6. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative repro- 9. James TN. Normal and abnormal consequences of apoptosis in the human ducibility and validity of systems for assessing cardiovascular functional heart. From postnatal morphogenesis to paroxysmal arrhythmias. Circulation class; advantages of a new specific activity scale. Circularion 1981;64: 1994;90:556-573. 1227-1234. 10. Sasse S, Brand NJ, Kyprianou P, Dhoot GK, Wade R, Arai M, Peria- 7. Soufer R, WohIgelernter D, Vita NA, Amuchestegui M, Sostman D, Berger samy M, Yacoub MH, Barton PJ. Troponin I gene expression during human HJ, Zaret BL. Intact systolic left ventricular function in clinical congestive heart cardiac development and in end-stage heart failure. Circ Res 1993;72: failure. Am J Cardiol 1985;55:1032-1036. 932-938. 8. Missov E, Calzolari C, Pau B. High circulating levels of cardiac Troponin I 11. Cummins B, Auckland ML, Cumtnins P. Cardiac-specific Troponin-I ra- in human congestive heart failure (abstr). J Am CON Cardiol 1996;27 (Suppl dioimmunoassay in the diagnosis of acute myocardial infarction. Am Heart J A):338A. 1987;113:1333-1344.

Effect of Reduced Muscle Bulk on the Ventilatory Response to Exercise in Chronic Congestive

Heart Failure Secondary to Idiopathic Dilated and lschemic Cardiomyopathy

Derek Harrington, MB, Andrew L. Clark, MD, Tuan Peng Chua, MD, Stefan D. Anker, MD,

Philip A. Poole-Wilson, MD, and Andrew J.S. Coats, DM

TABLE I Patient Characteristics

LVEF

Age (yd Diagnosis IW

67 67 67 52 59 52

Peak VO, ACE Inhibitor

(ml/min/kg) (X dose/day] Diuretic*

CAD 27 23.2 ElOxl 40 CAD 41 19.5 E5x 1 120 CAD 34 15.8 c5ox3 80 IDC 18 35.6 C 12.5 x 3 160 CAD 29 19.9 E20x 1 40 IDC 33 27.8 ElOxl 160 CAD 12 19.5 ElOxl 40 CAD 9 28 csox2 80 IDC 25 31.3 ElOxl 40 IDC 16 19.2 E20x 1 40 IDC 15 22.7 110x 1 40 IDC 20 21.8 C 6.25 x 3 40

P atients with chronic congestive heart failure (CHF) suffer from

the sensation of breathlessness, and as a consequence a reduced exercise tolerance. As in normal persons, the patients’ ventilation (VE) is closely associated with the rate of carbon dioxide production (7irCO,), so that the relation between \iE and \iCO, is a near straight line. For a given VC02, however, patients with CHF ventilate at 3 higher level; the slope of the VENCO;! regression line is thus steeper.‘** It has been suggested

62 56

53 55 67 62

*Diuretic dose is frusemide or frusemide equivalent (1 mg bum&amide equivalent to 40 mg of frusem- ide).

ACE = ongiotensin-converting enzyme; C = captopril; CAD = coronary artery disease; E = enalapril; IDC = idiopathic dilated cardiomyopathy; L = lisinopril; LVEF = I e ventricular ejection fraction. h

that increased dead space ventila- tion underlies this inefficency.394-6 An alternative explanation is that a non-CO2 stimulus to ventilation ex- ists, the close association between VE and VCO, . being maintained simply because VC02 passively follows \iE. Skele- tal muscle abnormalities have been well documented in CHF,‘,’ and it has been proposed that these intrin- sic changes contribute to the muscular fatigue that patients often have.’ We have recently demonstrated no difference in clinical and exercise characteristics in patients limited by breathlessness or fatigue.” It is thus possible that the same mechanisms are re- sponsible for the generation of both symptoms, and a muscle signal might reflexly drive ventilation dur- ing exercise. We sought to examine this hypothesis by evaluating the ventilatory response to exercise in CHF while exercising different muscle groups.

. . . We studied 12 patients (all men, mean age 60 +

2 [mean + SEMI years, and radio nucleotide left ventricular ejection fraction 24 2 3%). All patients had been stable for the preceding 3 months, with no alterations in their medication. All were taking an- giotensin-converting enzyme inhibitors. They un- derwent optimal diuresis with no residual peripheral or pulmonary edema. Clinical data are summarized in Table I. Subjects undertook bicycle exercise in 3- minute incremental stages using either their arms, both legs, or 1 leg on a manually adjusted mechan- ically braked cycle (Professional ergometer, Tunturi, Piispanristi, Finland). The stages began with un- loaded exercise and increased every 3 minutes in 25- W stages. Subjects were asked to exercise to their maximum at 50 rpm. During the arm test, the posi- tion of the cycle was adjusted so that body posture was the same as that used for the leg tests. Exercise tests were performed in random order over 2 con- secutive days, each test being separated by at least 4

From the Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London, United Kingdom. Dr. Coat’s address is: Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, United Kingdom. Manuscript received Sep tember 24, 1996; revised manuscript received and accepted March

3, 1997.

90 0 1997 by Excerpto Medica, Inc. 0002-9149/97/s 17.00 All rights reserved. PII SOOO2-9149(97)00293-2

hours. Patients were asked to take their usual medi- cation on the morning of the test. During exercise, subjects breathed through a mouthpiece and a l-way valve attached to a mass spectrometer (Amis 2000 system, Innovision, Odense, Denmark). This al- lowed on-line measurement of metabolic gas exchange and ventilation every 10 seconds using a standard inert gas dilution technique. All patients gave informed consent to the tests, which had been approved by the local ethics committee.

The least-squares method was used to calculate the linear regression coefficient for the relationship between VE and VC02. Comparisons of variables were made using analysis of variance for repeated measures. When significant differences were de- tected, comparisons were made using paired Stu- dent’s t tests. Results are presented as mean + SEM.

All subjects completed the 3 exercise tests with- out complication. Exercise times differed depending on the mode of exercise. Two-legged exercise lasted significantly longer than l-legged exercise, which it- self tended to last longer than arm exercise (794 +- 49 vs 576 + 26 vs 521 2 42 seconds, respectively). A similar respiratory exchange ratio was reached at peak exercise in all modes, suggesting similar levels of metabolic stress on the exercising muscle at max- imal exercise in all groups (Tables II and III). There were no significant differences in pulse or blood pressure at rest between tests. The differences in pulse and blood pressure observed at peak exercise are listed in Table II. Peak pulse rate was higher in 2-legged than l-legged exercise. Diastolic blood pressure was lower in both forms of leg exercise, although this difference was only a trend when com- paring l-legged exercise with arm exercise. Peak ox- ygen consumption (VO,) was higher in 2-legged ex- ercise than either l-legged or arm exercise (20.9 +- 1.7 vs 17.3 t 1.6 vs 16.6 & 1.7 ml/min/kg, respec- tively), whereas there was no difference in peak VO, when comparing arm exercise with 1 -legged exercise (Table III).

The VE/VCO, slope was significantly lower in 2- and l-legged exercise than arm exercise. This slope tended also to be higher in l-legged than in 2-legged exercise (31.6 t 2.4 vs 33.4 + 2.5 vs 37.5 + 2.7, respectively) (Table III and Figures 1 and 2). These differences were also present if the VEp\jC02 slope was calculated using only data obtained before to the anaerobic threshold (30.1 2 2.6 vs 32.1 + 2.8 vs 36.3 + 3.1, respectively; p co.01 arms vs 2 and 1 leg; p co.05 2 vs 1 leg). At rest there were no sig- nificant differences in end-tidal CO;?, VC02, VOz, or VE. At peak exercise end-tidal CO2 and VC02 were higher in 2-legged exercise than in arm and 1 -legged exercise, whereas there were no differences between l-legged and arm exercise (Table IV). There was no significant difference in VE at peak exercise between the 3 modes of exercise.

. . . If the primary stimulus to ventilation in CHF is

CO, production, then one would expect the relation between the 2 to remain constant in the different

TABLE II Pulse and Blood Pressure Data After Exercise

Peak Peak Exercise Systolic Diastolic

Time (set) Peak Pulse BP BP

Two legs 794 k A9* 143 + lo+ 143 +9 72 2 4t One leg 576 ? 26 135t 11 142t9 75 ” 5

Arms 520 2 42 139 +- 10 137k8 82 2 5

*p <O.OOOl 2 versus 1 leg and arms; ‘p <O.Ol 2 versus 1 leg; (p <O.Ol 2

legs versus arlns. Values ore expressed c15 mean 2 SEM. BP = blood pressure.

TABLE III Gas Exchange Data

Peak i/O, i/E/i/CO* R at Peak (ml/min/kg) Slope Exercise

Two legs 20.9 2 1.7* 31.6 2 2.4+$ 1.1 IO.05

One leg 17.3 2 1.6 33.4 f 2.5+ 1.07 + 0.03

Arms 16.6 + 1.7 37.5 k 2.7 1.05 -+ 0.03

l p <O.OOl 2 legs versus arms and 1 leg; ‘p <O.Ol 2 legs versus arms and 1 leg versus arms; tp = 0.09 2 versus 1 leg.

Values are expressed OS meon t SEM. R = respiratory exchange ratio; \jE = ventilation.

FIGURE 1. vE/kOz slope with different modes of exercise. Error bars indicate SEM. ‘p = 0.09 1 versus 2 leg exercise; **p <O.Ol arms versus 2- and 1 -leg exercise.

modes of exercise. In contrast, we have observed an acute change in the VE/VCO, slope depending on the muscle group exercising. Because it is unlikely that a patient’s ventilatory response to CO, is depen- dent on the source of that COz, the reason for the observed difference is probably a stimulus to venti-

BRIEF REPORTS 91

0 2 leg l Arms

45.0

39.6

35.5

0.3 0.5 0.7 0.9

CC02 (Urnin)

FIGURE 2. Ventilator resaonses to exercise usina different muscle groups in an indi- vidual patient. S ’

at peak arm exercise end tidal CO, decreased, while during 2-legged exercise it increased. These changes are reflected in changes in the VE/ VC02 slope.

The influence of lactate as an in- dependent drive for ventilation needs to be considered. Previous workers have demonstrated that in normal persons arm exercise is as- sociated with a lower anaerobic threshold.” This .could explain a higher overall VE/VC02 slope. However the differences are present from the outset of exercise and are actually more marked if only data obtained before the anaerobic threshold are used to calculate the VE/VCO* slope.

The commonly quoted explana- tion for the increase in the VEI VCO, slope in CHF is that of re- duced pulmonary perfusion relative to ventilation due to right ventricu- lar dysfunction.3*4-6 This would cause a ventilation-perfusion mis- match. If, in a patient with CHF, a

TABLE IV Gas Exchange Data at Peak Exercise

ETC02 i/CO? i/E

Two legs 5.3 k 0.24* 1.87 k 0.2’ 59.3 t A.4

One leg 4.86 2 0.22 1.5 + 0.17’ 51.9 + 3.6 Arms 4.76 _t 0.18 1.46 k 0.18 53.8 _’ 5.4

l p <O.Ol 2 versus 1 leg and arms; ‘p <O.OOl 2 verws I leg and arms. ETC02 = end-tidal carbon dioxide; other abbreviations CIS in Table III.

lation that reflects the relatively greater metabolic stress on the smaller bulk of exercising muscle. This stimulus must be independent of COZ delivery to the lungs. Because the difference in slope also depends on the muscle group exercising, it is also probable that this stimulus originates in the exercising muscle and is specific to that muscle, reflecting the relative amount of metabolic disturbance in that muscle. If the strength of the ventilatory signal depends on the workload, then smaller muscle groups performing the same external workload should generate the same ventilatory response. If, however, the ventilator-y re- sponse reflects the relative workload per unit muscle, then there would be a stronger signal and thus a greater respiratory response when exercising un- usually small muscle groups. We have previously documented this in normal persons.” In this study we observed similar results with a strong trend to- ward an increased VENCO* slope with single leg exercise compared with 2-legged exercise and a sig- nificant increase during arm exercise. If exercise with a smaller muscle bulk produces a greater stim- ulus to ventilation, this should result in a greater de- crease in arterial CO*. Although we did not measure arterial CO1 in this experiment, we did observe that

92 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 80

smaller muscle bulk is exercised, limiting right ven- tricular function is less likely to be reached and the VE/\;I’CO* slope should thus become less. We ob- served the opposite in our study because arm exer- cise with the smallest muscle bulk lead to the highest VENCO, slope. We have demonstrated that chang- ing the type of the exercising muscle can alter the ventilatory response to exercise. It is thus possible that changes in the leg muscles occurring as a part of the syndrome of CHF may also alter the ventila- tory response to exercise.

Skeletal muscle in CHF is abnormal. Function is impaired, and there is a loss of muscle bulk,13 and increased fatigue. I4315 strated weakness.14

Some groups have demon- Underlying these functional def-

icits, histologic changes have been documented, type II fibers are increased, and there appears to be a re- duction in oxidative capacity,14J6J7 with early onset of anaerobic metabolism during exercise.

This study has not considered the mechanism by which muscle may influence ventilation, although a stimulus dependent on the degree of metabolic stress experienced by the muscle seems likely. The pres- ence of the muscle metaboreflex (or ergoreflex) and its ability to stimulate ventilation has been recog- nized.‘8,19 More recently, it has been demonstrated that this reflex is increased in CHF, and that it may be reduced by local training.*’ Such a reflex could be the link between abnormal skeletal muscle and abnormal ventilation in CHF.

This study demonstrates that in CHF, altering the amount and type of the exercising muscle can change the ventilatory response to exercise. Signals emanat-

JUlY 1, 1997

ing from skeletal muscle may contribute to the ab- normal ventilatory response to exercise seen in CJ3F.

1. Fink LI, Wilson JR, Ferraro N. Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am J Curdiol 1986;57:249-253. 2. Buller NP, Poole-Wilson PA. Mechanism of the increased ventilatory re- sponse to exercise in patients with chronic heart failure. Br Heart J 1990;63:281-283,

3. Sulhvan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemody- namic and pulmonary abnormalities. Circulation 1988;77:552-559. 4. Rabin SA, Brown HV, Swan HJC. Arterial oxygenation and arterial oxygen transport in chronic myocardial failure at rest, during exercise and after hy- draladne treatment. Circulution 1982;66;143- 148. 5. Rajfer SA, Nemanich JW, Shurman AJ, Rossen JD. Metabolic responses to exercise in patients with heart failure. Circulution 1987;76(suppl VI):VI-46IV- 53. 6. Banning AP, Lewis NP, Elborn IS, Hall RJC. Exercise ventilation after bal- loon dilation of the mitral valve. Br Heart J 1995;73:386-389. 7. Minotti JR, Christoph I, Massie BM. Skeletal muscle function, morphology and metabolism in patients with congestive heart failure. Chesf 1992;lOl (suppl):333S-338s. 8. Wilson JR. Exercise intolerance in heart failure importance of skeletal mus- cle. Circulation 1995;91:559-561. 9. Wilson JR, Man&i DM, Dunkman WB. Exertional fatigue due to skeletal muscle dysfunction in patients with heart failure. Circulation 1993;87:470-475. IO. Clark AL, Sparrow JL, Coats AJS. Muscle fatigue and dyspnoea in chronic heart failure: two sides of the same coin? Eur Heart J 1995;16:49-52.

11. Clark AL, Piepoli M, Coats AJS. Skeletal muscle and the control of ven- tilation on exercise: evidence for metabolic receptors. Eur J Clin Invesr 1995;25:299-305. 12. Martin TW, Zeballos RJ, W&man IM. Gas exchange during maximal upper extremity exercise. Chest 1991;99:420-425, 13. Man&i DM, Walter G, Reichnek N, Lenkinski R, McCully KK, Mullen JL, Wilson JR. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle’metabolism in heart failure. Circulation 1992;85: 1364- 1373. 14. Lipkin D, Jones D, Round J, Poole-Wilson P. Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol 1988;18:187-195. 15. Buller NP, Jones D, Poole-Wilson PA. Direct measurements of skeletal muscle fatigue in patients with chronic heart failure. Br Heart J 1991;65:20- 24. 16. Drexler H, Riede U, Munzel T, Knight H, Funke E, Just H. Alterations of skeletal muscle in chronic heart failure. Circulation 1992;85:1751- 1759. 17. Mancini DM, Coyle E, Coggan A, Beltz J, Ferraro N, Montain S, Wilson JR. Contribution of intrinsic skeletal muscle changes to 3 1P NMR skeletal mus- cle abnormalities in patients with chronic heart failure. Circularion 1989;80:1338- 1346. 18. Kao FF. An experimental study of the pathways involved in exercise hy- perpnoea employing cross circulation techniques. In: Cunningham DJC, Lloyd BB, eds. The Regulation of Human Respiration. Oxford: Blackwell, 1963:461- 502. 19. Piepoli M, Clark AL, Coats AJS. Muscle metaboreceptors in hemodynamic, autonomic and ventilatory responses to exercise in men. Am J Physiol 1995;269:Hl428-H1436. 20. Piepoli M, Clark AL, Volterrani M, Adamopoulous S, Sleight P, Coats AJS. Contribution of muscle afferents to the hemodynamic, autonomic, and venti- latory responses to exercise in patients with chronic heart failure. Effects of physical training. Circulation 1996;93:940-952.

Endomyocardial Biopsy-Proven Li ht Chain Amyloidosis (AL) Without Echocar ar iographic

Features of Infiltrative Cardiomyopathy Morie A. Gertz, MD, Martha Grogan, MD, Robert A. Kyle, MD, and A. Jamil Taiik, MD

An myloidosis (AL) is a disorder in which immu- oglobulin light chains form fibrils. These fibrils

are deposited in the tissues as amyloid, resulting in widespread organ dysfunction and death.’ Cardiac involvement with AL, manifesting as congestive heart failure, is seen in approximately 25% of all patients with AL but is responsible for >50% of the deaths from this disorder.* Typically, echocardio- graphic evaluation of AL patients with unexplained nonischemic heart failure reveals typical findings of amyloid.3 An increased thickness of the ventricular wall and septum,4 highly refractile ethos (granular sparkling),5 and reduced systolic function6 as well as abnormal relaxation and restrictive hemodynamics point to the correct diagnosis. There are instances, however, when the echocardiographic features do not suggest amyloid, which could lead to inappro- priate treatment with digoxin7 or nifedipine8 and de-

From the Division of Hematology and Internal Medicine and the Di- vision of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Ma supported by t t:

o Foundation, Rochester, Minnesota. This study was e Quade Amyloidosis Research Fund and Program

Project Grant CA62242, National Cancer Institute, Bethesda, Mary land Dr Gertz’s address is: Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 5.5905. Manuscri t received November 6, 1996; revrsed manu- scrrpt received an 8 accepted March 10, 1997.

0 1997 by Excerpta Medico, Inc All rights reserved.

lay the introduction of therapy that can improve the survival of patients with AL.9,10

. . . A computerized search was conducted of the

dysproteinemia database at our institution. The rec- ords of all patients with the diagnosis of amyloi- dosis seen between January 1, 1978, and December 1, 1995, were reviewed. Before this date, echocar- diography was not routinely performed in all pa- tients with amyloidosis, and endomyocardial biopsy was an infrequently applied technique. During this period, there were 1,386 patients seen with biopsy- proven systemic amyloidosis. One hundred five pa- tients had an endomyocardial biopsy demonstrating amyloid deposits (7.6%). In 69 of the 105 patients, amyloid was of the immunoglobulin light chain type. All patients had (1) a monoclonal light chain in serum or urine, (2) a clonal population of plasma cells in the bone marrow, or (3) positive tissue im- munochemistry for kappa or lambda light chains. All patients had undergone a complete echocardio- graphic study. Five patients had a positive result of endomyocardial biopsy but no echocardiographic features of cardiac amyloid. These patients are pre- sented in Table I.

. . . The 5 patients were selected based on the official

echocardiographic report generated at the time of the

0002.9149/97/$17.00 93 PII SOOO2-9 149(97)00294-4