Mechanisms in heart failure and the role of angiotensin-converting enzyme inhibition

Mechanisms in Heart Failure and the Role of Angiotensin-Converting Enzyme Inhibition Jay N. Cohn, MD The four major diagnostic criteria for the syndrome of congestive heart failure are left ventricular dysfunction, exercise intolerance, pulmonary congestion or edema and ventricular arrhythmias. Activation of norepinephrine, angiotensin II, vasopressin and atrial natriuretic peptide may be a key factor in the vasoconstriction and increased impedance to left ventricular ejection in heart failure. Interventions that interfere with these vasoconstrictor mechanisms should have a salutary effect on left ventricular performance. Treatment with angiotensin-converting enzyme (ACE) inhibitors, cu-adzenoceptor blockers and vasopressln antagonists has resulted in hemodynamic benefits, but it has been more difficult to demonstrate long-term clinical effectiveness. Reductions in mortality have been demonstrated in patients with heart failure treated with vasodilators and ACE inhibitors. Improvement in the quality of life and prolongation of life are the only two appropriate goals in the management of heart failure. Further understanding of the role of angiotensln II and its interference by ACE inhibition in the tissue processes of heart failure is needed. (Am J Cardiol 1990;66:2D-6D)

From the Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota. Address for reprints: Jay N. Cohn, MD, Cardiovascular Division, University of Minnesota Medical School, Box 488 UMHC, 420 Delaware Southeast, Minneapolis, Minnesota 55455.

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rowing knowledgeabout the clinical syndromeof heart failure has led to controversiesabout its diagnosis and uncertainties as to how the complex pathophysiology contributes to the natural history of the syndrome. One key to the complex pathophysiology of heart failure has been the favorable clinical effects noted in responseto treatment with angiotensin-converting enzyme (ACE) inhibitors. Although this wasinitially acceptedas evidencefor the efficacy of vasodilator therapy, new understanding of the actions of angiotensin II and of the pharmacologic effects of ACE inhibitors has made even this observation less than simple. To set the stagefor the more focusedreview of the potential mechanisms of action of ACE inhibitors, I shall review in broad terms someof the pertinent clinical and pathophysiologic manifestations of heart failure.

G

DIAGNOSIS

OF HEART FAILURE

Ventricular dysfunction can be quantitated by a number of hemodynamic measurementsmadeeither at rest or during exerciseor other stresses.This quantitative assessment of ventricular function may provide a precisemeans of evaluating performance of the heart in physiologic terms. Recent experience,however,hasmadeit clear that considerableventricular dysfunction may exist in the absenceof symptoms,and thus the clinical syndromecannot accurately be describedby such quantitative assessment of pump function. Nonetheless, since heart failure is a syndrome that has its origin in heart muscledysfunction, demonstration of left ventricular dysfunction should be a sine qua non for the diagnosis. The chief clinical manifestation of heart failure is reduced exercisecapacity becauseof dyspneaor fatigue. Therefore, the simplestdefinition of heart failure is that it is a syndrome in which left ventricular dysfunction is accompanied by exerciseintolerance.’ Two other manifestations of the clinical syndrome are so common that they are best included in the primary diagnostic criteria. Sodium retention manifestedby pulmonary congestionor peripheral edema is often a hallmark of the diseaseand has led to use of the term congestive heart failure to describe the syndrome. Although most patients with heart failure do indeed have congestivesigns or symptoms, these are not necessaryfor the diagnosis.Thus, left ventricular dysfunction accompaniedby exerciseintolerancein the absenceof congestioncan still be diagnosedas heart failure. Ventricular arrhythmias, including premature ventricular depolarizations and runs of asymptomatic nonsustained ventricular tachycardia, are also commonly present in the syndrome.2Although not all patients have such ventricular arrhythmias, and their presenceis not necessaryfor the diagnosis of heart failure, their detec-

tion may best be accepted as a component of the syndromeand not an independentproblem that needsspecific evaluation. Thesefour major diagnostic criteria for the syndrome of heart failure are shown in Figure 1. The syndrome of clinical heart failure includes all patients with left ventricular dysfunction and exerciseintolerance, whereasthe diagnosis of congestiveheart failure should be confined to patients who also exhibit edema and congestion. NEUROHORMONAL IN HEART FAILURE

ACTIVATION

The relation between the clinical manifestations of heart failure (exerciseintolerance, sodium retention and ventricular arrhythmias) and the physiologic impairment in left ventricular function is not simple. A poor correlation betweeneachof thesevariables suggeststhat mechanisms other than the simple impairment of ventricular function contribute to these disturbances.3 Neurohormonal activation has beenproposedas a key contributor to the syndrome’sclinical manifestations and progression. The evidence that these systems are activated in heart failure comesfrom a variety of studiesin patients with the overt clinical syndrome. Activation of the sympathetic nervoussystemis manifestedby elevatedcirculating plasma norepinephrine levels,4~sby elevated norepinephrine spillover rates assessedby kinetic studies using tritiated norepinephrine,6and by increased efferent sympathetic nerve traffic measured from the peroneal nerve in patients with heart failure.7 In recent studieq8an increasein plasma norepinephrine has also been demonstrated in patientswith left ventricular dysfunction who do not have overt signsof heart failure. Thus, the increasedactivity of the sympatheticnervoussystemmay be a somewhatnonspecific responseto impaired left ventricular function. Activation of the renin-angiotensin system is also common in patients with heart failure. Indeed, somepatients exhibit exceedingly high levels of plasma renin activity indicative of intense renal release of renin9 The high levels are particularly common in patients with decompensatedheart failure, most of whom are also receiving large dosesof diuretics that might contribute to the stimulation of renin release from the kidney. In other patients, however, even some with severe symptoms of chronic congestive heart failure, plasma renin activity may be normal and may exhibit a relatively attenuated responseto sodium restriction and to furosemide.‘OThe mechanismof this heterogeneity of renin responsein patients with heart failure is not known. Plasma arginine vasopressin and atria1 natriuretic peptide levels are also increased in patients with heart failure.” Vasopressinlevelsaverageabout twice the normal level in patients with heart failure. The mechanism of this increase is not known, although it is thought to be largely nonosmotic in origin; the possible role of this vasopressinstimulation in contributing to water retention and hyponatremia remains an attractive hypothesis.i2 Atria1 peptide levelsincreasein responseto atria1 stretch, and the increasein heart failure appearsto correlate with the degree of venous congestion.13

\

Ventricular

/

FIGURE 1. The four major diagnostic criteria drome of congestive heart failure (CHF).

for the syn-

The potential physiologic effectsof this neurohormonal stimulation are well known to circulatory physiologists. An increase in vascular resistance and a decreasein vascular compliance are prominent vascular actions of norepinephrine, angiotensin II and vasopressin.i4Atria1 natriuretic peptide may exert vasodilator effects in some vascular bedsunder certain conditions, but its vasodilator effect appears not to be very potent and may downregulate with chronic stimulation.r5 Thus, the net effect of activation of thesefour hormonal systemsis an increase in vascular tone that raises impedance to left ventricular ejection. Since increased impedance is a critical determinant of left ventricular performance in patients with heart failure,t6 this neurohormonal activation may be a key factor in a progressive deterioration of left ventricular function that may contribute to the natural history of the syndrome. However, other actions of these systemsmay also be critically involved in the process.The sympathetic nervous system stimulates myocardial contractility through P-receptor effects, but long-term stimulation may result in downregulation of these0 receptorsand an impaired peak capacity for contractility. *I Coronary vasoconstrictor effects of all of thesehormonal systemsmay impair myocardial perfusion, particularly to the subendocardium, and may add a metabolic component to the ventricular dysfunction even in patients without ischemic heart disease.t8The renal vasoconstrictor and intrarenal effects of these hormones may contribute to sodium retention, water retention and congestive symptoms in heart failure.19 Furthermore, the adrenal stimulatory effect of angiotensin II contributes to hyperaldosteronism in heart failure and thus to hypokalemia, which may aggravate the metabolic abnormality.20 A recently recognized effect of angiotensin II is its direct effect on cellular growth. Both vascular and cardiac tissue may respond

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to this hormone by hyperplasia or hypertrophy,21-23 which could be a key to the progressivechanges in ventricular function and progressivechangesin vascular impedancethat contribute to the natural history of the syndrome. PHARMACOLOGIC INTERVENTION IN HEART FAILURE

If these neurohormonal mechanisms are key to the vasoconstriction and increased impedance in heart failure, interventions that interfere with these vasoconstrictor mechanisms should have a salutary effect on left ventricular performance. This has certainly been the case with short-term administration of or-adrenoceptor blockers,24ACE inhibitors25,26and vasopressin antagonists.27The problem in the last decade has not been to demonstrate a favorable hemodynamic effect of the administration of these drugs, but to demonstrate that this hemodynamic benefit can be translated into a long-term clinical response. Variable effects have been noted in previoustrials in terms of the four major clinical manifestations of heart failure. Although an acute increase in cardiac output and decline in left ventricular filling pressure are hallmarks of the responseto vasodilator drugs,28 long-term improvement of left ventricular performance as manifested by a reduction in heart size or an increase in ejection fraction has been more difficult to demonstrate. In some of the ACE inhibitor trials29 and in the Veterans Administration Cooperative Study (VHeFT),30 which used hydralazine and isosorbide dinitrate therapy, a modest increasein ejection fraction could be demonstrated. Exercise tolerance has been difficult to quantitate becauseof the variabilities in protocol design and end points used in different studies. In some trials, particularly those of ACE inhibitors, an increase in peak exercise performance has been demonstrated.29,31J2 Relief of congestion and edemawould be clear manifestations of an improvement in the clinical syndrome of heart failure, but the useof diuretics in most clinical trials has clouded this evaluation. In most patients, diuretic therapy has continued to be required despite the administration of effective vasodilator or neurohormonal-inhibiting agents. Although ventricular premature beats are a common manifestation of the syndrome of heart failure, it is not yet clear whether their inhibition should be considered a favorable effect.33In most trials, it has been difficult to demonstrate that treatment has had a favorable effect on the frequency of premature beats, although some3* have demonstrated a reduction in premature beats in responseto ACE inhibitors. Effects on mortality, which is a more definitive end point, have beendemonstrated in two controlled trials. In V-HeFT,30 the group treated with hydralazine and isosorbide dinitrate in addition to digoxin and a diuretic demonstrateda lower mortality than patients given placebo in addition to digoxin and a diuretic. The reduction in mortality appearedto demonstrate for the first time that the natural history of the syndrome could be favorably influenced by interference with the vasoconstrictor mechanismspresent in the disease.The CONSENSUS triaP4 4D

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in northern Scandinavia of patients with more severe heart failure demonstrated a remarkable reduction in 6and 12-month mortality in patients given enalapril compared with those given placeboin addition to more traditional therapy. These two studies have been interpreted as showing the potential efficacy of an effective vasodilator regimen in patients with heart failure. Comparing thesestudiesis somewhathazardous,however,becausethe patient populations were so different and the treatments were not identical. Nonetheless, at 1 year after randomizationthe only interval that could be directly comparedin these two trials-the magnitudes of the reductionsin mortality were similar. Thus, one interpretation of thesefindings is that both regimens reducedthe impedanceto left ventricular ejection that was contributing to the increasedmortality and that either drug could be used to produce a favorable effect. An alternate hypothesis,however,is that the drugs actually act by different mechanismsand that the vasodilator effect of the hydralazine and isosorbide dinitrate is quite different from the overall cardiovascular effect of the ACE inhibitor and that the 2 interventions might even be additive in their effect if they had been studied in that way. The V-HeFT II trial is now comparing enalapril and hydralazine-isosorbidedinitrate therapy in patients with mild to moderate heart failure. An appropriate future study might be the comparisonof either one of theseagentswith the other addedto it in order to assesstheir combined efficacy. MECHANISM

OF DEATH

The mechanismof death in patients with heart failure hasbeenno lesscontroversial than the pathophysiologyof the syndrome. Sudden,apparently instantaneousdeath is a common occurrencein patients with heart failure and is usually attributed to a lethal ventricular arrhythmia. Although this is probably true in many cases,recent documentation35of the frequent occurrenceof electromechanical dissociation in the absenceof arrhythmias as a cause of instantaneousdeath has raised someconcernabout the mechanismin thesepatients. The mechanismsof death in the V-HeFT and CONSENSUS trials appearedto be different. In V-HeFT, 44%of the deathswerereported as occurring suddenly in the setting of clinical stability, with arrhythmia as a likely cause.In CONSENSUS, the frequency of sudden death was lower, probably becausethe patients had both severeheart failure and severepump dysfunction that most often manifested itself as pump failure. Thus, the CONSENSUS trial could demonstrateno reduction in the occurrenceof suddendeathin responseto enalapril, whereasV-HeFT demonstrateda reduction in suddendeath as well as pump failure death with hydralazine-isosorbide dinitrate treatment. The classification of mechanisms of death in heart failure and the potential differential effect of various treatments on the mechanism of death will probably remain controversialuntil the classification systemis more universally applied and until more data can be obtained on rhythms recorded at the time of apparent sudden death.

riate goals in the management of patients with heart failure: improvement in the quality of life and prolongation of life. The other end points often usedin clinical trials can only serveas surrogates for the two major treatment goals. Although such quantitative measurementsas hemodynamics and peak exercise performance are often used as surrogates for quality of life, it is apparent that in long-term efficacy studiesthesemay not provide an adequate assessmentof the patient’s state of well-being. Self-assessmentquestionnaires that addressquestions directly related to the heart failure syndrome may be more appropriate, but they are not yet adequately validated as indices of the quality of life.36-38Much effort has been expended on identifying factors that contribute to the risk of mortality in heart failure, and we may be approaching the time when surrogatesfor mortality might be available. In the meantime, however,there appearsto be no substitute for the measurementof the effect of treatment on mortality to assessits capacity to alter the natural history of the syndrome. The natural history of the syndrome of heart failure is now a primary focus of interest in worldwide investigations. It is apparent that the syndrome may progress in the absenceof new insults to the myocardium related to the etiology of the heart disease.The role of neurohormonal and other mechanismsin contributing to the hypertrophy and dilation of the left ventricle and the hypertrophy and constriction of the peripheral vasculature may be critical componentsin the progression. New insights into the role of angiotensinII and its interference by ACE inhibition in these tissue processesare urgently needed. As this new information accumulates, it may be possible to expand our understanding of the role of ACE inhibition on both the circulating and the tissue renin-angiotensin system.Other new agentswill be developedthat may interfere at different points in the renin-angiotensin cascade and in the other systemsthat control vascular tone and myocardial growth. In the meantime, however, physicianshave beenprovided with powerful pharmacologic tools to interfere with the symptomatology and probably the mortality in this complex clinical syndrome. In the other contributions to this symposium, we shall explore the present state of knowledge and future directions for our study of ACE inhibitors. 1. Cohn JN. Current therapy of the failing heart. Circulation 1988;78:1099 1107. 2. Chakko CS, Cheoyiade M. Ventricular arrhythmias in severe htxart failure: incidence, significance, and effectiveness of antiarrhythmia therapy. Am Heart J 1984; 107:896-901. 3. Cohn JN, Rector TS. Prognosis of congestive heart failure and predictors of mortality. An? J Cardiol 1988;62:25A-30A. 4. Thomas JA, Marks BH. Plasma norepinephrine in congcstivc heart failure. Aln J Car&o1 1978;41:233-243. 5. Levine TB, Francis GS, Goldsmith SR, Simon A, Cohn JN. Activity of the sympathetic nervous system and rcnin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982;49:1659 1666. 6. Hasking GJ, Esler MD, Jennings GL, Burton D, Johnson JA, Korner PI. Noqxncphrinc spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circu-

lation 1986;73:615 -621. 7. Lcimbach WN, Wallin G, Vuztor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intrancuronal recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73:913-919. 8. Francis GS, Benedict C, Johnstone D, Kislin P, Ncubcrg G, Kubo S, Hosking .I, Liang C-S, Yusuf S, and Investigators for Studies of Left Ventricular Dysfunction. Differences in neurohormonal activation in patients with left ventricular dysfunction (abstr). J Am Coil Cnrdiol 1989;12:246A. 9. Curtiss C, Cohn JN, Vrobel T, Franciosa JA. Role of the rain-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978;58:763-770. 10. Cody RJ, Laragh JH. The renin-angiotcnsin-aldo5terone system in chronic heart failure: pathophysiology and implications for treatment. In: Cohn JN, ed. Drug Treatment of Heart Failure. Secaucus: Advanced Therapeutic Communications, 198X:79-104. 11. Cody RJ, Atlas SA, Laragh JH, Kubo SH, Covit AB, Ryman KS, Shaknovich A, Pondolfino K, Clark C, Camsrgo MJF, Scarborough RM, Lcwicki JA. Atrial natriuretic factor in normal wbjccts and heart failure patients: plasma levels and renal hormonal and hemodynamic responses to peptide infusion. J Clin lnoest 1986;78:1362&1374. 12. Pruszcynski W, Vahanian A, Ardaillou R. Role of antidiuretic hormone in impaired water excretion in patients with congestive heart failure. J Clin Endo&no1 Metnb 1984;58:599-605. 13. Raine AEG, Erne P, Burg&x E, Muller FB, Bolli P, Burkart F, Buhlcr FR. Atrial natriuretic pcptide and atria1 prcssurc in patients with congestive heart failure. N Engl J Med 1986;315:533-537. 14. Mock JE, Finkclstein SM, Eaton .I, Hatfield G, Cohn JN. Vaaoconstrictor drug effects on vascular compliance by pulse contour analysis. IfiEE/&‘ng Med Biol Sot Proc 1987;9:878- 880. 15. Cody RJ, Kubo SH, Atlas SA, Laragh JH, Ryman KS, Shaknovich A. Direct demonstration of the vasodilator properties of atrial natriuretic factor in normal man and heart failure patients (abstr). C/in Res 1986;34:476A. 16. Cohn JN. Vasodilator therapy for heart failure: the influence of impedance of left ventricular performance. Circulation I973;48:5-8. 17. Bristow M, Gisburg R, Minobe W, Cubicciotti RS, Sageman WS, Luric K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and beta adrcnergic receotor densitv in failine human hearts. N End .I Med 1982;307:205-23 i ’ 18. Katz AM. Cardiomyopathy of overload. A major determinant of prognosis in congestive hart failure. N Engl J Med 1990;322:100~110. 19.Hollenberg NK. The role ofthe kidney in heart failure. In: Cohn JN, ed. Drug Treatment of Heart Failure. Sccaucus: Advanced Therapeutic Communications, 1988:79-104. 20. 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 I987;82:504-5 10. 21. Ceistcrfer AAT, Peach MJ, Owens GK. Angiotensin II inducts hypertrophy, not hyperplasia, of cultured rat aorticsmooth musclecclls. Circ Res 1988;62:749756. 22. Clozcl J-P, Kuhn H, Hefti F. Decrease of vascular hypertrophy in Foul different types of arteries in spontaneously hypertensive rats. /Im J Med 1989;87(suppl 6B):925-955. 23. Michel JB, Lattion AL, S&man JI., Ccrol M, Phillipe M, Camilier~ JP, Corvol P. Hormonal and cardiac effects of converting enzyme inhibition in rat myocardial infarction. Circ Res 3988;62;641&650. 24. Miller RR, Vismara LA, Williams DO, Amsterdam EA, Mason UT. Phalmacological mechanism for left ventricular unloading in clinical congestive heart failure: differential effects of nitroprusside, phcntolamine and nitroglycerin on cardiac function and peripheral circulation. Circ Res 1976;39:127. 133. 25. Levine TB, Franciosa JA, Cohn JN. Acute and long term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure. Circzhtion 1980;62:35-41. 26. Levine TB, Olivari MT, Garberg V, Sharkey SW, Cohn JN. Hcmodynamic and clinical response to enalapril, a long-acting converting-enzyme inhibitor, in patients with congestive heart failure. Circulation 1984;69:548-553. 27. Nicod P, Waeber B, Bussien JP, Coy JJ, Turini G, Nussberger J, Hofbauer KG, Brunner IHR. Acute hcmodynamic effects of a vascular antagonist of vasoprcssin in patients with congestive heart failure. Am J Cardiol 1985;55: 1043 1047. 28. Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure. N Cngl J A4ed 1977;297:27-3 1,254.-258. 29. Captopril Multiccnter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive heart failure. JAm Coil Cardiol 1983;2:755763. 30. Cohn .JN, Archibald DC;, Zieschc S, Franciosa .JA, tiarston WE, Tristam 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 vasodiiator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study (V-HeFT). N Engl JMed 1986;3 14, 1547-1552. 31. Lcier CV, Huss P, Magorxn RD, Unverferth DV. lmprovcd exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate

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therapy for congestive heart failure. Circulation 1983;67:817-822. 32. Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988;259:539-544. 33. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321: 386-388. 34. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-1435. 35. Luu M, Stephenson WG, Stevenson LW, Baron K, Walden J. Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation 1989;80:1675-1680. 36. Guyatt GH, Thompson PJ, Berman LB, Sullivan MJ, Townsend M, Jones NL, Pug&y SO. How should we measure function in patients with chronic heart and lung disease? J Chronic Dis 1985;38:517-524. 37. Rector TS, Francis GS, Cohn JN. Patient’s self-assessment of their congestive heart failure. Part 1. Patient perceived dysfunction and its poor coorelation with maximal exercise tests. Heart Failure 1987;3:192-196. 38. Rector TS, Kubu SK, Cohn JN. Patient’s self-assessment of their congestive heart failure. Part 2. Content, reliability and validity of a new measure, The Minnesota Living with Heart Failure Questionnaire. Heart Failure 1987:3:198% 209.

DISCUSSION Dr. Stephen Gottlieb (Baltimore, Maryland): In patients with heart failure whom I follow, I find it difficult to determine which patients die suddenly. It seemsto me that it is impossible in a multicenter study. Furthermore, there is a recent report that sudden death, which appears to be secondary to ventricular arrhythmias, often is not. Do our arbitrary definitions really reflect the mechanism of death? Dr. Jay Cdhn (Minneapolis, Minnesota): Certainly, the fact that patients may die suddenly with a normal sinus rhythm throughout the terminal episode has been well established.It is not uncommon for acute electromechanical dissociation to be a terminal event in patients with severeheart failure. But the general feeling is that, although lethal bradyarrhythmias and electromechanical dissociation do occur, ventricular fibrillation is probably more common. We do, of course, run the risk of including thesebradyarrhythmias and electromechanical dissociations in the sudden death group. Dr. Swedberg, do you want to comment on this? Dr. Karl Swedberg (Gothenburg, Sweden): Among the 118 patients who died in our study, most of the patients who had a cardiac death died becauseof progression of heart failure. However, when we studied the type of arrhythmias in these patients, the arrhythmias were very complex. Accordingly, the arrhythmias expressthe myocardial disease.I also think it is unwise to extrapolate the findings from these patients to those with milder forms of heart failure. Dr. Cohn: How confident are you that it was a progression of heart failure and not sudden death in the presenceof heart failure? Dr. Swedberg: I am quite confident, because there were patients who had improved and had left the hospital in most cases.For example, one patient had a clear improvementbut was found dead in the hospital lobby when leaving for home. Dr. Alan Hirsch (Boston, Massachusetts): Dr. Cohn, you have discussed the importance of the sympathetic

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nervous systemand the renin-angiotensin systemin heart failure pathophysiology. If suddendeath reduction is an important end point, can the efficacy of a pharmacologic intervention be judged by its effect on the pretreatment predictors of mortality? In other words, can treatment with hydralazine and a nitrate lower plasma catecholamine levels in a manner predictive of improved survival? Alternatively, doesthe magnitude by which ACE inhibi‘tors lower plasma angiotensin II concentrations predict improvement in the suddendeath rate in any population studied? Dr. Cohn: There is as yet no data adequateto address the effect on survival of a drug-induced changein predictors of survival. Dr. Swedberg: We made up a prediction scorebased on the combined neuroendocrineactivation, and it is clear that patients who had neuroendocrineactivation died asa result of the progression of heart failure. Dr. Cohn: Our original data that the very high norepinephrine levels were a predictor of progressivepump fail‘ure death, not of sudden death, would fit in with Dr. Swedberg’sdata. In fact, among the patients with normal or modestly elevated norepinephrine levels who died, it was more commonly suddendeath. So there is no support from the data that the sympathetic nervoussystemis an important factor in suddendeath, whereasit certainly is a marker for, or a risk factor in, pump failure death. Of course,the limiting factor in all thesestudiesis that we do not have the luxury of obtaining hormonal measurements at the time the patient dies. Dr. Gary Francis (Minneapolis, Minnesota): We have recently reviewed someretrospectivedata on norepinephrine; becausethey are retrospective,they are not particularly strong. We also found that patients who tended to have a progressive rise in norepinephrine over time are more likely to die of progressivepump failure, whereas patients who died suddenly tended to have a relative lack of increase in plasma norepinephrine over time. Participant: We should consider other neurohormones as well; angiotensin II itself might be directly arrhythmogenic. Dr. Francis: What we found with renin, not angiotensin II, was that renin levels seem to reflect the clinical status of the patient. When patients experiencedecompensation, renin levels rise sharply, and when they are better, the renin levels decrease. Dr. Cohn: One observation that we have made from the Veterans Administration Cooperative Study (VHeFT) results is that patients who are going to die suddenly do so most often within the first year after the diagnosis and start of treatment and that the risk of sudden death decreaseswith time. Of course,the risk of pump failure death increaseswith time. If the patient has not had a ventricular arrhythmia for a year, he or sheis unlikely to have the substrate for ventricular fibrillation, whereas pump failure is a progressivepattern. I am not sure how to incorporate that into our management scheme, but it may be an important observation.