture that emerges is that whenever, and for whatever reason, there is a shift in autonomic balance such that sympathetic activity becomes relatively dominant and there is also a shift toward a relative dominance of 2-adrenergic receptors an arrhythmogenic milieu is created that may facilitate the occurrence of sudden cardiac death. Initial evidence also suggests that these alterations in the neural control of cardiac function might be under at least partial genetic control (21).
FOOTNOTES
Address for reprint requests and other correspondence: P. J. Schwartz, Dept. of Cardiology, IRCCS Fondazione Policlinico S. Matteo, Viale Golgi 19, 27100 Pavia, Italy (e-mail: pjqt{at}compuserve.com)
REFERENCES
2-Adrenoceptors and ventricular fibrillation. Pharmacol Ther 88: 1–14, 2000.[CrossRef][ISI][Medline]-adrenoceptor expression in dogs susceptible to ventricular fibrillation. Am J Physiol Heart Circ Physiol (August 24, 2007). doi:10.1152/ajpheart.00763.2007.
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