IACC V01 . 19, No . ? I.," r .1"- . 603 5% Effect of Long-Terdn Enalapril Therapy on Cardiopulmonary Exercise Performance in Men With Mild Heart Failure and Previous Myocardial Infarction KENNETH DICKSTEIN, MD. STALE B.ARVIK, MD, TORBJORN AARSLAND, RN Stora"ge" Noro ..y Forty-one men with documented myocardial infarction >6 months previously were randomized to long-term (48 weeksi therapy with placebo or enalapril an a double-blind basis . All .-king concurrent therapy with digitalis and a patients were re diuretic drug for symptomatic heart lettuce (fundional class tl yr 111). The mean age was 64 t 7 .3 years and no patient suffered hum exerlional cheat pain. Patients underwent maximal. -din pulmonary exercise testing to exhaustion on an a gameler cycle nine times over the course of 48 weeks. Gas exchange data were rnlleeted no a heath by breach hails with use nr a ermtinumas ramp protocol. in the placebo group (n = 21), the mean It 50) peak oxygen consumption IVO3) al baseline it, IRS t 5.1 versus 18.5 ae 5 .5 mtlkg per min at 48 waeks (-I od%, p = NS). In the enamprrl group (n = 2u), the corresponding values were 18 .1 t 3.1 versus 18.3 ± 2 .6 mllkg per min (+2 .8%, p = NS) . The mean VOa at the Vasodilator therapy with angiotensin-converting enzyme inhibition has an established role in the management of symplxnalic congestive heart failure (1,2). Improvement in clinical status (3 .4), hemodynamics (5.61 and exercise performanm (7 .8) has been demonstrated . Therapy is associated with a reduction in the mortality rate associated with piogressive congestive heart failure in patients in New York Heart Association functional class IV (9) . However. the effect of long-term therapy eat the functional capacity of patients with mild heart failure has not been sufficiently addressed . Most trials (10) have included patients in functional classes 11 to IV with heterogeneous causes of failure and the sample size was usually too small to permit proper analysis of the subset with mild heart failure . Few trials 111) have included objective measurement of functional capacity . Evaluation of the functional capacity in patients with heart fail ire may be accomplished by assessment of perfor • anaerobic threshold for The placebo group at baseline study was 13 .1 t 1.5 versus 12 .6 t 2.1 mV kit per min at 48 weeks i-2.2%, p = N51 . The corresponding values for the enalapril group were 11 .8 t 23 versus 11 .8 ±2.4 mlkg per mini +1 .4% . p = NSt. The mean tetnlexercise duration In the placebo group at baseline study was 589 t 153 snout 620 ± 181 sat 48 weeks (+5.4%, p = NS). The corresponding values for the enalepril group were 614 t 119 versus 632 ± 120 s (+3.599, p = N'S) . There were no significant intergroup differences at any time VISa, V0i at the anaernbk threshold err eseecse duration. 1-snQ-term anginlensince nerting enzyme inhibition with enalapril in men with mild hart failure after myocardial irfarelirn was not associated with signi8ant improvement in peak or submaximal rardiopatmanary exercse peefermartce. (I Am Corl Cardiet 1991 ;18.. P1~6dA with regard In peak mane during exercise 112) . Cardiopulmonary exercise testing permits objective determination of peak oxygen consumption (V0,) (13) and VO 1 at the anaerobic threshold (14). This technique provides a sensitive tool for evaluating the effect of a therapeutic intervention on functional capacity (15) . Therapy with diuretic drugs (16), inetropic agents (17). vasodilators (18) and exercise training programs 119) has demonstrated improvement in peak VO, in patients with symptomatic heart failure. We tested the hypothesis that chronic angiotensinconverting enzyme inhibition would improve the cardiopulmonary exercise performance of patients with mild heart failure_ Forty-one men with documented myocardial infarction. requiring therapy with digitalis and a diuretic drug for symptomatic heart failure. were randomized to concomitant placebo or enalapril therapy . Patients underwent nine maximal cardiopulmonary exercise tests over the course of 48 weeks . From the Tardioto;y llwmon. Medical Depanmeel . Central Hospital in Roseland . Sta - anler. Norway . This study was supported by a grant tam. Methods Merck . Sharp A poame Research tabotatornes, west Point. Penrsylsania and MSD-ono- en . Norvoy. Manuscnpt received October 17 . 1990: revised nanmetipt received January 21 . 1991, accepted February 10. 1991, Add- for ,e vdols: Kenneth Dickstein, MD, Cardiology Division, Medical Ikpmment . Central 8ospital in ttogabod . Stavanger.4011 Norvay . 0195, by Studypalicnts. Forty-onemenwith deeumentedmyueardial infarction (>6 months before inclusion) and peak oxygen consumption (VO,) <25 mIkg per min were included in the study . Myocardial infarction was confirmed by conven- s nm.dco.,cv usg.nrCa<di5,1my Downloaded From: http://umbrella.onlinejacc.org/ on 06/09/2014 r,Tlr'r09alYI ta .5ln IACC Vat. Ix . No . 2 nun- ISNI - SW,_rA2 DICKSTEIN ET AL. ENALA!'HII. AND EXERCISE IN CONGESTIVE HEART FAILURE Cllrrical Chart tretrtlosaid Baseline Compamblhty of 41 P gents Trenmemcrn1p Tehk I . hgr 11> Syslalic BPI .. Hgl Dmsmlic HI'Imm 14g1 Bell heart rare lb,S111.ifl Plaeeh" yr-7r m . 17 79 14 Weight Ikgl Prom n,a MI Q .- Ml Angrier MI Peek CK Minn Prak ^.SAT IUlIiler Peak LDH NAiten Redingmphie hoots sir tuna, Echo UV ammeter IInml >Ia1 PIC'day 0 24 h EEL[ Peek VQ Imikg per mint AT V0, 1 .14g per mint Learning dcralian Ia1 R IVCOJVO, I 19 la 35x I aax 972 c ` - III) 194 907 129 EnelapnI 61, _ , 115 c 17 xl_< 79 I e xI I1 F Il C III • WK 291 e7 hi I 'Ih t -A5 1_'5 re n nbII 13 1 549 , 1,111 m I 1 .5 753 a l4 , Is Ig .1 _ 1 I II :-1s 1 • 119 12:1 = 11.10 Hale are rcprnted as mete- ` SD . A S.AT - arpartare em Iransrernae.AT VU, = osrgen onsepaon a, 1,e --b,, ih-Ud RP blood pressoro: CKH = creative knee, ECG = ttrrIn dmgrarr Echo = echocardiographic: LDH = lanalc dchydmgcnaac : LV = left rtinmalar. MI = myocardial in6vetion : PVC= premanre •enoxular comyeser . R rupiraory exchange ratio : VCO, = carbon dioxide elimvooion : VCI, _ oxygen consumpttan . lional clinical, electrocardiographic IECG) and biochemical criteria . The mean (s- SD) age was 64 - 7.3 years and re patient suffered from exertional chest pain . All patients were in sinus rhythm and concurrently treated with digitalis and a diuretic drug for symptomatic heart failure . No patient was receiving concurrent beta-adrenergic blacker therapy . Concurrent use of ant arrhythmic agents was permitted . : vc patients received quinidine and four received disopyramide . Fourteen patients were taking a long %cling %hole and fear a calcium channel blacker . Thiriy-six patients were in New York Heart Association functional class 11 and See were in class III . Approximately 5g patients were screened and 41 note included in the study . The screening process was selective in that patients with pvslinfarclian anpra or marked symptoms of congestive heart failure were not eligicle for screening . A detailed description of the clinical characteristics of the study group is provided in Table I No smtistically significant intergroup differences were found Study pratnenl. The screening exercise protocol was based on a conventional format with stepwise 25-W inerements at 3-min intervals . All further testing was based on a continuous ramp protocol . Only candidates able to perform exercise until exhaustion on the cycle ergometer were m . eluded . Patients with exertional chest pain . >0 .2 mV ST segment depression on the ECG or peak VO, >25 mltkg per min were excluded . Before inclusion, patients underwent routine spirometry to rule out clinically significant respira- 597 lore dysfunction . Informed consent was obtained from each patient and the study protocol was approved by the Regional Ethic% Committee at the University of Bergen and the Norwegian State Drug Regulatory Agency in January 1987 . Eligible patients were screened a minimum of 6 months after myocardial rotor tiort and randomized I week later . Uunng the run-in week, all patients underwent three maximal cardiopulmonary exercise tests (one screening and two baseline), chest X-ray study, echocardiographic examination and a 24-h ambulatory ECG . After randomization . patients underwent exereinc testing at 4 . R . 12. and 48 weeks. Dosage schedule . During a 1-week run-in period . all patients received single-blind placebo therapy . At randomization . patients were assigned to either enalapril 110 mg once daily) or matching placebo in a double-blind manner . After 4 weeks . in patients without symptomatic hypotensian or an arterial systolic pressure <90 mm Hg, the dose of enalapril was dtraIed to 20 mg once daily . Patients continued to receive the dosage of digitalis and diuretic drug prescribed bel'ore inclusion. Potassium supplementation was administerrxd according to the results of frequent biochemiaty evaluation . Concurrent therapy with antiarrhythmic agents was permitted . Exercise testing prctocol- Testing occurred approximately 2 h after a light meal and always between 2 and 6 h after ir-, ;ion of the test medication . The exact timing interval was not standardized, Studies were performed using an apriuril . electrically braked, cycle argameter (Mijnhardt model KEM 111). After a 2-min rest on the cycle, patients began pedaling at a rate of approximately (5 rpm at a work rate that was programmed to increase smoothly by 15 W/min according to a continuous ramp protocol . Purirrltr Irrere instracted iv coercion maximally to syrnprnrnnrir, cuJ paints . A modified Burg scale was employed to facihtatc communication with the patient with regard to symptoms . A 12-lend FCC (Kane 620) was interfaced and heart rate recorded continuously . Systolic blood pressure was measured with a manometer cuff every 3 min . Exrrrise and gas exchange data here collected continua (Firth• with an automated breath by breath system manufactared by sledical Graphics Cmpomdon (System 201111) based on methods previously described by Beaver et al . 1201 . In this system . a clamp is placed on the hose and the patient hreathes through a mouthpiece attached tea nonrebreathing valve . Air is removed from the valve at a constant rate of !75 mlimin and delivered to the oxygen and carbon dioxide analyzers. The method utilizes a distributive processing technique inv'olv'ing a waveform analyzer and a host eamputer . Expired flow, carbon dioxide and oxygen are measured with use of rapid responding discrete analyzers (a prteu motachometer and a variable reluctance pressure transducer for flow, a dual-beam infrared absorption chamber for carbon dioxide and a permanent zirconium oxide-based electrochemical cel! for oxygen . These instruments were caltbrated before every test with use of a standard 3-liter Downloaded From: http://umbrella.onlinejacc.org/ on 06/09/2014 598 Al FNALAPRII. AND I XI:RC'ISF IN CONGESTIVE HEART FAILURE Nn . 2 Aupmt199159fi-fi )' OI('85T FIN El IACC V.I . I8. Teble 2 . LaLorulory Results in 41 PJllenls Treatment Group Placeho Hemoglobin IFIlurl w'Iu 1111^'Incr/ PlAdd, I Ill' 1lerl CreutimnelmmaVlnhl ASAT ILTiterl Al AT IL .28*1 (,t otr ImmoI hIeo Chnlesteml found liter) 'Inglycerides ImmoPlherl Grit ntid Immorinty Salwmlmmolihlcn n l',, jam Immnlnilcrl Chlor & Immnhlnol 11a1o aw reported as ratan ,ohm, mhrraShr*' jinn, gain Tahlc I Endopril W,;? , Bmelint 14.7 ] 1 .2 14 .5 t 0.5 49 a 1 .1 Bu.Seline 14.1 _ 0 .9 hR a 1 .1 48 '41 23G r 71 III 11 39 59 57 115 S 9 ± 1 .1 hI a, e'-2 34 39 A1 -91 S .7 * I .^- 6,9 z 1 .5 _ 405 m its 1411 4 .1 2 0.4 IIMI_'_ SO. AI . AT syringe and precision reference gases and were corrected for barometric pressure, ambient temperature and humidity . Exercise end points . Total exercise duration was recorded from the start of exercise to the point where the patient was unable to maintain a constant pedaling rate . Peak VO, was calculated as the average VO, value over the final 20-s period of exercise. A eanrpurerized algaralan Iran developed to approximate the manual modified V slope method of anaerobic threshold detection (21 .22). With this algorithm . carbon dioxide elimination (VCO,) is plotted against VO, on equal axes . The anaerobic threshold is located where the rate of rise of VCO, is greater than the rate of rise of VO, . coinciding with an increase in the slope of >1 . This increase in the slope results from accelerating VCO, and indicates that bicarbonate buff. ering of lactate is occurring (23). We (24) have demonstrated that this technique is rrpruducible and corresponds well to the lactate threshold . The manual method employs a 45' triangle that is brought in from the right, parallel to the VCO, versus VO, plot . This facilitates detection of the inflection occurring with a slope >1 . The computer program (22) automates this method and analyzes the subset of the plot with a work rate >5 W and a respiratory exchange ratio <I . This subset of data was chosen to minimize the obscuring effects of the hvperventiIRIiun response at the onset of exercise and the respiratory compensation that usually occmsjust before termination of peak exercise. A line with a dupe of 1 (S I) is drawn through the plot so that 5% of the data points lie below the line . The ventilatory anaerobic threshold is detected at the last inflection of the VCO, versus VO, curve from S1 . Statistical methods. Nonparametric statistical methods were used to analyze continuous variables . Before treatment . the rank-sum lest was used to compare the treatment groups and the signed-rank test was used to test intragroup h .9 a L7 48 239 ` m 105 . 14 24 * 7 18 17 SS 1 .1 72 a I .] M1.9 z 1 .7 23 . Lh 2.4 0 1 .9 424 ± 91 108 ± 1 :4 139U'_ 41 *_ 0.1 4.9 `_ III 11x3 91) ' 3 olanine ommn Imn,rcmac' WRC = while hlnod week, 14 .8 4 i .1 h .5 0 L4 229 2 45 106 x IS 24 r 6 '23 8 5 .5 1 7 .3 2 1 .1 2 .1 x L2 409 r. 128 141 _ 4 .30. '_ 4 99 '_ 3 cell mon1 ; changes from pretreatment values . Differences between the treatment groups with respect to changes from pretreatment in continuous variables were tested by using nonparametric analysis of covariance models . After rank transformation of the dependent variable, ordinary parametric analysis of a covariance model was employed . Fisher's exact test was used to compare the treatment groups with respect to dichotomous variables • such as the presence or absence of a specific adverse experience or a physical examination abnormality . The Wilcoxon rank-sum test was used to compare treatment groups with respect to ordinal variables . All values are reported as mean values y SD. Efficacy analyses for each time period were based on the per-protocol approach . Only patients with data both at baseline study and at the specified time were included . The second of the two baseline tests was used for all analyses to assure familiarity with the testing procedure and minimize training effect . Although the data were analyzed for each separate test during the trial, no formal adjustment to the p values for these multiple comparisons was made . This fact should be taken into account when interpreting the results Results Patient group characteristics and exercise performance (Tables t and 2) . The groups were found to be comparable at baseline study with regard to clinical characteristics and exercise performance (Table 1) . The exercise variables were reproducible . The mean peak oxygen consumption (V0) in the first baseline test was 18 .4 '_ 4 .4 versus 18 .7 '_ 4 .6 mllkg per min in the second baseline test. The mean difference of the change between baseline tests was 0 .29 mllkg per min with an SD of . 1 .65 and a Spearman correlation coefficient of o.91 . Downloaded From: http://umbrella.onlinejacc.org/ on 06/09/2014 1)ICKSTEIN ET AL . I-Ski :AYnlLANI)I .ki .nitNEINCONGESTIVEHt'ARTFAILCRE WC VA . IS. Nn Aug-11 . : :WI, nit Tahk 3- Exercnc Result, in 41 Polienls 11 v-k . 1 Yeak VU .Imrkp per min . Ylacebn Enalapril Vu; w AT Iml kg no mini INS - S' IN I - I I IN .lr1 .1 IN .I I niRvcimv' 1 I A c IIk • t 4 - 1 4 nutalion Il l Ylncchu Sd9 ' ft 1511 • iCl .sI ILrninpnl hll - II'1 .I' - I_'ll 1 ~Ic FIr.IV I nlncren« • , repwred as m- vahc, airnlnlrd 599 mom „~I~~mpnernl ~h.,E,, . trio 5i1) p - . vS In, .II s :si15 Ihnshold . Nlher athre5raauu, m in 1,hi, A1 . nn,ern1 I . Norm peak oxygen consumption NO .) (--SDI for 21 Ilacehu ( reated tupen drelesl and 20 enalapril-troatod Irlosod circles) paticms over II weeks . Swum A1141 patients completed the study as per protocol. There was one death due to recurrent myocardial infarction in the placebo group ; no deaths occurred in the enalapril group . The study was discontinued in three patients, all receiving placebo . because of possible drug-related adverse experiences . The average dose of enalapril was 18 .75 mg . No significant intergroup differences were observed during the trial with regard to overall evaluation or functional class . At baseline study . 36of the 41 patients were in New York Heart Association functional class 11 and 5 were in class 111 . At 48 weeks, 37 patients were in class 11 and 3 were in clal' 111 . There were no significant differences in body weight or rest heart rate between the placebo and enalapril groups during the study. Peak heart rate for the placebo group was 135 - 14 beatsanin at baseline compared with 132 x 14 bealstmin a148 weeks. In the enalapril group. peak heart rate was 139 ± 16 at baseline versus 139 - 211 beats/min at 48 weeks. Systolic blood pressure increased by 7 .7- 15 mm Hg in the placebo group and decreased by 3 .2 x 19 mm Hg in the eaalaprrl group Ip : 0.011 . There were no significant differences between groups with regard to any of the laboratory' variables measured during the course of the study . Specifically . serum creatinine and serum potassium showed no significantintragroup change (Table 2tPrakandsubmavlmnlexerclceperformance Table 3i . Nu statistically significant differences were Found between the placebo and enalapril groups at any time with regard to peak nr suhmaximal exercise performance variables . The peak respiratory exchange ratioIVCQ/VQl was 1 .2 s 0.15 in the placebo group and 12 - 0.08 in the enalapril group . This confirms that effort was both adequate and comparable- In the placebo group . the mean peak VO_ at baseline was 111 .8 ± 5.2 compared with 18 .' 5 .5 mhkg per min at 48 weeks I-1 .415 . p = NS) . In the enalapril group, the corresponding values were 18 .1 . 3 .t compared with 18.3 - 2 .6 ml/kg per min 102 .815 .p =NSI(Fig .II. The mean VO, at the anaerobic threshold for the placebo group at baseline was 13 .1 ` 3.5 versus 12 .8 ' 2 .1 mhkg per min at 48 weeks p -= NSI . The eonespon''ing values for the enalapril group were 11 .8 - 2 .3 versus 11 .8 - '_A mhkg per mini-1 .49 . p - NS) IFig . 21. The mean total exercise duration in the placebo group at baseline was 589 ± 153 census 620 - 181 sat 48 weeks 1+5 .49., p - NS) . The currespundil .g values for the enalapril group were 614 ± 119 versus 632 - 120 s (r3 .5Y . P - NS) (Fig. 3) . Discussion Role of renin-angiolensin system in heart failure. Excessive vascular resistance is characteristic of patients with reduced functional capacity due to inadequate delivery of blood to exercising tissues (25) . The renin-angiotensin system is mar' wily activated during both moderate and strena s exercise in patients with mild heart failure 126) . This is especially true fur patients on long-term diuretic therapy 1171 . Specifically . the angiotensin II response at peak escrow is particularly great in relation to the renin increase . This response may be due to either increased production or decreased degradation 1281 and may contribute substantially Finite 1. Pleas csyur eoosaniplioim VI),) ai thu anaerobic thrush' old Is5D1 Per 21 placebo-Ireated (open circles) and 20 enaletpriltrected 111 61 patients aver 48 weeks . 30 1 s 0 Downloaded From: http://umbrella.onlinejacc.org/ on 06/09/2014 Weeks U[CKSTFIN FT AI.L nNALAPRIL AND EXERCISE IN CONGESTIVE HEART FAILURE 000 840 reo 720 ado ego 540 4t0 420 jag 300 0 4 a 12 24 as 48 WeBM. csero iw durxr1nn (±Sn) for 21 20 enalapril-booted Nosed eiedesI Figure 3 . Moon told tapencirrkd and weeks . placebo-vealrd patients aver46 to the attenuated vasudilatur reserve in skeletal muscle observed to patients with heart failure (29,30) . Angiotensinconverting enzyme inhibition may partially correct this pathophysiologic response (31) . improve vasodilator capacity (32) and increase muscle blood flow (331 . In addition, long-term therapy has been shown to reduce the marked increase in adrenergic tone that accompanies exercise in these patients and further compromises tissue perfusion 1341 . We therefore hypothesized that long-term angiotensinconvening enzyme inhibition might improve the ability of skeletal muscle to extract oxygen at peak exercise and delay the onset of anaerohinxis . Effect of enalapril on exercise performance in mild versus severe heart failure, We were unable to detect any dilfercnces between the effects of enalapril and placebo on the peak or submarimal cardiopulmonary exercise performance of men with mild heart failure after myocardial infarction . This trial was not designed to evaluate the effects of longterm angiulensin-convening enzyme inhibition during the acute or convalescent phase . We chose to limit the study group to patients with confirmed myocardial infarction 6 months previously to obtain a relatively homogeneous group of patients and minimize the contribution of deconditioning to exercise impairment . Appropriate interprekation of the results requires a careful analysis of the study group . All patients were symptomatic (functional class Il or 111) and in sinus rhythm . Patients were judged to be clinically stable before inclusiu0 on their current dosage of digitalis and a diuretic drug . No formal attempt to withdraw these agents in order to establish their necessity was included in the screening procedure. It is therefore likely that some of the patients did not require diuretic therapy to prevent symptoms of congestive heart failure . The mean ecltocardiagraphic internal' dimensions indicate left venlrictdar dilation and imply systolic dss(unrrion . However, information regarding ejection fraction was not available . At the screening echocardiographic examination, JACC Vol. 18, No. 2 August 1491 :596-d 2 28 patients were classified as having a moderate left ventricular wall motion abnormality and 13 patients were found to have a severe wall motion abnormality . Although patients had a peak oxygen consumption (VO,) of < 25 mlikg per min on inclusion in the study, the baseline mean peak VO, values (18 .8 . 1 2 mtlkg per min in the placebo group and 18.1 t 3 .1 mllkg per min in the enalapril group) indicate only mildly reduced exercise capacity. It is likely that these ratients were well compensated hemodynamically with only mild left ventricular dysfunction . The sample size did not permit prospective subset analysis according to infarct type or location . Thirty-six of the 41 patients had a Q wave infarction and 24 had an anterior infarction. Convincing evidence (35.35) exists confirming symptomatic and functional improvement in patients with functional class III or IV heart failure treated with angiotensinconvetting enzyme inhibi .ors . However, the evidence in patients with mild heart failure is insufficient to permit routine use of these agents. Several trials (3,16,37,38) have demonstrated improved exercise performance in patients with mild to moderate heart failure . A few studies (8,39) have demonstrated improvement in patients with a peak VO, comparable with values observed at baseline study in our trial . Maximal cardiopulmonary exercise testing . This method is safe, noninvasive and has been shown to be a valuable tool in the clinical assessment of functional capacity (II) and prognosis (40) . It is our experience that peak effort can be more readily achieved in male subjects and therefore only men were included in this trial . We limited the study group to patients with confirmed myocardial infarction to obtain a homogeneous group of paskItts and to permit better definition of the clinical implications of the results . It has been demonstrated that peak oxygen consumption can be reliably achieved in patients with coronary artery disease (41) and we (42) have shown that the results are highly reproducible in such patients. Ventricular function and exercise performance. Thu lvngterm hemodynamic response to angiotensim-converting enzyme inhibition cannot he reliably predicted `ron, the initial short-term response (43) or from the baseline hemodyvem [441 or neurohumoral status (45) . Noninvasive and angio. graphic measurements of ventricular performance fail to predict exercise performance (25) . Exercise capacity in the presence of a low ejection fraction may be preserved by the augmentation of stroke volume by elevated filling pressure, preserved chronotroptc competence and increased oxygen extraction by skeletal muscle (46). Objective measurement of functional capacity requires assessment of the appropriate physiologic variable, namely, oxygen uptake . Although peak exercise results are readily determined, controversy exists regarding the most appropriate method for assessing submarimal exercise variables (47) . Progressive lactate accumulation reflects anaerobic glycolysis with increased conversion of pyruvate to lactate (48). The deflec- Downloaded From: http://umbrella.onlinejacc.org/ on 06/09/2014 Ia . No. 2 Aupu,t iv91 :5%-fiat [ACC Vu1 . E NArAPrtIL AND P lions in the respiratory exchange ratio IVCO,dVO.l ]ureely reflect the bicarbonate buffering of lactic acid (49) . The method chosen for anaerobic threshold analysis in this trial is based on the underlying physiology with detection of the increase in carbon dioxide elimination (VCO,) as a function of V0, 130) . This method has been validated against the lactate threshold with use of conventional le :hniyues 1711 . '[here was no significant intergoup difference in exercise performance observed at any rime during the course in this trial in patien€% with mild but syruplomate congestive heart failure . Despite repeated lestingand increa* - an familiarity with the test procedure, neither placebo nor active therapy resulted in increased peak VO,, increased 0, at the anaerobic threshold or increased exercise duration compared with baseline values, Not all trials 151 .521 of angioteasin-eoneerting enzyme inhibition in patients with mild congestive heart failure have demonstrated improved exercise performance . The clinical importance of apparently negative results is obvious 153) . Further investigation is required to more correctly profile patients likely to benefit from such intervention (541 . Comparison with previous studies . Attention has recently focused on this issue. In a study 1551 of asymptomatic patients with an ejection fraction "'SS5 randomized to eaptopril or placebo therapy in the early convalescent stage after acute anterior myocardial infarction, a difference of 44% in total exercise duration was observed between patients treated with active drug versus placebo . This improvement on therapy was observed only in the subset of patients with increased left ventricular volumes and severe wall motion abnormalities . As expected . the degree of activation of the renin-angiotensin-aldosterne system in these patients was correlated with the presence of loop diuretic therapy . However, this neurohurnoral activation was also correlated with the presence of Killip class >2 . >30`1 left ventricular wall akinesia and left ventricular aneurysm 156) . Similarly . the baseline neurohumoral data from the Studies of Left Ventricular Dysfunction ISOLVDI 1571 indicate that although neurohumoral activation occurs early in asymptomatic patients with an ejection traction <35rir (prevention arm). this is primarily limited to activation of the sympathetic nervous system and the release of atria) nairiuretic factor and arginine vasupressin . The renin-angintensin-aldosterone system becomes active at a later stage and only when symptomatic heart failure is established . especially in the presence of diuretic therapy (Ireatment arm) . Our data arc compatible with these recent findings . Only 13 of our patients had echocardiographic evidence of severe left ventricular dysfunction . The mean peak VO, values at baseline were only 2 miikg per min less than the mean peak VO, values at baseline in the SOLVD prevention arm 15A t . It is likely . therefore . that very few patients in our study had substantial activation of the renin-angiotensin-aldosterone system . Clinical implications . Is a therapeutic trial with angiotensin-converting enzyme inhibition appropnatc in patients with mild heart failure (591 1 Our trial addresses this issue . v EXCISE DICKSTEIN ET AL. IN CONGESTIVE HFART FAILURE 601 All of uur patients had documented myocardial infarction and were being treated for symptomatic heart failure . All patients completed the trial per protocol . Nine tests over the course of 48 weeks increased the power of detecting a treatment effect . The high peak respiratory exchange ratios confirmed peak effort . The gas exchange studies were perhuntedith rigorous detail 122 .24 .421. The mean peak VO, values indicated mildly reduced exercise capacity compatible with functional class 11 (H)I . J he results of this trial suggest that long-term angiotensin-converting enzyme inhibition will not improve peak or suhmaximal exercise variables in men with mildly reduced exercise capacity after myocardial inlirctian . Further attem (lon should be directed toward evaluating the efficacy of angiotensin-convr_ ;titlg enzyme inhibition in patients with moderately reduced exercise performance in an attempt to correctly profile patients likely to respond favorably . we truthfully aeknnn9edge Steven Snapinn . PhD. 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