Ventricular Anton P. M. Gorgels,
Arrhythmias
in Heart Failure
Marc A. Vos, PhD, Joep L. R. M. Smeets, Hein J. J. Wellens, MD, PhD
MD, PhD,
Heart failure is an increasingly common disorder leading to reduced quality and expectancy of lie. Asymptomatic and symptomatic ventrkxdar arrhythmias are a frequent complication and have been found to be independent prognostic predii tors for sudden cardiac death in patients with heart failure. Unfortunately, the posttive prediitie value for this finding is low, but in patients with sustained ventricular arrhythmias, variables indicating impaired pump function are the most important predictors of sudden and of nonsudden cardiac death. Arrhythmias in heart failure may have many diirent underlying mechanisms. Indications for, and mode of treatment of, arrhythmias in heart failure depend on the symptoms and prognostic significance of the arrhythmia. Primarily, pump function should be optimized and antiirrhythmic drug therapy i~uted only when the arrhythmia persists. In poorly tolerated and Me-threatening arrhythmias, implantable devices allowing pacing and defibrillation must be considered. No data are presently available indicatia a protectiie role of antiirrhythmic drugs in the prevention of sudden cardiac death in heart failure. Future directions should concentrate on the development of better stratifitiion of risk for sudden death, better delineation of mechanisms of arrhythmias in heart failure (allowing the development of mechanism-specific antiarrhythmic drugs), and research into new nonpharmacologic techniques such as cardiomyoplasty and molecular biok@c techniques to rebuild the failing heart muscles. (Am J Cardiil1932370:37C43C)
From the Department of Cardiology, Academic Hospital Maastricht and the Cardiovascular Research Institute, University of Limburg, Maastricht, The Netherlands. Address for reprints: Anton P. M. Gorgels, MD, PhD, Department of Cardiology, Academic Hospital Maastricht and the Cardiovascular Research Institute, University of Limburg, Maastricht, The Netherlands.
MD, PhD,
and
entricular arrhythmias are common in heart failure. Their prevalence has been reported to be 71-95% for couplets and multiform premature ventricular depolarizations and 28-80% for nonsustained ventricular tachycardia.l Ventricular arrhythmias in patients with pump dysfunction show a wide variability in their occurrence and symptomatology. They have also stimulated interest as possible predictors for death, especially sudden death, which in this setting is generally thought to be tachycardic in origin. When and how to treat these arrhythmias is a difficult dilemma. In clinical practice there are 2 indications for treatment of a disorder: to alleviate symptoms and/or to improve prognosis. In the presence of heart failure, antiarrhythmic drug therapy has been shown to be disappointing for both indications. The negative inotropic effect of many antiarrhythmic drugs restricts their use in heart failure. Proarrhythmic effects may cause the condition of the patient to deteriorate and/or increase the risk for sudden death. In addition, extracardiac side effects may limit the use of sometimes quite effective drugs such as amiodarone. Therefore, in spite of much effort to improve prognosis in heart failure, it has become clear that there is still a long way to go to achieve this goal. A more rational approach to the treatment of arrhythmias in heart failure requires answers to a number of questions. The first is to obtain a better knowledge of risk stratification in patients with heart failure: which patients are most at risk for developing life-threatening arrhythmias. The second is to gain better insight into arrhythmogenic mechanisms active in heart failure. It is not unlikely that similar mechanisms may lead both to pump failure and arrhythmogenicity. Understanding that mechanisms other than reentry may play a role in these patients may lead to the development of more specific antiarrhythmic drugs.
V
RISK STRATIFICATION Ventricular arrhythmias as indicators of risk for sudden cardiac death in heart failure: Heart
failure
carries a poor prognosis. A SYMPOSIUM:
HEART
FAILURE
Data from the MANAGEMENT
37c
Framingham study reveal l- and 5-year survival rates of 79 and 38% in men and 86 and 57% in women, respectively. Comparable results have been published in more recent studies.2 The incidence of sudden death varies between these studies but the majority report an occurrence of >40% of total cardiac deaths.l Many clinical and laboratory variables indicating pump dysfunction are related to (sudden) death, such as dyspnea class,3 the presence of pulmonary congestion, 4 left ventricular ejection fraction4 left ventricular size,5 and exercise time.6 Other variables indicating the role of the neuroendocrine system include plasma norepinephrine,6 plasma renin6 and biochemical derangements such as hyponatremia and hypokalemia.6 Asymptomaticventricular arrhythmias have been considered as indicators of risk and possible targets for prevention of arrhythmic death. In ventricular dysfunction after myocardial infarction, arrhythmic death has been found to be related to the number and severity of ventricular ectopic activity.7-10 This variable was found to be independent of the left ventricular ejection fraction.7>9J0 Also in other studies of patients with both ischemic heart disease and idiopathic dilated cardiomyopathy as the cause of chronic heart failure, ventricular extrasystoles were found to be related to mortality.6a8J0 In several other studiesll-l4 no correlation with mortality could be shown. These findings may be partially explained by patient selection. For instance, in the study of Holmes et allo l-year survival was 51%, whereas in the report of Huang et al” only 3 of 35 patients suffered cardiac death. Conflicting data are also reported in a recent analysis of data from the CAST study.14 Here mortality increased with increasing premature ventricular complex frequency and in patients with > 2 episodes of ventricular tachycardia. However, this was only found at baseline in the group randomized to active treatment and could not be confirmed in the placebo group. Because mortality was higher in patients with a higher incidence of preexisting arrhythmias, these findings may be explained by the proarrhythmic properties of the class IC antiarrhythmic drugs. Given the conflicting data, no conclusion can be reached as to the true prognostic relevance of ventricular ectopic activity in heart failure. Even in the studies showing a relation, the absence of ventricular ectopy reliably predicted good prognosis but the positive predictive accuracy was quite low. 3%
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Heart failure as an indimor of risk in patients with sustained ventricular tachycardia: The prognosis of a sustained ventricular tachycardia is clearly related to etiology and presence or absence of congestive heart failure. Even with the same etiology, prognosis may differ markedly in relation to pump function. In a recent analysis15 of factors related to sudden and nonsudden death in 200 patients with sustained ventricular tachycardia or ventricular fibrillation occurring in the subacute and chronic stage of myocardial infarction, 4 predictive clinical variables were identified. Two of these were expressions of compromised pump function, i.e., dyspnea functional class 3 or 4 and the presence of multiple myocardial infarctions. One other factor was also partially related to pump function, i.e., circulatory arrest at the time of the first spontaneous episode of arrhythmia. The fourth predictor was the early occurrence of sustained ventricular tachycardia or ventricular fibrillation after infarction (3 days to 2 months). Patients with 0 or 1 of these 4 variables had an incidence of sudden death of 2.8% and of 4.2% for nonsudden cardiac death after 2 years follow-up, whereas patients with > 2 variables had a 17.5% and 20.3% incidence of sudden and nonsudden death, respectively. The strongest predictor for sudden death was the occurrence of circulatory arrest during the first episode of the arrhythmia and for nonsudden death was the functional class of the patient. These findings stress the importance of parameters of pump function in assessing the prognosis of patients with sustained ventricular tachycardia. MECHANISMS OF ARRHYTHMIAS IN HEART FAILURE Heart failure can be caused by many different disorders, such as hypertension, coronary artery disease (including ischemia and myocardial infarction), valvular heart disease (including insufficient and stenotic valves), dilated and hypertrophic cardiomyopathy, congenital anomalies, brady- and tachyarrhythmias, and asynchronous ventricular contraction due to aberrant conduction or ventricular pacing. These types of diseases result in different mechanisms of pump dysfunction. These differences are based on such factors as: (1) the type and number of cardiac chambers involved in the disease process; (2) the phase of the cardiac cycle involved (systolic or diastolic); (3) the type and extent of disease in the chamber involved (global or localized, homogeneous or patchy; (4) the load imposed OCTOBER
8. 1992
-.
on the chamber: volume or pressure load; and (5) differences in energy supply: increased demand or decreased supply. As will be discussed below, many of these aspects of pump dysfunction are arrhythmogenic (Table I). Mechanisms of arrhythmias are divided into reentry, triggered activity, and abnormal automaticity. Reentry requires 2 different anatomically or functionally divided pathways, with unidirectional block in 1 and slowing of conduction in the other pathway. The latter mechanism can be induced by ischemia and fibrosis, but also by antiarrhythmic drugs such as class IA and IC drugs. Class IC drugs have a rate-related increase of slowing of conduction, which may result in initiation of reentrant tachycardias on reaching a critical heart rate (Figure 1).16 TRIGGERED ACTIVITY: Two types of triggered activity leading to ectopic spontaneous activity can be recognized: those based on early or on delayed after-depolarizations. l7 Early after-depolarizations probably play an important role in ventricular arrhythmias in the long QT syndrome (torsade de pointes). Occurrence of early after-depolarizations is promoted by electrolyte disturbances such as hypokalemia and hypomagnesemia, and some class IA and class III drugs are able to induce proarrhythmic effects based on early after-depolarizations in some patients. Triggered activity, based on delayed afterdepolarizations, was first recognized as the underlying mechanism of digitalis-induced arrhythmias in isolated tissue and later in digitalis-induced ventricular tachycardia in the intact heart.18 Also, elevated circulating catecholamines and other pathophysiologic conditions such as electrolyte
r
TABLE
I
Possible
Mechanisms
of Arrhythmias Reentry
Structural Scar Fibrosis Dilation Hypertrophy lschemia
in Heart
Failure
DAD
AA
EAD
+ + +
+ +
+
+
Neurocontrol Sympathetic
+
+
Electrolytes K+ Mgn+
+ +
+ +
+
f +
Drugs Digitalis Diuretics Vasodilation lnotropes Antiarrhythmic AA = abnormal after-depolarization.
agents automaticlly;
+ + +
+
+ + +
DAD = delayed
after-depolarization;
EAD = early
disturbances, ventricular hypertrophy, and damaged myocardial tissue, l9 have been found to promote induction of delayed after-depolarizations. In addition, stretch of Purkinje fibers (as in ventricular dilation, increased wall stress, or diastolic pressure elevation) has been found to increase the amplitude of delayed after-depolarizations.20 The common denominator in these pathophysiologic circumstances is intracellular calcium overload. This mechanism is thought to play a central role in heart failure, because in this condition the cardiac myocytes are not able to maintain a low cytoplasmic calcium level.21 Increased cytoplasmic calcium induces calcium release from the sarcoplasmic reticulum and subsequent sodium-calcium exchange through the sarcolemmal membrane. The latter results in triggered activity and delayed after-depolarizations.22
RGURE l. Class IC dru&induced slowing of conduction durie exercise ieadia to ventricular tachycardia. A, eiectrocardiogram recorded before exercise. 8, widening of the QR3 complex during exercise-imluced sinw tachycardia. C, widening of the QR3 corn piex during sinus tachycardia is followed by ventricular tachycardia.
“,j
--
--
H
A SYMPOSIUM:
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FAILURE
MANAGEMENT
400
msec
39c
Apart from delayed after-depolarizations, intracellular calcium overload leads to electrical uncoupling23 and subsequent electrical heterogeneity, which may act as possible mechanisms of ventricular tachycardia. 21Our group has demonstrated that calcium overload blockers such as flunarizine selectively suppress triggered activity (Figure 2).Ua25 Because many of the conditions mentioned are present in the intact failing heart, it is likely that in those patients, triggered activity is an important mechanism of clinical arrhythmias. ABNORMAL AUTOMATICITY: Abnormalautomaticity is spontaneous impulse formation arising from a reduced diastolic membrane potential.26 It occurs as a mechanism for ventricular tachycardia in the 24-hour myocardial infarction model in the canine heart. It may also play a role in myocardial ischemia because under these circumstances reduction of diastolic membrane potential is present.27 These considerations indicate that arrhythmias in heart failure may be based on different arrhythmogenic mechanisms alone or in combination. Scar tissue and fibrosis provide the anatomic substrate for delayed impulse reentry,28 whereas ischemia may promote premature reentry by inducing conduction. Ventricular dilation and hypertrophy may lead to delayed after-depolarizations and triggered activity. 2oa30p31 Dilation may also result in conduction block,32 abbreviation of the ventricular effective refractory period, dispersion of refractoriness, and an increase in epicardial and endocardial differences in duration of the refractory period.33 Those changes also favor the development of reentry arrhythmias.
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In humans, the presence of left ventricular hypertrophy has been found to be arrhythmogenic.34 Increased sympathetic tone may induce or accelerate occurrence of early after-depolarizations,35 delayed after-depolarizations,36 and abnormal automaticity.37
TREATMENT OF ARRHYTHMIAS AND PRRlENTlON OF ARRHYWMIC DEATH One of the most difficult dilemmas for the clinical cardiologist is when and how to treat arrhythmias in patients with heart failure. Arrhythmias occur in a complicated setting of electrical instability, ischemia, and/or pump failure (Figure 3). Therefore, ischemia and pump failure should be optimized before prescription of antiarrhythmic agents, because their negative inotropic properties and proarrhythmic effects may be hazardous. Figure 3 also shows that many of the factors influencing blood supply, pump function, and electrical behavior are dynamic and not static. For example, in ischemia, spasm or intimal rupture of a coronary artery leading to thrombosis may suddenly change the static situation of a fixed atherosclerotic narrowing. This indicates the necessity of individualization of treatment. Pump function must be optimized, ischemia must be corrected, and modulating factors must be controlled, for instance by P-blockade38 and/or angiotensin-converting enzyme (ACE) inhibition. Inotropic drugs that reduce, or at least do not increase, heart rate are important in this respect. From this point of view, digitalis is an interesting
AGURE 2. lllustratlon of the speclfk effect offlunarklne on delayed after-depolarkatlon-related trIggered actlvRy. Lower pane/: termlnatlon of dlgltallsInduced arrhythmia by flunarizlne. Upper panel: absence of effect of flunarlzlne on ventrludar tachycardla 24 hours after myocordial lnfarctlon (abnormal automatlclly).
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drug because it improves contractility without increasing heart rate. The decision to use antiarrhythmic therapy in heart failure, therefore, depends on the answers to the following questions: Is the arrhythmia already controlled by correcting ischemia and optimizing pump function? If no, does the arrhythmia produce symptoms, and is the arrhythmia of prognostic significance (increased risk of arrhythmic death)? If the arrhythmia is controlled by improving pump function and by controlling ischemia and the modulating factors, there is no obvious reason to institute antiarrhythmic drug treatment. Many arrhythmias, however, persist after these steps have been taken. An example is sustained ventricular tachycardia in the setting of an old myocardial infarction. Although ischemia may be present, coronary revascularization is insufficient to cure or prevent the arrhythmia and additional measures to control or remove the substrate are indicated. In case the arrhythmia produces symptoms, some form of antiarrhythmic treatment must be instituted. If the arrhythmia does not lead to circulatory arrest, antiarrhythmic drugs are usually sufficient. Drug selection may be helped by the evaluation of the effectiveness of the drug by programmed electrical stimulation,39>40 especially in the case of sustained forms of ventricular tachycardia, although the possible proarrhythmic and negative inotropic effects of antiarrhythmic drugs must be considered. Also, extracardiac side effects may limit the use of these drugs. In this regard, class IA drugs are less frequently indicated than other drugs with less negative inotropic effects. Evaluation of proarrhythmic effeck Class IA and class III antiarrhythmic drugs tend to induce
QT prolongation and torsade de pointes. In the case of class IA drugs, this complication frequently occurs within the first days of treatment, facilitating early recognition during clinical observation. A possible indicator of an increased tendency to develop this proarrhythmic complication is the opposite behavior of the QT, interval during exercise. Recent data suggest that during the recovery phase after exercise, the QT, interval tends to be prolonged in untreated patients prone to develop torsade de pointes. 41 The predictive value of this finding awaits further evaluation. Class IC drugs have a rate-related increase of slowing of conduction, which may lead to the induction of reentrant tachycardias.17 Therefore, exercise testing during class IC administration is mandatory to evaluate possible proarrhythmic effects of these drugs. Further control of proarrhythmic effects may be achieved by careful follow-up of kidney and liver function and plasma potassium and magnesium levels. In the cases of low drug efficacy using class IA, IC, or class III drugs, or other reasons for termination of the antiarrhythmic drug, the use of amiodarone41 should be considered. This drug has a high efficacy, good initial tolerance, minor negative inotropic and proarrhythmic effects, and easy dosing schedule. The high incidence of long-term side effects restricts widespread use and high dosing, although most side effects are reversible. Arrhythmias leading to circulatory arresk In arrhythmias leading to circulatory arrest, a more aggressive diagnostic and therapeutic approach must be followed. Programmed stimulation can be useful in initiating the clinical arrhythmia.39,40 If the tachycardia is hemodynamically tolerated, mapping of early local electrical activation may indicate the origin of the tachycardia. CHRONIC
STENOSIS
FIGURE 3. Model showing the interplay between different patho physiologic mechanisms in the induction of artiythmia. All mechanisms have static and dynamk components. Modulating (MOD.) factors include the autonomic nervous system, electrolytes, hormones (renin-angbtensin system), and drugs.
SIZE OF SCAR (+ LOCATION)
HEMODYNAMIC DYSFUNCTION -MOD.
ABNORMAL AUTOMATICITY
FACTORS
TRIGGERED ACTIVITY
A SYMPOSIUM:
HEART
FAILURE
MANAGEMENT
4u:
Accurate localization facilitates surgical or catheter destruction or isolation of the tissue from which the tachycardia originates. Subendocardial resection, endocardial circumcision, and aneurysmectomy combined with cryoablation are surgical options. Chemical, electrical, and radiofrequency ablation are catheter methods to ablate ventricular arrhythmogenic cardiac tissue. In tachycardias that are not hemodynamically tolerated, localizing the origin of tachycardia is difficult or impossible. Therefore, surgical treatment cannot be map-directed and implantation of internal antitachycardia devices will frequently be necessary. If no nonpharmacologic approach is possible, treatment with amiodarone is indicated, which may be combined with other drugs from class I or 111 4243 Asymptomatic arrhythmias indicating poor prognosis: As has been pointed out before, ventricular premature beats (especially when complex) and frequent and nonsustained ventricular tachycardias have been considered possible indicators of poor prognosis in patients after myocardial infarction and heart failure. Our current experience indicates that there are different reasons not to attempt to suppress these arrhythmias. Their predictive value is low, which means that overtreatment occurs in the patient group presenting with these arrhythmias. Also because of proarrhythmic effects, the induction of new or aggravation of existing arrhythmias is a potential risk. Prevention of sudden death in heart failure: Several studies44-46 such as Studies of Left Ventricular Dysfunction, (SOLVD), Vasodilator-Heart Failure Trial (V-HEFT), and the first Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I) have demonstrated that cardiac death rate can be diminished by treatment of moderate44 and severe46 heart failure. This has been shown for ACE inhibitors44s46 and isosorbide dinitrate plus hydralazine.45 Although initial studies did not show a reduction in sudden cardiac death, recent data comparing enalapril with hydralazine-nitrate47 suggest a reduction in sudden rather than nonsudden death. This finding may be explained by ACE inhibitorinduced reduction of neurohumoral stimulation. Increased mortality rates have been reported during prolonged use of P-adrenergic agonists such as xamotero148 and phosphodiesterase inhibitors such as milrinone in patients with severe heart failure.49 Limited experience is available in relation to 42C
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antiarrhythmic drug treatment and prevention of sudden cardiac death in heart failure.50 Studies are currently in progress, for example with amiodarone, on the effectiveness of antiarrhythmic drug therapy in relation to survival in heart failure. FUTURE DIRECTIONS There is a need for better stratification of patients with heart failure at risk of sudden death. There is a lack of a single noninvasive risk parameter with a sufficiently high positive predictive accuracy. Accurate identification of high-risk patients allows the evaluation of more aggressive pharmacologic and nonpharmacologic treatment, such as electrical devices with pacing and defibrillation capabilities. Early recognition and treatment of disease states leading to heart failure, such as ischemia, myocardial infarction, and hypertension, should be attempted. Further developments are required in relation to recognition and treatment of mechanisms of arrhythmias in heart failure. In particular, the relevance of delayed after-depolarization-induced triggered activity should be evaluated, since this may lead to more specific drugs and a lower incidence of proarrhythmia, negative inotropy, and extracardiac side effects. Future trials should be based on better information on the mechanisms underlying arrhythmias in heart failure: although presently most attention is given to pure class III antiarrhythmic drugs, it should be realized that these drugs are effective only in reentrant arrhythmias. The role of the latter in heart failure has-not been clarified. Finally, approaches to improve cardiac contractility have to be awaited, such as cardiomyoplasty, new pharmacologic interventions, and molecular biology techniques, which allow the heart muscle to be restored.
REFERENCES F Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardi01 1986; 57(suppl):357B. 2. Massie BM, Conway M. Survival of patients with congestive heart failure: past, present and future prospects. Circulation 1987;75(suppl IV):ll-19. 3. Califf RM, Bounous P, Harrell FE, M&ants B, Lee KL, M&inks RA, Rosati RM. The prognosis in the presence of coronary artery disease. In: Braunwald E, ed. Congestive Heart Failure: Current Research and Cl&xl Applications. New York: Grune & Stratton, 19823-40. 4.Bigger JT. Relation behveen left ventricular dysfunction and ventricular arrhythmias after myocardial infarction. Am J Card01 1986;57(suppl):SE14B. 5. Pfeffer MA, Pfeffer JM. Ventricular enlargement and reduced survival after myocardial infarction. Ck&& 1987;75(suppl Iv):93-97. 6. Dargie HJ, Cleland JGF, Leckie BJ, Inglis CG, East BW, Ford J. Relation
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of arrhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987;7S(suppl IV):98107. 7. Bigger JT, Fleiss JL, Kleiger R, Miller JPh, Romitzky LM, and the Multicenter Post-Infarction Research Group. The relationship among ventricular arrhythmias, left ventricular dysfunction and mortality in the 2 years after myocardial infarction. Circulation 1984;69:25&258. 8. Mukharji J, Rude RE, Poole WK, Gustafson N, Thomas IJ Jr, Strauss HW, Jaffe AS, Muller JE, Roberts R, Raabe DS Jr, Croft CH Passamani E, Braunwald E, WilIerson JT, and the MILIS Study Group. Risk factors for sudden death after acute myocardial infarction: two year follow up. Am J Cardiol1984;54:31-36.
9. Ruberman W, Weinblatt E, Goldberg JK Frank CW, Shapiro S. Ventricular premature beats and mortality after myocardial infarction. N Engl .I Med 1977;297:150-151. 10. Holmes J, Kubo SH, Cody RJ, Kligfield P. Arrhythmias in ischemic and non-ischemic dilated cardiomyopathy: prediction of mortality by ambulatory electrocardiography. Am J Cardiol 1985;55:14&151. IL Huang SK Messer JV, Denes P. Significance of ventricular tachycardia in idiopathic dilated cardiomyopathy: observations in 35 patients. Am J Car&l 1983;51:507-512. 12. Wilson JR, Schwartz JS, Sutton MSJ, Ferraro N, Horowitz LN, Reichek N, Josephson ME. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity. J Am Coil Cardiol 1983;2:403410. 13. Van Olshausen K, Schafer A, Mehmel HC, Schwarz F, Senges J, Kubler W. Ventricular arrhythmias in idiopathic dilated cardiomyopathy. Br Heart J 1984;51:195-201. 14. Denes P, Gillis AM, Pawitan Y, James M. Kammerlmg JM, WiIhehnsen L, Salerno DM, and the CAST Investigators. Prevalence, characteristics and significance of ventricular premature complexes and ventricular tachycardia detected by 24 hour continous electrocardiographic recording in the cardiac arrhythmia suppression trial. Am J Cardiol 1991;68:887-896. 15. Brugada P, Talajic M, Smeets J, Mulleneem R Wellens HJJ. Risk stratiiication of patients with ventricular tachycardia or ventricmar fibriUation after myocardial infarction. The value of the clinical history. Ew He&f J 1989;10:717752.
16. Ranger S, Talajic M, Lemety R, Roy D, Nattel S. Amplification of flecamide induced ventricular conduction slowing by exercise. Circulation 1989;79:1tXk& 1006. 17. Cranefield PF, Aronson RS. Cardiac arrhythmias: the role of triggered activity and other mechanisms. Mt. Kisco, NY: Futura Publishing, 1988. 18. Gorgels APM, De Wit B, Beckman HDM, Dassen WRM, Wellens HJJ. Triggered activity induced by pacing during digitalis intoxication. PACE 198710: 1309-1321. 19. Mulder BJM. Damage-induced propagated contractions in cardiac muscle: implications for cardiac arrhythmias. Thesis, University of Rotterdam. Rodopi Press, 1989. 20. Ferrier GR. The effects of tension on acetylstrophantidine-induced transient dep&nizations and after contractions in canine myocardial and Purkinje tissue. Circ Res 1976;38:156-162. 2L Morgan JP, Erny RE, Allen PD, Grossmann W, Gwathmey JK Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction on ventricular myocardium from patients with heart failure. Cinxlation 1990;81(suppl III):III-21-111-32. 22. Nordin C. Abnormal calcium handling and the generation of ventricular arrhythmias in congestive heart failure. Heati Failure 1989;5:143-154. 23. De Mello W. Effect of intracellular injection of calcium and strontium on cell communication. J Physiol1975;250:231-245. 24. Vos MA, Gorgels APM, Leunissen JDM, Wellens HJJ. Flunarizine allows differentiation between mechanisms of arrhythmias in the intact heart. Circulatin 1990;81:343-349. 25. Gorgels APM, Vos MG Smeets JLRM, Kriek E, Brugada P, WeUens HJJ. Delayed after depolarizations and atrial and ventricular arrhythmias. In: Rosen MR, Janse MJ, Wit AL, eds. Cardiac Electrophysiology: A Textbook. Mt. Kisco, NY: Futura Publishing 1990:341-354. 26. Dangman KM, Hoffman BF. Studies on overdrive stimulation of canine cardiac Purkinje fibers: Maximal diastolic potential as a determinant of the response. JAm Coil Cardiol1983;2:1183-1190. 27. Janse MJ, van CapeUe FJL, Morsink H, Kleber AG, Wi-Schopman F, Cardinal R, Naumann d’Alnon, Court C, Durrer D. Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ Res 1980,47:151-165. 28. De Bakker JMT, van CapelIe FJL, Janse MJ, Wilde AAM, Gxonel R,
Becker AE, Dingemans KP, van Hemel NM, Hauer RNW. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomical correlations. Circulation 1988;77:58%06. 29. Janse MJ, Wit AL. The electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989;69:1049-1169. 30. Bigger JT Jr. Electrical properties of cardiac muscle and possibie causes of cardiac arrhythmias. In: Dreifus IS, Likoff MJ, eds. Cardiac Arrhythmias. New York Grune & Stratton, 1973:13. 31. Aronson RS. Afterpotentials and triggered activity in hypertrophied myocardium from rats with renal hypertension. Circ Res 1981;48:72&727. 32. Cranefield PF, Klein HD, HofIman BF. Conduction of the cardiac impulse, I Delay, block and one-way block in depressed Purldnje fibers. Circ Res 1971;28:199-204. 33. Reiter MJ, Synhorst DP, Mann DE. Electrophysiological effects of acute ventricular dilatation in the intact heart. Circ Res 1988;65:554-562. 34. Aronow WS, Epstein S, Schwartz KS, Koenigsberg MO. Correlation of complex ventricular arrhythmias detected by ambulatory electrocardiophic monitoring with echocardiographic left ventricular hypertrophy in persons older than 62 years in a long term health care facility. Am J Cardiol1987;60:73&732. 35. Ben-David J, Zip-es DP. Differential response to right and left ansae subclaviae stimulation of early after depolatisations and ventricular tachycardia induced by cesium in dogs. Circularion 1988,78:1241-1250. 36.Hewett KW, Rosen MR. Alpha and beta adrenergic interactions with ouabain induced delayed afterdepolarizations. Phamacol Es, Ther 1984;229:188192. 37. Constantin L, Martins JB. Autonomic control of ventricular tachycardia. J Am Coil Cardiol1987;9:366-373.
38. Swedberg K, Hjahnarson A, Waagstein F, Wallentin J. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancet 1979;i: 13744376. 39. Josephson ME.
Treatment of ventricular arrhythmias after myocardial infarction. Cirnrlatin 1986;74:653-558. 40. Wellens HJJ, Brugada P. Treatment of cardiac arrhythmias: when, how and where? JAm Co11 Cardiol1989;14:1417-1429. 4F Kadiih AH, Weisman MF, Veltri EP, Epstein AE, Slepian MY, Levine JH. Paradoxical effects of exercise on the QT-interval in patients with polymorphic ventricular tachycardia receiving type Ia anti-atrhythmic agents. Circulation 1990;81:14-19. 42. Hamer AWF, Addes LB, Johns JA Beneficial effects of low dose amiodarone in patients with congestive heart failure. JAm Co[l Car&l 1989;14:17681775.
43. Kim SG, Felder SD, Figura I, Johnston DR, Waspe LE, Fisher JD. Value of Halter monitoring in predicting long-term efficacy and inefficacy of amiodarone used alone and in combination with class Ia antiarrhythmic agents in patients with ventricular tachycardia. JAm Co11 Car&~ 1987;9:169-174. 44. The SOLVD Investigators, Effect of enalaptil on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Etzgl J Med 1991;325:293-302. 45. Cohn JN, Archibald DF, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552. 46. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the cooperative North Scandinavian Enalaptil Survival Study (CONSENSUS). N&g2 JMed 1987;316:1429-1435. 47. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310. 48. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancef 1990;336:16. 49. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe J, Dibianco R,Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI, SoUano JA, Shannon J, Tandon PK DeMets DL for the PROMISE Study Research Group. Effect of oral mihiione on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468-1475, 50. Stewart RA, McKenna WJ, Polonicki JD, Michelson JK, Das SK, Morady E, Schork MA, Pitt B, Nicklas JM. Prospective randomized placebo-controlled trial of low dose amiodarone in patients with severe heart failure and frequent ventricular ectopy. Eur Heart J 1989;1O(suppl):229.
A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
a
Arrhythmias
in Heart Failure
Marc A. Vos, PhD, Joep L. R. M. Smeets, Hein J. J. Wellens, MD, PhD
MD, PhD,
Heart failure is an increasingly common disorder leading to reduced quality and expectancy of lie. Asymptomatic and symptomatic ventrkxdar arrhythmias are a frequent complication and have been found to be independent prognostic predii tors for sudden cardiac death in patients with heart failure. Unfortunately, the posttive prediitie value for this finding is low, but in patients with sustained ventricular arrhythmias, variables indicating impaired pump function are the most important predictors of sudden and of nonsudden cardiac death. Arrhythmias in heart failure may have many diirent underlying mechanisms. Indications for, and mode of treatment of, arrhythmias in heart failure depend on the symptoms and prognostic significance of the arrhythmia. Primarily, pump function should be optimized and antiirrhythmic drug therapy i~uted only when the arrhythmia persists. In poorly tolerated and Me-threatening arrhythmias, implantable devices allowing pacing and defibrillation must be considered. No data are presently available indicatia a protectiie role of antiirrhythmic drugs in the prevention of sudden cardiac death in heart failure. Future directions should concentrate on the development of better stratifitiion of risk for sudden death, better delineation of mechanisms of arrhythmias in heart failure (allowing the development of mechanism-specific antiarrhythmic drugs), and research into new nonpharmacologic techniques such as cardiomyoplasty and molecular biok@c techniques to rebuild the failing heart muscles. (Am J Cardiil1932370:37C43C)
From the Department of Cardiology, Academic Hospital Maastricht and the Cardiovascular Research Institute, University of Limburg, Maastricht, The Netherlands. Address for reprints: Anton P. M. Gorgels, MD, PhD, Department of Cardiology, Academic Hospital Maastricht and the Cardiovascular Research Institute, University of Limburg, Maastricht, The Netherlands.
MD, PhD,
and
entricular arrhythmias are common in heart failure. Their prevalence has been reported to be 71-95% for couplets and multiform premature ventricular depolarizations and 28-80% for nonsustained ventricular tachycardia.l Ventricular arrhythmias in patients with pump dysfunction show a wide variability in their occurrence and symptomatology. They have also stimulated interest as possible predictors for death, especially sudden death, which in this setting is generally thought to be tachycardic in origin. When and how to treat these arrhythmias is a difficult dilemma. In clinical practice there are 2 indications for treatment of a disorder: to alleviate symptoms and/or to improve prognosis. In the presence of heart failure, antiarrhythmic drug therapy has been shown to be disappointing for both indications. The negative inotropic effect of many antiarrhythmic drugs restricts their use in heart failure. Proarrhythmic effects may cause the condition of the patient to deteriorate and/or increase the risk for sudden death. In addition, extracardiac side effects may limit the use of sometimes quite effective drugs such as amiodarone. Therefore, in spite of much effort to improve prognosis in heart failure, it has become clear that there is still a long way to go to achieve this goal. A more rational approach to the treatment of arrhythmias in heart failure requires answers to a number of questions. The first is to obtain a better knowledge of risk stratification in patients with heart failure: which patients are most at risk for developing life-threatening arrhythmias. The second is to gain better insight into arrhythmogenic mechanisms active in heart failure. It is not unlikely that similar mechanisms may lead both to pump failure and arrhythmogenicity. Understanding that mechanisms other than reentry may play a role in these patients may lead to the development of more specific antiarrhythmic drugs.
V
RISK STRATIFICATION Ventricular arrhythmias as indicators of risk for sudden cardiac death in heart failure: Heart
failure
carries a poor prognosis. A SYMPOSIUM:
HEART
FAILURE
Data from the MANAGEMENT
37c
Framingham study reveal l- and 5-year survival rates of 79 and 38% in men and 86 and 57% in women, respectively. Comparable results have been published in more recent studies.2 The incidence of sudden death varies between these studies but the majority report an occurrence of >40% of total cardiac deaths.l Many clinical and laboratory variables indicating pump dysfunction are related to (sudden) death, such as dyspnea class,3 the presence of pulmonary congestion, 4 left ventricular ejection fraction4 left ventricular size,5 and exercise time.6 Other variables indicating the role of the neuroendocrine system include plasma norepinephrine,6 plasma renin6 and biochemical derangements such as hyponatremia and hypokalemia.6 Asymptomaticventricular arrhythmias have been considered as indicators of risk and possible targets for prevention of arrhythmic death. In ventricular dysfunction after myocardial infarction, arrhythmic death has been found to be related to the number and severity of ventricular ectopic activity.7-10 This variable was found to be independent of the left ventricular ejection fraction.7>9J0 Also in other studies of patients with both ischemic heart disease and idiopathic dilated cardiomyopathy as the cause of chronic heart failure, ventricular extrasystoles were found to be related to mortality.6a8J0 In several other studiesll-l4 no correlation with mortality could be shown. These findings may be partially explained by patient selection. For instance, in the study of Holmes et allo l-year survival was 51%, whereas in the report of Huang et al” only 3 of 35 patients suffered cardiac death. Conflicting data are also reported in a recent analysis of data from the CAST study.14 Here mortality increased with increasing premature ventricular complex frequency and in patients with > 2 episodes of ventricular tachycardia. However, this was only found at baseline in the group randomized to active treatment and could not be confirmed in the placebo group. Because mortality was higher in patients with a higher incidence of preexisting arrhythmias, these findings may be explained by the proarrhythmic properties of the class IC antiarrhythmic drugs. Given the conflicting data, no conclusion can be reached as to the true prognostic relevance of ventricular ectopic activity in heart failure. Even in the studies showing a relation, the absence of ventricular ectopy reliably predicted good prognosis but the positive predictive accuracy was quite low. 3%
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Heart failure as an indimor of risk in patients with sustained ventricular tachycardia: The prognosis of a sustained ventricular tachycardia is clearly related to etiology and presence or absence of congestive heart failure. Even with the same etiology, prognosis may differ markedly in relation to pump function. In a recent analysis15 of factors related to sudden and nonsudden death in 200 patients with sustained ventricular tachycardia or ventricular fibrillation occurring in the subacute and chronic stage of myocardial infarction, 4 predictive clinical variables were identified. Two of these were expressions of compromised pump function, i.e., dyspnea functional class 3 or 4 and the presence of multiple myocardial infarctions. One other factor was also partially related to pump function, i.e., circulatory arrest at the time of the first spontaneous episode of arrhythmia. The fourth predictor was the early occurrence of sustained ventricular tachycardia or ventricular fibrillation after infarction (3 days to 2 months). Patients with 0 or 1 of these 4 variables had an incidence of sudden death of 2.8% and of 4.2% for nonsudden cardiac death after 2 years follow-up, whereas patients with > 2 variables had a 17.5% and 20.3% incidence of sudden and nonsudden death, respectively. The strongest predictor for sudden death was the occurrence of circulatory arrest during the first episode of the arrhythmia and for nonsudden death was the functional class of the patient. These findings stress the importance of parameters of pump function in assessing the prognosis of patients with sustained ventricular tachycardia. MECHANISMS OF ARRHYTHMIAS IN HEART FAILURE Heart failure can be caused by many different disorders, such as hypertension, coronary artery disease (including ischemia and myocardial infarction), valvular heart disease (including insufficient and stenotic valves), dilated and hypertrophic cardiomyopathy, congenital anomalies, brady- and tachyarrhythmias, and asynchronous ventricular contraction due to aberrant conduction or ventricular pacing. These types of diseases result in different mechanisms of pump dysfunction. These differences are based on such factors as: (1) the type and number of cardiac chambers involved in the disease process; (2) the phase of the cardiac cycle involved (systolic or diastolic); (3) the type and extent of disease in the chamber involved (global or localized, homogeneous or patchy; (4) the load imposed OCTOBER
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-.
on the chamber: volume or pressure load; and (5) differences in energy supply: increased demand or decreased supply. As will be discussed below, many of these aspects of pump dysfunction are arrhythmogenic (Table I). Mechanisms of arrhythmias are divided into reentry, triggered activity, and abnormal automaticity. Reentry requires 2 different anatomically or functionally divided pathways, with unidirectional block in 1 and slowing of conduction in the other pathway. The latter mechanism can be induced by ischemia and fibrosis, but also by antiarrhythmic drugs such as class IA and IC drugs. Class IC drugs have a rate-related increase of slowing of conduction, which may result in initiation of reentrant tachycardias on reaching a critical heart rate (Figure 1).16 TRIGGERED ACTIVITY: Two types of triggered activity leading to ectopic spontaneous activity can be recognized: those based on early or on delayed after-depolarizations. l7 Early after-depolarizations probably play an important role in ventricular arrhythmias in the long QT syndrome (torsade de pointes). Occurrence of early after-depolarizations is promoted by electrolyte disturbances such as hypokalemia and hypomagnesemia, and some class IA and class III drugs are able to induce proarrhythmic effects based on early after-depolarizations in some patients. Triggered activity, based on delayed afterdepolarizations, was first recognized as the underlying mechanism of digitalis-induced arrhythmias in isolated tissue and later in digitalis-induced ventricular tachycardia in the intact heart.18 Also, elevated circulating catecholamines and other pathophysiologic conditions such as electrolyte
r
TABLE
I
Possible
Mechanisms
of Arrhythmias Reentry
Structural Scar Fibrosis Dilation Hypertrophy lschemia
in Heart
Failure
DAD
AA
EAD
+ + +
+ +
+
+
Neurocontrol Sympathetic
+
+
Electrolytes K+ Mgn+
+ +
+ +
+
f +
Drugs Digitalis Diuretics Vasodilation lnotropes Antiarrhythmic AA = abnormal after-depolarization.
agents automaticlly;
+ + +
+
+ + +
DAD = delayed
after-depolarization;
EAD = early
disturbances, ventricular hypertrophy, and damaged myocardial tissue, l9 have been found to promote induction of delayed after-depolarizations. In addition, stretch of Purkinje fibers (as in ventricular dilation, increased wall stress, or diastolic pressure elevation) has been found to increase the amplitude of delayed after-depolarizations.20 The common denominator in these pathophysiologic circumstances is intracellular calcium overload. This mechanism is thought to play a central role in heart failure, because in this condition the cardiac myocytes are not able to maintain a low cytoplasmic calcium level.21 Increased cytoplasmic calcium induces calcium release from the sarcoplasmic reticulum and subsequent sodium-calcium exchange through the sarcolemmal membrane. The latter results in triggered activity and delayed after-depolarizations.22
RGURE l. Class IC dru&induced slowing of conduction durie exercise ieadia to ventricular tachycardia. A, eiectrocardiogram recorded before exercise. 8, widening of the QR3 complex during exercise-imluced sinw tachycardia. C, widening of the QR3 corn piex during sinus tachycardia is followed by ventricular tachycardia.
“,j
--
--
H
A SYMPOSIUM:
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FAILURE
MANAGEMENT
400
msec
39c
Apart from delayed after-depolarizations, intracellular calcium overload leads to electrical uncoupling23 and subsequent electrical heterogeneity, which may act as possible mechanisms of ventricular tachycardia. 21Our group has demonstrated that calcium overload blockers such as flunarizine selectively suppress triggered activity (Figure 2).Ua25 Because many of the conditions mentioned are present in the intact failing heart, it is likely that in those patients, triggered activity is an important mechanism of clinical arrhythmias. ABNORMAL AUTOMATICITY: Abnormalautomaticity is spontaneous impulse formation arising from a reduced diastolic membrane potential.26 It occurs as a mechanism for ventricular tachycardia in the 24-hour myocardial infarction model in the canine heart. It may also play a role in myocardial ischemia because under these circumstances reduction of diastolic membrane potential is present.27 These considerations indicate that arrhythmias in heart failure may be based on different arrhythmogenic mechanisms alone or in combination. Scar tissue and fibrosis provide the anatomic substrate for delayed impulse reentry,28 whereas ischemia may promote premature reentry by inducing conduction. Ventricular dilation and hypertrophy may lead to delayed after-depolarizations and triggered activity. 2oa30p31 Dilation may also result in conduction block,32 abbreviation of the ventricular effective refractory period, dispersion of refractoriness, and an increase in epicardial and endocardial differences in duration of the refractory period.33 Those changes also favor the development of reentry arrhythmias.
1
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In humans, the presence of left ventricular hypertrophy has been found to be arrhythmogenic.34 Increased sympathetic tone may induce or accelerate occurrence of early after-depolarizations,35 delayed after-depolarizations,36 and abnormal automaticity.37
TREATMENT OF ARRHYTHMIAS AND PRRlENTlON OF ARRHYWMIC DEATH One of the most difficult dilemmas for the clinical cardiologist is when and how to treat arrhythmias in patients with heart failure. Arrhythmias occur in a complicated setting of electrical instability, ischemia, and/or pump failure (Figure 3). Therefore, ischemia and pump failure should be optimized before prescription of antiarrhythmic agents, because their negative inotropic properties and proarrhythmic effects may be hazardous. Figure 3 also shows that many of the factors influencing blood supply, pump function, and electrical behavior are dynamic and not static. For example, in ischemia, spasm or intimal rupture of a coronary artery leading to thrombosis may suddenly change the static situation of a fixed atherosclerotic narrowing. This indicates the necessity of individualization of treatment. Pump function must be optimized, ischemia must be corrected, and modulating factors must be controlled, for instance by P-blockade38 and/or angiotensin-converting enzyme (ACE) inhibition. Inotropic drugs that reduce, or at least do not increase, heart rate are important in this respect. From this point of view, digitalis is an interesting
AGURE 2. lllustratlon of the speclfk effect offlunarklne on delayed after-depolarkatlon-related trIggered actlvRy. Lower pane/: termlnatlon of dlgltallsInduced arrhythmia by flunarizlne. Upper panel: absence of effect of flunarlzlne on ventrludar tachycardla 24 hours after myocordial lnfarctlon (abnormal automatlclly).
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drug because it improves contractility without increasing heart rate. The decision to use antiarrhythmic therapy in heart failure, therefore, depends on the answers to the following questions: Is the arrhythmia already controlled by correcting ischemia and optimizing pump function? If no, does the arrhythmia produce symptoms, and is the arrhythmia of prognostic significance (increased risk of arrhythmic death)? If the arrhythmia is controlled by improving pump function and by controlling ischemia and the modulating factors, there is no obvious reason to institute antiarrhythmic drug treatment. Many arrhythmias, however, persist after these steps have been taken. An example is sustained ventricular tachycardia in the setting of an old myocardial infarction. Although ischemia may be present, coronary revascularization is insufficient to cure or prevent the arrhythmia and additional measures to control or remove the substrate are indicated. In case the arrhythmia produces symptoms, some form of antiarrhythmic treatment must be instituted. If the arrhythmia does not lead to circulatory arrest, antiarrhythmic drugs are usually sufficient. Drug selection may be helped by the evaluation of the effectiveness of the drug by programmed electrical stimulation,39>40 especially in the case of sustained forms of ventricular tachycardia, although the possible proarrhythmic and negative inotropic effects of antiarrhythmic drugs must be considered. Also, extracardiac side effects may limit the use of these drugs. In this regard, class IA drugs are less frequently indicated than other drugs with less negative inotropic effects. Evaluation of proarrhythmic effeck Class IA and class III antiarrhythmic drugs tend to induce
QT prolongation and torsade de pointes. In the case of class IA drugs, this complication frequently occurs within the first days of treatment, facilitating early recognition during clinical observation. A possible indicator of an increased tendency to develop this proarrhythmic complication is the opposite behavior of the QT, interval during exercise. Recent data suggest that during the recovery phase after exercise, the QT, interval tends to be prolonged in untreated patients prone to develop torsade de pointes. 41 The predictive value of this finding awaits further evaluation. Class IC drugs have a rate-related increase of slowing of conduction, which may lead to the induction of reentrant tachycardias.17 Therefore, exercise testing during class IC administration is mandatory to evaluate possible proarrhythmic effects of these drugs. Further control of proarrhythmic effects may be achieved by careful follow-up of kidney and liver function and plasma potassium and magnesium levels. In the cases of low drug efficacy using class IA, IC, or class III drugs, or other reasons for termination of the antiarrhythmic drug, the use of amiodarone41 should be considered. This drug has a high efficacy, good initial tolerance, minor negative inotropic and proarrhythmic effects, and easy dosing schedule. The high incidence of long-term side effects restricts widespread use and high dosing, although most side effects are reversible. Arrhythmias leading to circulatory arresk In arrhythmias leading to circulatory arrest, a more aggressive diagnostic and therapeutic approach must be followed. Programmed stimulation can be useful in initiating the clinical arrhythmia.39,40 If the tachycardia is hemodynamically tolerated, mapping of early local electrical activation may indicate the origin of the tachycardia. CHRONIC
STENOSIS
FIGURE 3. Model showing the interplay between different patho physiologic mechanisms in the induction of artiythmia. All mechanisms have static and dynamk components. Modulating (MOD.) factors include the autonomic nervous system, electrolytes, hormones (renin-angbtensin system), and drugs.
SIZE OF SCAR (+ LOCATION)
HEMODYNAMIC DYSFUNCTION -MOD.
ABNORMAL AUTOMATICITY
FACTORS
TRIGGERED ACTIVITY
A SYMPOSIUM:
HEART
FAILURE
MANAGEMENT
4u:
Accurate localization facilitates surgical or catheter destruction or isolation of the tissue from which the tachycardia originates. Subendocardial resection, endocardial circumcision, and aneurysmectomy combined with cryoablation are surgical options. Chemical, electrical, and radiofrequency ablation are catheter methods to ablate ventricular arrhythmogenic cardiac tissue. In tachycardias that are not hemodynamically tolerated, localizing the origin of tachycardia is difficult or impossible. Therefore, surgical treatment cannot be map-directed and implantation of internal antitachycardia devices will frequently be necessary. If no nonpharmacologic approach is possible, treatment with amiodarone is indicated, which may be combined with other drugs from class I or 111 4243 Asymptomatic arrhythmias indicating poor prognosis: As has been pointed out before, ventricular premature beats (especially when complex) and frequent and nonsustained ventricular tachycardias have been considered possible indicators of poor prognosis in patients after myocardial infarction and heart failure. Our current experience indicates that there are different reasons not to attempt to suppress these arrhythmias. Their predictive value is low, which means that overtreatment occurs in the patient group presenting with these arrhythmias. Also because of proarrhythmic effects, the induction of new or aggravation of existing arrhythmias is a potential risk. Prevention of sudden death in heart failure: Several studies44-46 such as Studies of Left Ventricular Dysfunction, (SOLVD), Vasodilator-Heart Failure Trial (V-HEFT), and the first Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I) have demonstrated that cardiac death rate can be diminished by treatment of moderate44 and severe46 heart failure. This has been shown for ACE inhibitors44s46 and isosorbide dinitrate plus hydralazine.45 Although initial studies did not show a reduction in sudden cardiac death, recent data comparing enalapril with hydralazine-nitrate47 suggest a reduction in sudden rather than nonsudden death. This finding may be explained by ACE inhibitorinduced reduction of neurohumoral stimulation. Increased mortality rates have been reported during prolonged use of P-adrenergic agonists such as xamotero148 and phosphodiesterase inhibitors such as milrinone in patients with severe heart failure.49 Limited experience is available in relation to 42C
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antiarrhythmic drug treatment and prevention of sudden cardiac death in heart failure.50 Studies are currently in progress, for example with amiodarone, on the effectiveness of antiarrhythmic drug therapy in relation to survival in heart failure. FUTURE DIRECTIONS There is a need for better stratification of patients with heart failure at risk of sudden death. There is a lack of a single noninvasive risk parameter with a sufficiently high positive predictive accuracy. Accurate identification of high-risk patients allows the evaluation of more aggressive pharmacologic and nonpharmacologic treatment, such as electrical devices with pacing and defibrillation capabilities. Early recognition and treatment of disease states leading to heart failure, such as ischemia, myocardial infarction, and hypertension, should be attempted. Further developments are required in relation to recognition and treatment of mechanisms of arrhythmias in heart failure. In particular, the relevance of delayed after-depolarization-induced triggered activity should be evaluated, since this may lead to more specific drugs and a lower incidence of proarrhythmia, negative inotropy, and extracardiac side effects. Future trials should be based on better information on the mechanisms underlying arrhythmias in heart failure: although presently most attention is given to pure class III antiarrhythmic drugs, it should be realized that these drugs are effective only in reentrant arrhythmias. The role of the latter in heart failure has-not been clarified. Finally, approaches to improve cardiac contractility have to be awaited, such as cardiomyoplasty, new pharmacologic interventions, and molecular biology techniques, which allow the heart muscle to be restored.
REFERENCES F Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardi01 1986; 57(suppl):357B. 2. Massie BM, Conway M. Survival of patients with congestive heart failure: past, present and future prospects. Circulation 1987;75(suppl IV):ll-19. 3. Califf RM, Bounous P, Harrell FE, M&ants B, Lee KL, M&inks RA, Rosati RM. The prognosis in the presence of coronary artery disease. In: Braunwald E, ed. Congestive Heart Failure: Current Research and Cl&xl Applications. New York: Grune & Stratton, 19823-40. 4.Bigger JT. Relation behveen left ventricular dysfunction and ventricular arrhythmias after myocardial infarction. Am J Card01 1986;57(suppl):SE14B. 5. Pfeffer MA, Pfeffer JM. Ventricular enlargement and reduced survival after myocardial infarction. Ck&& 1987;75(suppl Iv):93-97. 6. Dargie HJ, Cleland JGF, Leckie BJ, Inglis CG, East BW, Ford J. Relation
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of arrhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987;7S(suppl IV):98107. 7. Bigger JT, Fleiss JL, Kleiger R, Miller JPh, Romitzky LM, and the Multicenter Post-Infarction Research Group. The relationship among ventricular arrhythmias, left ventricular dysfunction and mortality in the 2 years after myocardial infarction. Circulation 1984;69:25&258. 8. Mukharji J, Rude RE, Poole WK, Gustafson N, Thomas IJ Jr, Strauss HW, Jaffe AS, Muller JE, Roberts R, Raabe DS Jr, Croft CH Passamani E, Braunwald E, WilIerson JT, and the MILIS Study Group. Risk factors for sudden death after acute myocardial infarction: two year follow up. Am J Cardiol1984;54:31-36.
9. Ruberman W, Weinblatt E, Goldberg JK Frank CW, Shapiro S. Ventricular premature beats and mortality after myocardial infarction. N Engl .I Med 1977;297:150-151. 10. Holmes J, Kubo SH, Cody RJ, Kligfield P. Arrhythmias in ischemic and non-ischemic dilated cardiomyopathy: prediction of mortality by ambulatory electrocardiography. Am J Cardiol 1985;55:14&151. IL Huang SK Messer JV, Denes P. Significance of ventricular tachycardia in idiopathic dilated cardiomyopathy: observations in 35 patients. Am J Car&l 1983;51:507-512. 12. Wilson JR, Schwartz JS, Sutton MSJ, Ferraro N, Horowitz LN, Reichek N, Josephson ME. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity. J Am Coil Cardiol 1983;2:403410. 13. Van Olshausen K, Schafer A, Mehmel HC, Schwarz F, Senges J, Kubler W. Ventricular arrhythmias in idiopathic dilated cardiomyopathy. Br Heart J 1984;51:195-201. 14. Denes P, Gillis AM, Pawitan Y, James M. Kammerlmg JM, WiIhehnsen L, Salerno DM, and the CAST Investigators. Prevalence, characteristics and significance of ventricular premature complexes and ventricular tachycardia detected by 24 hour continous electrocardiographic recording in the cardiac arrhythmia suppression trial. Am J Cardiol 1991;68:887-896. 15. Brugada P, Talajic M, Smeets J, Mulleneem R Wellens HJJ. Risk stratiiication of patients with ventricular tachycardia or ventricmar fibriUation after myocardial infarction. The value of the clinical history. Ew He&f J 1989;10:717752.
16. Ranger S, Talajic M, Lemety R, Roy D, Nattel S. Amplification of flecamide induced ventricular conduction slowing by exercise. Circulation 1989;79:1tXk& 1006. 17. Cranefield PF, Aronson RS. Cardiac arrhythmias: the role of triggered activity and other mechanisms. Mt. Kisco, NY: Futura Publishing, 1988. 18. Gorgels APM, De Wit B, Beckman HDM, Dassen WRM, Wellens HJJ. Triggered activity induced by pacing during digitalis intoxication. PACE 198710: 1309-1321. 19. Mulder BJM. Damage-induced propagated contractions in cardiac muscle: implications for cardiac arrhythmias. Thesis, University of Rotterdam. Rodopi Press, 1989. 20. Ferrier GR. The effects of tension on acetylstrophantidine-induced transient dep&nizations and after contractions in canine myocardial and Purkinje tissue. Circ Res 1976;38:156-162. 2L Morgan JP, Erny RE, Allen PD, Grossmann W, Gwathmey JK Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction on ventricular myocardium from patients with heart failure. Cinxlation 1990;81(suppl III):III-21-111-32. 22. Nordin C. Abnormal calcium handling and the generation of ventricular arrhythmias in congestive heart failure. Heati Failure 1989;5:143-154. 23. De Mello W. Effect of intracellular injection of calcium and strontium on cell communication. J Physiol1975;250:231-245. 24. Vos MA, Gorgels APM, Leunissen JDM, Wellens HJJ. Flunarizine allows differentiation between mechanisms of arrhythmias in the intact heart. Circulatin 1990;81:343-349. 25. Gorgels APM, Vos MG Smeets JLRM, Kriek E, Brugada P, WeUens HJJ. Delayed after depolarizations and atrial and ventricular arrhythmias. In: Rosen MR, Janse MJ, Wit AL, eds. Cardiac Electrophysiology: A Textbook. Mt. Kisco, NY: Futura Publishing 1990:341-354. 26. Dangman KM, Hoffman BF. Studies on overdrive stimulation of canine cardiac Purkinje fibers: Maximal diastolic potential as a determinant of the response. JAm Coil Cardiol1983;2:1183-1190. 27. Janse MJ, van CapeUe FJL, Morsink H, Kleber AG, Wi-Schopman F, Cardinal R, Naumann d’Alnon, Court C, Durrer D. Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ Res 1980,47:151-165. 28. De Bakker JMT, van CapelIe FJL, Janse MJ, Wilde AAM, Gxonel R,
Becker AE, Dingemans KP, van Hemel NM, Hauer RNW. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomical correlations. Circulation 1988;77:58%06. 29. Janse MJ, Wit AL. The electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989;69:1049-1169. 30. Bigger JT Jr. Electrical properties of cardiac muscle and possibie causes of cardiac arrhythmias. In: Dreifus IS, Likoff MJ, eds. Cardiac Arrhythmias. New York Grune & Stratton, 1973:13. 31. Aronson RS. Afterpotentials and triggered activity in hypertrophied myocardium from rats with renal hypertension. Circ Res 1981;48:72&727. 32. Cranefield PF, Klein HD, HofIman BF. Conduction of the cardiac impulse, I Delay, block and one-way block in depressed Purldnje fibers. Circ Res 1971;28:199-204. 33. Reiter MJ, Synhorst DP, Mann DE. Electrophysiological effects of acute ventricular dilatation in the intact heart. Circ Res 1988;65:554-562. 34. Aronow WS, Epstein S, Schwartz KS, Koenigsberg MO. Correlation of complex ventricular arrhythmias detected by ambulatory electrocardiophic monitoring with echocardiographic left ventricular hypertrophy in persons older than 62 years in a long term health care facility. Am J Cardiol1987;60:73&732. 35. Ben-David J, Zip-es DP. Differential response to right and left ansae subclaviae stimulation of early after depolatisations and ventricular tachycardia induced by cesium in dogs. Circularion 1988,78:1241-1250. 36.Hewett KW, Rosen MR. Alpha and beta adrenergic interactions with ouabain induced delayed afterdepolarizations. Phamacol Es, Ther 1984;229:188192. 37. Constantin L, Martins JB. Autonomic control of ventricular tachycardia. J Am Coil Cardiol1987;9:366-373.
38. Swedberg K, Hjahnarson A, Waagstein F, Wallentin J. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancet 1979;i: 13744376. 39. Josephson ME.
Treatment of ventricular arrhythmias after myocardial infarction. Cirnrlatin 1986;74:653-558. 40. Wellens HJJ, Brugada P. Treatment of cardiac arrhythmias: when, how and where? JAm Co11 Cardiol1989;14:1417-1429. 4F Kadiih AH, Weisman MF, Veltri EP, Epstein AE, Slepian MY, Levine JH. Paradoxical effects of exercise on the QT-interval in patients with polymorphic ventricular tachycardia receiving type Ia anti-atrhythmic agents. Circulation 1990;81:14-19. 42. Hamer AWF, Addes LB, Johns JA Beneficial effects of low dose amiodarone in patients with congestive heart failure. JAm Co[l Car&l 1989;14:17681775.
43. Kim SG, Felder SD, Figura I, Johnston DR, Waspe LE, Fisher JD. Value of Halter monitoring in predicting long-term efficacy and inefficacy of amiodarone used alone and in combination with class Ia antiarrhythmic agents in patients with ventricular tachycardia. JAm Co11 Car&~ 1987;9:169-174. 44. The SOLVD Investigators, Effect of enalaptil on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Etzgl J Med 1991;325:293-302. 45. Cohn JN, Archibald DF, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552. 46. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the cooperative North Scandinavian Enalaptil Survival Study (CONSENSUS). N&g2 JMed 1987;316:1429-1435. 47. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310. 48. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancef 1990;336:16. 49. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe J, Dibianco R,Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI, SoUano JA, Shannon J, Tandon PK DeMets DL for the PROMISE Study Research Group. Effect of oral mihiione on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468-1475, 50. Stewart RA, McKenna WJ, Polonicki JD, Michelson JK, Das SK, Morady E, Schork MA, Pitt B, Nicklas JM. Prospective randomized placebo-controlled trial of low dose amiodarone in patients with severe heart failure and frequent ventricular ectopy. Eur Heart J 1989;1O(suppl):229.
A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
a
