Daily energy expenditure in free-living heart failure - Michael Goran

Daily energy expenditure in free-living heart failure patients

MICHAEL J. TOTH, STEPHEN S. GOTTLIEB, MICHAEL I. GORAN, MICHAEL L. FISHER, AND ERIC T. POEHLMAN Divisions of Gerontology and Cardiology, Department of Medicine, University of Maryland, and Geriatric Research Education and Clinical Center, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; and Department of Medicine, University of Verm.ont, Burlington, Vermont 05405

Toth, Michael J., Stephen S. Gottlieb, Michael I. Goran, Michael L. Fisher, and Eric T. Poehlman. Daily energy expenditure in free-living heart failure patients. Am. J. Physiol. 272 (EndocrinoZ. Metah. 35): E469-E475, 1,997.-We examined the hypothesis that weight loss in heart failure patients is associated with elevated daily energy expenditure. Twelve cachectic patients [age = 73 t 6 yr; weight loss = 15 5 6 kg; body mass index (BMI) = 21 t 5 kg/m”], 13 noncachectic patients (age = 67 t 5 yr; BMI = 27 t 5 kg/m”), and 50 healthy elderly controls (age = 69 ? 6 yr; BMI = 26 t 4 kg/m2) were studied. Daily energy expenditure and it components were measured using doubly labeled water and indirect calorimetry and body composition by dual-energy X-ray absorptiometry. Fat mass and fat-free mass were lower (P < 0.05) in cachectic patients compared with noncachectic patients and healthy controls. Daily energy expenditure was lower (P < 0.05) in cachectic patients (1,870 2 347 kcal/day) compared with noncachectic patients (2,349 2 545 kcal/day) and healthy controls (2,543 t 449 kcal/day). Differences in daily energy expenditure were primarily due to lower (P < 0.05) physical activity energy expenditure in cachectic (269 t_ 307 kcal/day) and noncachectic patients (416 t 361 kcal/day) compared with healthy controls (728 5 374 kcal/day). A lower (P < 0.05) resting energy expenditure was also noted in cachectic patients (1,414 t 210 kcal/day) compared with noncachectic patients (1,698 t 252 kcal/day) and healthy controls (1,561 _t 223 kcal/day). These findings show that daily energy expenditure is not higher, but significantly lower, in cachectic heart failure patients due to lower physical activity and resting energy expenditure. These results argue against the hypothesis that an abnormally elevated daily energy expenditure is associated with weight loss in heart failure.

cardiac cachexia; doubly labeled water

PATIENTS WITH CHRONIC heart failure frequently experi- ence significant weight loss during the course of the disease (3, 4). Weight loss may lead to cardiac atrophy and further decompensation (1). Moreover, weight loss is associated with increased mortality (13, 28). At present, the etiology of weight loss in patients with heart failure is not understood.

Weight loss results from an imbalance between daily energy intake and daily energy expenditure. Whereas measurement of energy intake is subject to error from recording inaccuracies (10, 25>, assessment of energy expenditure is more reliable. No study, however, has measured daily energy expenditure in free-living heart failure patients. Thus it is unknown whether reduced energy intake, elevated energy expenditure, or a combi-

nation of both factors contributes to weight loss in heart failure.

Previous investigations examining energy expenditure in heart failure patients have focused on resting energy expenditure because of its large contribution (60-80%) to daily energy expenditure. These studies found elevated resting energy expenditure in heart failure patients compared with healthy controls (23, 24). Although these findings appear to support the hypothesis that elevated energy expenditure contributes to weight loss in heart failure patients (20), resting energy expenditure represents only one component of daily energy expenditure. The remaining and most variable fraction of daily energy expenditure, which consists largely of physical activity energy expenditure, has not been directly measured in free-living heart failure patients. Thus, to support the hypothesis that elevated energy expenditure predisposes to weight loss in heart failure, it must be demonstrated that daily energy expenditure is elevated.

Assessment of daily energy expenditure in free-living humans, until recently, has been problematic due to methodological limitations. The availability of the doubly labeled water technique provides a method to accurately measure daily energy expenditure in free- living humans over extended periods of time (26). This technique, in combination with indirect calorimetry, provides an assessment of daily energy expenditure and derivation of its components (resting energy expenditure and physical activity energy expenditure). The measurement of physical activity energy expenditure is particularly important, since it is the primary determinant of individual variation in daily energy expenditure in elderly individuals (10).

In the present study, we tested the hypothesis that daily energy expenditure is elevated in heart failure patients. To examine the relationship of daily energy expenditure to weight loss, we compared daily energy expenditure and its components in a cohort of cachectic heart failure patients with noncachectic patients and healthy controls.

METHODS

Subjects. Twenty-five patients (24 men, 1 woman; 52% Caucasian, 48% African-American) with heart failure were recruited from the Heart Failure Service of the Baltimore Veterans Administration Medical Center and the University of Maryland Medical Center. Mean left ventricular ejection fraction was 23 t 9% (range 10 to 45%), as determined by radionuclide ventriculography. Twelve patients had coronary

0193-1849/97 $5.00 Copyright o 1997 the American Physiological Society E469

E470 ENERGY EXPENDITURE IN HEART FAILURE

artery disease, defined as a history of myocardial infarction or significant obstruction on a cardiac catherization. Thirteen patients had dilated cardiomyopathy unrelated to coronary artery disease. At the time of testing, patients were hemody- namically stable, free of visible edema (peddle or pitting edema), and were taking two or more of the following medications: diuretics (n = 25; loo%;), vasodilators (angioten- sin-converting enzyme inhibitor or hydralazine-nitrates; n = 21; 84%), and digoxin (n = 23; 88%). Two patients had non-insulin-dependent diabetes mellitus and were taking oral hypoglycemic drugs. Patients were defined by the New York Heart Association functional scale as class II (n = 9), class III (n = ll), and class IV (n = 5). Heart failure subjects were divided into cachectic and noncachectic groups. Cachexia was defined as a loss of 10% or greater of a subject’s reported premorbid body weight. Twelve patients (11 men, 1 woman; 42% Caucasian, 58% African-American) were classified as cachectic and 13 as noncachectic (13 men; 62%~ Caucasian, 38% African-American). Weight loss in 10 of the 12 cachectic patients was further verified by examination of medical records. All subjects were free of cigarette use for at least 3 mo before evaluation, although 11 patients had a history of cigarette use (4 cachectic, 7 noncachectic).

Fifty healthy, nonsmoking, elderly (48 men, 2 women; 60% Caucasian, 40% African-American) subjects were used as a nondiseased control group. Data from 28 Caucasian men were previously published (29). Healthy subjects were recruited by newspaper advertisements and community organi- zations. Healthy African-Americans (n = 20) were recruited from Baltimore, MD, and surrounding areas. Healthy Cauca- sians (n = 30) were recruited from Burlington, VT, and surrounding areas. Healthy subjects met the following criteria: 1) no symptoms or signs of heart disease or diabetes, 2) normal resting electrocardiogram, 3) normal electrocardiogram response to an exercise stress test, 4) absence of medicinal or nonmedicinal drugs that could affect cardiovas- cular or metabolic function, and 5) weight stability (52 kg) within 6 mo before testing. The nature, purpose, and possible risks of the study were explained to volunteers before they gave consent. This study was approved by the Committee on Human Research for the Medical Sciences of the University of Vermont and the Institutional Review Board of the Univer- sity of Maryland.

Experimental protocol. All measurements were made over a lo-day period. On the first day, each subject received an oral dose of doubly labeled water after a baseline urine sample was obtained. The following morning, resting energy expenditure and body composition were measured and two urine samples were collected to mark the beginning of the doubly labeled water measurement period. After being provided with a scale and instructions for recording their dietary intake, subjects left the research center and resumed their daily activities (i.e., free-living conditions). Ten days after the beginning of the doubly labeled water measurement period, subjects returned to provide two urine samples and under- went an assessment of peak oxygen consumption (vo2>.

Daily energy expenditure. Free-living daily energy expenditure was determined over a IO-day period using the doubly labeled water technique, as previously described (10). Each subject consumed a mixed, oral dose of “HZ0 and Hz’“0 (0.078 and 0.092 g/kg body mass, respectively) after providing a baseline urine sample (between the hours of 1200 and 1600). A weighed 1:400 dilution (dose:tap water) was prepared from each subject’s dose, and a sample of the water used for the dilution was saved and analyzed with each subject’s sample set. Two urine samples were obtained the morning after dosing to mark the beginning of the measurement period and

10 days later to mark the end (all between 0800 and 1200). All subjects were weight stable and consumed a self-selected diet during the doubly labeled water measurement period. Urine samples from both the Vermont and Maryland cohorts were stored in sealed vacutainers at -20°C until analysis in triplicate by isotope ratio mass spectrometry at the Biomedi- cal Mass Spectrometry Facility at the University of Mary- land. Samples were analyzed for isotopic enrichment of “Ha0 and H21g0 using the off-line zinc reduction procedure of Kendall and Copelan (11) and CO2 equilibration technique (5), respectively. The “H and Iti0 enrichment of samples was expressed on the relative delta per mil scale (%).

To prepare urine samples for analysis of I80 enrichment, 1 ml of sample was injected into lo-ml vacutainers along with 0.25 ml of 99.9% pure C02. In addition, l-ml aliquots of the diluted dose and water used for the dilution were similarly prepared. All samples were shaken overnight at room tempera- ture to allow for the equilibration of I80 in the samples with injected CO2. Equilibrated COZ was injected into the mass spectrometer after separation by gas chromatography (VG Isochrom ugas, Middlewich, Cheshire, UK). The ratio of mass 46:44 was monitored using an isotope ratio mass spectrometer (Optima, Fisons Instruments, Middlewich). Quality control samples of known I80 isotopic enrichment were analyzed along with each subject’s sample batch to ensure the integrity of the analysis. The average SD for 164 sets of triplicate HJHO analysis was 0.27% at a mean sample enrichment of 43.08%.

The zinc reduction procedure for preparation of urine samples for “H enrichment analysis was identical to proce- dures previously described (10). The ratio of mass 3:2 was determined by isotope ratio mass spectrometry. A dilution of the dose given to each subject and water used for the dilution were prepared similarly and analyzed with each subject’s sample set. The average SD for 172 sets of triplicate ZH20 analysis was 4.34% at a mean sample enrichment of 449.3%.

The rate of carbon dioxide production (rc~o,) was calculated using Eq. 2 of Speakman et al. (27)

r,loz(mollday) = 0.4554 x N (K,, - (DSR) &)

where N is body water pool and is equal to [Do + (D,,/DSR)]/2; Do and Dii are the HZlsO and gHZO dilution spaces in moles, respectively, Ko and KH are the turnover rates of H2180 and “HzO, respectively, in days-l, and DSR is the dilution space ratio (DH/Do). Turnover rates and zero-time enrichment of HZIHO and “H20 were determined from the slope and inter- cept, respectively, of the semilogarithmic plot of urinary enrichment (%) vs. time (days). Isotope dilution spaces were calculated using the equation of Coward (7). Because no differences were found among the proposed DSR of Speakman et al. (1.0427 t 0.0218), the DSR of cachectic patients (1.0408 -f 0.0159), noncachectic patients (1.0462 2 0.0118), or healthy controls (1.0488 t_ 0.0144), a fixed DSR of 1.0427 was used.

rcO, was used to calculate daily energy expenditure from Eq. 12 of Weir (30), assuming a respiratory quotient of 0.85 (2). The group mean food quotient did not differ among cachectic patients (0.87 2 0.03), noncachectic patients (0.87 t 0.03), and healthy controls (0.87 t 0.04) or from the assumed respiratory quotient.

Resting energy expenditure. Resting energy expenditure was measured in the morning (-0800) after a 12-h overnight fast in healthy volunteers and on an outpatient basis in heart failure patients at a similar time and after a similar overnight fast. Resting metabolic rate was measured by indirect calorimetry using the ventilated hood method for 45 min (Deltatrac, Sensormedics, Yorba Linda, CA). On arriving at the hospital, heart failure patients were transported to the

ENERGY EXPENDITURE IN HEART FAILURE E471

testing area by wheelchair and allowed to rest quietly in a (FQ) was calculated from the following equation: FQ = dark room for 20 min before measurement to ensure resting [(l.OO X V&carbohydrate) + (0.81 X ?&protein) + (0.71 X

conditions. Energy expenditure was calculated using the %fat> + (0.67 X %alcohol)l/lOO, where each nutrient is equation of Weir (30). All subjects were asked to refrain from expressed as the percentage of the total kilocalories con- any exercise or heavy exertion the day before measurement. sumed.

Physical activity energy expenditure. Physical activity energy expenditure was calculated on the basis of the three- component model of daily energy expenditure, as previously described (10). Physical activity energy expenditure was calculated [(0.9 X daily energy expenditure) - resting energy expenditure], with the assumption that the thermic effect of food constitutes 10% of daily energy expenditure in older individuals (2 1).

Body composition. Fat mass and fat-free mass were measured by dual-energy X-ray absorptiometry with the use of a Lunar DPX-L densitometer (Madison, WI). All scans were analyzed with the use of the Lunar version 1.3 DPX-L extended analysis program for body composition. The hydration fraction of fat-free mass, an indicator of the hydration state of the body, was calculated by dividing total body water measured with isotope dilution by fat-free mass measured with dual-energy X-ray absorptiometry. Because patients were free of edema and the hydration fraction of fat-free mass did not differ among groups (75 t 4 vs. 75 +- 4 vs. 76 t 6%), we conclude that fat-free mass obtained from dual-energy X-ray absorptiometry provides a reliable measure of the metabolically active tissue in heart failure patients.

Statistics. Differences in physical and metabolic characteristics among groups were assessed by a one-way analysis of variance. If a significant group effect was found, a Student- Newman-Keuls test was used to identify the location of differences among groups. Differences in clinical characteristics between the two groups of heart failure patients were determined using an unpaired Student’s t-test. Analysis of covariance was used to test for differences in peak VO, and resting energy expenditure after the effects of fat-free mass had been statistically removed. Because tumor necrosis factor-a data were not normally distributed, differences in tumor necrosis factor-a were determined by Mann-Whitney U-test. The relationship between tumor necrosis factor-a and body composition, energy expenditure, and energy intake data was determined by Spearman’s rank-correlation analysis. Signifi- cance level was set at P < 0.05. All values are expressed as means t SD.

RESULTS

Tumor necrosis factor-a. Human tumor necrosis factor-c-x was measured from plasma samples by sandwich enzyme- linked immunosorbent assay using commercial reagents (En- dogen). All samples were analyzed in the same assay. Polysty- rene plates (Maxisorp, Nunc) were coated with capture mouse monoclonal antibodies against tumor necrosis factor-cc in phosphate-buffered saline overnight at 24°C. Plates were washed five times in 50 mM tris(hydroxymethyl)aminometh- ane, 0.2% Tween-20 (pH 7.0-7.5) and blocked for 90 min at 25°C in a 1:l mixture of 2.5%) casein and assay buffer (phosphate-buffered saline containing 4%~ bovine serum albumin and 0.01% Thimerosal; pH 7.2-7.4). The wells were washed four times, as described above, and 50 ul of sample or standard prepared in assay buffer were incubated at 37°C for 2 h. Wells were washed four times, and 100 ul of biotinylated rabbit polyclonal anti-tumor necrosis factor-a antibody in assay buffer were added and incubated for 1 h at 25°C. Wells were washed four more times and strepavidin-peroxidase (Dako) in assay buffer was added and incubated at 25°C for 30 min. After four washes, 100 ul of a commercially prepared substrate (3,3’,5,5’-tetramethylbenzidine; Dako) were added and incubated at 25°C for 30 min. The reaction was stopped with 100 ul of 2 N HCl, and the absorbance at 450 nm was read on a microplate reader (Dynatech). A curve was fit to the standards using a computer program (Deltagraph for Macintosh), and tumor necrosis factor-a concentration was calculated.

Because no differences in daily energy expenditure or its components were noted between African-American and Caucasian patients in the healthy or heart failure groups, data were pooled. Table 1 shows the physical characteristics of cachectic, noncachectic, and healthy control groups. Cachectic patients were older (P < 0.05) than noncachectic and healthy controls. No differences in height were noted among groups. Body mass index was lower (P < 0.05) in cachectic patients compared with noncachectic patients and healthy controls. Cachec- tic patients weighed less than the other groups due to a lower quantity of fat mass and fat-free mass (all P < 0.05).

Table 2 shows the clinical characteristics of cachectic and noncachectic patients. By design, absolute weight loss and the percentage of premorbid weight lost were greater in cachectic compared with noncachectic patients (P < 0.01). The distribution of New York Heart Association classification showed that cachectic patients were more symptomatic. Ejection fraction and peak VO, did not differ among groups. Serum albumin levels were lower (P < 0.01) in cachectic compared with noncachectic patients.

Peak VO,. Peak %z was assessed by a treadmill test to volitional exhaustion using an open-circuit indirect calorimetry system. Peak VO, was available for 16 heart failure patients.

Table 1. Physical characteristics of cachectic and noncachectic heart failure patients and healthy controls

Variable Cachectic Patients

Noncachectic Patients

Healthy Controls

Dietary intake. Dietary intake was measured for 3 days (1 weekend day and 2 weekdays) during the doubly labeled water measurement period, as previously described (22). Each subject was supplied with a 5-lb metabolic scale and instructed on the accurate measurement and recording of intake. Subjects were strongly encouraged not to change their dietary habits during the recording period. Food records were analyzed using the Nutritionist 4.1 program for Windows (First DataBank C omputing, San Bruno, CA). Food quotient

n 12 13 50 Age, Yr 73 -+ 6:‘: 67 -+ 5 69 t 6 Height, cm 17029 174-+6 17327 Weight, kg 62 2 14t 84-+ 13 78+15 Body mass index, kg/m” 21 -+ 5-b 27 -+ 5 2624 Fat mass, kg 12 -t 94 25 + 11 2128 Fat-free mass, kg 50 ? 8-i- 59 + 5 58 k 9

Values are means + SD; n = no. of subjects. ‘:‘P < 0.05 greater than noncachectic and healthy control groups; +P < 0.05 less than noncachectic and healthy control groups.


Table 2. Clinical characteristics of cachectic and noncachectic heart failure patients

Cachectic Noncachectic Variable Patients Patients

Weight loss, kg 1526 2% 4* Percent of weight lost (%premorbid 20+8 2 & 4:‘:

weight) New York Heart Association class II (n = 2) II (n = 7)

III (n = 6) III (n = 5) IV (n = 4) IV (72 = 1)

Ejection fraction, %I 2127 26210 Adjusted peak VOW, Vmin 1.0 + 0.2 1.3 + 0.2 Serum albumin, g/d1 4.0 A 0.4 4.3 + 0.4”’ Number receiving

Diuretics 12 (100%) 13 (100%) Vasodilators 10 (83%) 11 (85%) Digoxin 11 (92%) 11(85%)

Values are means 2 SD. Peak oxygen consumption (peak v02) was adjusted for fat-free mass using analysis of covariance for IZ. = 8 cachectic patients and IZ = 8 noncachectic patients. *P < 0.01.

Table 3 shows data for the doubly labeled water experiment. Day 1 and day 10 2H20 enrichment did not differ among groups. H2180 enrichment in healthy controls was greater (P < 0.05) than in the cachectic group on day 1 and greater than in both heart failure groups on day IO. The turnover rates of 2H20 and H2180 were greater (P < 0.05) in the noncachectic group compared with the cachectic and healthy control groups. The zero-time dilution spaces of 2H20 and H2180 were lower (P < 0.05) in the cachectic group compared with noncachectic and healthy controls. rco, (corrected for fractionation) was lower (P < 0.05) in the cachectic group compared with the noncachectic and healthy control groups.

Measured and adjusted energy expenditure and energy intake data for the groups are reported in Table 4 and shown in Fig. 1. Measured daily energy expenditure was lower (P < 0.05) in cachectic patients compared with the noncachectic and healthy control groups. Lower daily energy expenditure persisted in cachectic

Table 3. Data for doubly labeled water experiment in cachectic and noncachectic heart failure patients and healthy controls

Cachectic Noncachectic Healthy Variable Patients Patients Controls

2H120: day 1, %c 8542155 863k112 910 5 218 “HzO: day 10, % 427+112 375+112 451+144 H2180: day 1, %o 7927 go+10 97 + 559: HzlsO: day 10, %o 3426 34klO 44-+16-j- KH, days l -0.07 50.01 -0.09~0.03$ -0.08kO.02 &I, days -- i -0.09 + 0.01 -0.12 + 0.03$ -0.10 Ir 0.02 Dn, time 0, mol 2,053+3645 2,409*265 2,403+356 Do, time 0, mol 1,974? 3615 2,303+258 2,291+ 335 w,, moVday 15.4 2 2.98 19.3 + 4.5 20.9k3.7

Values are means + SD. Enrichments of “Hz0 and Hz180 on days 1 and 10 are delta per mil (SO) above predosing values; Kn and Ko are turnover rates of “Hz0 and H zls 0, respectively; Dn and Do are dilution spaces of 2Hz0 and H 2180, respectively; ~0, is rate of carbon dioxide production corrected for fractionation. *‘P < 0.05 greater than cachectic; ‘i-P < 0.05 greater than cachectic and noncachectic; $P < 0.05 greater than cachectic and healthy controls; $P < 0.05 less than noncachectic and healthy controls.

Table 4. Daily energy expenditure, its components, and energy intake in cachectic and noncachectic heart failure patients and healthy controls

Cachectic Noncachectic Healthy Variable Patients Patients Controls

Daily energy expenditure 1,870 t 347* 2,349 ? 545 2,543 + 449 Physical activity energy

expenditure 2695307 416+361 728+374-i- Resting energy expendi-

ture 1,414 + 210:” 1,698 + 252 1,561_+ 223 Resting energy expendi-

ture (adjusted for fat- free mass) 1,559 + 182 1,639 + 173$ 1,542? 169

Reported energy intake 1,987 + 529 1,836 + 509 2,125 -e 576

Values are means + SD in kcal/day. *P < 0.05 less than noncachectic and healthy controls; tP < 0.05 greater than noncachectic and cachectic patients; $P = 0.09 greater than cachectic and healthy controls.

patients after statistical control for fat-free mass (P < 0.05). Differences in daily energy expenditure were primarily due to lower (P < 0.05) free-living physical activity energy expenditure in cachectic and noncachectic patients compared with healthy controls. Lower (P < 0.05) r es ing t energy expenditure was found in cachectic patients compared with noncachectic and healthy controls. After statistical adjustment for fat- free mass, resting energy expenditure was similar between cachectic patients and healthy controls, although a trend (P < 0.09) toward an elevated resting energy expenditure was found in noncachectic patients compared with cachectic patients and healthy controls. Reported energy intake did not differ among groups.

Tumor necrosis factor-a levels were measured in a subgroup of 16 heart failure patients (8 cachectic; 8 noncachectic). No differences in tumor necrosis factor-a (274 -+ 239 vs. 205 t 275 pg/ml) were found between groups. Tumor necrosis factor-a was not related to ejection fraction (r = 0.03), New York Heart Association

Cachectic Patients

Non- Cachectic Patients

Healthy Controls

Fig. 1. Daily energy expenditure and its components in cachectic patients, noncachectic patients, and healthy controls. REE, resting energy expenditure; PAEE, physical activity energy expenditure; and TEF, thermic effect of food. :“P < 0.05 less than noncachectic and healthy groups.


class (r = OX), percent weight loss (r = -0.237), fat mass (r = 0.09), fat-free mass (r = 0.X>, resting energy expenditure (r = 0.23), daily energy expenditure (r = 0.16), or reported energy intake (r = 0.00).

DISCUSSION

This is the first study to measure daily and physical activity energy expenditure in free-living heart failure patients with the use of stable isotopes. Use of the doubly labeled water technique represents a methodological advance over previous studies that have measured only resting energy expenditure in this popula- tion (23, 24). We examined the hypothesis that weight loss in heart failure patients is associated with elevated daily energy expenditure. We did not find an elevated daily energy expenditure in cachectic patients. In fact, cachectic patients had lower daily energy expenditure compared with noncachectic patients and healthy controls. Our findings argue against the hypothesis that an abnormally elevated daily energy expenditure contributes to weight loss in heart failure.

Differences in daily energy expenditure among groups were primarily due to differences in physical activity energy expenditure (Fig. 1). Physical activity energy expenditure was 459 and 312 kcal/day lower in cachectic and noncachectic patients, respectively, compared with healthy controls. Previous studies using motion detectors have reported reduced physical activity in heart failure patients (8, 19). However, the present study is the first to quantify the caloric cost of physical activity in heart failure patients with the use of stable isotopes. These results underscore the importance of physical activity as a determinant of daily energy expenditure in heart failure patients and demonstrate the need to accurately measure daily energy expenditure and its components in free-living heart failure patients before drawing conclusions about the absence or presence of a hypermetabolic state.

Decreased physical activity may contribute to skeletal muscle atrophy and exercise intolerance in heart failure patients (9, 15). Elevated rates of myofibrillar protein breakdown have been identified as a contributing factor to skeletal muscle atrophy in heart failure patients (17). Although it is presently unclear whether alterations in protein kinetics are a consequence of physical inactivity, it is possible that therapeutic inter- ventions designed to increase physical activity, such as exercise training, may preserve skeletal muscle mass by increasing myofibrillar protein synthesis (3 1).

Another contributing factor to the lower daily energy expenditure in cachectic patients was their lower resting energy expenditure. Resting energy expenditure was lower in cachectic patients by 284 and 147 kcal/day compared with noncachectic and healthy controls, respectively. However, because groups differed with respect to fat-free mass, the principal determinant of resting energy expenditure, we also examined differences in resting energy expenditure after statistical control for fat-free mass. With this adjustment, resting energy expenditure was similar between cachectic patients and healthy controls, whereas a trend toward an

elevated resting energy expenditure was found in noncachectic patients. Thus lower resting energy expenditure in cachectic patients compared with healthy controls is principally due to reduced metabolically ‘active tissue.

The absence of an elevated resting energy expenditure in cachectic and noncachectic patients compared with healthy controls differs from previous findings (23, 24) but may be explained by the heterogeneity of these groups with respect to weight loss and disease severity. Prior weight loss may explain the absence of an elevated resting energy expenditure in cachectic heart failure patients. Reductions in resting energy expenditure designed to prevent the further depletion of body cell mass are a well-known adaptation to weight loss (12). Thus, in cachectic patients, absence of a hypermetabolic state at rest may be due to weight loss-induced reductions in resting energy expenditure. Although one may question the categorization of cachexia based on the history of weight loss because of shifts in fluid status associated with diuresis, the lower fat mass, fat-free mass, and the fact that weight loss was expressed relative to premorbid body weight suggest that weight loss was primarily the result of reductions in body cell mass and not diuresis-associated reductions in body water.

In noncachectic patients, absence of resting hypermetabolism may be explained by their low to moderate symptom severity, as indicated by New York Heart Association functional class. Noncachectic patients in the present study (n = 13) were primarily classified as New York Heart Association functional classes II (n = 7) and III (n = 5), whereas subjects in our previous study (23) were largely grouped in functional classes III (n = 14) and IV (n = 4). Recent work from our laboratory showed that resting energy expenditure increases in heart failure patients with increasing functional class (18). Thus, although we noted a trend toward an increased resting energy expenditure in noncachectic patients, the examination of more symptomatic patients may be necessary to observe a significant resting hypermetabolism. Collectively, these findings demonstrate how spurious conclusions can be drawn regarding the presence of elevated daily energy expenditure when only resting energy expenditure is measured.

Tumor necrosis factor-e is a proinflammatory cyto- kine that causes weight loss in experimental animals (6). Tumor necrosis factor-a is elevated in some heart failure patients (14) and may contribute to weight loss. Thus we examined whether tumor necrosis factor-a was elevated in cachectic heart failure patients and its relationship to energy expenditure. No difference in tumor necrosis factor-a was noted between cachectic and noncachectic patients. Furthermore, no relationship was found between tumor necrosis factor-a and ejection fraction, New York Heart Association function class, percent weight loss, body composition, energy expenditure, or energy intake. Our results differ from those of McMurray et al. (16), who found increased tumor necrosis factor-a in cachectic compared with


noncachectic heart failure patients. Moreover, no difference in tumor necrosis factor-a was found in the present heart failure cohort when subjects were grouped as cachectic (n = 11; 164 t 101 pg/ml) and noncachectic (n = 5; 404 t 393 pg/ml) according to the criteria used by McMurray et al. (body fat percentage ~27% in males and <29% in females). Thus divergent results between studies are probably not due to the criteria used for grouping subjects as cachectic and noncachectic. Longi- tudinal studies are needed to clarify the possible contribution of tumor necrosis factor-a to weight loss in heart failure.

Because no evidence for an elevated daily energy expenditure in cachectic patients was found, we suggest that reduced energy intake accounts for the weight loss in heart failure patients. Although estimates of energy intake in the present study do not substantiate this hypothesis, the inaccuracy of self-reported intake diaries (10, 25) precludes a thorough testing of this hypothesis. In agreement with previous findings from our laboratory (lo), noncachectic patients and healthy controls were found to underreport energy intake. Interestingly, however, cachectic patients slightly over- estimated dietary energy intake. Although subjects were instructed to record any amount of food that was not consumed during the meal, failure to do so may have contributed to an overestimation of energy intake in cachectic patients. Several factors, including abdomi- nal pain and distension, gastrointestinal hypomotility, and delayed gastric emptying, have been suggested to contribute to anorexia in heart failure patients (20). Further studies that covertly monitor food intake in heart failure patients in response to perturbations in energy balance are needed to examine the regulation of energy intake.

Because of the cross-sectional nature of our study, we cannot rule out the possibility that an elevated daily energy expenditure in the precachectic state contributes to weight loss. The fact that daily energy expenditure was not elevated in noncachectic patients, however, argues against an elevated daily energy expenditure preceding weight loss. A longitudinal examination of changes in energy expenditure and body composition in heart failure patients is needed to fully elucidate the determinants of weight loss.

Our results do not support the hypothesis that elevated daily energy expenditure is related to weight loss in heart failure patients. In fact, daily energy expenditure was lower in cachectic patients due to lower physical activity and resting energy expenditure. We conclude from these findings that inadequate energy intake, not elevated energy expenditure, accounts for the weight loss in heart failure patients.

The authors thank all of the subjects who participated in this study.

This work was supported by grants (AG-00219, AG-00608, AG- 07857, RR-109, and AG-00564) from the National Institutes of Health and the Geriatrics and Gerontology Education and Research Pro- gram of the University of Maryland. M. J. Toth was the recipient of a Scholarship for Research in the Biology of Aging from the American Federation for Aging Research/Glenn Foundation.

Address for reprint requests: E. T. Poehlman, Dept. of Medicine, Univ. of Vermont, Given Bldg. C-247, Burlington, VT 05405.

Received 10 September 1996; accepted in final form 19 November 1996.

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Daily energy expenditure in free-living heart failure - Michael Goran

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