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Cheyne-stokes respiration and prognosis in congestive heart failure
Cheyne-Stokes Respiration Prognosis in Congestive Heart Stefan Andreas, MD, Gerrit Hagenah, MD, Carsten Mijller, Gerald S. Werner, MD, and Heinrich Kreuzer, MD
and Failure MD,
Patients with congestive heart failure (CHF) frequently demonstrate Cheyne-Stokes respiration (CSR) with repetitive arousals and oxygen desaturations during sleep. Although it was evident from early publications that CSR during the daytime is a poor prognostic indicator in patients with CHF, it was speculated recently that CSR occurring during sleep could impede left ventricular function and even survival. We therefore followed up 36 patients with CHF and a left ventricular ejection fraction 540% who underwent a sleep study at our institution. The patients showed a reduced ejection fraction (20 2 8%) and CSR with a median of 19% of total sleep time (lower and upper quartiles 9% and 56%). In 12 -+ 9% of their time in bed, the arterial oxygen saturation was <90%. No patient was lost to follow-up, which lasted for 32 ? 15 months (range 11 to 53). One-year survival was 86 2 6%, and 2-year survival was 66 5 8%. Univariate comparisons for survival between groups strat-
ified by the amount of CSR revealed no significant difference (log rank test, p = 0.84). However, the 20 patients with a left ventricular ejection fraction <20% had a shorter mean survival time than patients with an ejection fraction ~20% (9.5 vs 28.3 months; log rank test, p = 0.013). Two patients with CSR during the daytime died within 1 month. No other patient had CSR during the daytime, and only 1 patient without daytime CSR died within 1 month (chi-square test, p
atients with congestive heart failure (CHF) frequently demonstrate Cheyne-Stokes respiration P (CSR) during sleep.lm3Although it was evident from
study. Patients younger than 75 years were eligible if they met the following criteria: at least 1 episode of cardiac decompensation, ejection fraction 140%, and stable condition (no rales on auscultation or tibial edema) during cardiac medication. Exclusion criteria were myocardial infarction within 1 year of entry, significant obstructive lung disease as defined by a forced expiratory volume in 1 second/forced vital capacity <65%, primary valvular heart disease, or evidence of obstructive sleep apnea (> 10% of the apneas and hypopneas obstructive). The study was approved by the local ethics committee. Informed written consent was obtained from all patients. Some of the patients included had taken part in a previous published study.15 Follow-up of the patients was determined by regular visits to our clinic and by telephone interview of the referring physician and/or patient. Death occurring out of the hospital and without symptomatic deterioration was ‘considered “sudden.” The death of a patient with progressive symptomatic and/or hemodynamic deterioration was classified as resulting from progressive CHF.
Cheyne’s case study and the publications following 4,5that CSR during the daytime is a poor sign for short-term prognosis, it was later noted that this is not necessarily true for CSR occurring only during sleep. CSR occurring transiently during an episode of pulmonary edema also has no prognostic impact.6 However, it was speculated recently that nocturnal CSR, per se, could impede left ventricular function and even survival,7-9 possibly as a result of hypoxia, hypercapnia, and arousals that occur repetitively during CSR and increase sympathetic activity.“,” Increased sympathetic nerve activity and other markers of sympathetic system activation are present in CHF and are related to impaired exercise tolerance and mortality in these patients.‘2,‘3 Similarly, right ventricular dysfunction, which may be induced by increased right ventricular afterload due to hypoxic pulmonary vasoconstriction, is related to impaired exercise tolerance and survival.‘4 We therefore followed up 36 patients with CHF and a left ventricular ejection fraction <40% who underwent a sleep study Echocardiography, spirometry, and resting ventilaat our institution. tion: Left ventricular end-diastolic and left atria1 diameters were evaluated by echocardiography from a METHODS left parastemal view. l6 Left ventricular ejection fracPatients: All patients with severe CHF admitted to tion at rest was determined by technetium-99mthe department of cardiology were candidates for the gated blood pool scintigraphy.” Spirometry was performed and vital capacity, forced expiratory volume From the Department ot Cardiology and Pneumology, Georg August in 1 second, and diffusion capacity for carbon monUniversity, Giittingen, Germany. Manuscript received February 12, oxide are given as percentage predicted.” Resting 1996; revised manuscript received and accepted April 17, 1996. ventilation was evaluated postprandially in the Address for reprints: Stefan Andreas, MD, Department of Cardiology and Pneumology, Robert-Koch-Str. 40, 37075 Giittingen, Germany, morning over 10 minutes while the subject was 1260
01996 by Excerpto Medico, All rights reserved.
inc.
0002.9 149/96/s 15.00 PII SOOO2-9149(96)00608-X
was monitored by strain gauges. Arterial oxygen saturation was measured transcutaneously on the tip of Doto, and Amount the index finger by pulse oximetry (Micro span 3040G). The data were stored on an optical disc by Gender [women/men) 5/31 a commercially available computer system (CNS 54k12 Age (yd 1.9 rt 0.2 Body surface area (m’) sleep lab, [Jager, Wtirzburg, Germany] l,OOO/ Body moss index (kg/m’) 25 k 4 AMPS). The polysomnogram was visually analyzed Left atrial diameter (mm) 51 ?6 in 30-second epochs for sleep stages according to Left ventricular end-diastolic diameter (mm) 73 ? 7 Rechtschaffen and Kales.20Arousals were scored acLeft ventricular ejection fraction (%) 20? 8 84215 Vital capacity (% predicted) cording to standard criteria. CSR was considered Forced expiratory volume in 1 s (% predicted) 85?19 present when there were at least 3 regular cycles of 83 5 24 Lung transfer factor for carbon monoxide (% predicted) increasing and decreasing air flow as well as increasCO? end-tidal partial pressure (mm Hg) 3426 ing and decreasing thoracic and abdominal efforts. CheyneStokes respirotion/TST (%) 19 (9/56) Hypopnea was defined as a decrease in oronasal air Cheyne-Stokes respiration with apneo/TST (%) 3 [O/24) Transit time (s) 42e17 flow >50% of baseline for > 10 seconds. Apnea was Mean oxygen desoturation during CSR (“A) 8.6 k 5.4 defined as the absence of oronasal air flow for the 22 +-21 Apnea-hypopnea index (/h) same period. Accordingly, CSR was classified as Percentage of time in bed with SaOz 190% 12?9 CSR with hypopnea and CSR with apnea. The apTotal sleep time (min) 376 t 84 Woke (in % time in bed] lB? 15 nea-hypopnea index was defined as the total number Stage 1 (% TST) 31 ?20 of sleeping apneas and hypopneas divided by the to49k18 Stage 2 (% TST) tal sleep time in hours. For every cycle, the minimal 1 t2 Slow-wave sleep (% TST) and maximal arterial oxygen saturation was meaREM sleep (% TST) 18?8 sured. The mean oxygen desaturation during CSR Arousals (/h) 18& 12 was calculated by subtracting the former from the CO? = carbon dioxide; CSR = Cheyne-Stokes respiration; REM = rapid eye latter. The amount of time the arterial oxygen satumovement; So02 = oxygen saturation in arterial blood; TST = total sleep time. ration was <90% corrected for time in bed was computed. The transit time between the increase in ventilation and the nadir TABLE II Doto of Patients Stratified by Survival in arterial oxygen saturation during CSR was averaged over 5 cycles. Survivors Nonsurvivors Characteristic (n = 20) (n = 16) p Value Statistical analysis: All variables were tested for normal distri572 10 51 i 14 0.17 Age lyrl bution2’ and are given as mean t 25.4 2 3.8 24.7 c 4.0 Body moss index (kg/m’) 0.59 5027 Lehatrial diameter (mm) 5325 0.22 SD for normal distribution and as 72 2 7 Left ventricular end-diastolic diameter (mm) 75 ? 7 0.31 median (upper/lower quartile) if not 22 k 8 1826 0.12 left ventricular ejection fraction (%) normally distributed. The groups 81 + 16 85k14 Vital capacity (% predicted) 0.43 were compared with the unpaired 79519 Forced expiratory volume in 1 s (% predicted) 85~18 0.23 Student’s t test for normal distribu34 t6 34 k 5 CO? endtidol partial pressure (mm Hg) 0.78 21 (l/55) CheyneStokes respiration/TST (%) 20 (l/72) 0.68 tion and by the unpaired WilcoxCheyneStokes respiration with apneo/TST (%) 0.72 6 (O/26) 5 (O/321 on’s test for non-normal distribution. Two-tailed tests were used. Abbreviations os in Table I. Dichotomous data were analyzed by chi-square test. The probability of breathing room air in a seated position. Minute ven- survival from the time of initial evaluation was antilation and respiratory rate were measured with a alyzed by the life-table method. The association of low-resistance pneumotachograph (A. Fleisch, Ba- individual variables with survival was assessed by sel, Switzerland), while the end-tidal carbon dioxide univariate analysis (log rank test). To allow mean(CO,) partial pressure was monitored continuously ingful univariate comparisons between groups, we by withdrawing expired gas from the mouthpiece analyzed the continuous variables as stratified ordi(Datex Normocap, Helsinki, Finland). In the absence nal variables: age (<54 vs ~-54 years), amount of of significant obstructive lung disease, the end-tidal CSR (<20% vs ~20% of total sleep time), amount CO2 partial pressure correlates closely to arterial CO2 of CSR with apnea (0% vs ~0% of total sleep time), partial pressure.” CSR during the daytime was con- and left ventricular ejection fraction (<20% vs sidered to be present if there were regular cycles of 220%). A p value <0.05 was considered significant. increasing and decreasing air flow with apneas durRESULTS ing this registration. Four patients had coronary artery disease and 32 Sleep study: As described previously,‘5 electrodes were placed for an electroencephalogram (C3A2 and had idiopathic dilated cardiomyopathy with comproC4Al of the international lo-20 system), electro- mised left ventricular function (Table I). Five paoculogram, electromyogram, and electrocardiogram. tients had atria1 fibrillation. Five patients were Air flow over the nose and mouth was recorded by women. Medications consisted of a diuretic in 34 thermistors, and thorax and abdominal wall motion patients, an angiotensin-converting enzyme inhibitor TABLE I Anthropomorphic,
Cardiac, of CheyneStokes
and Pulmonary Function Respiration in 36 Patients
CONGESTIVE
HEART FAItURE/CHEYNE-STOKES
RESPIRATION AND PROGNOSIS
1261
p=o.o13
p=O.84
3
ao
0 .-> ?
60
a0
60
3 UY z ‘3 0 i
40
E ;
20
0 0
36
24
12
Time
48
0
(month)
in 36, ,0-acetyldigoxin in 32, a vasodilator in 15, and amiodarone in 4 patients. A cardioverter-defibrillator was implanted in 5 patients because of sustained ventricular tachycardia or ventricular fibrillation before entry into the study. No patient received nocturnal oxygen or continuous positive airway pressure as treatment for CSR. The patient group showed impaired left ventricular function and restrictive ventilatory defects; they presented a wide range of CSR, oxygen desaturations, and impaired sleep (Table I). No patient was lost to follow-up, which lasted 32 +- 15 months (range 11 to 53). There were 14 deaths, all considered to be cardiac. Two patients who underwent urgent cardiac transplantation were grouped as nonsurvivors because they both showed progressive CHF during optimal medical therapy and needed a mechanical circulatory assist system for some days before transplantation. Eight deaths were considered sudden. One-year survival was 86 + 6%, 2-year survival was 66 + 8%, and 4-year survival was 48 t 10%. When survivors were compared with nonsurvivors, no significant differences were found (Table II). There were also no significant differences in medication or diagnosis between groups. Univariate comparisons of survival between groups stratified by age (log rank test, p = 0.91), amount of CSR (log rank test, p = 0.84; Figure l), and amount of CSR with apnea (log rank test, p = 0.45) revealed no significant differences. However, the 20 patients with a left ventricular ejection fraction <20% had a shorter mean survival time than patients with an ejection fraction 220% (9.5 vs 28.3 months; log rank test, p = 0.013; Figure 2). When survival between the groups stratified by the amount of CSR was analyzed after 3 months, there were more deaths in the group with 220% CSR corrected for total sleep time THE AMERICAN JOURNAL OF CARDIOLOGY@
I
1
I
I
12
24
36
48
Time
FIGURE 1. Univariate corn risons of survival between groups stratified by the amount o p”Cheyne-Stokes respiration per total sleep time (CSR/TST).
1262
01
VOL. 78
(month)
FIGURE 2. Univariate comparisons of survival between groups stratified by left ventricular ejection fraction (LVEF).
than in the group with <20%, although this difference was not significant (4 of 20 vs 1 of 16; chisquare test, p = 0.24). Two patients with CSR during the daytime (while awake) died within 1 month after initial evaluation. The ejection fraction of these patients was 14% and 15%, respectively. No other patient had daytime CSR, and only 1 patient without daytime CSR died within 1 month (chi-square test, p
DISCUSSION CSR occurring during the daytime (while the patients were awake) was related to poor short-term prognosis in our patients. However, this finding does not indicate whether daytime CSR is an independent prognostic sign, since the ejection fraction in the 2 patients who died within 1 month was also very low. That CSR occurring during the daytime is related to a poor prognosis is consistent with the old published reports, which evaluated respiration during the day but not during the night. 4~5,22 In the study of Lange and Hecht,** 7 of 9 patients who had CSR while awake died within 2 to 24 months. In our study, there was no significant prognostic impact of nocturnal CSR on survival. This contrasts with a recent study on 16 patients with CHF showing that nocturnal CSR was related to reduced survival.23 DECEMBER 1, 1996
heart transplantation with a mean ejection fraction of 22%. The low CSR/TST <20% CSR/TST ~20% incidence of sudden cardiac death Characteristic (n = 16) (n = 20) p Value may be due to the implantation of a cardioverter-defibrillator in 5 of our 4ak 14 59 2 7 0.01 Age (yr) 25.5 2 3.4 24.8 k 3.4 0.61 Body mass index (kg/n?) patients. 49 ? 6 53 2 5 0.029 left atrial diameter (mm) The pathogenesis of CSR in paLeft ventricular end-diastolic tients with CHF can be described by 73 i 7 73 k a 0.84 diameter (mm) mathematic models as an oscillation 20 2 9 20 + 6 0.95 Left ventricular ejection fraction (70) aa+ 16 782 13 0.046 Vital capacity (% predicted) of the feedback loop controlling Forced expiratory volume in 1 s ventilation.27,28 Following this 87521 80% 17 0.28 (% predicted) model, the major mechanisms be36 t5 32 5 6 0.028 CO? end-tidal partial pressure [mm Hg) hind CSR include reduced body 33 2 9 Transit time (s) 502 19 0.003 stores of oxygen and carbon dioxide CSR = CheyneStokes respiration; other abbreviations os in Table I. due to pulmonary congestion,24.29 and prolonged circulation time between the lung and the carotid body, mainly due to increased cardiac diThis contradiction might be explained by the differ- mensions.15q28,30 Other mechanisms include disturent patient characteristics. Those patients studied bance of ventilation and respiratory control due to were older than the patients we studied and were arousals2* a relatively high hypercapneic ventilatory originally recruited to evaluate the role of hypocap- response,15,2*and a low metabolic rate.*’ Sleep favors nia in the pathogenesis of CSR.24Compared with the the occurrence of CSR for various reasons, such as patients without CSR, the patients with CSR had in- unstable ventilatory control, a low apneic threshold creased mortality but also a lower arterial CO;?partial for carbon dioxide, and reduced lung volumes in the pressure, possibly reflecting more severe CHF, and supine position. But a mild cyclic respiratory pattern a reduced ejection fraction, although the latter dif- is also observed during the daytime in patients with ference was not statistically significant. The inves- CHF.31 Corroborating the model describing CSR as an tigators therefore conceded that the development of CSR may simply reflect more severe cardiac im- oscillation of the ventilatory feedback loop, the sepairment. 23Because they studied only patients with verity of CSR was related to left atria1 diameter, tranCHF due to ischemic heart disease, it is also con- sit time, reduced vital capacity, and reduced endceivable that nocturnal hypoxia causes more severe expiratory CO2 partial pressure in our patients (Table cardiac sequelae in these patients than in patients III). It is conceivable that left atria1 diameter but not with idiopathic dilated cardiomyopathy, as we have ejection fraction was related to CSR, because ejection fraction is poorly correlated with cardiac index, studied to a large extent. A study using an ambulatory monitoring device one denominator of lung to chemoreceptor circulafocused on the occurrence of CSR in 108 men aged tion time. The other denominator is the blood volume >60 years, of whom about 40% had CHF.*’ It was between lung capillaries and chemoreceptors, which noted that patients with severe CSR had reduced sur- is increased by pulmonary congestion and by invival and enlarged cardiac size. This finding is also creased atria1 and ventricular dimensions. Two other mainly explained by the association of CHF and studies also reported that ejection fraction was not CSR and cannot prove the hypothesis that nocturnal related to CSR, whereas hypocapnia due to pulmoCSR, per se, is related to impaired survival. In 1985, nary congestion was.24,29That higher age was assoFindley et al’ reported on 15 patients with a history ciated with CSR in our patients confirms earlier findof CHF; 6 of their patients had >5 apneas per hour ings in healthy older men32and might be explained of sleep and all of them died within 6 months, by the reduction in CO2 production and oxygen conwhereas only 3 of 9 nonapneic patients died within sumption following a reduction in the basal metathis time. However, the mean follow-up was not re- bolic rate with increasing age.28 We have not studied a large sample of patients ported, the patients were not treated with angiotensin-converting enzyme inhibitors, and a sleep study with CHF. However, it seems unlikely that the was performed in only 7 of their patients, making it amount of nocturnal CSR will emerge as an independent prognostic factor in a larger study because difficult to compare these results with our findings. It is not surprising that left ventricular ejection some of the mechanisms leading to CSR are also fraction was related to survival in our patients, be- indicative of the severity of CHF. We performed cause ejection fraction was found to be a strong prog- only a baseline assessmentof CSR and cannot prove nostic marker in larger previous studies on patients that it was constant throughout the follow-up. It is with CHF.26 The prognosis of our patient group was conceivable that short-term, but not necessarily longcomparable to that in other studies using similar term, prognosis is predicted by CSR, because the For example, DiSalvo et all4 severity of CSR may vary over time and the promedical treatment. 14,26 demonstrated l- and 2-year survival rates of about gression of CHF over a longer period may be more 80% and 70% in patients referred for evaluation of influenced by factors other than CSR.33 TABLE III Data of Patients Stratified
by the Amount
of Cheyne-Stokes
CONGESTIVE
HEART
Respiration
FAILURE/CHEYNE-STOKES
RESPIRATION
AND
PROGNOSIS
1263
1. Findley LJ, Zwillich CW, Ancoli-Israel S, Kripke D, Tisi G, Moser KM. Cheyne-Stokes respiration during sleep in patients with left ventricular heart failure. Sourh Med .I 198$78:11-U. 2. Hanly PJ, Milar TW, Steljes DG, Baert R, Frais MA, Kryger MH. Respiration and abnormal sleep in patients with congestive heart failure. Chest 1989;96:480-488, 3. Javaheti S, Parker TJ, Wexler L, Michaels SE, Stanberry E, Nishyama H, Roselle GA. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med 1995;122:487-492. 4. Cheyne J. A case of apoplexy, in which the fleshy part of the heart was converted into fat. Dublin Hospital Report 1818;2:216-223. 5. Stokes W. The Disease of the Heart and the Aorta. Dublin: Hodges & Smith, 1854:323-326. 6. Hoffman R, Agatston A, Krieger B. Cheyne-Stokes respiration in patients recovering from acute cardiogenic pulmonary edema. Chest 1990;97:410-412. 7. Kryger MH. Sieep and heart failure. Eur Respir J 1990;3: 1103- 1104. 8. Butler GC, Naughton MT, Rahman MA, Bradley TD, Floras JS. Continuous positive airway pressure increases heart rate variability in congestive heart failure. .I Am Cdl Cardiol 1995;25:672-679. 9. Andreas S, Clemens C, Sandholzer H, Figulla HR. Kreuzer H. Improvement of exercise capacity with treatment of Cheyne-Stokes respiration inpatients with congestive heart failure. J Am Co11 Cardiol 1996;27: 1486- 1490. 10. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. .I Clin Invest 1995;96: 1897- 1904. 11. Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes long lasting sympathetic activation in humans. J Appl Physiol 1995;79:205-213. 12. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Co11 Cardiol 1993;22(suppl A):72A-84A. 13. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD, Adverse consequences of high sympathetic nervous activity in the failing heart. JAm Co11 Cardiol 1995;26:1257-1263. 14. DiSalvo TG, Mathier M, Semigran MJ, Dee GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart faiwe. J Am Co11 Cardiol 1995;25:1143-1153. 15. Andreas S, Breska BV, Kopp E, Figulla HR. Kreuzer H. Periodic respiration in patients with heart failure. Clin Invest 1993;71:281-285. 16. Sahn DJ, DeMaria A, Kiss10 A, Weyman J. Recommendation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1081. 17. Luig H, Bartella R, Domovitz S, Reuter R, Emrich D, Facorro L, Schicha H, Graf M, Karsch M, Rentrop P, Kreuzer H. The determination of left ventricular volume curve without background correction and its validation by direct
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intercomparison with the ejection fraction as determined by biplane laevocardiography. J Nucl Med 1979;18:120-126. 18. Quanjer PH, Tammeling GC, Cotes JE, Pedersen OF, Pesling R, Yemault JC. Lung volumes and forced ventilatoty flows. Eur Respir J 1993;6(suppl 16):5-40. 19. Cummin ARC, Alison J, Jacobi MS, Iyawe VI, Saunders KB. Ventilatory sensitivity to inhaled carbon dioxide around the control point during exercise. Clin Sci 1986;71:17-22. 20. Rechtschaffen A, Kales A. Manual of Standardized Terminology Techniques and Scoring System for Sleep Stages of Human Subjects. Nat Inst Health Publ. 1968; No. 204. 21. Martinez J, Iglewicz B. A test for departure based on a biweight estimator of scale. Biometrika 1981;68:331-336. 22. Lange RL, Hecht HH. The mechanism of Cheyne-Stokes respiration. J Clin Invest 1962;41:42-52. 23. Hanly P, Zuberi-Khokhar N. Increased mortality associated with CheyneStokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996;153:272-276. 24. Hanly P, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure. Chest 1993;104:1079-1084. 25. Anconi-Israel S, Engler RL, Friedman PJ, Klauber MR, Ross PA, Kripke DF. Comparison of patients with central sleep apnea with and without CheyneStokes respiration. Chest 1994;106:780-786. 26. Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, Smith R, Fletcher R. Ejection fraction, peak exercise oxygen consumption and plasma norepinephrine as determinants to prognosis in heart failure. Circulation 1993;87(suppl VI):VI-5-VI-16. 27. Longobardo GS, Chemiak NS, Fishman AP. Cheyne-Stokes breathing produced by a model of the human respiratory system. J Appl Physiol 1966;21:1839-1846. 28. Khoo MCK, Gottschalk A, Pack AI. Sleep-induced periodic breathing and apnea: a theoretical study. J Appl Physiol 1991;70:2014-2024. 29. Naughton MT, Benard D, Tam A, Rutherford R, Bradley TD. Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure. Am Rev Respir Dis 1993;148:330-338. 30. Guyton AC, Crowell JW, Moore JW. Basic oscillating mechanism of Cheyne-Stokes breathing. Am J Physiol 1956;187:395-398. 3 1. Feld H, Priest F. A cyclic breathing pattern in patients with poor left ventricular function and compensated heart failure: a mild form of Cheyne-Stokes respiration? JAm Co11 Cardiol 1993;21:971-974. 32. Webb P. Periodic breathing during sleep. JAppl Physiol1974;37:899-903. 33. Figulla HR Stille-Siegener M, Mall G, Heim A, Kramer H. Myocardial entemvirus infection with left ventricular dysfunction: a benign disease compared with idiopathic dilated cardiomyopathy. J Am Co11Cordial 1995;25: 1170-l 175.
DECEMBER 1, 1996
and Failure MD,
Patients with congestive heart failure (CHF) frequently demonstrate Cheyne-Stokes respiration (CSR) with repetitive arousals and oxygen desaturations during sleep. Although it was evident from early publications that CSR during the daytime is a poor prognostic indicator in patients with CHF, it was speculated recently that CSR occurring during sleep could impede left ventricular function and even survival. We therefore followed up 36 patients with CHF and a left ventricular ejection fraction 540% who underwent a sleep study at our institution. The patients showed a reduced ejection fraction (20 2 8%) and CSR with a median of 19% of total sleep time (lower and upper quartiles 9% and 56%). In 12 -+ 9% of their time in bed, the arterial oxygen saturation was <90%. No patient was lost to follow-up, which lasted for 32 ? 15 months (range 11 to 53). One-year survival was 86 2 6%, and 2-year survival was 66 5 8%. Univariate comparisons for survival between groups strat-
ified by the amount of CSR revealed no significant difference (log rank test, p = 0.84). However, the 20 patients with a left ventricular ejection fraction <20% had a shorter mean survival time than patients with an ejection fraction ~20% (9.5 vs 28.3 months; log rank test, p = 0.013). Two patients with CSR during the daytime died within 1 month. No other patient had CSR during the daytime, and only 1 patient without daytime CSR died within 1 month (chi-square test, p
atients with congestive heart failure (CHF) frequently demonstrate Cheyne-Stokes respiration P (CSR) during sleep.lm3Although it was evident from
study. Patients younger than 75 years were eligible if they met the following criteria: at least 1 episode of cardiac decompensation, ejection fraction 140%, and stable condition (no rales on auscultation or tibial edema) during cardiac medication. Exclusion criteria were myocardial infarction within 1 year of entry, significant obstructive lung disease as defined by a forced expiratory volume in 1 second/forced vital capacity <65%, primary valvular heart disease, or evidence of obstructive sleep apnea (> 10% of the apneas and hypopneas obstructive). The study was approved by the local ethics committee. Informed written consent was obtained from all patients. Some of the patients included had taken part in a previous published study.15 Follow-up of the patients was determined by regular visits to our clinic and by telephone interview of the referring physician and/or patient. Death occurring out of the hospital and without symptomatic deterioration was ‘considered “sudden.” The death of a patient with progressive symptomatic and/or hemodynamic deterioration was classified as resulting from progressive CHF.
Cheyne’s case study and the publications following 4,5that CSR during the daytime is a poor sign for short-term prognosis, it was later noted that this is not necessarily true for CSR occurring only during sleep. CSR occurring transiently during an episode of pulmonary edema also has no prognostic impact.6 However, it was speculated recently that nocturnal CSR, per se, could impede left ventricular function and even survival,7-9 possibly as a result of hypoxia, hypercapnia, and arousals that occur repetitively during CSR and increase sympathetic activity.“,” Increased sympathetic nerve activity and other markers of sympathetic system activation are present in CHF and are related to impaired exercise tolerance and mortality in these patients.‘2,‘3 Similarly, right ventricular dysfunction, which may be induced by increased right ventricular afterload due to hypoxic pulmonary vasoconstriction, is related to impaired exercise tolerance and survival.‘4 We therefore followed up 36 patients with CHF and a left ventricular ejection fraction <40% who underwent a sleep study Echocardiography, spirometry, and resting ventilaat our institution. tion: Left ventricular end-diastolic and left atria1 diameters were evaluated by echocardiography from a METHODS left parastemal view. l6 Left ventricular ejection fracPatients: All patients with severe CHF admitted to tion at rest was determined by technetium-99mthe department of cardiology were candidates for the gated blood pool scintigraphy.” Spirometry was performed and vital capacity, forced expiratory volume From the Department ot Cardiology and Pneumology, Georg August in 1 second, and diffusion capacity for carbon monUniversity, Giittingen, Germany. Manuscript received February 12, oxide are given as percentage predicted.” Resting 1996; revised manuscript received and accepted April 17, 1996. ventilation was evaluated postprandially in the Address for reprints: Stefan Andreas, MD, Department of Cardiology and Pneumology, Robert-Koch-Str. 40, 37075 Giittingen, Germany, morning over 10 minutes while the subject was 1260
01996 by Excerpto Medico, All rights reserved.
inc.
0002.9 149/96/s 15.00 PII SOOO2-9149(96)00608-X
was monitored by strain gauges. Arterial oxygen saturation was measured transcutaneously on the tip of Doto, and Amount the index finger by pulse oximetry (Micro span 3040G). The data were stored on an optical disc by Gender [women/men) 5/31 a commercially available computer system (CNS 54k12 Age (yd 1.9 rt 0.2 Body surface area (m’) sleep lab, [Jager, Wtirzburg, Germany] l,OOO/ Body moss index (kg/m’) 25 k 4 AMPS). The polysomnogram was visually analyzed Left atrial diameter (mm) 51 ?6 in 30-second epochs for sleep stages according to Left ventricular end-diastolic diameter (mm) 73 ? 7 Rechtschaffen and Kales.20Arousals were scored acLeft ventricular ejection fraction (%) 20? 8 84215 Vital capacity (% predicted) cording to standard criteria. CSR was considered Forced expiratory volume in 1 s (% predicted) 85?19 present when there were at least 3 regular cycles of 83 5 24 Lung transfer factor for carbon monoxide (% predicted) increasing and decreasing air flow as well as increasCO? end-tidal partial pressure (mm Hg) 3426 ing and decreasing thoracic and abdominal efforts. CheyneStokes respirotion/TST (%) 19 (9/56) Hypopnea was defined as a decrease in oronasal air Cheyne-Stokes respiration with apneo/TST (%) 3 [O/24) Transit time (s) 42e17 flow >50% of baseline for > 10 seconds. Apnea was Mean oxygen desoturation during CSR (“A) 8.6 k 5.4 defined as the absence of oronasal air flow for the 22 +-21 Apnea-hypopnea index (/h) same period. Accordingly, CSR was classified as Percentage of time in bed with SaOz 190% 12?9 CSR with hypopnea and CSR with apnea. The apTotal sleep time (min) 376 t 84 Woke (in % time in bed] lB? 15 nea-hypopnea index was defined as the total number Stage 1 (% TST) 31 ?20 of sleeping apneas and hypopneas divided by the to49k18 Stage 2 (% TST) tal sleep time in hours. For every cycle, the minimal 1 t2 Slow-wave sleep (% TST) and maximal arterial oxygen saturation was meaREM sleep (% TST) 18?8 sured. The mean oxygen desaturation during CSR Arousals (/h) 18& 12 was calculated by subtracting the former from the CO? = carbon dioxide; CSR = Cheyne-Stokes respiration; REM = rapid eye latter. The amount of time the arterial oxygen satumovement; So02 = oxygen saturation in arterial blood; TST = total sleep time. ration was <90% corrected for time in bed was computed. The transit time between the increase in ventilation and the nadir TABLE II Doto of Patients Stratified by Survival in arterial oxygen saturation during CSR was averaged over 5 cycles. Survivors Nonsurvivors Characteristic (n = 20) (n = 16) p Value Statistical analysis: All variables were tested for normal distri572 10 51 i 14 0.17 Age lyrl bution2’ and are given as mean t 25.4 2 3.8 24.7 c 4.0 Body moss index (kg/m’) 0.59 5027 Lehatrial diameter (mm) 5325 0.22 SD for normal distribution and as 72 2 7 Left ventricular end-diastolic diameter (mm) 75 ? 7 0.31 median (upper/lower quartile) if not 22 k 8 1826 0.12 left ventricular ejection fraction (%) normally distributed. The groups 81 + 16 85k14 Vital capacity (% predicted) 0.43 were compared with the unpaired 79519 Forced expiratory volume in 1 s (% predicted) 85~18 0.23 Student’s t test for normal distribu34 t6 34 k 5 CO? endtidol partial pressure (mm Hg) 0.78 21 (l/55) CheyneStokes respiration/TST (%) 20 (l/72) 0.68 tion and by the unpaired WilcoxCheyneStokes respiration with apneo/TST (%) 0.72 6 (O/26) 5 (O/321 on’s test for non-normal distribution. Two-tailed tests were used. Abbreviations os in Table I. Dichotomous data were analyzed by chi-square test. The probability of breathing room air in a seated position. Minute ven- survival from the time of initial evaluation was antilation and respiratory rate were measured with a alyzed by the life-table method. The association of low-resistance pneumotachograph (A. Fleisch, Ba- individual variables with survival was assessed by sel, Switzerland), while the end-tidal carbon dioxide univariate analysis (log rank test). To allow mean(CO,) partial pressure was monitored continuously ingful univariate comparisons between groups, we by withdrawing expired gas from the mouthpiece analyzed the continuous variables as stratified ordi(Datex Normocap, Helsinki, Finland). In the absence nal variables: age (<54 vs ~-54 years), amount of of significant obstructive lung disease, the end-tidal CSR (<20% vs ~20% of total sleep time), amount CO2 partial pressure correlates closely to arterial CO2 of CSR with apnea (0% vs ~0% of total sleep time), partial pressure.” CSR during the daytime was con- and left ventricular ejection fraction (<20% vs sidered to be present if there were regular cycles of 220%). A p value <0.05 was considered significant. increasing and decreasing air flow with apneas durRESULTS ing this registration. Four patients had coronary artery disease and 32 Sleep study: As described previously,‘5 electrodes were placed for an electroencephalogram (C3A2 and had idiopathic dilated cardiomyopathy with comproC4Al of the international lo-20 system), electro- mised left ventricular function (Table I). Five paoculogram, electromyogram, and electrocardiogram. tients had atria1 fibrillation. Five patients were Air flow over the nose and mouth was recorded by women. Medications consisted of a diuretic in 34 thermistors, and thorax and abdominal wall motion patients, an angiotensin-converting enzyme inhibitor TABLE I Anthropomorphic,
Cardiac, of CheyneStokes
and Pulmonary Function Respiration in 36 Patients
CONGESTIVE
HEART FAItURE/CHEYNE-STOKES
RESPIRATION AND PROGNOSIS
1261
p=o.o13
p=O.84
3
ao
0 .-> ?
60
a0
60
3 UY z ‘3 0 i
40
E ;
20
0 0
36
24
12
Time
48
0
(month)
in 36, ,0-acetyldigoxin in 32, a vasodilator in 15, and amiodarone in 4 patients. A cardioverter-defibrillator was implanted in 5 patients because of sustained ventricular tachycardia or ventricular fibrillation before entry into the study. No patient received nocturnal oxygen or continuous positive airway pressure as treatment for CSR. The patient group showed impaired left ventricular function and restrictive ventilatory defects; they presented a wide range of CSR, oxygen desaturations, and impaired sleep (Table I). No patient was lost to follow-up, which lasted 32 +- 15 months (range 11 to 53). There were 14 deaths, all considered to be cardiac. Two patients who underwent urgent cardiac transplantation were grouped as nonsurvivors because they both showed progressive CHF during optimal medical therapy and needed a mechanical circulatory assist system for some days before transplantation. Eight deaths were considered sudden. One-year survival was 86 + 6%, 2-year survival was 66 + 8%, and 4-year survival was 48 t 10%. When survivors were compared with nonsurvivors, no significant differences were found (Table II). There were also no significant differences in medication or diagnosis between groups. Univariate comparisons of survival between groups stratified by age (log rank test, p = 0.91), amount of CSR (log rank test, p = 0.84; Figure l), and amount of CSR with apnea (log rank test, p = 0.45) revealed no significant differences. However, the 20 patients with a left ventricular ejection fraction <20% had a shorter mean survival time than patients with an ejection fraction 220% (9.5 vs 28.3 months; log rank test, p = 0.013; Figure 2). When survival between the groups stratified by the amount of CSR was analyzed after 3 months, there were more deaths in the group with 220% CSR corrected for total sleep time THE AMERICAN JOURNAL OF CARDIOLOGY@
I
1
I
I
12
24
36
48
Time
FIGURE 1. Univariate corn risons of survival between groups stratified by the amount o p”Cheyne-Stokes respiration per total sleep time (CSR/TST).
1262
01
VOL. 78
(month)
FIGURE 2. Univariate comparisons of survival between groups stratified by left ventricular ejection fraction (LVEF).
than in the group with <20%, although this difference was not significant (4 of 20 vs 1 of 16; chisquare test, p = 0.24). Two patients with CSR during the daytime (while awake) died within 1 month after initial evaluation. The ejection fraction of these patients was 14% and 15%, respectively. No other patient had daytime CSR, and only 1 patient without daytime CSR died within 1 month (chi-square test, p
DISCUSSION CSR occurring during the daytime (while the patients were awake) was related to poor short-term prognosis in our patients. However, this finding does not indicate whether daytime CSR is an independent prognostic sign, since the ejection fraction in the 2 patients who died within 1 month was also very low. That CSR occurring during the daytime is related to a poor prognosis is consistent with the old published reports, which evaluated respiration during the day but not during the night. 4~5,22 In the study of Lange and Hecht,** 7 of 9 patients who had CSR while awake died within 2 to 24 months. In our study, there was no significant prognostic impact of nocturnal CSR on survival. This contrasts with a recent study on 16 patients with CHF showing that nocturnal CSR was related to reduced survival.23 DECEMBER 1, 1996
heart transplantation with a mean ejection fraction of 22%. The low CSR/TST <20% CSR/TST ~20% incidence of sudden cardiac death Characteristic (n = 16) (n = 20) p Value may be due to the implantation of a cardioverter-defibrillator in 5 of our 4ak 14 59 2 7 0.01 Age (yr) 25.5 2 3.4 24.8 k 3.4 0.61 Body mass index (kg/n?) patients. 49 ? 6 53 2 5 0.029 left atrial diameter (mm) The pathogenesis of CSR in paLeft ventricular end-diastolic tients with CHF can be described by 73 i 7 73 k a 0.84 diameter (mm) mathematic models as an oscillation 20 2 9 20 + 6 0.95 Left ventricular ejection fraction (70) aa+ 16 782 13 0.046 Vital capacity (% predicted) of the feedback loop controlling Forced expiratory volume in 1 s ventilation.27,28 Following this 87521 80% 17 0.28 (% predicted) model, the major mechanisms be36 t5 32 5 6 0.028 CO? end-tidal partial pressure [mm Hg) hind CSR include reduced body 33 2 9 Transit time (s) 502 19 0.003 stores of oxygen and carbon dioxide CSR = CheyneStokes respiration; other abbreviations os in Table I. due to pulmonary congestion,24.29 and prolonged circulation time between the lung and the carotid body, mainly due to increased cardiac diThis contradiction might be explained by the differ- mensions.15q28,30 Other mechanisms include disturent patient characteristics. Those patients studied bance of ventilation and respiratory control due to were older than the patients we studied and were arousals2* a relatively high hypercapneic ventilatory originally recruited to evaluate the role of hypocap- response,15,2*and a low metabolic rate.*’ Sleep favors nia in the pathogenesis of CSR.24Compared with the the occurrence of CSR for various reasons, such as patients without CSR, the patients with CSR had in- unstable ventilatory control, a low apneic threshold creased mortality but also a lower arterial CO;?partial for carbon dioxide, and reduced lung volumes in the pressure, possibly reflecting more severe CHF, and supine position. But a mild cyclic respiratory pattern a reduced ejection fraction, although the latter dif- is also observed during the daytime in patients with ference was not statistically significant. The inves- CHF.31 Corroborating the model describing CSR as an tigators therefore conceded that the development of CSR may simply reflect more severe cardiac im- oscillation of the ventilatory feedback loop, the sepairment. 23Because they studied only patients with verity of CSR was related to left atria1 diameter, tranCHF due to ischemic heart disease, it is also con- sit time, reduced vital capacity, and reduced endceivable that nocturnal hypoxia causes more severe expiratory CO2 partial pressure in our patients (Table cardiac sequelae in these patients than in patients III). It is conceivable that left atria1 diameter but not with idiopathic dilated cardiomyopathy, as we have ejection fraction was related to CSR, because ejection fraction is poorly correlated with cardiac index, studied to a large extent. A study using an ambulatory monitoring device one denominator of lung to chemoreceptor circulafocused on the occurrence of CSR in 108 men aged tion time. The other denominator is the blood volume >60 years, of whom about 40% had CHF.*’ It was between lung capillaries and chemoreceptors, which noted that patients with severe CSR had reduced sur- is increased by pulmonary congestion and by invival and enlarged cardiac size. This finding is also creased atria1 and ventricular dimensions. Two other mainly explained by the association of CHF and studies also reported that ejection fraction was not CSR and cannot prove the hypothesis that nocturnal related to CSR, whereas hypocapnia due to pulmoCSR, per se, is related to impaired survival. In 1985, nary congestion was.24,29That higher age was assoFindley et al’ reported on 15 patients with a history ciated with CSR in our patients confirms earlier findof CHF; 6 of their patients had >5 apneas per hour ings in healthy older men32and might be explained of sleep and all of them died within 6 months, by the reduction in CO2 production and oxygen conwhereas only 3 of 9 nonapneic patients died within sumption following a reduction in the basal metathis time. However, the mean follow-up was not re- bolic rate with increasing age.28 We have not studied a large sample of patients ported, the patients were not treated with angiotensin-converting enzyme inhibitors, and a sleep study with CHF. However, it seems unlikely that the was performed in only 7 of their patients, making it amount of nocturnal CSR will emerge as an independent prognostic factor in a larger study because difficult to compare these results with our findings. It is not surprising that left ventricular ejection some of the mechanisms leading to CSR are also fraction was related to survival in our patients, be- indicative of the severity of CHF. We performed cause ejection fraction was found to be a strong prog- only a baseline assessmentof CSR and cannot prove nostic marker in larger previous studies on patients that it was constant throughout the follow-up. It is with CHF.26 The prognosis of our patient group was conceivable that short-term, but not necessarily longcomparable to that in other studies using similar term, prognosis is predicted by CSR, because the For example, DiSalvo et all4 severity of CSR may vary over time and the promedical treatment. 14,26 demonstrated l- and 2-year survival rates of about gression of CHF over a longer period may be more 80% and 70% in patients referred for evaluation of influenced by factors other than CSR.33 TABLE III Data of Patients Stratified
by the Amount
of Cheyne-Stokes
CONGESTIVE
HEART
Respiration
FAILURE/CHEYNE-STOKES
RESPIRATION
AND
PROGNOSIS
1263
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