Author + information
- Received January 7, 2008
- Revision received April 4, 2008
- Accepted April 7, 2008
- Published online September 16, 2008.
- Mohan C. Madala, MD⁎,
- Barry A. Franklin, PhD⁎,
- Anita Y. Chen, MS†,
- Aaron D. Berman, MD, FACC⁎,
- Matthew T. Roe, MD†,
- Eric D. Peterson, MD, FACC†,
- E. Magnus Ohman, MD, FACC†,
- Sidney C. Smith Jr, MD, FACC‡,
- W. Brian Gibler, MD§,
- Peter A. McCullough, MD, FACC⁎,⁎ (, )
- CRUSADE Investigators
- ↵⁎Reprint requests and correspondence:
Dr. Peter A. McCullough, Division of Nutrition and Preventive Medicine, William Beaumont Hospital, 4949 Coolidge Highway, Royal Oak, Michigan 48073
Objectives Because excess adiposity is one of the most important determinants of adipokines and inflammatory factors associated with coronary plaque rupture, we hypothesized that obesity was associated with myocardial infarction at earlier ages.
Background The developing obesity pandemic of the past 50 years has gained considerable attention as a major public health threat.
Methods The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines) registry was a voluntary observational data collection and quality improvement initiative that began in November 2001, with retrospective data collection from January 2001 to January 2007. The CRUSADE initiative included high-risk patients with unstable angina and non–ST-segment elevation myocardial infarction (NSTEMI). We retrospectively examined, among 189,065 patients with acute coronary syndrome (between January 2001 and September 2006) in the CRUSADE initiative, the relationship of body mass index (BMI) with patient age of first NSTEMI.
Results A total of 111,847 patients with NSTEMI were included in the final analysis. There was a strong, inverse linear relationship between BMI and earlier age of first NSTEMI. The mean patient ages (± SD) of first NSTEMI were 74.6 ± 14.3 years and 58.7 ± 12.5 years for the leanest (BMI ≤18.5 kg/m2) and most obese (BMI >40.0 kg/m2) cohorts, respectively (p < 0.0001). After adjustment for baseline demographic data, cardiac risk factors, and medications, the age of first NSTEMI occurred 3.5, 6.8, 9.4, and 12.0 years earlier with ascending levels of adiposity (BMI 25.1 to 30.0, 30.1 to 35.0, 35.1 to 40.0, and >40.0 kg/m2, respectively; referent 18.6 to 25.0 kg/m2) (p < 0.0001 for each estimate).
Conclusions Excess adiposity is strongly related to first NSTEMI occurring prematurely.
We are in the midst of an obesity pandemic. Overall, incidence rates of overweight have increased 2-fold and obesity more than 3-fold over the past 50 years (1). The National Health and Nutrition Examination Survey in 2003 to 2004 found that 33.1% and 32.2% of Americans were overweight and obese, respectively (2). Similarly, the Behavioral Risk Factor Surveillance System reported that the prevalence of obesity increased by 24% from 2000 to 2005. However, the prevalence of extreme and super obesity (body mass index [BMI] >40 and >50 kg/m2) increased by 50% and 75%, 2 and 3 times faster, respectively (3). As obesity rates increase, so do associated cardiac risk factors including hypertension, diabetes, and dyslipidemia as well as potentially deleterious comorbidities including sleep apnea, atrial fibrillation, and chronic kidney disease (4,5). Additionally, obesity has recently been associated with emerging risk factors including systemic inflammation (6).
Specifically, abdominal adiposity is directly related to increased inflammatory markers such as interleukin-6 produced by adipocytes, which stimulates hepatocytes to produce high-sensitivity C-reactive protein (hsCRP) (7). We hypothesized that there might be a link between excess adiposity and occurrence of first myocardial infarction (MI) on the basis of the expected clustering of risk factors and presence of high levels of systemic inflammation in the obese (8,9).
Due to these associations, we postulated that excess adiposity might be associated with the occurrence of first MI at an earlier age. With data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association [ACC/AHA] Guidelines) registry, we examined the relationship between BMI and patient age of onset of first non–ST-segment elevation myocardial infarction (NSTEMI), adjusting for baseline demographic data, cardiac risk factors, and medications.
The CRUSADE registry was a voluntary observational data collection and quality improvement initiative that began in November 2001, with retrospective data collection from January 2001 to January 2007 (10). The CRUSADE initiative was designed to track guideline adherence, provide feedback about performance, and develop quality improvement tools to improve adherence to ACC/AHA recommendations for the treatment of acute ischemic symptoms.
The CRUSADE registry included high-risk patients with unstable angina and NSTEMI, the 2 conditions that collectively comprise non–ST-segment elevation acute coronary syndromes. Data were available from 566 sites on 189,065 patients from January 1, 2001, to September 30, 2006. Patients were excluded from the analysis for the following reasons: unstable angina (n = 15,939), insufficient data regarding prior MI (n = 2,544), a history of prior MI (n = 50,733), missing age (n = 175), and inadequate data for the calculation of BMI (n = 7,827). Thus, we derived a final population of 111,847 with first NSTEMI and calculated BMI.
All patients in the CRUSADE initiative must have presented at a participating hospital within 24 h of experiencing acute ischemic symptoms (lasting for at least 10 min) at rest. Patients with NSTEMI were required to demonstrate a characteristic rise and fall in cardiac troponin or creatine kinase-myocardial band with ≥1 confirmatory signs or symptoms including anginal chest pain equivalents, ST-segment depression ≥0.5 mm, transient ST-segment elevation 0.5 to 1.0 mm (lasting for <10 min), or an angiographically-documented occluded culprit vessel. Patients were ineligible for the CRUSADE registry if they transferred to a participating hospital >24 h after the last episode of ischemic symptoms.
Hospitals participating in the CRUSADE registry collected detailed process of care and in-hospital outcomes data through retrospective chart review. Data were collected anonymously during the initial hospital stay with trained data collectors and standardized definitions. Information regarding height and weight were taken from the medical record, which could have been derived by patient self-report or direct measurement. Because no patient identifiers were collected, individual informed consent was not required. The institutional review board of each hospital or medical center approved participation in the CRUSADE registry. All participating institutions were required to comply with local regulatory and privacy guidelines before beginning participation in the CRUSADE registry. Blood pressure and heart rate were recorded on presentation. Serum lipids/lipoproteins were measured within the first 24 h of hospital admission.
Body mass index was categorized into the following groups: ≤18.5, 18.6 to 25.0, 25.1 to 30.0, 30.1 to 35.0, 35.1 to 40.0, and >40.0 kg/m2. Overweight was defined as BMI ≥25 kg/m2, obesity class I as BMI 30.1 to 35.0 kg/m2, obesity class II as BMI 35.1 to 40.0 kg/m2, and extreme obesity as BMI >40 kg/m2. Hypertension was defined as resting systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg on repeated measurements or treatment with anti-hypertensive medications. Diabetes was defined as having an established diagnosis of diabetes mellitus or using insulin or oral hypoglycemic drugs. Hyperlipidemia was defined as total cholesterol >200 mg/dl or treatment with a lipid-lowering agent.
Patient demographic data, clinical characteristics, and prescribed medications were compared across BMI groups. Continuous variables were reported as mean ± SD, and categorical variables were reported as frequencies. To test for independence across BMI groups and patient characteristics and care patterns, stratum-adjusted Cochran-Mantel-Hanzel statistics for trend was used, where stratification is by hospital. In addition, Spearman correlation was used to evaluate the relationship between age of first NSTEMI and BMI. Furthermore, the relationship between age of first NSTEMI and BMI was evaluated, with specific reference to gender.
To investigate the factors associated with age of first NSTEMI, the generalized estimating equations method was used to adjust for patient characteristics and prescribed medications including gender, BMI categories, white race, family history of premature coronary artery disease, hypertension, diabetes, current/recent smoker, dyslipidemia, prior percutaneous coronary intervention, coronary artery bypass grafting, heart failure or stroke, renal insufficiency, electrocardiographic presentation (ST-segment depression, transient ST-segment elevation vs. none), clinical signs of heart failure at hospital admission, presenting heart rate and systolic blood pressure, and prescribed medications (aspirin, beta-blocker, statin, and angiotensin-converting enzyme inhibitor) (11). Because patients admitted to the same hospital tend to be more similar to each other than those in different hospitals (i.e., within-hospital clustering of responses), the generalized estimating equations method was employed. A p value <0.05 was considered significant for all tests. All analyses were performed with SAS software (version 9.1, SAS Institute, Cary, North Carolina).
Of 111,847 patients (59.4% men) with first NSTEMI, the mean ± SD age, body weight, and BMI were 66.1 ± 14.4 years, 83.2 ± 21.8 kg (183.0 lbs), and 28.8 ± 6.8 kg/m2, respectively. Table 1 details baseline demographic data and prescribed medications by ascending BMI category. There was a strong, inverse linear relationship between BMI and earlier patient age of first NSTEMI. The mean patient ages of first NSTEMI were 74.6 ± 14.3 years and 58.7 ± 12.5 years for the leanest (BMI ≤18.5 kg/m2) and most obese (BMI >40 kg/m2), respectively (p < 0.0001). The patient age of first NSTEMI according to BMI group for men and women is shown in Figure 1. The correlation between age and BMI was r = −0.30 (p < 0.0001). Women were predominant in both the leanest and most obese groups (Table 1). Rates of conventional cardiac risk factors are shown in Table 1 and Figure 2. A history of hypertension predominated in all BMI cohorts. However, there was a sharp rise in the frequency of diabetes from lowest to highest BMI group, 17.0% to 49.0%, respectively (p < 0.001). Likewise, there were progressively increasing frequencies of dyslipidemia with increasing BMI (p < 0.0001). Overall, 28.9% were currently smoking, and this proportion was similar across all BMI groups (p = 0.76). In concordance with increasing levels of cardiac risk factors, rates of prescribed cardioprotective medications, including beta-blockers, statins, and angiotensin-converting enzyme inhibitors, were all higher across ascending BMI groups (p < 0.0001 for each) (Table 1).
Overall rates of prior percutaneous coronary intervention and coronary artery bypass surgery were relatively low, 10.8% and 11.8%, respectively. Likewise, prior stroke, heart failure, and renal insufficiency occurred in 8.4%, 12.1%, and 10.6%, respectively, of the total sample. All of these comorbidities occurred in <16% of each BMI group.
Upon presentation, the mean systolic blood pressure was elevated in all patient subsets, with a trend for higher levels in ascending BMI groups. Mean values were 138.6 ± 34.1 mm Hg and 150.0 ± 31.9 mm Hg for the leanest (BMI ≤18.5 kg/m2) and most obese (BMI >40 kg/m2), respectively (p < 0.0001). In contrast, the mean resting heart rate, 86.2 ± 23.5 beats/min, was similar across all BMI groups. There was ischemic ST-segment depression in 29.2%, a peak troponin value greater than the upper limit of normal (ULN) in 95.8%, and a peak creatine kinase-myocardial band greater than the ULN in 85.9% of patients within 24 h of admission. The measured total cholesterol, low-density lipoprotein cholesterol, and triglycerides were all slightly higher across ascending BMI categories at time of presentation of NSTEMI. In addition, the mean high-density lipoprotein cholesterol was slightly lower in those with greater degrees of adiposity (Fig. 3).
The multivariate modeling adjusted baseline characteristics including BMI, cardiac risk factors, and prescribed medications for the outcome of patient age at first NSTEMI. Extreme obesity (BMI >40 kg/m2) had the strongest relationship with patient age of first MI. Compared with BMI ≤18.5 kg/m2, extreme obesity was independently related to a 12.0-year-earlier presentation of NSTEMI (p < 0.0001) (Fig. 4). Current/recent smoking was the next most important variable with a 9.7-year-earlier presentation (p < 0.0001) (Fig. 4). Other baseline factors considered in the model were found to have <3-year differential impact on age of first NSTEMI; yet given the large sample size, all were found to be statistically significant related to a younger age at presentation, including dyslipidemia and prior percutaneous coronary intervention.
In this large retrospective analysis of 111,847 patients in the CRUSADE initiative, approximately 36% were overweight and approximately 35% were obese. Extremely obese patients (BMI >40 kg/m2, approximately 6% of the sample) experienced their first MI on average approximately 16 years earlier than their lean counterparts. After adjustment for potential confounders, the age differential remained substantial at approximately 12 years. Although there were higher rates of almost all cardiovascular risk factors in the obese patients, these were countered with higher rates of prescribed cardioprotective drugs at baseline. A previous CRUSADE study confirmed higher rates of risk factors and prescribed cardioprotective drugs in this patient subset. The investigators reported that obese individuals received more aggressive coronary management, which was associated with improved outcomes (12).
Our multivariate analysis confirmed that higher BMI reduced the age of first NSTEMI more than any other variable, followed by current smoking, which resulted in a 9.7-year-earlier presentation. Our findings are consistent with a previous report in 906 consecutive patients who presented with acute MI and had a 10.6-year age difference between the BMI categories of <25 and >30 kg/m2 (13). In this study, BMI was independently related to earlier age of presentation but not higher morbidity or mortality. Previously reported results from the CRUSADE registry and the Primary Angioplasty in Acute Myocardial Infarction databases also indicate that obese patients do not have worsened mortality or complications after MI, largely due to their younger age (12,14).
Obesity, particularly in those with excess intra-abdominal adipose tissue, has been postulated to be a cardiovascular risk state mediated through a variety of pathways. Our data suggest that 1 pathway is a central factor in a cluster of elevated risk factors that include hypertension, diabetes, and dyslipidemia (15). A previous report from the CRUSADE registry found that 89.5% of all patients with NSTEMI had at least 1 traditional cardiovascular risk factor not including obesity (16). Although not measured in our study, we speculate that obesity plays a supporting role in “inflammation.” Intra-abdominal adiposity has been associated with elevations in interleukin-6 as well as other cytokines/adipokines that have been linked to the pathogenesis of atherosclerotic plaque accumulation and rupture. Interleukin-6, produced from adipocytes, is the major stimulus for hepatic production of hsCRP. Approximately 70% of the variation in hsCRP is explained by adiposity along with associated conventional risk factors (17). Thus, the link between adiposity, plaque rupture, and NSTEMI might be explained by higher levels of systemic inflammation and their chronic effect on coronary atherosclerosis over time. As a result, even though subjects in our extremely obese group were considerably younger than their leaner counterparts, inflammation and the aforementioned risk factors might trigger plaque rupture and myocardial injury prematurely in the natural history of atherosclerosis.
The present findings have enormous public health implications. The severe and extremely obese cohorts are the fastest growing populations in the U.S. (1–3). As the numbers in these BMI groups swell, we can anticipate significantly higher rates of first NSTEMI occurring in younger individuals. With the mean age below 65 years for all categories of obesity with first NSTEMI, we can expect a significant impact with respect to lost productivity, medical disability, increased long-term medical costs, and likely shortened survival over the following years. It seems that obesity will shift MI from a health event that commonly occurs in retirement years to one that occurs in the prime working years of life, and thus the personal, family, and social implications could be staggering for Westernized countries.
A large proportion of the overweight and obese populations are attempting to lose weight. Voluntary weight reduction in multiple studies has been associated with a concomitant decrease in all-cause and cardiac mortality (18–23). The explanation for improved outcomes is partly explained by favorable modifications in dietary and exercise habits, reductions in risk factors, increased compliance with cardioprotective medications, or combinations thereof (19). However, involuntary weight loss in patients after MI has been associated with higher mortality (24). Our study could not make inferences with respect to individual efforts at weight loss or weight trajectory, because we had only cross-sectional BMI data.
Our investigation has all of the limitations of retrospective studies. We relied on a combination of self-report and measured values to calculate BMI: thus, a methodological source of variation around the true value. We had no direct measure of adiposity or of lean body mass, and we had no measure of central adiposity—all of which would have made our assessment of body composition more precise. Although BMI is highly correlated with more direct measures of body fat in most populations, it might be a less useful indicator of adiposity among elderly persons, who tend to shift their body weight from peripheral to central sites (meaning an increase in waist-to-hip ratio but no change in BMI). We believe that a waist measurement might have created greater differentiation among racial subgroups in the normal or overweight categories, in whom BMI might not be a sensitive indicator of excess adiposity (25). Our results can only be generalized to the first NSTEMI and not to all types of acute coronary syndromes, because these data were available from the CRUSADE database. Those with greater degrees of adiposity were generally treated with more cardioprotective therapies; however, we did not have information relative to the chronic control of blood pressure, dyslipidemia, and diabetes. Finally, we do not have measures of important biologic parameters that link adiposity to atherosclerosis, including markers of insulin resistance, cytokines, and inflammation.
We and others have recently demonstrated that weight reduction in the extremely obese, as a single intervention, can substantially reduce multiple cardiac risk factors and measures of inflammation simultaneously (26,27). Thus, predicted Framingham risk is markedly attenuated. However, there are no long-term studies demonstrating that marked and sustained weight reduction in the obese increases the age at which first NSTEMI can be expected. Given the tight relationships between cardiac risk factors and other mechanisms by which excess adiposity promotes atherosclerosis, there is hope that significant and sustained weight reduction in those with considerable obesity can be a strategy to reduce cardiovascular risk and potentially forestall the age at which first MI or cardiovascular death will occur (28).
Excess adiposity is strongly related to first NSTEMI occurring prematurely. These data suggest that the constellation of established risk factors and additional metabolic derangements associated with excess adiposity predispose to early plaque rupture and myocardial injury despite higher rates of baseline cardioprotective therapies. As obesity becomes even more prevalent, we can expect higher rates of NSTEMI occurring during the working years of life.
- Abbreviations and Acronyms
- body mass index
- high-sensitivity C-reactive protein
- myocardial infarction
- non–ST-segment elevation myocardial infarction
- Received January 7, 2008.
- Revision received April 4, 2008.
- Accepted April 7, 2008.
- American College of Cardiology Foundation
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