Clinical research
European Heart Journal
doi:10.1093/eurheartj/ehm220
65
5
10
The impact of obesity on mortality in UA/non-STsegment elevation myocardial infarction
Heinz J. Buettner1*, Christian Mueller1,2, Michael Gick1, Marek Ferenc1, Juergen Allgeier1,
Thomas Comberg1, Klaus D. Werner1, Christian Schindler3, and Franz-Josef Neumann1
1
Interventional Cardiology, Herz-Zentrum, Südring 15, D-79189 Bad Krozingen, Germany; 2Department of Internal Medicine,
University Hospital, Basel, Switzerland; and 3Institute of Social and Preventive Medicine, Basel, Switzerland
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Received 7 September 2006; revised 23 April 2007; accepted 3 May 2007
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KEYWORDS
20
Unstable angina;
Myocardial infarction;
Obesity;
Revascularization
25
30
35
Aims Obesity is associated with diabetes mellitus and advanced coronary artery disease (CAD). Once
a non-ST-elevation acute coronary syndrome has occurred, the association between obesity and
prognosis is poorly defined. This study was designed to assess the impact of obesity on outcome after
unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) treated with early
revascularization.
Methods and results In a prospective cohort study in 1676 consecutive patients with UA/NSTEMI we
examined the association between presence of obesity and all-cause mortality. All patients underwent
coronary angiography and, if appropriate, early catheter-based revascularization. Patients were divided
into four groups according to body mass index (BMI): normal, 18.5–24.9 (n ¼ 551); overweight, 25–29.9
(n ¼ 824); obese, 30–34.9 (n ¼ 244); and very obese, above 35 (n ¼ 48). Obese and very obese patients
were younger and had a higher incidence of hypertension, diabetes mellitus, elevated cardiac troponin
T, and C-reactive protein levels. The angiographic extent of CAD was similar among the BMI groups.
Median follow-up was 17 (interquartile range 6–31) months. Cumulative 3-year mortality rates were
9.9% for normal BMI, 7.7% for overweight, 3.6% for obese, and 0 (no death) for very obese (log-rank
P ¼ 0.043). Obese and very obese patients had less than half the long-term mortality when compared
with normal BMI patients [hazard ratio (HR) 0.38, 95% confidence interval (CI) 0.18–0.81, P ¼ 0.012].
This result remained significant after adjustment for confounding prognostic factors including coronary
status and left ventricular function (adjusted HR 0.27, 95% CI 0.08–0.92, P ¼ 0.036).
Conclusion Obesity is associated with improved outcome after UA/NSTEMI treated with early
revascularization.
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Introduction
The epidemic of obesity has attained increasing recognition.
One in five Europeans and more than half of US adults are
overweight or obese.1 Annual health-care costs attributable
to obesity have been estimated to be approximately $68
billion, with an additional $30 billion being spent on
weight-reduction programmes and special diets.1 Obesity
is associated with higher levels of insulin resistance, as
well as hyperinsulinaemia, increases in triglyceride and
cholesterol levels, and increases in sympathetic nervous
system activity. Moreover, obesity is an important risk
factor for the development of diabetes mellitus, hypertension, coronary artery disease, ventricular dysfunction, congestive heart failure, stroke, and cardiac arrhythmias.2–5
In patients with established coronary atherosclerosis, the
body mass index (BMI) was associated with unstable angina
and myocardial infarction (MI).6 In addition, long-term
studies had shown that obesity is associated with excess
mortality in the general population.7–10
Approximately 2–2.5 million patients worldwide are hospitalized for unstable angina/non-ST-segment elevation
myocardial infarction (UA/NSTEMI) each year.11–13 Within
the last 3 years, early coronary angiography and revascularization has been established as the most appropriate management strategy in these patients.11–13 The impact of
obesity on outcomes in UA/NSTEMI receiving contemporary
treatment with an early invasive strategy remains unknown.
The purpose of this study was to evaluate the impact of
obesity on long-term outcomes following UA/NSTEMI in a
large cohort of consecutive unselected patients treated
with an early invasive strategy.
Methods
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Study population
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* Corresponding author. Tel: þ49 7633 4020; fax: þ49 7633 402743.
E-mail address: achim.buettner@herzzentrum.de
Consecutive patients admitted to our centre with UA/NSTEMI from
January 1996 to December 1999 were included in this analysis.
The study protocol required typical chest pain at rest and early
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& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Page 2 of 8
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150
coronary angiography. We excluded patients with de novo angina
pectoris on exertion or worsening angina during exertion only,
patients with persistent ST-elevation, patients in whom angiography
was not performed due to patient refusal (n ¼ 6) or extremely
severe concomitant disease (n ¼ 9) with severe dementia or
advanced malignancy, and patients with no information regarding
body weight or height (n ¼ 24). The study was carried out according
to the principles of the Declaration of Helsinki and approved by the
Institutional Review Board. Informed consent was obtained from all
participating patients. Arterial hypertension was defined as a known
history of hypertension or treatment with blood pressure lowering
drugs. Hypercholesterolaemia was defined as a known history of
hypercholesterolaemia, admission LDL cholesterol levels above
130 mg/dL, or treatment with cholesterol-lowering drugs. Diabetes
was defined as a known history of diabetes mellitus treated currently with either diet, oral glucose-lowering agents, or insulin. At
hospital discharge, all patients were counselled to use a lowcholesterol diet and statins if necessary to achieve an LDL cholesterol below 100 mg/dL during follow-up.
Body mass index
BMI was calculated as weight in kilograms divided by the square of
height in metres. Of the commonly used measures of obesity, BMI
is the body size measurement that correlates best with body fat
content.14 As recommended by the World Health Organization, a
BMI below 18.5 was classified as underweight, between 18.5 and
24.9 as normal, between 25 and 29.9 as overweight, between 30
and 34.9 as obese, and 35 as very obese.15
H.J. Buettner et al.
the following morning. In addition, cardiac markers (CK and
CK-MB) were determined at 8–24 h after the intervention, and
additionally whenever ischaemic symptoms developed. The statistical analyses were performed using the SPSS/PC (version 12.0, SPSS
Inc., Chicago, IL, USA) software package. A statistical significance
level of 0.05 was used. Comparisons were made using analysis of
variance for independent samples and x2 tests as appropriate. All
hypothesis testing was two-tailed. Cox proportional-hazards
regression analysis was used as the appropriate method throughout.
Multivariable Cox regression analysis was performed to identify
independent predictors of death. Together with BMI, all baseline,
demographic, clinical, laboratory, and angiographic variables were
entered in a univariable Cox regression analysis. All variables associated with long-term mortality in univariable analysis (P , 0.05)
were entered into the multivariable model. The linearity assumption was assessed by additionally including the square of the
respective covariate in the regression model. For each of the predictor variables, we tested the proportional hazard assumption by
including its interaction with time of follow-up into the regression
model. As measure of overall kidney function, the glomerular
filtration rate was entered.16 We calculated the glomerular
filtration rate with the use of the abbreviated Modification of Diet
in Renal Disease study equation:16 Glomerular filtration rate
(in mL/min/1.73 m2 of body surface area) ¼ 186 (serum creatinine in mg/dL)21.154 (age in years)20.203 0.742 in female
subjects 1.210 in black subjects. Additionally, the range of
hazard ratios obtained for obesity from all possible models with
two predictors, including those that were not significant in a univariable setting, was calculated. The cumulative survival curves
were constructed with the use of the Kaplan–Meier method.
190
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215
Patient management
155
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165
Patients with persistent chest pain underwent immediate coronary
angiography. In patients asymptomatic while on medical therapy,
coronary angiography was performed within 24 h of admission.
Whenever possible, coronary stenting of the culprit lesion was performed immediately after angiography. Stenting was not restricted
to patients with one- and two-vessel disease, but also favoured in
patients with three-vessel disease with suitable lesions. If revascularization was indicated, but percutaneous coronary intervention
was not considered the optimal treatment option (unprotected
left main disease, diffuse three-vessel disease), patients were
scheduled for early coronary artery bypass grafting.
Follow-up
170
175
All patients were scheduled for outpatient visits at 6 months. In
addition, patients were contacted by questionnaire on a regular
basis. For patients reporting cardiac symptoms, at least one clinical
and electrocardiographic examination was performed at the outpatient clinic or by the referring physician. All information derived
from contingent hospital re-admission records or provided by the
referring physician or by the outpatient clinic was reviewed and
entered into the computer database.
Endpoints and statistical analysis
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185
The primary endpoint was defined as death from all causes. As secondary endpoints, we assessed non-fatal MI and the composite of
death and non-fatal MI. MI was defined as typical chest pain at
rest followed by an increase in creatine phosphokinase (CK and
CK-MB beyond two times the upper limit of normal and five times
the upper limit of normal after coronary artery bypass grafting) or
new Q-waves in the electrocardiogram. To meet this endpoint criterion, patients who had initially presented with MI had to have
new ST-segment changes and an increase in CK of at least 50%
over the previous trough level in at least two samples reaching at
least three times the upper limit of normal. All patients underwent
electrocardiographic recordings immediately after percutaneous
coronary intervention or coronary artery bypass grafting and on
Results
Baseline characteristics
A total of 1676 unselected consecutive patients with symptoms of myocardial ischaemia at rest without persistent
ST-segment elevation were enrolled in the study. The
median BMI was 26.4 (inter-quartile range 24.3–28.8).
Table 1 describes the baseline, demographic, clinical, angiographic, and procedural characteristics of the cohort divided
into groups according to their BMI. One-third of the patients
had a normal BMI (n ¼ 551), half of the patients were
overweight (n ¼ 824), and 18% were obese or very obese
(n ¼ 292). Obese and very obese patients were younger,
had less often a prior MI, had a higher incidence of hypertension and diabetes mellitus, and more often elevated levels
of troponin T and C-reactive protein. The angiographic
extent of coronary artery disease and left ventricular function was similar among the groups. Discharge medication
was different among BMI groups with a higher use of
statins, ACE-inhibitors, and beta-blockers in obese and
very obese patients.
Only nine patients (0.5% of the study cohort) were underweight with a BMI below 18.5. Because of the small number
of patients and limited statistical power in this group, all
analyses were restricted to normal, overweight, obese,
and very obese patients.
220
225
230
235
240
245
Revascularization
About 70% of patients underwent revascularization. Percutaneous coronary intervention was the predominant revascularization strategy and was performed very early at a
median of 5.3 h from admission. Percutaneous coronary
intervention was not restricted to patients with one- or
250
Impact of obesity on mortality in UA/NSTEMI
Table 1
Page 3 of 8
Baseline patient, angiographic, and procedural characteristics according to body mass index on admission
255
P-valuea
Underweight
(BMI , 18.5)
Normal (BMI
18.5–24.9)
Overweight
(BMI 25–29.9)
Obese (BMI
30–34.9)
Very obese
(BMI 35)
All obese
(BMI 30)
n¼9
66.1 + 12
5 (56)
17.7 + 0.6
0
0
0
n ¼ 551
65.9 + 11
182 (33)
23.1 + 1.4
203 (37)
72 (13)
104 (19)
n ¼ 824
64.7 + 10
203 (25)
27.2 + 1.4
315 (38)
107 (13)
179 (22)
n ¼ 244
63.6 + 10
73 (30)
31.8 + 1.3
76 (31)
27 (11)
42 (17)
n ¼ 48
58.4 + 11
17 (35)
37.0 + 2.0
6 (13)
2 (4)
7 (15)
n ¼ 292
62.7 + 11
90 (31)
32.7 + 2.4
82 (28)
29 (10)
49 (17)
3 (33)
5 (56)
6 (67)
0
116 (21)
333 (60)
304 (55)
92 (17)
203
556
513
150
(25)
(68)
(62)
(18)
54 (22)
164 (67)
171 (70)
57 (23)
15
38
34
15
(31)
(80)
(71)
(31)
69 (24)
202 (69)
205 (70)
72 (25)
0
8 (89)
0
1 (11)
75 (14)
317 (58)
62 (11)
97 (18)
109 (13)
487 (59)
99 (12)
129 (16)
41 (17)
141 (58)
33 (14)
29 (12)
13 (27)
19 (40)
8 (17)
8 (17)
54 (19)
160 (55)
41 (14)
37 (13)
0
0
4 (44)
0.10
(0.00–0.36)
5 (71)
4 (57)
2 (29)
0.8 + 0.4
102 + 33
4 (0.7)
57 (10)
171 (31)
0.02
(0.00–0.21)
222 (56)
184 (46)
232 (60)
1.0 + 1.0
91 + 29
9 (1.1)
81 (10)
235 (29)
0.01
(0.00–0.15)
336 (59)
241 (43)
372 (63)
0.9 + 0.4
92 + 27
0
22 (9)
65 (27)
0.03
(0.00–0.18)
113 (65)
90 (52)
124 (70)
0.9 + 0.3
90 + 26
0
2 (4)
15 (31)
0.05
(0.00–0.72)
23 (72)
20 (63)
31 (86)
0.9 + 0.3
93 + 30
0
24 (8)
80 (27)
0.02
(0.00–0.18)
136 (66)
110 (53)
155 (72)
0.9 + 0.3
91 + 27
0.187
0.605
0.463
0.202
0.044
0.026
0.007
0.038
0.627
340
2 (22)
135 (25)
194 (24)
63 (27)
15 (32)
78 (28)
0.549
345
261 + 67
244 + 77
232 + 75
232 + 71
237 + 53
233 + 68
0.020
0.169
2
4
1
2
3
(22)
(44)
(11)
(22)
(33)
89 (16)
124 (23)
130 (24)
208 (38)
338 (61)
97 (12)
179 (22)
204 (25)
344 (42)
548 (67)
30 (12)
60 (25)
69 (28)
85 (35)
154 (63)
9 (19)
12 (25)
9 (19)
18 (38)
27 (56)
39 (13)
72 (25)
78 (27)
103 (35)
181 (62)
0.108
1 (11)
106 (19)
126 (15)
38 (16)
2 (4)
40 (14)
0.064
5 (56)
309 (56)
475 (58)
145 (60)
29 (60)
174 (60)
0.612
5 (100)
0
256 (83)
33 (12)
373 (79)
41 (10)
122 (84)
22 (17)
26 (90)
5 (20)
148 (85)
27 (18)
0.225
0.040
1 (11)
67 (12)
129 (16)
33 (14)
7 (15)
40 (14)
0.184
3 (33)
9.0 (5.5–16)
175 (32)
6.0 (3.0–10)
220 (27)
7.0 ( 4.0–11)
66 (27)
6.0 (3.0–10)
12 (25)
6.0 (3.3–13)
78 (27)
6.0 (4.0–11)
0.098
0.212
8 (89)
0
6 (67)
4 (44)
463 (87)
23 (4)
401 (75)
273 (51)
702 (88)
38 (5)
645 (81)
452 (57)
207 (88)
16 (7)
191 (81)
157 (67)
39 (83)
3 (6)
39 (83)
30 (64)
246 (87)
19 (7)
230 (81)
186 (66)
0.686
0.309
0.024
,0.001
2 (22)
2 (22)
2 (22)
0
0
62 (12)
112 (21)
303 (57)
39 (7)
23 (4)
85 (11)
159 (20)
526 (66)
64 (8)
41 (5)
40 (17)
56 (24)
166 (70)
21 (9)
19 (8)
6 (13)
13 (28)
33 (70)
3 (6)
0
46 (16)
69 (24)
199 (70)
24 (9)
19 (7)
0.046
0.304
,0.001
0.820
0.340
320
260
265
270
275
280
285
290
295
300
305
310
Age (years)
Female sex (%)
Body mass index
Prior myocardial infarction (%)
Prior coronary bypass grafting (%)
Prior coronary angioplasty (%)
Risk factors (%)
Smoker
Hypercholesterolaemia
Hypertension
Diabetes mellitus
Current cardiac disease (%)
Angina at rest .48 h
Angina at rest ,48 h
Non-Q myocardial infarction
Angina at rest .48 h to 8 weeks
post-myocardial infarction
Cardiogenic shock (%)
ST-depression .0.1 mV (%)
T-wave inversion (%)
Troponin T [median (inter-quartile
range), mg/L]
Troponin T 0.01 mg/L (%)
Troponin T 0.03 mg/L (%)
C-reactive protein 3 mg/L (%)
Creatinine (mg/dL)
Glomerular filtration rate
(mL/min/1.73 m2)
White blood cell count
10103 mL21 (%)
Platelet count (103 mL21)
Number of coronary vessels with
50% stenosis (%)
0
1
2
3
Two or three coronary vessels with
50% stenosis (%)
Left ventricular ejection fraction
40% (%)
Percutaneous coronary
intervention (%)
Proportion with stent (%)
Proportion with glycoprotein
IIb/IIIa antagonist (%)
Coronary artery bypass
grafting (%)
Medical therapy (%)
Duration of hospital stay (median
[inter-artile range], days)
Medication at discharge (%)
Aspirin
Oral anticoagulation
Beta-blocker
ACE-inhibitor or angiotensin
receptor blocker
Calcium channel blocker
Diuretics
Statins
Oral hypoglycaemic agents (%)
Insulin (%)
0.301
0.009
,0.001
0.015
0.155
325
330
335
BMI, body mass index; ACE, angiotensin-converting enzyme.
a
Comparison between BMI groups normal, overweight, and all obese.
315
,0.001
0.002
,0.001
0.007
0.349
0.145
350
355
360
365
370
375
Page 4 of 8
380
385
390
395
400
405
410
415
420
two-vessel disease but was also performed in patients with
three-vessel disease and suitable lesions. Coronary stents
were implanted in about 80% of the PCI patients. Percutaneous coronary intervention was performed almost four
times more often than coronary artery bypass grafting.
Patients received 3.2 + 0.9 distal bypass graft anastomoses
including left internal mammary artery grafts in 89%. Proportions of invasive treatment with percutaneous coronary
intervention or coronary artery bypass grafting were
similar among the BMI groups (Table 1).
Outcome
Ninety-one deaths and 74 non-fatal MI occurred during a
median follow-up of 17 (inter-quartile range 6–31) months.
Ninety-two per cent of deaths were from cardiovascular
causes. In-hospital rates for mortality and non-fatal MI
were low and similar in all groups (Table 2). In-hospital
stroke occurred in one (0.1%) patient with overweight BMI
and in two (0.7%) patients with obese BMI.
During total follow-up, all-cause and cardiovascular mortality was significantly lower among obese and very obese
patients. Obese and very obese patients had less than half
the long-term mortality when compared with normal
BMI patients (for all-cause mortality HR 0.38, 95% CI
0.18–0.81, P ¼ 0.012; for cardiovascular mortality HR
0.37, 95% CI 0.16–0.82, P ¼ 0.014). There was also a significant reduction in the combined endpoint of all-cause death
or non-fatal MI during total follow-up for obese and very
obese compared with normal BMI patients (HR 0.51, 95% CI
0.29–0.89, P ¼ 0.017). The number of events per personyear of follow-up was 0.046 in normal, 0.030 in overweight,
and 0.018 in obese or very obese patients for all-cause mortality, and 0.067, 0.061, and 0.035 for the combined endpoint of death or MI, respectively.
The Kaplan–Meier survival analysis showed cumulative allcause mortality rates at 3 years of 9.9% for patients with
normal BMI, 7.7% for overweight, 3.6% for obese, and 0
(no death) for very obese patients (log-rank P ¼ 0.043)
(Figure 1). The corresponding mortality rates at 1 year
were 6.5, 4.1, 2.5 and 0%, and the mortality rates at 2
years were 8.7, 5.5, 3.6, and 0%. When examined as a
continuous variable, BMI was significantly associated with
mortality (hazard ratio 0.91, 95% CI 0.85–0.97, P ¼ 0.003
for each unit increase in BMI).
425
Subgroup analysis
430
Figure 2 shows the reductions in all-cause mortality for
obese patients during total follow-up among subgroups. Survival benefit for obese patients compared with normal BMI
patients was realized for all subgroups irrespective of
gender, age, prior MI, diabetes mellitus, hypertension, the
extent of coronary artery disease, the elevation of
markers of myocardial necrosis or inflammation, or treatment modalities.
435
440
Multivariable analysis
Baseline variables associated with mortality in univariable
analysis were: age, ST-segment depression, previous MI,
elevated cardiac troponin T, elevated white blood count,
platelet count, kidney function, left ventricular function,
angiographic extent of coronary artery disease, C-reactive
H.J. Buettner et al.
protein, and obesity. In a multivariable Cox regression analysis that adjusted for all these variables, obesity (BMI 30)
remained a significant independent predictor of all-cause
mortality during long-term follow-up (adjusted HR 0.27,
95% CI 0.08–0.92, P ¼ 0.036) (Table 3). For none of the predictor variables in question, there was evidence for a violation of the proportional hazard assumption. All interaction
terms between the predictor variables and time of follow-up
had P-values above 0.1. The range of hazard ratios obtained
for obesity from all possible models with two predictors,
including those that were not significant in a univariable
setting, was 0.166–0.512.
Discussion
This large prospective study in consecutive unselected
patients with UA/NSTEMI receiving contemporary treatment
with early revascularization evaluated the impact of obesity
on long-term mortality. Our major finding was that obese
and very obese patients had less than half the mortality
when compared with normal BMI patients. The reduction
in mortality rates was consistent among all subgroups and
persisted after multivariable adjustment. This contrasts
with primary prevention studies that implicate BMI as a
strong risk factor for mortality.
The findings of this study complement and extend our
knowledge regarding the impact of obesity on cardiovascular
disease by suggesting that the prognostic impact of obesity
is confounded by a cardiovascular event.1–10 Obesity is a
risk factor for the development of diabetes mellitus and coronary artery disease.2–4 When coronary artery disease is
present, obesity is associated with unstable angina and
MI.5 However, once unstable angina/non-ST-segment
elevation MI develops and is treated with an early revascularization strategy as in our study, obesity is associated
with a significant reduction in long-term mortality. The
hypothesis that the history of a coronary event may
change the association between obesity and mortality is supported by several recent studies.17–21 In the GUSTO IV-ACS
trial examining the glycoprotein IIb/IIIa inhibitor abciximab
in patients with UA/NSTEMI not scheduled for coronary
intervention, higher body weight was even associated with
reduced 1-year mortality.20 Patients with body weight
,75 kg had a 1-year mortality of 9.6% compared with 7.4%
in patients with body weight 75–90 kg and 6.6% in patients
with body weight .90 kg (P , 0.001).20 Moreover, similar
results were reported in a combined analysis of the
SYMPHONY and 2nd SYMPHONY trials.21 These trials evaluated the oral platelet glycoprotein IIb/IIIa inhibitor sibrafiban, which was never approved for clinical use. Eisenstein
et al. found that overweight and obese BMI classifications
were associated with better intermediate-term survival.
Our findings extend this observation to patients treated
with the most contemporary management strategy and
importantly documents that the association between
obesity and mortality persists after multivariable adjustment including left ventricular function, angiographic
extent of coronary artery disease, and C-reactive protein
levels.
This finding of a better prognosis of obese patients with
UA/NSTEMI receiving contemporary treatment is supported
by predominately favourable short-term data from large
angioplasty registries and the BARI trial.22–25 Moreover, a
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450
455
460
465
470
475
480
485
490
495
500
Impact of obesity on mortality in UA/NSTEMI
505
510
515
520
Page 5 of 8
Table 2 Association between body mass index and outcome
At 30 days
Death (n)
Non-fatal myocardial infarction (n)
Combination of death, non-fatal
myocardial infarction, or stroke (n)
During total follow-up
Death, (n)
Non-fatal myocardial infarction (n)
Target vessel revascularization (n)
Combination of death or non-fatal
myocardial infarctionb (n)
Combination of death, non-fatal
myocardial infarction, or target
vessel revascularization
Hazard ratioa (95% CI)
Normal (n ¼ 551)
Overweight (n ¼ 824)
All obese (n ¼ 292)
11
17
28
19
25
45
3
6
11
0.51 (0.14–1.81)
0.66 (0.26–1.66)
0.73 (0.36–1.46)
0.294
0.372
0.373
41
22
68
60
42
43
111
84
8
9
43
16
0.38
0.77
1.21
0.51
(0.18–0.81)
(0.35–1.67)
(0.82–1.77)
(0.29–0.89)
0.012
0.508
0.337
0.017
120
179
55
0.88 (0.64–1.21)
0.414
P-value
570
575
580
585
a
For all obese relative to the group with normal body mass index.
b
Counting only the first event per patient.
525
530
535
540
545
Figure 1 Cumulative rates of death in relation to body mass index (log-rank
P ¼ 0.043).
550
555
560
565
recent study including 9633 patients with predominately
stable coronary artery disease undergoing percutaneous coronary intervention showed that obese patients had a lower
risk of in-hospital and 1-year mortality when compared
with patients with a normal BMI.23 However, in-hospital mortality seemed to be increased in patients with severe
obesity.21,24 Although only a moderate number of patients
with severe obesity were included in this study, our data
do not support this finding of a worse outcome in very
obese patients. In contrast, the very obese patients
showed the lowest mortality of all BMI groups examined,
suggesting a linear association between BMI and mortality
in patients with UA/NSTEMI receiving contemporary
treatment.
It is important to note that mortality in our study was
lower than reported for a comparable cohort of patients
with UA/NSTEMI treated with medical therapy and similar
to studies applying contemporary early revascularization
strategy.11–13,20
The improved long-term outcome of obese patients
observed in our study cannot be explained by an excess mortality in underweight patients, as they were excluded from
our analysis. Underweight patients have consistently been
shown to have increased in-hospital mortality, both after
percutaneous coronary intervention and coronary artery
bypass grafting.22–27
Given the observational nature of our cohort, we were
limited to describe the association between obesity and
improved outcome in UA/NSTEMI. Thus, further research is
necessary to elucidate the underlying pathophysiological
mechanisms responsible for the more favourable outcome
in obese patients. Possible mechanisms may include the
following.
Because obese patients have more detectable and potentially modifiable risk factors for cardiovascular disease,
medical treatment of the underlying clinical conditions
including hypercholesterolaemia, diabetes, and hypertension, eventually combined with increased exercise, change
in diet, and intentional weight loss, might have a stronger
impact on prognosis in obese when compared with nonobese patients. Corresponding to their higher incidence of
arterial hypertension and hypercholesterolaemia, obese
patients in our study were treated more often with
statins, ACE-inhibitors, and beta-blockers when compared
with normal weight patients. As these agents have been
shown to reduce mortality in patients with CAD, medical
treatment differences might account for some of the difference in long-term prognosis.13 In addition, even a modest
intentional weight loss can improve or prevent
obesity-related cardiovascular risk factors like diabetes mellitus and arterial hypertension.28,29 Exercise, even in the
absence of weight loss, decreases insulin resistance in
obese individuals.29
Other potential mediators of the improved outcome of
obese patients with UA/NSTEMI include the endogenous cannabinoids, lower platelet count, excess triglyceride content
in heart tissue including areas of healed MI, and lower age.
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615
620
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630
Page 6 of 8
H.J. Buettner et al.
695
635
700
640
705
645
710
650
715
655
720
660
725
665
Figure 2 Subgroup analyses for the association between obesity and long-term mortality. MI, myocardial infarction; TnT, cardiac troponin T; PCI, percutaneous
coronary intervention; CABG, coronary artery bypass grafting.
Table 3 Independent predictors of long-term mortality in
multivariable analysis
670
675
680
Platelet count (continuous)
White blood count
10103 mL21
Age (continuous)
Obesity (body mass index 30)a
Hazard ratio
(95% CI)
P-value
1.006 (1.002–1.009)
3.17 (1.36–7.39)
0.001
0.008
1.05 (1.00–1.10)
0.27 (0.08–0.92)
0.033
0.036
Baseline variables associated with mortality in univariable analysis and
entered into the multivariable model were: age, ST-segment depression,
previous MI, elevated cardiac troponin T, elevated white blood count,
platelet count, kidney function, left ventricular function, angiographic
extent of coronary artery disease, C-reactive protein, and obesity. CI, confidence interval.
a
All obese vs. normal body mass index.
685
690
Endogenous cannabinoids, which are upregulated in obese
patients, might have important protective cardiovascular
effects.30–34 Besides their central nervous effects, endogenous cannabinoids are also present in other cell types like
endothelial cells, activated macrophages, and platelets.30,31
They are potent vasodilators in the coronary and cerebrovascular beds.32 Endocannabinoid receptor agonists exert a
cardioprotective effect in ischaemia–reperfusion models
with a delay in the formation of necrotic zones and an
improved cardiac resistance to arrhythmias that is mediated
mainly through CB (2) cannabinoid receptors.33 In addition,
low-dose oral cannabinoid therapy reduced the progression
of atherosclerosis in an animal model.34
Platelets seem to play a major role in the pathophysiology
of acute coronary syndromes, as well as the outcome after
percutaneous coronary intervention with stent implantation.11–13,35 Interestingly, our data indicate that obese
patients with UA/NSTEMI have a significantly lower platelet
count when compared with normal weight patients. In
addition to the lower platelet count, platelet magnesium
depletion36 may contribute to reduced platelet function in
obese patients with UA/NSTEMI. Obesity alters the levels
of procoagulant and anticoagulant plasma proteins. The
net effect of obesity on haemostasis in UA/NSTEMI remains
unknown.37,38
Sudden cardiac death due to malignant ventricular
arrhythmias is responsible for the majority of deaths in
patients with UA/NSTEMI.13 Excess triglyceride content in
heart tissue including areas of healed MI might influence
the vulnerability to ventricular arrhythmias in obese compared with normal weight patients.39
As possible indicators for an earlier stage of coronary
artery disease, obese patients were younger compared
with normal and overweight patients and less often had
730
735
740
745
750
755
Impact of obesity on mortality in UA/NSTEMI
760
765
770
775
780
785
790
795
800
805
810
815
prior MI. On the other hand, the angiographic extent of coronary artery disease was similar among the groups. Furthermore, the association between obesity and lower long-term
mortality persisted in multivariable analysis after adjustment for age, left ventricular function, and angiographic
extent of coronary artery disease.
Limitations
Several limitations apply to this study. First, the present
study does not take into account the recent weight loss
and shifts in body weight, which may be associated with
risk. Unfortunately, this information is not available in our
data set. However, even without this additional information,
our findings have considerable clinical impact as risk is typically assessed according to actual BMI rather than BMI
changes. In addition, cumulative mortality rates seem to
separate early after the index event. Changes in body
weight seem less likely to account for a difference in early
when compared with late mortality. Secondly, the percentage of patients with a BMI of 40 or greater in this study
was similar to other European studies and lower than in
some previous US studies resulting in a low absolute
number of patients in this extreme group.17–25 Therefore,
the finding of an improved outcome after UA/NSTEMI
should not be extrapolated to patients with very severe
obesity. Thirdly, BMI may reflect also muscle mass. Other
measures of obesity such as waist-to-hip ratio might better
reflect body fat content and distribution when compared
with BMI. Fourthly, the presented results based on the categorization of BMI rely on a simplification of the relation
between BMI and mortality.
Our analysis has five particular strengths. First, it is
derived from a prospective study of consecutive unselected
patients rather than a randomized trial. This eliminates
selection bias and eases the extrapolation of findings into
clinical practice. Secondly, it includes long-term follow-up.
Thirdly, coronary angiography was performed in all patients.
The incidence of significant CAD was 87% in obese patients
when compared with 84% in normal weight patients. Moreover, 62% had coronary multivessel disease and 66% had an
elevated cardiac troponin following their chest pain
episode. Therefore, we can reliably exclude that obese
patients had a higher incidence of non-coronary causes of
chest pain that might have resulted in the favourable prognosis observed. Fourthly, a uniform revascularization strategy was applied in all patients. Fifthly, the extent of
coronary artery disease and left ventricular function was
quantified in all patients and included in the multivariable
analysis as potential cofounder.
Conclusions
This large prospective study in consecutive unselected
patients with UA/NSTEMI receiving contemporary treatment
with early revascularization showed that obese and very
obese patients had less than half the mortality when
compared with normal BMI patients. This observation
was consistent among all subgroups and persisted after
multivariable adjustment.
Conflict of interest: none declared.
Page 7 of 8
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