Arrhythmias and Mortality in Congestive Heart Failure John Kjekshus, MD
The extent and severity of myocardial dysfunction and risk of dying are associated with the occurrence of ventricular arrhythmias. However, there is a dissociation between the frequency of ventricular arrhythmias and the prevalence of sudden death among patients with congestive heart failure. Sudden death occurs in 8 to iO% of New York Heart Association functional class I patients and in 20% of class II, Ill and IV patients, despite increased frequency of malignant arrhythmlas and functional deterioration. Yearly mortality rates increase from 12 to 15% in class I and II and is 60% in class IV. Sudden death in class I and II is JO to 60% of all deaths, whereas in class IV it amounts to only 20 to 30%. The most important cause of death in class IV is progressive congestive heart failure. Ventricular arrhythmia is a trigger event in the development of fatal arrhythmia which depends on a substrate of myocardial scar tissue, hypertrophy and aberrant conducting pathways. However, regional myocardial ischemia, transmembrane electrolyte differences and myocardial stores of catecholamines are important modulators. Depletion of myocardial catecholamines and down-regulation of myocardial Badrenergic receptors in the myocardiurn may explain tolerance to ventricular tachyarrhythmias observed in patients with severe congestive heart failure and intolerance to conventional antiarrhythmic drugs. Although angiotensin-converting enzyme (ACE) inhibitors may reduce ventricular arrhythmias, the important role of ACE inhibitors in severe congestive heart failure is to prevent progression of myocardial dysfunction and congestive heart failure. To date, however, ACE inhibitors have not been demonstrated to have a significant effect on the incidence of sudden death. This does not preclude an effect on fatal arrhythmias among patients with milder heart failure and intact stores of myocardial catecholamines. (Am J Cardiol l-65:42 I-48 I)
From the Department of Medicine, Baerum Hospital, Sandvika, Norway. Address for reprints: John Kjekshus, MD, Department of Medicine, Bierurn Hospital, Sandvika- 13 16, Norway.
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P
atients with chronic congestiveheart failure have a high incidenceof ventricular arrhythmia and sudden death.‘-” It is generally assumedthat ventricular arrhythmia may degenerateto ventricular fibrillation, the fatal arrhythmia in most patients who die suddenly.lO-l4 Patients with frequent arrhythmias usually have extensive coronary artery diseasewhich is often associatedwith recent myocardial infarction, hypertrcF phy and dysfunction.15-l9The extent of myocardial dysfunction is clearly related to overall mortality and cardiac death.20The prevalenceof malignant arrhythmias, especially nonsustainedventricular tachycardia (VT), is also related to the extent of myocardial dysfunction. Functional derangement of patients is associated with increasednonsustainedVT, asrevealedby 24-hour electrocardiogram, in less than 10% of patients in New York Heart Association functional classI to 70%among class IV patients (Fig. 1).2-4,7,9,20m22 The question remains, however,whether there is an independentrole of ventricular ectopic activity as a determinant for suddendeath or if it is incidental to the myocardial dysfunction. ARRHYTHMIAS IN CONGESTIVE HEART FAILURE
The trigger event to VT is assumedto be reentrant activity, or enhanced automaticity, induced by a substrate of arrhythmogenic myocardium (Table I). This involvesextensivescarring, dilatation and hypertrophy of the myocardium. The occasional degeneration of arrhythmias to ventricular fibrillation may be modulated by severemyocardial ischemia or by loss of autonomic control with increasedneurohormonal activation and loss of inhibitory vagal activity. 23,24 An increasein myocardial wall tension and heart rate frequently observedin congestiveheart failure may contribute to regional myocardial ischemia,resulting in marked dispersionof the membrane potential which may further enhance electrical instability. Electrolyte disturbances,especiallyhypokalemia and hypomagnesemia,are caused by elevation of circulating catecholamines,angiotensin and aldosterone, and from useof diuretics and digitalis and are associated with increased occurrence of ventricular fibrillation. In addition, catecholamines increase the automaticity of Purkinje fibers by increasingthe slopeof phase4 depolarization. Therapy with antiarrhythmic drugs, digitalis, /3adrenergic agonists and phosphodiesteraseinhibitors may be arrhythmogenic by enhancedtriggering of ectopic activity or subsequentlyto their depressanteffect on the myocardium (i.e., these drugs may be arrhythmogenie either directly, by precipitating ventricular dilata-
80-
FlGUREl.ThereModip lw4weenNewYorkHaartAssoclation (NYHA) fumcthd
l
60-
0
0
das9andtheprewalenceof 0
: 40-
NYHA Functional
Class
in 81% of casesof sudden death13and was precededby VT in most patients. The occurrence of malignant arrhythmias, especiallyVT, has beenassumedto be instrumental in precipitating suddendeath. Therefore, VT has beenassumedto be of prognosticimportance and accordMODE OF DEATH IN CONGESTIVE ingly should be treated to prevent sudden death.25+26 HEART FAILURE The association between VT and death is probably The major causesof death in congestiveheart failure are sudden death and death from progressiveheart fail- independent of etiology. Ikegawa et a127showedthat in ure. More infrequent causes of death are myocardial patients with idiopathic cardiomyopathy the incidenceof rupture, asystole,stroke and death from noncardiac ori- suddendeath was highly predictable when occurrenceof gins (Table II), Sudden death is assumedto be death nonsustained VT and frequent ventricular premature resulting from cardiac arrhythmia. Sudden death, de- complexes (VPCs) of more than loo/hour were comfined as unexpected death within 1 hour after onset of bined. Bigger et a12’jdemonstratedthat nonsustainedVT symptoms,is presagedby arrhythmias in 90% of all such had marked effects on survival and on arrhythmic death events.‘OVentricular fibrillation wasthe terminal rhythm amongpatients after infarction. However, the 92 patients with VT were sicker than the 728 without VT. Yet, when adjustments were made for recorded differences in risk rABLE I Arrhythmias and Sudden Death in Congestive Heart variables, the presenceof VT nearly doubled the risk of Failure dying within a 3 1-month follow-up period. Other imporTriggering activities tant risk variables may have beenoperative as well. EpiReentrant activity sodesof silent ischemia, neurohormonal activation, exEnhanced automaticity tent of myocardial dysfunction and hypertrophy were not Delayed after potentials tion, or secondarily to the chronotropic and inotropic effects that may aggravate the myocardial oxygen demand/supply ratio).
Myocardial substrates Scar tissue Aneurysm Hypertrophy Ventricular dilatation Ventricular dysfunction Modulating events Myocardial ischemia Electrolyte deficits Myocardial release of cathecholamines Sympatoadrenergic activation Myocardial stretch Antiarrhythmic drugs lnotropic drugs Diuretics
TABLE
II Mode
of Death
in Congestive
Heart
Failure
Sudden death (4 hour) Ventricular fibrillation Progressive myocardial failure Asystole Secondary ventricular fibrillation Recurrent myocardial infarction Other circulatory disorders Myocardial rupture Stroke Pulmonary embolism Noncardiac cause
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FIGURE 2. lb proportion atldeathacau#dbywdtl8n ~accodngtol-year EzY!2xz (NYHA) class I to%if$il
of
‘”
irom lldifhmntstudies.'-" 0
20-
0 I 20
I 40
% Overall Mortality
I 60
I 60
I 100
(12 month follow-up)
determined in this study and may have accounted for observeddifferences between groups. Congestiveheart failure appearsto be an ill-defined heterogenoussyndrome and mode of death seemsto differ according to different expressionsof the syndrome. Total mortality among patients with mild heart failure is low. However, the proportion of patients dying suddenly is large; 50 to 70% of all deaths are suddenin classI and II.‘-’ l Serious arrhythmias are relatively infrequent among these patients. The occurrence of malignant arrhythmia increaseswith the severity of the myocardial dysfunction (Fig. 1). Patients in classIII and IV have an overall yearly mortality of 40 to 60%. The proportion of patients dying suddenly,relative to all deaths,amountsto lessthan 30%(Fig. 2). The major causeof death in severe congestiveheart failure (class III and IV) is from progressive deterioration of myocardial function, whereas the rate of sudden death remains comparable to that in class II and accounts for 10 to 30% of all patients irrespectiveof functional class (Fig. 3). Analysis of arrhythmias and mode of death reported in studiesof congestive heart failure according to functional classtherefore suggestsno clear associationbetweenoccurrenceof ventricular arrhythmias and sudden, presumably, arrhythmic death.
tricular fibrillation occurs when myocardial &hernia is coupled with sympathetic nervous stimulation of the myocardium and catecholamineexcessfrom the myocardium. After severingthe stellate ganglion, the myocardiurn becametolerant to the sameischemia, and ventricular arrhythmias were no longer inducible.33Depletion of catecholamine storesby reserpine preventedventricular fibrillation during experimental coronary occlusion. The dissociation between frequently occurring ventricular tachyarrhythmias and the relatively low prevalence of sudden death in severecongestiveheart failure may be related to depletion of myocardial catecholamine stores and consequentblunting of the modulating effect on trigger events.
ARRHYTHMIC DEATH AND MYOCARDIAL ISCHEMIA Lack of neurohormonal control is associatedwith a high risk of dying among patients with myocardial dysfunction.29This is reflected in monotonoustachycardia with very low variation in beat-to-beat RR interval. Re gional myocardial ischemia and release of myocardial catecholaminestogether with loss of vagal control may therefore have an important enhancing effect on the triggering activity. Recordings of 24-hour electrocardiograms, obtained in patients dying suddenly, have shown that immediate precursorsof suddendeath, in addition to ARRHYTHMIC DEATH AND frequent ventricular ectopicactivity, wasST-segmentdeNEUROHORMONAL ACTIVITY Patients with severecongestiveheart failure havehigh viation before ventricular fibrillation.34 Frank myocardilevelsof circulating catecholaminesthat are closelyrelat- al infarction may be the initiating event that causedared to a poor prognosis.24,28>29 Increasedneurosympathetic rhythmias; however,coagulation myocytolysis necrosisis This stimulation down-regulates myocardial /3 receptors,30 found in 71% of the patients dying suddenly.35q36 and myocardial catecholamine stores are markedly de- finding is typically associatedwith states of excessive pleted3’ becauseof reduced reuptake of releasedcate- catecholamineexcretion. The autopsy findings of Davies cholamines.32Experiments in dogs have shown that ven- and Thomas37showedthat 74%of the patients who died
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-w-B
Total Death Sudden Death
FIGURE 3. Prevalence of total (#Dfo&en he) and 6lJdden ckath (so/id line) by Rew YOkbkWtA86OCh~ (IWHA) ftadenal class and
l-yearmortalityadapted fm1n6dWr~mtstud~,hZ4.~.9,11
NYHA Functional
unexpectedly, i.e., within 6 hours, had subocclusiveintraluminal thrombi; 20% had plaque fissuresand very few, 5%, did not have occlusive lesions. This finding lends support to the importance of episodesof regional ischemia and catecholaminereleaseasa contributing mechanism. ARRHYTHMIC
DEATH AND INTERVENTION
Recent information from the Cardiac Arrhythmia SuppressionTrial, a prospective double-blind, randomized trial, suggested that conventional antiarrhythmic drugs may actually increasemortality among patients in mild to moderate heart failure after acute myocardial infarction.38*39Generally, information from studies on mild to moderate heart failure is not applicable to patients with severeheart failure. ClassIV patients havenot been studied with respectto the effect of antiarrhythmic treatment on mortality becauseof their overall low tolerance to conventional antiarrhythmic drugs. A trend toward increasing mortality with milrinone suggeststhat inotropic drugs may be harmful as we11.40 In contrast, flreceptor antagonists that block sympathetic stimulation of the myocardium have beenshown to reduce mortality and sudden death, specifically, during and after acute myocardial infarction.6,41This effect is not associated with an effect on ventricular tachyarrhythmias.41Protection by B blockade is not restricted to patients with coronary disease;similar results are suggestedby studies in patients with dilated cardiomyopathy without coronary artery disease.42Prevention of myocardial ischemia by reducing heart rate seemsto be instrumental in prolonging survival.43 Experience from coronary surgery suggeststhat prevention of ischemia by revascularization of main stem lesions prevents death within 24 hours after onset of symptoms.44
Class
It has been suggestedthat reduction of myocardial pre- and afterload by nitrates and angiotensin-converting enzyme (ACE) inhibitors, which improves myocardial residual flow, can reduce ventricular arrhythmias in patients with mild to moderate heart failure.45m47 Only 1 mortality study has been performed with vasodilators among patients with severecongestiveheart failure who are prone to frequent arrhythmias.9 The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) studied patients with severe heart failure (New York Heart Association class IV). Patients (n = 253) were randomizedto treatment with placeboand the ACE inhibitor enalapril. One-year mortality among patients taking placebo was 52% and among those taking enalapril 36%. The major cause of death in the CONSENSUS was progressiveheart failure. Treatment effects were accounted for by the subset of patients for which prevention of progressive deterioration of heart failure was obtained (Fig. 4). Patients who died unexpectedly,within 1 hour after onsetof symptoms,accounted for 20%of all deathsand no treatment effect could be documentedwith this subset(Fig. 5). This latter observation is at variance with previous studies of patients with moderateheart failure demonstrating a reduction of ventricular ectopic activity with ACE inhibitors.45-47The differential effect of enalapril on progressiveheart failure and sudden death was consistent among patients with myocardial dysfunction caused by ischemic as well as nonischemicheart disease.9,48 The subsetof patients dying suddenly was small, and it may be argued that classification of death may be influenced by the effect of enalapril on the clinical condition. However, death was blindly classified by 2 independent investigators. A subsetof patients in the CONSENSUS wereexamined with 24-hour electrocardiographicanalysesat base-
THE AMERICAN JOURNAL OF CARDIOLOGY MAY 22, 1990
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60
FlGURE 4. Martality due to pmgmssh of congestive heart fake-intent&n to treat analysis in tlw Cooperative North Scandlnavi~ Edapril Swvival Study. (Adapted with psmtlssi~ from Am J Cadiol.~
Enalapril
I
I
123456789
I 10
line and after 6 weeks of treatment. All patients had frequent VPCs, averaging 200 to 300 VPCs/hour. There was no difference between survivors and deceasedwith respect to ectopic activity. Seventy percent of all the patients had nonsustainedVT at baseline.No difference in the rate of subsequent6-month mortality wasobserved
I 11
I@ 12
irrespectiveof whether VT waspresentor not. Reduction in ventricular ectopicactivity wasnot related to changein mortality or mode of death. All patients were examinedwith respectto neurohormonal activation at baselineand at 6 weeks.In general, catecholamines,angiotensin,aldosteroneand atria1natri-
A
3.0-
200
250
300
350
Days FIGURE 5. MoHaHty due to addem death within 1 hour (We-t&k lrom Am J CardM@) Suwlval Stwty. (Adepted with pennisslon
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
anatysis) in the &operative
North Scandinavian
EMbpril
uretic peptide (ANP) were greatly elevated. Neurohor- only beendemonstratedto causefewer deaths from promonal activation was variable in all patients; however,no gressivecongestiveheart failure, not sudden death. relationship was found between catecholamines,angiotensin II or aldosteroneand the occurrenceof ventricular REFERENCES 1. Franciosa JA, Wilen M, Ziesche S, Cohn JN. Survival in men with severe VPCs or VT. chronic left ventricular failure due to either coronary heart disease or idiopathic In contrast, ANP was related to occurrence of VT. dilated cardiomyopathy. Am J Cardiol 1983;51:832-836, ANP releasedafter increasedstretch of the atria reflect- 2. Wilson JR, Schwartz S, St John Sutton M, Ferraro N, Horowitz LN, Reichek N, Josephson ME. Prognosis in severe heart failure: relation to hemodynamic ed increased left ventricular ftlling pressures.Patients measurements and ventricular ectopic activity. JACC 1983:2:403-4/O. with VPCs combined with runs of VT had higher ANP 3. Meinertz T. Hofmann T, Kasper W, Treese N, Bechtold H, Stienin U, Pop T, concentrations than patients with VPCs alone. This sug- van Leithner E, Andresen D. Meyer J. Significance of ventricular arrhythmias in dilated cardiomyopathy. Am J Cardiol 1984;53:902-907. gests that VT is dependent on myocardial dysfunction 4.idiopathic Chakko CS, Gheorghiade M. Ventricular arrhythmias in severe heart failure: and may explain the associationbetweenVT and progno- incidence, significance and effectiveness of antiarrhythmic therapy. Am Heart J 1985;109:497-504. sis.i5 5. Hinkle L. The immediate antecedents of sudden death. Acta Med Sand Enalapril effectively reduced ANP after 6 weeks of 1981;21O:suppl 681:207-217. treatment, whereasANP in the placebo group remained 6. Lund-Johansen P. The Norwegian Multicenter Study on Timolol after myocardial infarction. Part II. Effect in different risk groups, causes of death, heart unchanged.29The reduction in ANP may reflect a reduc- arrest, reinfarctions, rehospitalizations and adverse experiences. Acta Med Sand tion in filling pressureand improved hemodynamiccondi- 1981:21O:suppl 681.243-252. tions during administration of enalapril and may explain 7. Maskin CS, Siskind SJ, LeJemtel TH. High prevalence of nonsustained ventachycardia in severe congestive heart failure. Am Heart J 1984;107:896the reduction of arrhythmias observedwith ACE inhibi- tricular 901. 8. Cleland JGF, Dargie HJ, Ford 1. Mortality in heart failure: clinical variables of tors.45,46 value. Br Heart J 1987:58:5?2-582. Lack of relationship betweenchangesin norepineph- 4.oroenostic ?he CONSENSUS trial study group. Effects of enalapril on mortality in rine, angiotensin, aldosterone and ventricular arrhyth- severe congestive heart failure. IV Eng/ J Med 1987;316:1429-1435. mias does not preclude the importance of myocardial 10. Goldstein S, Friedman L, Hutchinson R, Canner P, Romhilt D, Schlant R, R, Verter J, Wasserman A, Aspirin myocardial infarction study group. neurohormonal activation as a mechanism for fatal ar- Sobrino Timing, mechanism and clinical setting of witnessed deaths in postmyocardial rhythmias. Down-regulation of myocardial /3 receptor infarction patients. JACC 1984;3:11 II-1 117. and depletion of myocardial catecholaminestoresin these 11. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting enzyme inhibition in patients with severe patients may confer relative protection against arrhyth- chronic heart failure. Circukztion 1986:73:257-267. 12. Savage HR, Kissane JQ, Becher EL, Maddocks WQ, Murtaugh JT, Dizadji mias. H. Analysis of ambulatory electrocardiograms in 14 patients who experienced The neurohormonesare important predictors of death sudden death during monitoring. Clin Cardiol 1987;10:621-632. in congestiveheart failure.29By combining the neurohor- 13. Nicolic G, Bishop RL, Singh JB. Sudden death recorded during Halter monitoring. Circulation 1982,66:218-225. mones at baseline, a predictive score was derived that 14. Kempf FC, Josephson ME. Cardiac arrest recorded on ambulatory electrodefined a 6-month mortality of 20%among nonactivators cardiogram. Am J Cardiol 1984;53:1577-1582. to almost 100% among patients with the largest neuro- 15. The Multicenter Postinfarction Research Group. Risk stratification and hormonal activation.29Thesescoresidentified a group of survival after myocardial infarction. N Engr J h4ed 1983:309:33/L336. 16. McLennachan JM, Henderson E, Morris Kl, Dargie HJ. Ventricular arhigh activators with marked effect of enalapril on overall rhythmias in patients with hypertensive left ventricular hypertrophy. N Eng/ J mortality and a group of low activators without docu- Med 1987;317:787-792. 17. Kreger BE, Cupples A, Kannel WB. The electrocardiogram in prediction of mentedeffect of enalapril on mortality. Patientswho died sudden death: Framinaham studv exoerience. Am Heart J 1987:113:377-R2. from progressive heart failure were almost exclusively 18. Messerli FH, Vet&a HO, &.a;di DJ, Dunn FG, Frohlich ED. Hypertenamong high activators, whereassuddendeath wasevenly sion and sudden death. Am J Med /9X4:77:18-22 19. Norris RM, Barnaby PF, Brandt PWT, Geary CC, Whitlcck RM, Wild CJ, distributed among high and low activators. High circulat- Barratt-Boyes BG. Prognosis after recovery from first acute myocardial infarcing hormonal activity in this study is therefore not a tion: determinants of reinfarction and sudden death. Am J Cardiol 1984;53:408predictor of increasedsusceptibility to suddendeath, but 413. Rocco MB, Sherman H, Cook EF, W&berg M, Flatley M, Goldman L. may predict death from progressionof congestiveheart 20. Correlates of cardiac and sudden death after ambulatory monitoring in a commufailure. The level of circulating hormonal activity also nity hospital. J Chron Dis 1987:40:977-984, Huang SK, Messer JV, Denes P. Significance of ventricular tachycardia in identified patients who benefited from ACE inhibitor 21. idiopathic dilated cardiomyopathy: observations in 35 patients. Am J Cardiol treatment. Reducedstoresof myocardial catecholamines 1983;51:507-512. or blocking of p receptorsmay be clinically important in 22. Lichstein E, Morganroth J, Harrist R, Hubble E, BHAT study group. Effect propranolol on ventricular arrhythmias. The Beta-Blocker-Heart Attack Trial blunting the modulating effect of sympathetic stimula- ofExperience. Circulation 1983.67:suppl 1:1-5-I-10. tion on ventricular arrhythmias. 23. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic CONCLUSION
The extent of myocardial dysfunction is associated with increasedoccurrenceof malignant arrhythmias, yet in severe congestive heart failure, death is generally causedby progressionof congestiveheart failure and not sudden death. Sudden death is more often observed among asymptomatic or less symptomatic patients. It is unclear whether ACE inhibitors reduce arrhythmias in congestiveheart failure, and so far ACE inhibition has
control in patients with heart disease. N EngI J Med 1971;285:877-883. 24. Francis G. Neuroendocrine manifestations of congestive heart failure. Am J Cardiol 1988.62:9A-13A. 25. Bigger JT. Why patients with congestive heart failure die: arrhythmias and sudden cardiac death. Circuhaion 1987:75:2X-35 26. Bigger JT, Fleiss JL, Rolnitzky -Lb, Multicenter postinfarction research group. Prevalence, characteristics and significance of ventricular tachycardia detected by 24-hour continuous electrocardiographic recordings in the late hospital phase of acute mywardial infarction. Am J Cardiol 1986:58:1151-1160. 27. Ikegawa T, Chino M, Hasegawa H, Usaba F, Suzuki S, Ookura M, Mishihawa K. Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with dilative cardiomyopathy: a prospective study. Cbn Cardiol 1987:10:78-82. 28. Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to
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prognosis in patients with chronic congestive heart failure. N Eng/ J Med 1984;311:819-823. 29. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation; in press. 30. Bristow MR. Ginsburg R, Minobe W, Cubicciotti RS, Sageman WR, Billingham M, Stinson E, Harrison DC. Decreased catecholamine sensitivity and beta-adrenergic receptor density in failing human hearts. N Eng/ J Med 1982;307:205-211. 31. Chidsey CA, Braunwald E, Morrow AG, Mason DT. Myocardial norepinephrine concentration in man: effects of reserpine and congestive heart failure. N Engl .I Med 1963:269:653-658. 32. Henderson EB, Kahn JK, Corbett JR, Hansen DE, Pippin JJ, Kulkami P, Ugolini V, Akers MS, Hansen CHR, Buja LM, Parkey RW, Willerson JT. Abnormal I-123 metaiodobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive cardiomyopathy. Circulation 1988:78:1192-l 199. 33. Schwartz PJ, Billman GE, Stone HL. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. Circulation 1984,69:790-800. 34. Gottlieb SO, Gottlieb SH, Achuff SC, Baumgardner R, Mellitsa ED, Weisfeldt ML, Gerstenblith G. Silent &hernia on Halter-monitoring predicts mortality in high-risk postinfarction patients. JAMA 1988;259:1030-1035. 39. Baroldi G, Falzi G, Mariani F. Sudden coronary death. A post mortem study in 208 selected cases compared to 97 “control subjects.” Am Heart J 1979,98:2027. 36. Baroldi G. Different morphological types of myocardial cell death in man. Recent advances in studies on cardiac structure and metabolism. In: Fleckenstein A, Rona G, eds. Pathophysiology and Morphology of Myocardial Cell Alteration. Baltimore, London, Tokyo: University Park Press, 1975;16:383-397. 37. Davies MJJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137-1140. 36. The Cardiac Arrhythmia Suppression Trial investigators preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia.
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Suppression after myocardial infarction. N Engl J Med 1989:321;406-412. 39. Stewart RA, McKenna WJ, Poloniecki JD, Michelson JK, Das SK, Morady F, Shark MA, Pitt B, Niclas JM. Prospective, randomized, double blind, placebo controlled trial of low dose amicdarone in patients with severe heart failure and frequent ventricular ectopy (abstr). Eur Heart J 1989:10:229. 40. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral milorinone, digoxine and their combinations in the treatment of patients with chronic heart failure. N Engl J Med 1989920:677-683. 41. Ryden L, Arimego R, Arneman K, Herlitz J, Hjalmarson A, Holmberg S, Reyes C, Smedglrd P, Swedberg K, Vedin A, Waagstein F, Waldenstrqm A, Wilhelmsson C, Wedel H, Yamamoto M. A double-blind trial of metoprolol in acute myocardial infarction. N l@gl J Med 1983;308:614-618. 42. Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancer 1979; 1:1374-1376. 43. Kjekshus J. Importance of heart rate in determining beta blocker efficacy in acute and long term acute myocardial infarction intervention trials. Am J Cardiol 1986;57:43F-49F. 44. Holmes DR, Davis KB, Mock MB, Fisher LD, Gersh BJ, Killip T, Pettinger M, and Participants in the Coronary Artery Surgery Study. The effect of medical and surgical treatment on subsequent sudden cardiac death in patients with coronary artery disease: a report from the Coronary Artery Surgery Study. Circulation 1986:73:1254-l 263. 45. Webster MWI, Fitzpatrick A. Nicholls G. Ikram H. Wells E. Effects of enalapril on ventricular arrhythmias in congestive heart f&re. Am J Cardiol 1985.56.566-569. 46. Cleland JGF, Dargie HJ, H&man GP, Ball SG, Robertson JIS, Morton JJ, East BW, Robertson I, Murray GD, Gillen G. Captopril in heart failure. A double blind controlled trial. Br Heart J 1984;52.530-535. 47. Dennick LG, Masin CS, Meyer JH, Schotz WE, Brown BW. Enalapril for congestive heart failure. N Engl J Med 1987;137:1349-1350. 46. Swedberg K, Kjekshus J. The CONSENSUS Trial Study Group. Effect of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol 1988,62:6OA-66A.
The extent and severity of myocardial dysfunction and risk of dying are associated with the occurrence of ventricular arrhythmias. However, there is a dissociation between the frequency of ventricular arrhythmias and the prevalence of sudden death among patients with congestive heart failure. Sudden death occurs in 8 to iO% of New York Heart Association functional class I patients and in 20% of class II, Ill and IV patients, despite increased frequency of malignant arrhythmlas and functional deterioration. Yearly mortality rates increase from 12 to 15% in class I and II and is 60% in class IV. Sudden death in class I and II is JO to 60% of all deaths, whereas in class IV it amounts to only 20 to 30%. The most important cause of death in class IV is progressive congestive heart failure. Ventricular arrhythmia is a trigger event in the development of fatal arrhythmia which depends on a substrate of myocardial scar tissue, hypertrophy and aberrant conducting pathways. However, regional myocardial ischemia, transmembrane electrolyte differences and myocardial stores of catecholamines are important modulators. Depletion of myocardial catecholamines and down-regulation of myocardial Badrenergic receptors in the myocardiurn may explain tolerance to ventricular tachyarrhythmias observed in patients with severe congestive heart failure and intolerance to conventional antiarrhythmic drugs. Although angiotensin-converting enzyme (ACE) inhibitors may reduce ventricular arrhythmias, the important role of ACE inhibitors in severe congestive heart failure is to prevent progression of myocardial dysfunction and congestive heart failure. To date, however, ACE inhibitors have not been demonstrated to have a significant effect on the incidence of sudden death. This does not preclude an effect on fatal arrhythmias among patients with milder heart failure and intact stores of myocardial catecholamines. (Am J Cardiol l-65:42 I-48 I)
From the Department of Medicine, Baerum Hospital, Sandvika, Norway. Address for reprints: John Kjekshus, MD, Department of Medicine, Bierurn Hospital, Sandvika- 13 16, Norway.
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P
atients with chronic congestiveheart failure have a high incidenceof ventricular arrhythmia and sudden death.‘-” It is generally assumedthat ventricular arrhythmia may degenerateto ventricular fibrillation, the fatal arrhythmia in most patients who die suddenly.lO-l4 Patients with frequent arrhythmias usually have extensive coronary artery diseasewhich is often associatedwith recent myocardial infarction, hypertrcF phy and dysfunction.15-l9The extent of myocardial dysfunction is clearly related to overall mortality and cardiac death.20The prevalenceof malignant arrhythmias, especially nonsustainedventricular tachycardia (VT), is also related to the extent of myocardial dysfunction. Functional derangement of patients is associated with increasednonsustainedVT, asrevealedby 24-hour electrocardiogram, in less than 10% of patients in New York Heart Association functional classI to 70%among class IV patients (Fig. 1).2-4,7,9,20m22 The question remains, however,whether there is an independentrole of ventricular ectopic activity as a determinant for suddendeath or if it is incidental to the myocardial dysfunction. ARRHYTHMIAS IN CONGESTIVE HEART FAILURE
The trigger event to VT is assumedto be reentrant activity, or enhanced automaticity, induced by a substrate of arrhythmogenic myocardium (Table I). This involvesextensivescarring, dilatation and hypertrophy of the myocardium. The occasional degeneration of arrhythmias to ventricular fibrillation may be modulated by severemyocardial ischemia or by loss of autonomic control with increasedneurohormonal activation and loss of inhibitory vagal activity. 23,24 An increasein myocardial wall tension and heart rate frequently observedin congestiveheart failure may contribute to regional myocardial ischemia,resulting in marked dispersionof the membrane potential which may further enhance electrical instability. Electrolyte disturbances,especiallyhypokalemia and hypomagnesemia,are caused by elevation of circulating catecholamines,angiotensin and aldosterone, and from useof diuretics and digitalis and are associated with increased occurrence of ventricular fibrillation. In addition, catecholamines increase the automaticity of Purkinje fibers by increasingthe slopeof phase4 depolarization. Therapy with antiarrhythmic drugs, digitalis, /3adrenergic agonists and phosphodiesteraseinhibitors may be arrhythmogenic by enhancedtriggering of ectopic activity or subsequentlyto their depressanteffect on the myocardium (i.e., these drugs may be arrhythmogenie either directly, by precipitating ventricular dilata-
80-
FlGUREl.ThereModip lw4weenNewYorkHaartAssoclation (NYHA) fumcthd
l
60-
0
0
das9andtheprewalenceof 0
: 40-
NYHA Functional
Class
in 81% of casesof sudden death13and was precededby VT in most patients. The occurrence of malignant arrhythmias, especiallyVT, has beenassumedto be instrumental in precipitating suddendeath. Therefore, VT has beenassumedto be of prognosticimportance and accordMODE OF DEATH IN CONGESTIVE ingly should be treated to prevent sudden death.25+26 HEART FAILURE The association between VT and death is probably The major causesof death in congestiveheart failure are sudden death and death from progressiveheart fail- independent of etiology. Ikegawa et a127showedthat in ure. More infrequent causes of death are myocardial patients with idiopathic cardiomyopathy the incidenceof rupture, asystole,stroke and death from noncardiac ori- suddendeath was highly predictable when occurrenceof gins (Table II), Sudden death is assumedto be death nonsustained VT and frequent ventricular premature resulting from cardiac arrhythmia. Sudden death, de- complexes (VPCs) of more than loo/hour were comfined as unexpected death within 1 hour after onset of bined. Bigger et a12’jdemonstratedthat nonsustainedVT symptoms,is presagedby arrhythmias in 90% of all such had marked effects on survival and on arrhythmic death events.‘OVentricular fibrillation wasthe terminal rhythm amongpatients after infarction. However, the 92 patients with VT were sicker than the 728 without VT. Yet, when adjustments were made for recorded differences in risk rABLE I Arrhythmias and Sudden Death in Congestive Heart variables, the presenceof VT nearly doubled the risk of Failure dying within a 3 1-month follow-up period. Other imporTriggering activities tant risk variables may have beenoperative as well. EpiReentrant activity sodesof silent ischemia, neurohormonal activation, exEnhanced automaticity tent of myocardial dysfunction and hypertrophy were not Delayed after potentials tion, or secondarily to the chronotropic and inotropic effects that may aggravate the myocardial oxygen demand/supply ratio).
Myocardial substrates Scar tissue Aneurysm Hypertrophy Ventricular dilatation Ventricular dysfunction Modulating events Myocardial ischemia Electrolyte deficits Myocardial release of cathecholamines Sympatoadrenergic activation Myocardial stretch Antiarrhythmic drugs lnotropic drugs Diuretics
TABLE
II Mode
of Death
in Congestive
Heart
Failure
Sudden death (4 hour) Ventricular fibrillation Progressive myocardial failure Asystole Secondary ventricular fibrillation Recurrent myocardial infarction Other circulatory disorders Myocardial rupture Stroke Pulmonary embolism Noncardiac cause
THE AMERICAN
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FIGURE 2. lb proportion atldeathacau#dbywdtl8n ~accodngtol-year EzY!2xz (NYHA) class I to%if$il
of
‘”
irom lldifhmntstudies.'-" 0
20-
0 I 20
I 40
% Overall Mortality
I 60
I 60
I 100
(12 month follow-up)
determined in this study and may have accounted for observeddifferences between groups. Congestiveheart failure appearsto be an ill-defined heterogenoussyndrome and mode of death seemsto differ according to different expressionsof the syndrome. Total mortality among patients with mild heart failure is low. However, the proportion of patients dying suddenly is large; 50 to 70% of all deaths are suddenin classI and II.‘-’ l Serious arrhythmias are relatively infrequent among these patients. The occurrence of malignant arrhythmia increaseswith the severity of the myocardial dysfunction (Fig. 1). Patients in classIII and IV have an overall yearly mortality of 40 to 60%. The proportion of patients dying suddenly,relative to all deaths,amountsto lessthan 30%(Fig. 2). The major causeof death in severe congestiveheart failure (class III and IV) is from progressive deterioration of myocardial function, whereas the rate of sudden death remains comparable to that in class II and accounts for 10 to 30% of all patients irrespectiveof functional class (Fig. 3). Analysis of arrhythmias and mode of death reported in studiesof congestive heart failure according to functional classtherefore suggestsno clear associationbetweenoccurrenceof ventricular arrhythmias and sudden, presumably, arrhythmic death.
tricular fibrillation occurs when myocardial &hernia is coupled with sympathetic nervous stimulation of the myocardium and catecholamineexcessfrom the myocardium. After severingthe stellate ganglion, the myocardiurn becametolerant to the sameischemia, and ventricular arrhythmias were no longer inducible.33Depletion of catecholamine storesby reserpine preventedventricular fibrillation during experimental coronary occlusion. The dissociation between frequently occurring ventricular tachyarrhythmias and the relatively low prevalence of sudden death in severecongestiveheart failure may be related to depletion of myocardial catecholamine stores and consequentblunting of the modulating effect on trigger events.
ARRHYTHMIC DEATH AND MYOCARDIAL ISCHEMIA Lack of neurohormonal control is associatedwith a high risk of dying among patients with myocardial dysfunction.29This is reflected in monotonoustachycardia with very low variation in beat-to-beat RR interval. Re gional myocardial ischemia and release of myocardial catecholaminestogether with loss of vagal control may therefore have an important enhancing effect on the triggering activity. Recordings of 24-hour electrocardiograms, obtained in patients dying suddenly, have shown that immediate precursorsof suddendeath, in addition to ARRHYTHMIC DEATH AND frequent ventricular ectopicactivity, wasST-segmentdeNEUROHORMONAL ACTIVITY Patients with severecongestiveheart failure havehigh viation before ventricular fibrillation.34 Frank myocardilevelsof circulating catecholaminesthat are closelyrelat- al infarction may be the initiating event that causedared to a poor prognosis.24,28>29 Increasedneurosympathetic rhythmias; however,coagulation myocytolysis necrosisis This stimulation down-regulates myocardial /3 receptors,30 found in 71% of the patients dying suddenly.35q36 and myocardial catecholamine stores are markedly de- finding is typically associatedwith states of excessive pleted3’ becauseof reduced reuptake of releasedcate- catecholamineexcretion. The autopsy findings of Davies cholamines.32Experiments in dogs have shown that ven- and Thomas37showedthat 74%of the patients who died
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
-w-B
Total Death Sudden Death
FIGURE 3. Prevalence of total (#Dfo&en he) and 6lJdden ckath (so/id line) by Rew YOkbkWtA86OCh~ (IWHA) ftadenal class and
l-yearmortalityadapted fm1n6dWr~mtstud~,hZ4.~.9,11
NYHA Functional
unexpectedly, i.e., within 6 hours, had subocclusiveintraluminal thrombi; 20% had plaque fissuresand very few, 5%, did not have occlusive lesions. This finding lends support to the importance of episodesof regional ischemia and catecholaminereleaseasa contributing mechanism. ARRHYTHMIC
DEATH AND INTERVENTION
Recent information from the Cardiac Arrhythmia SuppressionTrial, a prospective double-blind, randomized trial, suggested that conventional antiarrhythmic drugs may actually increasemortality among patients in mild to moderate heart failure after acute myocardial infarction.38*39Generally, information from studies on mild to moderate heart failure is not applicable to patients with severeheart failure. ClassIV patients havenot been studied with respectto the effect of antiarrhythmic treatment on mortality becauseof their overall low tolerance to conventional antiarrhythmic drugs. A trend toward increasing mortality with milrinone suggeststhat inotropic drugs may be harmful as we11.40 In contrast, flreceptor antagonists that block sympathetic stimulation of the myocardium have beenshown to reduce mortality and sudden death, specifically, during and after acute myocardial infarction.6,41This effect is not associated with an effect on ventricular tachyarrhythmias.41Protection by B blockade is not restricted to patients with coronary disease;similar results are suggestedby studies in patients with dilated cardiomyopathy without coronary artery disease.42Prevention of myocardial ischemia by reducing heart rate seemsto be instrumental in prolonging survival.43 Experience from coronary surgery suggeststhat prevention of ischemia by revascularization of main stem lesions prevents death within 24 hours after onset of symptoms.44
Class
It has been suggestedthat reduction of myocardial pre- and afterload by nitrates and angiotensin-converting enzyme (ACE) inhibitors, which improves myocardial residual flow, can reduce ventricular arrhythmias in patients with mild to moderate heart failure.45m47 Only 1 mortality study has been performed with vasodilators among patients with severecongestiveheart failure who are prone to frequent arrhythmias.9 The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) studied patients with severe heart failure (New York Heart Association class IV). Patients (n = 253) were randomizedto treatment with placeboand the ACE inhibitor enalapril. One-year mortality among patients taking placebo was 52% and among those taking enalapril 36%. The major cause of death in the CONSENSUS was progressiveheart failure. Treatment effects were accounted for by the subset of patients for which prevention of progressive deterioration of heart failure was obtained (Fig. 4). Patients who died unexpectedly,within 1 hour after onsetof symptoms,accounted for 20%of all deathsand no treatment effect could be documentedwith this subset(Fig. 5). This latter observation is at variance with previous studies of patients with moderateheart failure demonstrating a reduction of ventricular ectopic activity with ACE inhibitors.45-47The differential effect of enalapril on progressiveheart failure and sudden death was consistent among patients with myocardial dysfunction caused by ischemic as well as nonischemicheart disease.9,48 The subsetof patients dying suddenly was small, and it may be argued that classification of death may be influenced by the effect of enalapril on the clinical condition. However, death was blindly classified by 2 independent investigators. A subsetof patients in the CONSENSUS wereexamined with 24-hour electrocardiographicanalysesat base-
THE AMERICAN JOURNAL OF CARDIOLOGY MAY 22, 1990
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60
FlGURE 4. Martality due to pmgmssh of congestive heart fake-intent&n to treat analysis in tlw Cooperative North Scandlnavi~ Edapril Swvival Study. (Adapted with psmtlssi~ from Am J Cadiol.~
Enalapril
I
I
123456789
I 10
line and after 6 weeks of treatment. All patients had frequent VPCs, averaging 200 to 300 VPCs/hour. There was no difference between survivors and deceasedwith respect to ectopic activity. Seventy percent of all the patients had nonsustainedVT at baseline.No difference in the rate of subsequent6-month mortality wasobserved
I 11
I@ 12
irrespectiveof whether VT waspresentor not. Reduction in ventricular ectopicactivity wasnot related to changein mortality or mode of death. All patients were examinedwith respectto neurohormonal activation at baselineand at 6 weeks.In general, catecholamines,angiotensin,aldosteroneand atria1natri-
A
3.0-
200
250
300
350
Days FIGURE 5. MoHaHty due to addem death within 1 hour (We-t&k lrom Am J CardM@) Suwlval Stwty. (Adepted with pennisslon
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
anatysis) in the &operative
North Scandinavian
EMbpril
uretic peptide (ANP) were greatly elevated. Neurohor- only beendemonstratedto causefewer deaths from promonal activation was variable in all patients; however,no gressivecongestiveheart failure, not sudden death. relationship was found between catecholamines,angiotensin II or aldosteroneand the occurrenceof ventricular REFERENCES 1. Franciosa JA, Wilen M, Ziesche S, Cohn JN. Survival in men with severe VPCs or VT. chronic left ventricular failure due to either coronary heart disease or idiopathic In contrast, ANP was related to occurrence of VT. dilated cardiomyopathy. Am J Cardiol 1983;51:832-836, ANP releasedafter increasedstretch of the atria reflect- 2. Wilson JR, Schwartz S, St John Sutton M, Ferraro N, Horowitz LN, Reichek N, Josephson ME. Prognosis in severe heart failure: relation to hemodynamic ed increased left ventricular ftlling pressures.Patients measurements and ventricular ectopic activity. JACC 1983:2:403-4/O. with VPCs combined with runs of VT had higher ANP 3. Meinertz T. Hofmann T, Kasper W, Treese N, Bechtold H, Stienin U, Pop T, concentrations than patients with VPCs alone. This sug- van Leithner E, Andresen D. Meyer J. Significance of ventricular arrhythmias in dilated cardiomyopathy. Am J Cardiol 1984;53:902-907. gests that VT is dependent on myocardial dysfunction 4.idiopathic Chakko CS, Gheorghiade M. Ventricular arrhythmias in severe heart failure: and may explain the associationbetweenVT and progno- incidence, significance and effectiveness of antiarrhythmic therapy. Am Heart J 1985;109:497-504. sis.i5 5. Hinkle L. The immediate antecedents of sudden death. Acta Med Sand Enalapril effectively reduced ANP after 6 weeks of 1981;21O:suppl 681:207-217. treatment, whereasANP in the placebo group remained 6. Lund-Johansen P. The Norwegian Multicenter Study on Timolol after myocardial infarction. Part II. Effect in different risk groups, causes of death, heart unchanged.29The reduction in ANP may reflect a reduc- arrest, reinfarctions, rehospitalizations and adverse experiences. Acta Med Sand tion in filling pressureand improved hemodynamiccondi- 1981:21O:suppl 681.243-252. tions during administration of enalapril and may explain 7. Maskin CS, Siskind SJ, LeJemtel TH. High prevalence of nonsustained ventachycardia in severe congestive heart failure. Am Heart J 1984;107:896the reduction of arrhythmias observedwith ACE inhibi- tricular 901. 8. Cleland JGF, Dargie HJ, Ford 1. Mortality in heart failure: clinical variables of tors.45,46 value. Br Heart J 1987:58:5?2-582. Lack of relationship betweenchangesin norepineph- 4.oroenostic ?he CONSENSUS trial study group. Effects of enalapril on mortality in rine, angiotensin, aldosterone and ventricular arrhyth- severe congestive heart failure. IV Eng/ J Med 1987;316:1429-1435. mias does not preclude the importance of myocardial 10. Goldstein S, Friedman L, Hutchinson R, Canner P, Romhilt D, Schlant R, R, Verter J, Wasserman A, Aspirin myocardial infarction study group. neurohormonal activation as a mechanism for fatal ar- Sobrino Timing, mechanism and clinical setting of witnessed deaths in postmyocardial rhythmias. Down-regulation of myocardial /3 receptor infarction patients. JACC 1984;3:11 II-1 117. and depletion of myocardial catecholaminestoresin these 11. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting enzyme inhibition in patients with severe patients may confer relative protection against arrhyth- chronic heart failure. Circukztion 1986:73:257-267. 12. Savage HR, Kissane JQ, Becher EL, Maddocks WQ, Murtaugh JT, Dizadji mias. H. Analysis of ambulatory electrocardiograms in 14 patients who experienced The neurohormonesare important predictors of death sudden death during monitoring. Clin Cardiol 1987;10:621-632. in congestiveheart failure.29By combining the neurohor- 13. Nicolic G, Bishop RL, Singh JB. Sudden death recorded during Halter monitoring. Circulation 1982,66:218-225. mones at baseline, a predictive score was derived that 14. Kempf FC, Josephson ME. Cardiac arrest recorded on ambulatory electrodefined a 6-month mortality of 20%among nonactivators cardiogram. Am J Cardiol 1984;53:1577-1582. to almost 100% among patients with the largest neuro- 15. The Multicenter Postinfarction Research Group. Risk stratification and hormonal activation.29Thesescoresidentified a group of survival after myocardial infarction. N Engr J h4ed 1983:309:33/L336. 16. McLennachan JM, Henderson E, Morris Kl, Dargie HJ. Ventricular arhigh activators with marked effect of enalapril on overall rhythmias in patients with hypertensive left ventricular hypertrophy. N Eng/ J mortality and a group of low activators without docu- Med 1987;317:787-792. 17. Kreger BE, Cupples A, Kannel WB. The electrocardiogram in prediction of mentedeffect of enalapril on mortality. Patientswho died sudden death: Framinaham studv exoerience. Am Heart J 1987:113:377-R2. from progressive heart failure were almost exclusively 18. Messerli FH, Vet&a HO, &.a;di DJ, Dunn FG, Frohlich ED. Hypertenamong high activators, whereassuddendeath wasevenly sion and sudden death. Am J Med /9X4:77:18-22 19. Norris RM, Barnaby PF, Brandt PWT, Geary CC, Whitlcck RM, Wild CJ, distributed among high and low activators. High circulat- Barratt-Boyes BG. Prognosis after recovery from first acute myocardial infarcing hormonal activity in this study is therefore not a tion: determinants of reinfarction and sudden death. Am J Cardiol 1984;53:408predictor of increasedsusceptibility to suddendeath, but 413. Rocco MB, Sherman H, Cook EF, W&berg M, Flatley M, Goldman L. may predict death from progressionof congestiveheart 20. Correlates of cardiac and sudden death after ambulatory monitoring in a commufailure. The level of circulating hormonal activity also nity hospital. J Chron Dis 1987:40:977-984, Huang SK, Messer JV, Denes P. Significance of ventricular tachycardia in identified patients who benefited from ACE inhibitor 21. idiopathic dilated cardiomyopathy: observations in 35 patients. Am J Cardiol treatment. Reducedstoresof myocardial catecholamines 1983;51:507-512. or blocking of p receptorsmay be clinically important in 22. Lichstein E, Morganroth J, Harrist R, Hubble E, BHAT study group. Effect propranolol on ventricular arrhythmias. The Beta-Blocker-Heart Attack Trial blunting the modulating effect of sympathetic stimula- ofExperience. Circulation 1983.67:suppl 1:1-5-I-10. tion on ventricular arrhythmias. 23. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic CONCLUSION
The extent of myocardial dysfunction is associated with increasedoccurrenceof malignant arrhythmias, yet in severe congestive heart failure, death is generally causedby progressionof congestiveheart failure and not sudden death. Sudden death is more often observed among asymptomatic or less symptomatic patients. It is unclear whether ACE inhibitors reduce arrhythmias in congestiveheart failure, and so far ACE inhibition has
control in patients with heart disease. N EngI J Med 1971;285:877-883. 24. Francis G. Neuroendocrine manifestations of congestive heart failure. Am J Cardiol 1988.62:9A-13A. 25. Bigger JT. Why patients with congestive heart failure die: arrhythmias and sudden cardiac death. Circuhaion 1987:75:2X-35 26. Bigger JT, Fleiss JL, Rolnitzky -Lb, Multicenter postinfarction research group. Prevalence, characteristics and significance of ventricular tachycardia detected by 24-hour continuous electrocardiographic recordings in the late hospital phase of acute mywardial infarction. Am J Cardiol 1986:58:1151-1160. 27. Ikegawa T, Chino M, Hasegawa H, Usaba F, Suzuki S, Ookura M, Mishihawa K. Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with dilative cardiomyopathy: a prospective study. Cbn Cardiol 1987:10:78-82. 28. Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to
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prognosis in patients with chronic congestive heart failure. N Eng/ J Med 1984;311:819-823. 29. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation; in press. 30. Bristow MR. Ginsburg R, Minobe W, Cubicciotti RS, Sageman WR, Billingham M, Stinson E, Harrison DC. Decreased catecholamine sensitivity and beta-adrenergic receptor density in failing human hearts. N Eng/ J Med 1982;307:205-211. 31. Chidsey CA, Braunwald E, Morrow AG, Mason DT. Myocardial norepinephrine concentration in man: effects of reserpine and congestive heart failure. N Engl .I Med 1963:269:653-658. 32. Henderson EB, Kahn JK, Corbett JR, Hansen DE, Pippin JJ, Kulkami P, Ugolini V, Akers MS, Hansen CHR, Buja LM, Parkey RW, Willerson JT. Abnormal I-123 metaiodobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive cardiomyopathy. Circulation 1988:78:1192-l 199. 33. Schwartz PJ, Billman GE, Stone HL. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. Circulation 1984,69:790-800. 34. Gottlieb SO, Gottlieb SH, Achuff SC, Baumgardner R, Mellitsa ED, Weisfeldt ML, Gerstenblith G. Silent &hernia on Halter-monitoring predicts mortality in high-risk postinfarction patients. JAMA 1988;259:1030-1035. 39. Baroldi G, Falzi G, Mariani F. Sudden coronary death. A post mortem study in 208 selected cases compared to 97 “control subjects.” Am Heart J 1979,98:2027. 36. Baroldi G. Different morphological types of myocardial cell death in man. Recent advances in studies on cardiac structure and metabolism. In: Fleckenstein A, Rona G, eds. Pathophysiology and Morphology of Myocardial Cell Alteration. Baltimore, London, Tokyo: University Park Press, 1975;16:383-397. 37. Davies MJJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137-1140. 36. The Cardiac Arrhythmia Suppression Trial investigators preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia.
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Suppression after myocardial infarction. N Engl J Med 1989:321;406-412. 39. Stewart RA, McKenna WJ, Poloniecki JD, Michelson JK, Das SK, Morady F, Shark MA, Pitt B, Niclas JM. Prospective, randomized, double blind, placebo controlled trial of low dose amicdarone in patients with severe heart failure and frequent ventricular ectopy (abstr). Eur Heart J 1989:10:229. 40. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral milorinone, digoxine and their combinations in the treatment of patients with chronic heart failure. N Engl J Med 1989920:677-683. 41. Ryden L, Arimego R, Arneman K, Herlitz J, Hjalmarson A, Holmberg S, Reyes C, Smedglrd P, Swedberg K, Vedin A, Waagstein F, Waldenstrqm A, Wilhelmsson C, Wedel H, Yamamoto M. A double-blind trial of metoprolol in acute myocardial infarction. N l@gl J Med 1983;308:614-618. 42. Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancer 1979; 1:1374-1376. 43. Kjekshus J. Importance of heart rate in determining beta blocker efficacy in acute and long term acute myocardial infarction intervention trials. Am J Cardiol 1986;57:43F-49F. 44. Holmes DR, Davis KB, Mock MB, Fisher LD, Gersh BJ, Killip T, Pettinger M, and Participants in the Coronary Artery Surgery Study. The effect of medical and surgical treatment on subsequent sudden cardiac death in patients with coronary artery disease: a report from the Coronary Artery Surgery Study. Circulation 1986:73:1254-l 263. 45. Webster MWI, Fitzpatrick A. Nicholls G. Ikram H. Wells E. Effects of enalapril on ventricular arrhythmias in congestive heart f&re. Am J Cardiol 1985.56.566-569. 46. Cleland JGF, Dargie HJ, H&man GP, Ball SG, Robertson JIS, Morton JJ, East BW, Robertson I, Murray GD, Gillen G. Captopril in heart failure. A double blind controlled trial. Br Heart J 1984;52.530-535. 47. Dennick LG, Masin CS, Meyer JH, Schotz WE, Brown BW. Enalapril for congestive heart failure. N Engl J Med 1987;137:1349-1350. 46. Swedberg K, Kjekshus J. The CONSENSUS Trial Study Group. Effect of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol 1988,62:6OA-66A.
