Download The prognostic importance of body mass index after

156
Correspondence
JACC Vol. 45, No. 1, 2005
January 4, 2005:154–64
10. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to
maintain sinus rhythm in patients with long-lasting persistent atrial
fibrillation: a prospective and randomized study. Circulation 2002;106:
331– 6.
11. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the
incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction
(SOLVD) trials. Circulation 2003;107:2926 –31.
The Prognostic Importance of Body Mass Index After Complicated Myocardial Infarction
dose percent (MSDD%) was calculated as mean percentage of the
study drug target dose (captopril/losartan) during each patient’s
follow-up. We denoted significance to be p ⬍ 0.05.
Baseline BMI ranged from 13.2 to 49.4 kg/m2. Table 1 depicts
baseline characteristics. Median follow-up was 2.8 years (range 1 to
1,471 days). Table 2 shows the main results of univariate and
multivariate analyses. Additionally, BMI categories had similar adjusted risk of cancer death (n ⫽ 83), CHF hospitalization (n ⫽ 585),
and number of CHF hospitalizations (n ⫽ 916) and CHF hospitalization days (n ⫽ 8,646). One-week mortality was comparable among
BMI categories (1.8% to 2.5%). The BMI category was independently (p ⫽ 0.018) related to the number of AMIs (n ⫽ 975)—
adjusted relative frequency compared with normal-weight: underweight, 0.93; overweight, 0.78; obese, 0.82.
In univariate analysis, there was a significant association between BMI category and MSDD%: underweight, 68.55; normal
weight, 70.24; overweight, 74.13; obese, 76.91. In univariate
analysis, a higher MSDD% was significantly protective of all end
points (p ⬍ 0.0001), except cancer death. However, the addition of
MSDD% to the multivariate analyses did not attenuate the
independent associations shown in Table 2.
To the Editor: Obesity is related to cardiovascular risk factors
and is an independent risk factor for coronary artery disease
(CAD) and premature death (1,2). However, the importance of
obesity to mortality and morbidity in patients with established
CAD is not well defined. The present analysis evaluated the
importance of body mass index (BMI) to prognosis after complicated acute myocardial infarction (AMI).
In post-hoc analysis, we examined the impact of baseline BMI
on all-cause death, cardiac death (death from AMI, chronic heart
failure [CHF], other cardiac causes, and sudden cardiac death),
cancer death, and AMI and CHF hospitalization in 5,388 patients
with complicated AMI who were included in the OPtimal Trial In
Myocardial infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) (3). Prior to data analysis, patients were
categorized into four BMI groups: underweight, ⬍22.00; normal
weight, 22.00 to 24.99; overweight, 25.00 to 29.99; obese, ⱖ30.00
kg/m2. Univariate and multivariate logistic regression analysis and
analysis of variance were performed (StatView 5.0.1, SAS Institute, Cary, North Carolina). Multivariate analyses adjusted for 46
variables comprising demographics, patient history, medication,
physical examination, and biochemical analyses. Mean study drug
Table 1. Baseline Characteristics by Baseline BMI Group
Baseline BMI Group
Underweight
n ⴝ 485 (9%)
Normal
n ⴝ 1421 (26%)
Overweight
n ⴝ 2520 (47%)
Obese
n ⴝ 962 (18%)
Baseline Characteristic
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Age (yrs)
Pulse rate (beats/min)
Systolic blood pressure (mm Hg)
Triglycerides (mmol/l)
HDL (mmol/l)
LDL (mmol/l)
Hemoglobin (g/l)
Potassium (mmol/l)
Uric acid (␮mol/l)
Serum creatinine (mmol/l)
Glucose (mmol/l)
70.3
75.6
120.3
1.60
1.24
3.42
129.8
4.17
321.3
97.6
7.09
10.70
14.17
17.85
0.66
0.34
1.03
15.41
0.49
111.7
26.27
2.80
68.9
74.6
120.7
1.72
1.19
3.33
132.0
4.16
330.4
100.1
7.19
10.02
14.49
16.09
0.76
0.32
1.03
14.29
0.44
101.9
24.51
2.90
66.6
75.3
123.0
1.97
1.15
3.38
135.0
4.16
345.6
100.4
7.56
9.55
13.94
16.72
0.93
0.29
1.12
13.87
0.46
93.6
20.95
3.15
65.5
75.3
126.5
2.18
1.12
3.32
136.0
4.14
362.7
99.4
7.98
9.19
14.06
17.42
1.10
0.28
1.23
14.54
0.45
96.8
22.68
3.16
n
%
n
%
n
%
n
%
605
796
121
448
836
444
2412
2098
1655
1242
1437
24.0
31.6
4.8
17.8
33.2
17.6
95.7
83.3
65.7
49.3
57.0
342
303
74
255
374
179
92.1
796
705
501
516
35.6
31.5
7.7
26.5
38.9
18.6
95.7
82.7
73.3
52.1
53.6
Female gender
Current smoker
History of CHF
History of diabetes
History of hypercholesterolemia
History of AMI
In-hospital aspirin
In-hospital beta-blocker
In-hospital diuretic
In-hospital statin
In-hospital thrombolytic
209
216
37
48
121
92
457
354
315
176
253
43.1
44.5
7.6
9.9
24.9
19.0
94.2
73.0
64.9
36.3
52.2
388
487
102
179
434
259
1357
1166
918
641
747
27.3
34.3
7.2
12.6
30.5
18.2
95.5
82.1
64.6
45.1
52.6
AMI ⫽ acute myocardial infarction; BMI ⫽ body mass index; CHF ⫽ chronic heart failure; HDL ⫽ high-density lipoprotein cholesterol; LDL ⫽ low-density lipoprotein
cholesterol.
Correspondence
JACC Vol. 45, No. 1, 2005
January 4, 2005:154–64
Table 2. Association Between BMI Category and All-Cause
Death, Cardiac Death and Recurrent AMI in Univariate and
Multivariate Analyses (Comparison With Normal-Weight BMI
Category)
End Point
Variable
OR*
95% CI
p Value
Underweight
Overweight
Obese
Underweight
Overweight
Obese
1.660
0.799
0.745
1.523
0.899
0.928
1.30–2.11
0.67–0.95
0.60–0.93
1.13–2.06
0.73–1.12
0.70–1.23
⬍0.0001
0.0112
0.0105
0.0061
0.3311
0.5994
Underweight
Overweight
Obese
Underweight
Overweight
Obese
1.695
0.812
0.772
1.471
0.865
0.928
1.30–2.21
0.67–0.99
0.60–0.99
1.06–2.04
0.68–1.10
0.69–1.26
0.0001
0.0371
0.0469
0.0201
0.2289
0.6281
Underweight
Overweight
Obese
Underweight
Overweight
Obese
0.978
0.802
0.776
0.966
0.829
0.752
0.74–1.30
0.67–0.96
0.61–0.98
0.72–1.30
0.68–1.01
0.58–0.97
0.8755
0.0189
0.0365
0.8197
0.0574
0.0269
All-cause death
(n ⫽ 908)
Univariate
Multivariate
Cardiac death
(n ⫽ 677)
Univariate
Multivariate
Recurrent AMI
(n ⫽ 750)
Univariate
Multivariate
*Risk of experiencing the end point in the BMI categories versus the normal BMI
category.
AMI ⫽ acute myocardial infarction; BMI ⫽ body mass index; CI ⫽ confidence
interval; OR ⫽ odds ratio.
After complicated AMI, compared with normal-weight patients, overweight/obese patients did not show a higher risk of
mortality or recurrent AMI or CHF hospitalization. On the
contrary, in univariate analysis, being overweight/obese was associated with lower risk of mortality and recurrent AMI, and the
lower risk of recurrent AMI in obese patients remained significant
in multivariate analysis. Underweight patients had 52% higher
adjusted mortality risk than normal-weight patients. Being overweight or obese, compared with being underweight, was independently predictive of more than 50% better survival (results not
shown).
The results may seem remarkable considering the vast range of
comorbidity associated with obesity, including CAD. Obesity may
confer excess risk by producing an inflammatory state, promoting
thrombosis and activating the sympathetic nervous system and the
renin-angiotensin system (4,5). Because obesity increases the risk
of CAD and mortality in the population (1,2,6), it might be
anticipated that obesity also increases mortality in patients with
AMI. Nevertheless, our results are supported by previous studies in
patients undergoing percutaneous coronary intervention/cardiac
surgery; the risk of mortality and cardiovascular events was
decreased in obese patients and/or increased in underweight
patients (7,8). However, in patients with CAD, elevated BMI was
associated with increased risk of acute coronary events (9). Previous results in patients after AMI are contradictory; obesity was
associated with increased risk of recurrent coronary events during
three years of follow-up in one study (5), but with lower one-year
mortality in another (10). Conversely, obesity independently predicted in-hospital death in older, but not in younger, patients (10).
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The reasons for the findings of the present study are probably
multifactorial. Overweight/obese patients may have better tolerance to afterload-reducing medication, which may lead to ingestion of higher doses of renin-angiotensin system inhibitors and
improved survival (11). In the present study, MSDD% increased
with increasing BMI, which may partly explain our findings.
Another possible explanation is related to the fact that neurohormonal activation may be important to the increased cardiovascular
risk associated with obesity (4). In our study, much of the negative
effects of obesity might have been attenuated by the treatment
given; all patients received renin-angiotensin system inhibition and
75% had beta-blockade. Consequently, any beneficial effects associated with being overweight/obese might have come into play,
such as a higher metabolic reserve, providing better resistance
against the metabolic stress associated with heart failure (12).
Variations in the use of neurohormonal blockers also might
possibly explain different study results concerning the impact of
BMI in patients with CAD (5,7–10).
Our observation that underweight patients had the worst
prognosis is supported by studies in patients with CAD (7,8) and
CHF (12,13). Cachectic patients with CHF demonstrate multiple
alterations in physiologic, biochemical, and neurohormonal pathways, leading to hemodynamic, immunologic, endocrine, metabolic, and muscular abnormalities (14). Perhaps, after complicated
AMI, lean patients may have similar deleterious abnormalities.
One may argue that our results were skewed by the younger age
in overweight/obese patients. Indeed, when excluding age from the
multivariate analyses, overweight and obese patients had significantly lower risk of death and recurrent AMI, and overweight
patients also had lower risk of cardiac death (data not shown).
Thus, age seems to be the major factor explaining why being
overweight or obese was not independently protective of mortality
compared with being at a normal weight. However, despite
adjustment for age and numerous other variables, the adjusted
mortality risk of being overweight or obese was still not higher
compared with being at a normal weight but was rather lower,
although not statistically significant.
*Linn M. A. Kennedy, MS
Kenneth Dickstein, MD, PhD
Stefan D. Anker, MD, PhD
Krister Kristianson, PhD
Ronnie Willenheimer, MD, PhD
for the OPTIMAAL Study Group
*Department of Cardiology
Malmö University Hospital
S-205 02 Malmö, Sweden
E-mail: [email protected]
doi:10.1016/j.jacc.2004.10.001
Please note: Dr. Kristianson has been an employee at Merck & Co. (now retired).
This study was supported by a grant from Merck & Co.
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as determinants of cardiovascular risk: the Framingham experience.
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index with outcome after percutaneous coronary intervention. Am J
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January 4, 2005:154–64
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between obesity and mortality in patients with heart failure. J Am Coll
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Increased Skeletal Muscle Amino Acid Release With Light Exercise in
Deconditioned Patients With Heart Failure
To the Editor: The existence of muscle metabolic alterations in
patients with chronic heart failure (CHF) (1) led us to test the
hypothesis that even a light exercise mimicking a daily life activity
(2) in CHF may induce an excess of muscle amino acid release. We
focused in particular on phenylalanine (Phe) release because this
amino acid is neither synthesized nor degraded within muscle (3).
Twenty untrained, clinically stable, normonourished fasting
male patients (Table 1) with moderate to severe CHF at morning
underwent hemodynamic procedures to measure femoral blood
flow, arterial and venous amino acid concentrations (branched
chain amino acids [BCAAs: valine, leucine, isoleucine], histidine,
alanine, glutamic acid, glutamine, and taurine), as well as pH and
lactate and free fatty acid (FFA) levels both at baseline and at 20
W bicycle exercise oxygen consumption (VO2, ml·kg⫺1·min⫺1)
steady state.
The net uptake and/or release of muscle amino acids was
calculated as: Net balance ⫽ ([A] ⫺ [V]) ⫻ F where A ⫺ V is the
femoral arteriovenous difference in amino acid concentrations and
F is leg blood flow. Thus, a net muscle uptake means amino acid
utilization, whereas a net muscle release indicates increased protein
breakdown and/or amino acid alteration.
At rest, controls and CHF had similar arterial amino acid concentrations (unpaired t test). Net muscle uptake and/or release of amino
acids by controls and CHF, at rest and during exercise, are illustrated
in Figure 1. At rest, CHF took up all amino acids except taurine,
which was released, whereas controls released amino acids with the
exception of glutamic acid and taurine, which were taken up. During
exercise, CHF, but not controls, released significant amounts of Phe
(from 38.2 ⫾ 2.4 to ⫺42.3 ⫾ 3.2 ␮mol·l⫺1·min⫺1; p ⬍ 0.01), the
three BCAAs; histidine, alanine (p ⬍ 0.05 in all cases), and glutamine
(p ⬍ 0.01). The uptake of glutamic acid declined (p ⬍ 0.01) and
taurine was taken up (p ⬍ 0.01), resulting in levels higher than in
controls (p ⬍ 0.05) (paired t test).
At rest, arterial FFA concentration as well as FFA release was
higher in CHF than in controls (p ⬍ 0.05 and ⬍0.001, respectively).
During exercise the difference in FFA release between CHF and
controls declined but remained significant (p ⬍ 0.01). At rest, blood
femoral vein was acidotic in CHF (pH ⫽ 7.34 ⫾ 0.02 vs. 7.41 ⫾ 0.01
in controls; p ⬍ 0.05); during the effort, the pH of CHF further
decreased (7.31 ⫾ 0.01; p ⬍ 0.01).
This investigation shows that patients with CHF exercising at a
light workload have a net muscle release of both Phe and other
amino acids. The mechanisms responsible for the net release of
Phe during exercise in CHF patients may include alterations in
intermediary and energy metabolism within muscle cells, intracellular acidosis, and cytokine production. Indeed, the low intramuscular glycogen concentration in resting CHF patients (4) may
make muscle energy metabolism more dependent on alternative
substrates such as amino acids derived from cellular-free pool
Table 1. Clinical, Functional, Hemodynamic, and Hormonal
Characteristics of Controls and CHF Patients
Parameters
Age (yrs)
Weight (kg)
Duration of disease
⬍18 months
ⱖ18 months
NYHA functional class II/III
Medications
ACE inhibitors
Digoxin
Diuretics
Oral nitrates
Left ventricular ejection fraction (%)
Peak VO2 (ml·kg⫺1·min⫺1)
Cardiac index (l·min⫺1·m⫺2)
Pulmonary wedge pressure (mm Hg)
Right atrial pressure (mm Hg)
Hemoglobin (g·dl⫺1)
Noradrenaline (pg·ml⫺1)
Serum sodium level (mEq·l⫺1)
Arterial lactate concentration (mg·dl⫺1)
Midarm muscle area (cm2)
Controls
(n ⴝ 10)
Patients
(n ⴝ 20)
60.2 ⫾ 2.1
70.5 ⫾ 3.5
59.5 ⫾ 2.5
72.3 ⫾ 9.1
—
—
—
8/20
12/20
12/8
—
—
—
—
56.5 ⫾ 1.5
33.3 ⫾ 1.4
—
—
—
14.1 ⫾ 0.8
278 ⫾ 72
140 ⫾ 5
3.9 ⫾ 1.1
46 ⫾ 2.1
17/20 (85%)
7/20 (35%)
20/20 (100%)
8/20 (40%)
22 ⫾ 0.9*
13.5 ⫾ 0.4*
2.16 ⫾ 0.15
17.6 ⫾ 2.5
6.7 ⫾ 0.9
13.3 ⫾ 0.11
412 ⫾ 22*
136 ⫾ 3
4.3 ⫾ 1.2
46.0 ⫾ 1.6
Values are expressed as mean ⫾ SEM. Statistical analysis: unpaired t test controls vs.
patients. *p ⬍ 0.01.
ACE ⫽ angiotensin-converting enzyme; CHF ⫽ congestive heart failure; NYHA
⫽ New York Heart Association.