factors causing arrhythmias in chronic congestive heart failure

Factors causing arrhythmias in chronic congestive heart failure

Severe congestive heart failure (CHF) is a common syndrome with a high mortality rate (about 50% in 1 year among patients with symptoms at rest). Severity of left ventricular dysfunction is the most important adverse prognostic factor. Serious arrhythmias are common in CHF and also increase the mortality rate. Sudden death is the mode of death in about 40% of patients with severe heart failure. Multiple factors contribute to arrhythmias in CHF, including left ventricular dysfunction, myocardial ischemia, catecholamines, electrolyte disturbances, and drugs used to treat the heart failure. Minimizing or correcting these influences may be important in reducing serious arrhythmias. Antiarrhythmic drugs may be important in reducing the incidence of sudden death among patients with severe heart failure, although this has not yet been proved. (AM HEART J 1987;114:1267.)

William W. Parmley, M.D. San Francisco, Calif.

Congestive heart failure (CHF) is a common clinical syndrome seen by almost all physicians. It has been estimated’ that about 1% of the United States population has CHF and that this prevalence increases with age to reach approximately 10% at age 75 years and older. Over the past two decades a number of new agents have appeared for use in both acute and chronic CHF. These have included a variety of intravenous and oral vasodilator agents,2 some new inotropic agents, and combination inotrope-vasodilator drugs. Studies of such agents have focused primarily on treatment of the symptoms of CHF, including dyspnea on exertion and fatigue. Most studies have used hemodynamic measurements as a marker to correlate with these symptoms. For example, a reduction in pulmonary capillary wedge pressure at rest and during exercise has been used as a hemodynamic marker of the beneficial treatment of dyspnea. Similarly, an increase in cardiac output, both at rest and with exercise, has been linked to relief of fatigue, which is presumably related to inadequate perfusion of exercising skele- tal muscles. In most of these studies, end points have consisted of both subjective symptomatic improvement and objective measures of improved performance, such as increased exercise tolerance.3 Studies have indicated that when added to digitalis

From the School of Medicine, University of California, and the Moffitt/ Long Hospitals.

Reprint requests: William W. Parmley, M.D., Division of Cardiology, 1186-Moffitt Hospital, San Francisco, CA 94143.

and diuretics, venodilators such as nitrates and angiotensin-converting enzyme (ACE) inhibitors, can increase exercise tolerance, whereas arteriolar dilators, such as hydralazine, cannot.2 There is recent information that vasodilator drugs can improve survival. The Multicenter Veterans Admin- istration study, V-HEFTl, demonstrated that the addition of hydralaxine and isosorbide dinitrate to the treatment of patients already receiving digoxin and diuretics reduced the mortality rate as compared to a control group of patients receiving placebo.4

From studies with vasodilators and other agents, it has become apparent that the mortality rate for severe heart failure is considerable. In class IV patients treated with vasodilator drugs, there is an approximate 50% mortality rate in 1 year.’ It has also become apparent that up to one half of these deaths occur suddenly. Not uncommonly, these deaths occur in individuals who appear to be doing well symptomatically, relative to dyspnea and fatigue. Thus it is intuitively apparent that serious ventricular arrhythmias play an important role in this high mortality rate among such patients. The purpose of this article is to discuss those factors that lead to serious arrhythmias in patients with severe CHF.

PROGNOSTIC FACTORS IN CHF

Table I lists the primary factors that have been correlated with subsequent death in patients with CHF. The most important factor is the level of left ventricular function, however measured. After myo-

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0 10 20 30 40 50 60 70 Radkmcide Ejection Fraction ( % )

Fig. 1. Left ventricular function after thrombolysis. In 1248 patients after myocardial infarction, the relationship is shown between predischarge radionuclide ejection fraction and l-year mortality rate. Broken lines represent 95% confidence limits of data. (From Serruys et al. Am J Cardiol 1986;7:8B-14B. Reproduced with permission.)

Fig. 2. Relationship between ventricular premature depolarizations (VPD) on predischarge 24-hour ECG and postmyocardial infarction mortality rate. Survival after myocardial infarction in 766 patients stratified as to ejection fraction and VPDs/hr in a 24-hour predischarge continuous ECG recording. Low ejection fraction and VPDs >lO/hr contributed to increasing mortality rate. (From Bigger Am J Cardiol 1986;5738B-14B. Reproduced with permission.)

cardial infarction, both the level of stroke work index6 and ejection fraction6 have been correlated with subsequent survival. In a study by Serruys et al.> the relationship between ejection fraction and the l-year survival rate was hyperbolic, as shown in Fig. 1. The additional prognostic effect of arrhythmias on survival after myocardial infarction was reported by Bigger? in 1966 (Fig. 2). Survival curves A and B with an ejection fraction greater than 30% are much better than curves C and D with ejection

fractions less than 30%. In each pair of ejection fraction curves, the addition of 10 or more ventricular premature depolarizations per hour worsened the prognosis, particularly in patients with an ejection fraction less than 30%.

Formation of aneurysms after myocardial infarction has also been linked with a poor prognosis. In a study by Meixlish et al.,* 18 patients with an aneurysm and an initial ejection fraction of 27% had a l-year mortality rate of 61%) compared with 33 patients without aneurysm and an ejection fraction of 31% who had only a 9 % mortality rate.

Studies in patients with chronic CHF have also emphasized the importance of left ventricular function as the most important long-term prognostic factor.’ Meinertz et al.9 reported that the addition of significant arrhythmias in patients with severe heart failure also worsened the prognosis. A study by Schultze et aLlo suggested that patients at high risk for sudden death are those with ejection fractions less than 40% and complicated ventricular premature contractions. Pooled data from eight studies” found that the incidence of ventricular ectopy (cou- plets, multiformed premature ventricular contractions, or both) was 87 % , with an incidence of 54 % of nonsustained ventricular tachycardia. Therefore, not only are arrhythmias frequent in patients with severe heart failure, but the two factors seen to have added significance in terms of prognosis, particularly the appearance of sudden death.12

The cause of chronic CHF also has a bearing on the mortality rate. In our own experience, approximately two thirds of the patients seen with severe CHF had underlying coronary artery disease. The

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Table I. Prognostic factors in CHF

Left ventricular function Arrhythmias Aneurysm formation Cause of heart failure Exercise tolerance

Table III. Factors producing CHF I

Volume overload Pressure overload Loss of muscle Ischemia Decreased contractility

Table II. CHF: Effect of cause on prognosis

Mortality rates by cause

Time Study ho) Zschemic Nonischemic

Franciosa et al.13 12 46% 23% (1983)

Holmes et a1.14 12 54% 44% (1985)

Francis*’ (1986) 70 59% 50% Simonton et al. 5 68% 52%

(1987)

Table IV. Proarrhythmic factors in CHF

Left ventricular dysfunction Myocardial ischemia Cellular damage Catecholamines Electrolyte disturbances Inotropic agents Diuretics Antiarrhythmic drugs Vasodilators

next most common group was that with dilated cardiomyopathy. Other groups, such as patients with burned-out hypertension or valvular heart disease, were far less common than these two major groups. Data tend to suggest that there might be a slightly worse prognosis for patients with coronary artery disease and heart failure compared to nonischemic dilated cariomyopathy (Table II). The four studies summarized in Table II demonstrated a trend toward a lower mortality rate in the nonischemic group in a given time period for similar degrees of CHF. 11*13-16 This suggests a potential role for ischemia or myocardial infarction in initiating serious arrhythmias in such patients.

Exercise tolerance is also an independeqt factor related to surviva1.16* l7 However, there is very little relationship between ejection fraction and exercise tolerance in many studies of patients with chronic CHF.lB In a variety of studies, however, it is clear that both of these factors may bear independently on long-term prognosis, although left ventricular function appears to be the most powerful of those determinants. In the recently completed V-HEFT study, total body oxygen uptake, Vo,, was a highly significant predictor of death and more powerful than duration of exercise.lg

PREVALENCE OF SUDDEN DEATH IN CHF

In 12 studies summarized by Francis,” the aver- age ratio of sudden to total deaths was 44%.” Another summary of pooled data reported by Pack-

er,12 in patients with severe heart failure, noted percentages for sudden death ranging from 33% to 47% of total deaths. This number appeared to remain relatively constant, even in studies including patients with less severe heart failure. In general, therefore, approximately 40% of deaths in patients with CHF occur suddenly, a circumstance that would lend itself to consideration of appropriate antiarrhythmic therapy if such therapy could be shown to prevent sudden death in a significant number of such patients.

FACTORS PRODUCING CHF

The five primary factors that produce CHF (Ta- ble III) include volume overload, pressure overload, loss of muscle (myocardial infarction), acute ischemia, and decreased contractility (congestive cardiomyopathy). It should also be remembered that some patients have symptoms of dyspnea as a result of restriction of filling and diastolic dysfunction. Such patients are not included in this discussion, which relates only to patients with systolic dysfunction.

In all of the syndromes mentioned here, it appears that a final common pathway of heart failure is a gradual reduction in myocardial contractility associated with the underlying process. With prolonged pressure or volume overload, there are a number of accompanying biochemical changes that presumably contribute to this decline in contractility. In patients with myocardial infarction, there is probably an increased volume overload on the remaining normal muscle, which in time leads to a depression of contractility in this region, even though it may


Amerlcan Heart Journal

have a normal blood supply. In patients with congestive cardiomyopathy, there is a diffuse decrease in contractility associated with involvement of all chambers of the heart in the myopathic process.

PROARRHYTHMIC FACTORS IN CHF

Table IV lists the primary factors that have been associated with increased rhythm disturbances in patients with CHF. A number of studies indicate the close relationship between increasing arrhythmias and increasing severity of CHF.7* 11* 12* 2o The relationship between left ventricular dysfunction and arrhythmias has already been described.7s 11, l* Myo- cardial ischemia is also known to produce arrhythmias, perhaps in part because of alteration in the temporal dispersion of recovery times with the opportunity for reentrant ventricular arrhythmias. Increased automaticity may also play a role, especially soon after myocardial infarction. Cellular damage may also contribute to arrhythmias, such as is seen in patients with left ventricular aneurysm. The site of arrhythmias in patients with intractable ventricular arrhythmias appears to be at the rim of the aneurysm and can frequently be eradicated by resection of the aneurysm.

A number of experimental and clinical studies have implicated the potential importance of catecholamines in producing serious arrhythmias in patients with CHF.21 Since catecholamines tend to be elevated in proportion to the severity of heart failureF2 this is an important contributing factor to such arrhythmias.

The potential role of the catecholamine system in arrhythmias is seen by examining the results of beta blocker studies after myocardial infarction where there has been a reduction in the frequency and complexity of ventricular arrhythmias and sudden death.23 These effects also appear to be more prom- inent in individuals who have more severe heart failure. Thus beta blockers appear to have a salutory role in the treatment of arrhythmias in this setting, although they are frequently contraindicated in patients with severe heart failure. ACE inhibitors also reduce arrhythmias2* compared to placebo, which may also be a reflection of the withdrawal of sympathetic tone accompanying the use of ACE inhibitors. An alternative explanation is the effect of these agents in reducing myocardial oxygen demand and in maintaining levels of serum potassium. The improved survival rate among patients taking ACE inhibitors who have low serum sodium levels and marked activation of the renin-angiotension-alclo- sterone system may be partly the result of the protective effects mentioned previously.25,26

Electrolyte disturbances are frequent in patients with CHF. In part, these may be the result of intrinsic alterations in renal function, although most commonly they are produced by diuretic agents. Potassium and magnesium depletion with subsequent hypokalemia and hypomagnesemia appear to be important contributors to serious arrhythmias in patients with CHF.27

Hypokalemia is found in up to 50% of patients with cardiovascular disease who are being treated with thiazide diuretics. Hypomagnesemia has been identified in about 40% of patients with hypokalemia, and muscle magnesium levels have been reported to be below normal in about 40% of patients with CHF who are receiving diuretics.2s These data emphasize the necessity for preventive therapy in not allowing either potassium or magnesium defi- ciencies to occur.

Inotropic agents are particularly suspect in producing arrhythmias in patients with heart failure. From early studies with digitalis and catecholamines to the newer inotrope vasodilators, there is considerable evidence to suggest their potential for inducing rhythm disturbances.15-2s

Although antiarrhythmic drugs can relieve arrhythmias, they can also produce proarrhythmic effects in a certain proportion of patients.30 It appears that all antiarrhythmic drugs have this potential. Proarrhythmic effects may occur in as many as 30% of patients treated with antiarrhythmic drugs.30 It may be that proarrhythmic effects are even more common in patients with severe heart failure than in other groups of patients treated for serious arrhythmias. It may also be true that in patients with large areas of scarring in the left ventricle, beneficial ant&rhythmic effects may be very difficult to achieve. Vasodilator drugs may also have the potential for producing arrhythmias. For example, potent arteriolar vasodilators may lead to reflex activation of the sympathetic nervous system with subsequent arrhythmias. Furthermore, drugs that markedly reduce blood pressure can contribute to hypotension, ischemia, and subsequent arrhythmias.

Vasodilator therapy may reduce arrhythmias by reducing wall stress. This may have been a factor in the V-HEFT trial,* in which nitrates were one arm of the therapy that lowered pulmonary capillary wedge pressure. A reduction in wall stress, and perhaps stretch-induced arrhythmias, may be an important role for vasodilator drugs, in addition to their ability to reduce oxygen consumption and improve cardiac performance.

It should be clear from the list in Table IV that it

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is often difficult, if not impossible, to precisely implicate those factors that may be more important in producing arrhythmias in patients with CHF. It should be emphasized, however, that correctable factors in Table IV should be given special attention in treating patients who have serious arrhythmias at the same time they are experiencing signs and symptoms of severe CHF.

ROLE OF ANTIARRHYTHMIC DRUGS IN CHRONIC

HEART FAILURE

Several studies suggest the possibility that antiarrhythmic therapy may be beneficial in patients with chronic CHF. In a study by Brodsky et a1.,31 20 patients with ventricular fibrillation or ventricular tachycardia were managed with antiarrhythmic drug therapy. The l-year survival rate was 89% compared with reports in the literature of survival rates of 40% to 60%. Complex and combination antiarrhythmic drug therapy was often required, including beta-blocking drugs. Although not a placebo-controlled trial, this provides suggestive benefit. In a retrospective study by Simonton et a1.,15 it also appeared that patients given antiarrhythmic drugs had a lower incidence of sudden death than those patients not given antiarrhythmic therapy. All patients in this latter study were also receiving potent inotrope-vasodilator drugs.

Although the previous studies are suggestive, definitive proof of antiarrhythmic efficacy requires a large, multicenter, randomized, placebo-controlled tria1.32

CONCLUSIONS

The level of left ventricular function is the most important prognostic factor in chronic CHF. Serious arrhythmias are common in severe heart failure and independently worsen the prognosis. Sudden death is common and is the cause of death in about 40 % of patients with chronic heart disease. Although not yet proved, there is suggestive evidence that antiarrhythmic drugs may reduce sudden death in such patients.

REFERENCES

1. McFate Smith W. Epidemiology of congestive heart failure. Am J Cardiol 1985;55:3A-8A.

2. Levine BT. Role of vasodilators in the treatment of congestive heart failure. Am J Cardiol 1985;55:32A-5A.

3. Weber KT, Janicki JS. Cardiopulmonary exercise testing for evaluation of chronic cardiac failure, Am J Cardiol 1985; 55:22A%A.

4. Cohn JN, Archibald M, Ziesche RN, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure, results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52.

Factors causing arrhythmias in chronic CHF 1271

5. Chatterjee K, Swan HJC, Kaushik VS, Jobin G, Magnusson P. Forrester JS. Effects of vasodilator therapy for severe .--- pump failure in acute myocardial infarction on short term and late prognosis. Circulation 1976;53:797-802.

6. Serruys PW, Simoons ML, Suryapranata H, et al. Preserva- tion of global and regional left ventricular function after early thrombolysis in acute myocardial infarction. J Am Co11 Cardiol 1986;7:729-42.

7. Bigger Jr JT. Relation between left ventricular dysfunction and ventricular arrhythmias after myocardial infarction. Am .J Cardiol 1986:57:8B-14B.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Meizlish JL, Berger HJ, Plankey M, Errico D, Levy W, Zaret BL. Functional left ventricular aneurysm formation after acute anterior transmural myocardial infarction. Incidence, natural history and prognostic implications. N Engl J Med 1984;311:1001-6. Meinertz T, Hofman T, Kasper W, et al. Significance of ventricular arrhythmias in idiopathic dilated cardiomyopathy. Am J Cardiol 1984;53:902-7. Schultze RA Jr, Strauss HW, Pitt B. Sudden death in the year following myocardial infarction. Relation to ventricular premature contractions in the late hospital phase and left ventricular ejection fraction. Am J Med 1977;62:192-9. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol 1986;57:3B-7B. Packer M. Sudden unexpected death in patients with congestive heart failure: a second frontier. Circulation 1985;72: 681-5. Franciosa JA, Wilen M, Ziesche SM, Cohn JN. Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1983;51:831-6. Holmes J, Kubo SH, Cody RJ, et al. Arrhythmias in ischemic and nonischemic dilated cardiomyopathy: prediction of mortality by ambulatory electrocardiography. Am J Cardiol 1985;55:146-51. Simonton CA, Daly P, Kereiakes D, Sata H, Modin G, Chatterjee K. Survival in severe congestive heart failure treated with the new nonglycosidic nonsympathomimetic oral inotropic agents. Chest 1987;92:118-23. Hammermeister KE, DeRouen TA, Dodge HT. Variables predictive of survival in patients with coronary disease. Circulation 1979;59:421-30. Franciosa JA. Exercise testing in chronic congestive heart failure. Am J Cardiol 1984;53:1447-53. Franciosa JA, Park M, Levine B. Lack of correlation between exercise capacity and indices of left ventricular performance in heart failure. Am J Cardiol 1981;47:33-9. Cohn JH, Ziesche S, Archibald DG (VA Cooperative Study Group, West Haven, Conn, and Minneapolis, Minn). Quanti- tative exercise tolerance as a predictor for mortality in congestive heart failure: the V-HEFT study [Abstract]. Cir- culation 1986; 11-447. Wilson JR, Schwartz JS, Sutton MS-J, et al. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity. J Am Co11 Cardiol 1983; 2:403-10. Rosen MR, Hoffman BF. Electropbysiologic determinants of normal cardiac rhythms and arrhythmias. In: Rosen MR, Hoffman BF, eds. Cardiac therapy. Boston: Martinus Nijhoff Publishers, 1983:1-21. Francis GA. Neurohumoral mechanisms involved in congestive heart failure. Am J Cardiol 1985;55:15A-22A. May GS, Eberlein KA, Furberg CD, Passamani ER, DeMets DL. Secondary prevention after myocardial infarction: a review of long-term trials. Prog Cardiovasc Dis 1982;24:331- 52.

24. Cleland JGF, Dargie HJ, Hodsman GP, et al. Captopril in heart failure. A double-blind controlled trial. Br Heart J 1984;52:530-4.

25. Lee WH, Packer M. Prognostic value of serum sodium


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concentration in severe heart failure and its modification by converting-enzyme inhibition [Abstract]. Circulation 1984; 7O(suppl II):II-113.

26. Furberg C, Yusuf S. Effect of vasodilators on survival in chronic congestive heart failure. Am J Cardiol 1985;55:1110- 14.

27. Packer M, Gottlieb SS, Blum MA. Immediate and long-term pathophysiologic mechanisms underlying the genesis of sudden cardiac death in patients with congestive heart failure. Am J Med 1987;82:4-10.

28. Dyckner T, Wester PO. Postassium/magnesium depletion in natients with cardiovascular disease. Am J Med 1987:82: h-17.

29. Packer M, Medina N, Yushak M. Hemodynamic and clinical limitations on long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984;70:1038-47.

30. Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by ant&rhythmic drugs. Circulation 1982;65:886-94.

31. Brodsky MS, Allen BJ, Baron D, et al. Enhanced survival in patients with heart failure and life-threatening ventricular tachyarrhythmias. AM HEART J 1986;112:166-72.

32. The CAPS Investigators. The cardiac arrhythmia pilot study (CAPS). Am J Cardiol 1986;57:91-5.

ship between arrhythmias and death persists in all subgroups. It may not be the same in those who have had bypass surgery or those who have had a previous myocardial infarction, for example.

DR. PARMLEY. Certainly in patients who have had a myocardial infarction, beta blockers provide antiarrhythmic protection; since, in this group, there has been a reduction in sudden death and total mortality rates. This circumstantial evidence shows that arrhythmias do play some role in death after myocardial infarction, and that the arrhythmia/death connection does persist. Otherwise, we do not really have enough data to make claims about other subgroups.

DR. ARNSDORF. Dr. Parmley, you brought up hypokalemia and hypermagnesemia in your article. What is the significance of plasma levels vs whole body content of these electrolytes in terms of potentiation of arrhythmias in CHF?

DR. PARMLEY. A recent symposiumzs pointed out that about 50% of all patients on diuretic therapy-certainly our mainstay in CHF-will, in fact, have lower plasma potassium levels and perhaps lowered stores of potassium. In those patients who are on diuretic therapy, one has to be especially careful about trying to maintain both plasma potassium level and body stores of potassium.

Diuretic-induced changes in magnesium have also been implicated in arrhythmias. The previously mentioned symposiumz8 also showed that muscle tissue and plasma are both depleted of magnesium in many patients receiving diuretics.

DR. ZAMAN. What about calcium changes in CHF? Do they play a role in arrhythmias?

DR. PARMLEY. I think we are in an area where knowledge is incomplete. It is difficult to be more specific about calcium other than to say it might be important.

DR. PODRID. Is ventricular arrhythmia a wholly independent mortality risk factor in patients with CHF or is it rather a manifestation of severe heart failure with com- promised left ventricular function?

DR. PARLEY. I think the data suggest that arrhythmias have an effect on risk independent of left ventricular function. However, investigations with ACE inhibitors show that left ventricular dysfunction can be treated, wedge pressure probably can be reduced, and maybe even potassium levels can be raised, reducing arrhythmias. Whether this will actually improve the mortality rate thereby is not yet known.

DR. KOSTIS. I think we have to ask whether the relation-

factors causing arrhythmias in chronic congestive heart failure

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