SCHWARTZ, PETER

VANOLI, EMILIO

English

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

 doi:10.1152/ajpheart.01106.2007  293:2631-2633, 2007. First published Sep 28, 2007;Am J Physiol Heart Circ PhysiolPeter J. Schwartz and Emilio Vanoli  You might find this additional information useful...24 articles, 9 of which you can access free at: This article cites  http://ajpheart.physiology.org/cgi/content/full/293/5/H2631#BIBLincluding high-resolution figures, can be found at: Updated information and services  http://ajpheart.physiology.org/cgi/content/full/293/5/H2631 can be found at: AJP - Heart and Circulatory Physiologyabout Additional material and information  http://www.the-aps.org/publications/ajpheartThis information is current as of November 8, 2007 .    http://www.the-aps.org/.ISSN: 0363-6135, ESSN: 1522-1539. Visit our website at Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society. intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year (monthly) by the Americanlymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the  publishes original investigations on the physiology of the heart, blood vessels, andAJP - Heart and Circulatory Physiology on November 8, 2007 ajpheart.physiology.orgDownloaded from Editorial FocusFrom exercise training to sudden death prevention via adrenergic receptorsPeter J. Schwartz1,2,3,4,5,6 and Emilio Vanoli1,71Section of Cardiology, Department of Lung, Blood, and Heart, University of Pavia and 2Department of Cardiologyand 3Molecular Cardiology Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione PoliclinicoS. Matteo, Pavia and 4Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico, Milan, Italy; 5Departmentof Medicine, University of Stellenbosch, Stellenbosch and 6Cardiovascular Genetics Laboratory, Hatter Institute forCardiovascular Research, Department of Medicine, University of Cape Town, Cape Town, South Africa; and 7Departmentof Cardiology, Policlinico di Monza, Monza, ItalyTHE DAUNTING PROBLEM of sudden cardiac death has many facets.One of these has revolved around the triggering role of sym-pathetic activation on one hand and around the seeminglyprotective effect of exercise training on the other. In theirrecent article in the American Journal of Physiology-Heart andCirculatory Physiology, Holycross et al. (9) add an importantand novel piece of information that contributes to approach thesolution of the puzzle.A quantum leap for the understanding of sudden arrhythmicdeath during acute myocardial ischemia was provided in aprevious issue of the Journal in 1969, when—by using thetechnique of single-fiber recording—Malliani et al. (13) dem-onstrated that myocardial ischemia elicits within seconds anexcitatory cardio-cardiac sympathetic reflex. This reflex isindependent of blood pressure changes and of baroreceptivereflexes, because it is present also at the spinal level, and isdirectly associated with the onset of ventricular tachyarryth-mias as demonstrated by their disappearance following dorsalroot section, a beautifully selective intervention that eliminatesthe sensory traffic from the heart while leaving intact theefferent cardiac-bound sympathetic activity (19). The conse-quent abrupt release of norepinephrine in the ischemicmyocardium obviously provides an important arrhythmo-genic milieu. Indeed, when the physiological sympatheticreflex was mimicked by direct electrical stimulation of the leftstellate ganglion, either after a coronary artery occlusion orduring a transient myocardial ischemia, it led to the frequentoccurrence of ventricular fibrillation (VF) (7, 23). These find-ings and the related concept did contribute to the initial andsuccessful use of -blockers for the reduction of sudden deathamong patients surviving a myocardial infarction (MI) (2) andexplain the impressive and significant reduction in sudden death(from 21% to 3.5%) produced by left cardiac sympathetic dener-vation in a high-risk subgroup of post-MI patients (20).Despite the numerous limitations inherent in clinical studiesbased on exercise training, in which randomization and adher-ence to therapeutic protocols are especially difficult to imple-ment and monitor, there has been multiple and growing evidenceindicating that—among post-MI patients—exercise training isassociated with decreases in cardiac mortality and in suddencardiac death (16). A wealth of hypotheses have been proposedto explain this beneficial effect, but the underlying mechanismsare not yet fully elucidated. It is nonetheless fair to say thatsignificant evidence points to an important role for exercisetraining-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 vagalactivity. Using a valid methodology for a reliable quantifica-tion of autonomic reflexes, predominantly vagal, as that knownas baroreflex sensitivity (BRS) (12, 25), Billman et al. (3)provided the first evidence that exercise training can improve adepressed BRS present in high-risk post-MI dogs and at thesame time reduce the probability of VF during a transientmyocardial ischemia occurring during submaximal exercise,used as a means to physiologically increase sympathetic activ-ity. This animal model for sudden cardiac death (18) is thesame as that used by Holycross et al. in the study underdiscussion (9).Multiple findings have pointed to vagal activation being amajor player in the antifibrillatory protective effect of exercisetraining. Numerous experiments in anesthetized preparations(for a review, see Ref. 6) and clear evidence in the samepostinfarction conscious dog model (28) have demonstratedthat vagal stimulation at the onset of acute myocardial ischemiacan effectively prevent VF. These experimental findings havebeen successfully translated to the clinical level. La Rovereet al. (11) have done—with the appropriate differences—inpost-MI patients something very similar to what Billman et al.(3) had done in their dogs. They identified 95 patients with afirst and recent MI and, after careful matching for severalvariables (including age, sex, site of MI, left ventricular ejec-tion fraction, extent of coronary artery disease, and BRS) theywere randomized to either 30 days of exercise training or 30days of rest. BRS increased significantly in the exercise groupand remained unchanged in the other group (11). The focus ofthe analysis was on those patients who had shown an increasein BRS 3 ms/mmHg, regarded as a sign of adequate increasein reflex vagal activity. At 10-yr follow-up there was a strikingdifference in mortality (23% vs. 0; P  0.04) patients withinsufficient increase in BRS (including also several of thoserandomized to exercise) to those with clear-cut BRS increases.This study showed that exercise training per se is not sufficientfor 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 etal. (9).Indeed, in the article under discussion (9), Billman andassociates have continued in their tireless exploration of theunderlying mechanisms that may shed light on the protectiveeffect of exercise training. Using the animal model describedtogether with Schwartz in 1984 (18), they have investigated theeffects of endurance exercise on the expression of 1- and2-adrenergic receptors in dogs known to be at high risk for VF(the so-called “susceptible” dogs). The main findings of theAddress 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@compuserve.com).Am J Physiol Heart Circ Physiol 293: H2631–H2633, 2007;doi:10.1152/ajpheart.01106.2007.0363-6135/07 $8.00 Copyright © 2007 the American Physiological Societyhttp://www.ajpheart.org H2631 on November 8, 2007 ajpheart.physiology.orgDownloaded from study were that 1) the high-risk dogs show a decrease in1-adrenergic receptors, thus creating an imbalance with rela-tive dominance of 2-adrenergic receptors; 2) exercise trainingrestores the 1-adrenergic receptors in these animals; 3) therewas no difference in 2-adrenergic receptors between high-and low-risk animals; and, finally, 4) among the low-risk dogsthe 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 consis-tent with the hypothesis that 2-adrenergic receptor activationcould play a particularly important role in the onset of VFduring acute myocardial ischemia. This intriguing concept hasbeen recently supported by an important genetic finding. So-toodehnia et al. (26) have investigated a possible relationshipbetween specific polymorphisms of the 2-adrenergic receptorgene and occurrence of sudden cardiac death in a large popu-lation (26). They found that individuals homozygous forGln27Glu had a significantly higher risk for sudden cardiacdeath (hazard ratio 1.56; 95% confidence interval 1.17–2.09)and concluded that their results demonstrate an associationbetween functionally significant genetic variants and suddencardiac death. In turn, this finding is supported by—and sup-ports—the previous observation by Altschuld and Billman (1)that selective blockade of the 2-adrenergic receptors preventsVF in the canine model for sudden death.Do these data translate into the results of clinical trials? Toa certain extent, yes. Trials with metoprolol (8, 27) and withatenolol (10), both 1-adrenergic receptor blockers, have failedto reduce the incidence of VF despite reductions in totalmortality, whereas propranolol and carvedilol have reducedboth total mortality and sudden deaths (14, 24). This picture issomewhat more blurred in heart failure, another condition inwhich there is a downregulation of 1-adrenergic receptors (4),where clinical trials showed that the prevention of sudden deathis similar when using selective (metoprolol and bisoprolol) andnonselective (carvedilol) -blockers (5, 15, 17). But suddendeath after MI and in heart failure are different cups of tea.The finding by Holycross et al. (9) that among dogs at highrisk for VF the expression and protein content of 1-adrenergicreceptors are decreased and that endurance exercise trainingrestores the original ratio between 1- and 2-adrenergic re-ceptors is important. When coupled with the previous evidencethat these high-risk dogs show signs of impaired ability toreflexly increase cardiac vagal activity (22), the picture thatemerges is that whenever, and for whatever reason, there is ashift in autonomic balance such that sympathetic activity be-comes relatively dominant and there is also a shift toward arelative dominance of 2-adrenergic receptors an arrhythmo-genic milieu is created that may facilitate the occurrence ofsudden cardiac death. Initial evidence also suggests that thesealterations in the neural control of cardiac function might beunder at least partial genetic control (21).REFERENCES1. Altschuld RA, Billman GE. 2-Adrenoceptors and ventricular fibrilla-tion. Pharmacol Ther 88: 1–14, 2000.2. Beta-Blocker Heart Attack Study Group. The beta-blocker heart attacktrial. JAMA 246: 2073–2074, 1981.3. Billman GE, Schwartz PJ, Stone HL. The effects of daily exercise onsusceptibility to sudden cardiac death. Circulation 69: 1182–1189, 1984.4. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmus-sen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB. Beta-1 andbeta-2 adrenergic receptor subpopulations in nonfailing and failing humanventricular myocardium: coupling of both receptor subtypes to musclecontraction and selective beta 1 receptor down-regulation in heart failure.Circ Res 59: 297–309, 1986.5. CIBIS II Investigators and Committees. The Cardiac InsufficiencyBisoprolol Study II (CIBIS II): a randomised trial. Lancet 353: 9–13,1999.6. De Ferrari GM, Vanoli E, Schwartz PJ. Vagal activity and ventricularfibrillation. In: Vagal Control of the Heart: Experimental Basis andClinical Implications, edited by Levy MN and Schwartz PJ. Armonk, NY:Futura, 1994, p. 613–636.7. Harris AS, Otero H, Bocage AJ. The induction of arrhythmias bysympathetic activity before and after occlusion of a coronary artery in thecanine heart. J Electrocardiol 4: 34–43, 1971.8. Hjalmarson A, Elmfeldt D, Herlitz J, Holmberg S, Málek I, Nyberg G,Rydén L, Swedberg K, Vedin A, Waagstein F, Waldenström A,Waldenström J, Wedel H, Wilhelmsen L, Wilhelmsson C. Effect onmortality of metoprolol in acute myocardial infarction. A double-blindrandomised trial. Lancet 2: 823–827, 1981.9. Holycross BJ, Kukielka M, Nishijima Y, Altschuld RH, Carnes CA,Billman GE. Exercise training normalizes -adrenoceptor expressionin dogs susceptible to ventricular fibrillation. Am J Physiol Heart CircPhysiol (August 24, 2007). doi:10.1152/ajpheart.00763.2007.10. ISIS-1 (First International Study of Infarct Survival) CollaborativeGroup. Mechanisms for the early mortality reduction produced by beta-blockade started early in acute myocardial infarction: ISIS-1. Lancet 1:921–923, 1988.11. La Rovere MT, Bersano C, Gnemmi M, Specchia G, Schwartz PJ.Exercise-induced increase in baroreflex sensitivity predicts improvedprognosis after myocardial infarction. Circulation 106: 945–949, 2002.12. La Rovere MT, Schwartz PJ. Baroreflex sensitivity. In: CardiacElectrophysiology. From Cell to Bedside (3rd ed.), edited by Zipes DPand Jalife J. Philadelphia, PA: Saunders, 2000, p. 771–781.13. Malliani A, Schwartz PJ, Zanchetti A. A sympathetic reflex elicited byexperimental coronary occlusion. Am J Physiol 217: 703–709, 1969.14. McMurray J, Køber L, Robertson M, Dargie H, Colucci W,Lopez-Sendon J, Remme W, Sharpe DN, Ford I. Antiarrhythmiceffect of carvedilol after acute myocardial infarction. Results of theCarvedilol Post-Infarct Survival Control in Left Ventricular Dysfunc-tion (CAPRICORN) Trial. J Am Coll Cardiol 45: 525–530, 2005.15. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heartfailure: Metoprolol CR/XL Randomized Intervention Trial in CongestiveHeart Failure (MERIT-HF). Lancet 353: 2001–2007, 1999.16. O’Connor GT, Buring JE, Yusuf S, Goldhaber SZ, Olmstead EM,Paffenbarger RS Jr, Hennekens CH. An overview of randomized trialsof rehabilitation with exercise after myocardial infarction. Circulation 80:234–244, 1989.17. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, GilbertEM, Shusterman NH. The effect of carvedilol on morbidity and mortalityin patients with chronic heart failure. N Engl J Med 334: 1349–1355,1996.18. Schwartz PJ, Billman GE, Stone HL. Autonomic mechanisms in ven-tricular fibrillation induced by myocardial ischemia during exercise indogs with healed myocardial infarction. An experimental preparation forsudden cardiac death. Circulation 69: 790–800, 1984.19. Schwartz PJ, Foreman RD, Stone HL, Brown AM. Effect of dorsal rootsection on the arrhythmias associated with coronary occlusion. Am JPhysiol 231: 923–928, 1976.20. Schwartz PJ, Motolese M, Pollavini G, Lotto A, Ruberti U, Trazzi R,Bartorelli C, Zanchetti A, Italian Sudden Death Prevention Group.Prevention of sudden cardiac death after a first myocardial infarctionby pharmacologic or surgical antiadrenergic interventions. J CardiovascElectrophysiol 3: 2–16, 1992.21. Schwartz PJ, Vanoli E, Crotti L, Spazzolini C, Goosen A, Heradien M,Bacchini S, Turco A, La Rovere MT, Bartoli A, George AL Jr, BrinkPA. Neural control of heart rate modifies arrhythmia risk in congenitallong QT syndrome. J Am Coll Cardiol. In press.22. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, BillmanGE, Foreman RD. Autonomic mechanisms and sudden death. Newinsights from analysis of baroreceptor reflexes in conscious dogs with andwithout a myocardial infarction. Circulation 78: 969–979, 1988.Editorial FocusH2632AJP-Heart Circ Physiol • VOL 293 • NOVEMBER 2007 • www.ajpheart.org on November 8, 2007 ajpheart.physiology.orgDownloaded from 23. Schwartz PJ, Vanoli E, Zaza A, Zuanetti G. The effect of antiarrhyth-mic drugs on life-threatening arrhythmias induced by the interactionbetween acute myocardial ischemia and sympathetic hyperactivity. AmHeart J 109: 937–948, 1985.24. Shivkumar K, Schultz L, Goldstein S, Gheorghiade M. Effects ofpropranolol in patients entered in the Beta-Blocker Heart Attack Trial withtheir first myocardial infarction and persistent electrocardiographic ST-segment depression. Am Heart J 135: 261–267, 1998.25. Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterialpressure during sleep in man. A quantitative method of assessing barore-flex sensitivity. Circ Res 24: 109–121, 1969.26. Sotoodehnia N, Siscovick DS, Vatta M, Psaty BM, Tracy RP, TowbinJA, Lemaitre RN, Rea TD, Durda JP, Chang JM, Lumley TS, KullerLH, Burke GL, Heckbert SR. Beta2-adrenergic receptor genetic variantsand risk of sudden cardiac death. Circulation 113: 1842–1848, 2006.27. The MIAMI Trial Research Group. Metoprolol in acute myocardialinfarction (MIAMI). A randomised placebo-controlled international trial.Eur Heart J 6: 199–226, 1985.28. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, ForemanRD, Schwartz PJ. Vagal stimulation and prevention of sudden death inconscious dogs with a healed myocardial infarction. Circ Res 68: 1471–1481, 1991.Editorial FocusH2633AJP-Heart Circ Physiol • VOL 293 • NOVEMBER 2007 • www.ajpheart.org on November 8, 2007 ajpheart.physiology.orgDownloaded from 

From exercise training to sudden death prevention via adrenergic receptors.

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From exercise training to sudden death prevention via adrenergic receptors.

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