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J Am Coll Cardiol, 2003; 41:521-528, doi:10.1016/S0735-1097(02)02862-0
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: CORONARY DISEASE IN THE YOUNG

Long-term follow-up of coronary artery disease presenting in young adults

Jason H. Cole, MD*, Joseph I. Miller, III, MD*,*, Laurence S. Sperling, MD* and William S. Weintraub, MD, FACC*

* Emory Center for Outcomes Research and Section of Preventive Cardiology, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA

Manuscript received June 5, 2002; revised manuscript received October 8, 2002, accepted October 17, 2002.

* Reprint requests and correspondence: Dr. Joseph I. Miller III, Division of Cardiology, Emory University School of Medicine, Emory University, 1525 Clifton Road, Suite 207, Atlanta, Georgia 30322, USA.
joseph_miller{at}emoryhealthcare.org


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: This study evaluated long-term survival and predictors of elevated risk for young adults diagnosed with coronary artery disease (CAD).

BACKGROUND: Coronary artery disease is rarely seen in young adults. Traditional cardiac risk factors have been studied in small series; however, many questions exist.

METHODS: We identified 843 patients under age 40 with CAD diagnosed by coronary angiography from 1975 to 1985. Death, hypertension, gender, family history, prior myocardial infarction (MI), diabetes, heart failure, angina class, number of diseased vessels, ejection fraction (EF), Q-wave infarction, in-hospital death, and initial therapy were studied. Patients were followed for 15 years.

RESULTS: The mean age was 35 for women (n = 94) and 36 for men (n = 729). The average EF was 55%. Fifty-eight percent of the subjects had single-vessel disease, and 10% were diabetic. The strongest predictors of long-term mortality were a prior MI (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.00 to 1.73), New York Heart Association class II heart failure (HR 1.75, 95% CI 1.03 to 2.97), and active tobacco use (HR 1.59, 95% CI 1.14 to 2.21). Revascularization, rather than medical therapy, was associated with lower mortality (coronary angioplasty: HR 0.51, 95% CI 0.32 to 0.81; coronary artery bypass graft: HR 0.68, 95% CI 0.50 to 0.94). Overall mortality was 30% at 15 years. Patients with diabetes had 15-year mortality of 65%. Those with prior MI had 15-year mortality of 45%, and patients with an EF <30% a mortality of 83% at 15 years.

CONCLUSIONS: Coronary disease in young adults can carry a poor long-term prognosis. A prior MI, diabetes, active tobacco abuse, and lower EF predict a significantly higher mortality.

Abbreviations and Acronyms
  CABG
  coronary artery bypass graft surgery
  CAD
  coronary artery disease
  CI
  confidence interval
  EF
  ejection fraction
  HR
  hazard ratio
  MI
  myocardial infarction

Coronary artery disease (CAD) is predominately manifest in older individuals, but the disease process begins in the young. Although the prevalence of coronary atherosclerosis in young adults is difficult to estimate, there are data on the risk of developing CAD at an older age based on risk factors present while young (1). Although myocardial infarction (MI) registries estimate that 2% to 6% of all infarctions involve individuals under the age of 45 (2), autopsies of young adults under the age of 34 have shown that 50% have intimal atherosclerosis (3). Prior literature emphasizes that cigarette smoking, cocaine use (4–6), diabetes, and dyslipidemia are prominent risk factors in the development of early atherosclerosis (1,2,4–15).

Small studies comparing younger and older patients with MI show that young patients are discharged with higher ejection fractions (EF), have fewer comorbidities, and are more likely to return to work (7). Also, short-term mortality studies indicate that these patients have a more favorable outcome (2,7,9,11,12).

Even with this information, however, many questions regarding young patients with CAD still exist. For instance, little data exist regarding follow-up beyond 10 years, and the effect of treatment strategies on mortality has not been definitively reported. Multivariate analysis of risk factors as correlates of long-term mortality has not been done in a large series. In order to better study these issues, we identified a large population of young individuals with angiographically proven CAD.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
The Emory Cardiac Database was retrospectively queried to identify patients treated between 1975 and 1985, who were under the age of 40 and who had a minimum of one angiographically documented coronary artery stenosis >50%. Follow-up data from the last 15 years were analyzed to address cardiovascular morbidity and mortality.

Data collection.   All data were collected on standardized forms and subsequently entered into a computerized database. Initial evaluations were made by clinical staff. At the time of presentation, patients underwent history and physical examination by a physician. Patient variables recorded included gender, age, family history of CAD in first-degree relatives before age 50, hypertension (defined by current or previous therapy or history of blood pressure >140/95), prior MI (by history), and history of and type of diabetes mellitus. Diabetes was defined by ongoing oral or insulin therapy or diet control, provided the clinician also had laboratory evidence of hyperglycemia. Each patient was also classified as a nonsmoker, active smoker, or former smoker, defined as no smoking in at least three months. Angina class was based on the Canadian classification (16) and heart failure was defined by New York Heart Association criteria (17). Electrocardiography diagnosis of Q-wave infarction was determined at initial presentation. All patients included in the study underwent angiography. Angiographers made a subjective assessment of EF and extent of coronary stenosis. Cases of inpatient mortality were recorded. Fifteen years of follow-up data were obtained by telephone interview and hospital encounters.

Statistical analysis
Categorical data were displayed as proportions and continuous data as mean ± SD. Categorical data were compared using chi-squared. Continuous data in two groups were compared using unpaired t test, and between multiple groups using analysis of variance. Survival over 15 years of follow-up was displayed using the Kaplan-Meier method, with comparison between groups by generalized Wilcoxon rank-sum. Correlates of long-term survival were determined by Cox model analysis. All p values were two-tailed and values of <0.05 were considered statistically significant. All confidence intervals (CIs) were calculated to the 95th percentile. Comparisons of clinical characteristics were made between women and men, diabetic and nondiabetic patients, and those treated with medical therapy, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft surgery (CABG). In the long-term survival model, variables defined were age, gender, presence of hypertension, prior MI, diabetes, heart failure, angina class, EF, active tobacco use, former tobacco use, number of diseased vessels, left main disease, Q-wave infarction, and in-hospital death. Each of these variables was considered a potential correlate of long-term mortality, and hazard ratios (HRs) were calculated on the basis of the backward-elimination Cox model. Finally, mode of initial therapy was entered into the model. This variable, which is most subject to selection bias, was considered separately so that analysis could be performed either with or without consideration of initial treatment.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Initial characteristics and in-hospital mortality.   We identified 843 patients under the age of 40 with CAD documented by coronary angiography. Though full details of the initial admission were not available for all patients, the most common presenting diagnoses included chest pain, abnormal stress test, and unstable angina. Only 2% of the patients presented with acute MI. Complete characteristics of the cohort, divided by gender, are shown in Table 1. Eleven percent of the patients were women. The mean age at presentation was 35 for women and 36 for men. The average EF in the study was 55% to 57%. Approximately one-half of the patients had prior MI (51% to 57%) at the time of initial admission. Smoking was a common risk factor; current and former smokers represented the majority of the patients (65%). Interestingly, 81% of the nonsmokers had a family history of CAD versus 53% and 57% of the smokers and former smokers (p < 0.0001). Active smokers (36% of the patient population) were more likely to have angina than the former smokers or nonsmokers (53% vs. 41% to 42%; p = 0.03). The active smokers did not have statistically higher rates of in-hospital mortality or Q-wave infarction. Men and women predominately had single-vessel disease (55% to 60%) and a similar distribution of diseased vessels. Only 2% of the patients had left main disease. Ten percent of the patients with CAD were diabetic, including a significantly higher percentage of the women (30% women were diabetic vs. 9% men, p < 0.0001). The available information on the diabetics revealed that 93% of the women and 72% of the men were on insulin. A family history of early CAD was present in 60% to 70% of the group.


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  		Table 1 Clinical Characteristics

 
Because of the known significant risk of early CAD in diabetic patients, clinical characteristics were compared between diabetic and nondiabetic patients, with results detailed in Table 2. Briefly, diabetic patients were more likely to have hypertension (50% vs. 25%; p < 0.0001) or heart failure (14% vs. 4.3%; p < 0.001), and were more likely to have suffered a Q-wave infarction (6.33% vs. 1.14%; p < 0.003). Both groups had a low risk of death while in the hospital (<1%).


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  		Table 2 Clinical Characteristics

 
In order to evaluate patients on the basis of initial treatment, clinical characteristics and in-hospital mortality of patients treated with medical therapy, coronary angioplasty, and CABG are presented in Table 3. This "initial treatment" reflects the initial treatment decision after angiography. All three treatment groups had very low in-hospital mortality. Given the options available, treatment was appropriate by current recommendations. Eighty-six percent of the insulin-requiring patients underwent CABG or medical therapy. Eighty percent of the patients referred for coronary angioplasty had single-vessel disease (p < 0.0001) and 67% undergoing CABG had two- or three-vessel disease (p < 0.0001). Ejection fraction was similar across the treatment groups (52% to 60%). Patients with heart failure on admission were more likely to undergo initial medical therapy versus revascularization (p = 0.0005). Compared with the other two groups, patients undergoing coronary angioplasty were less likely to have a prior history of infarction (30% vs. 60% to 74%; p < 0.0001).


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  		Table 3 Clinical Characteristics

 
Long-term mortality
Follow-up was obtained for 823 of the 843 patients. At 15 years, 253 of the patients with follow-up had died (31%), but subgroup analysis was able to demonstrate certain elements of the study population with greater risk. As shown in Figure 1, diabetic patients had a 15-year survival of only 35%, with a survival curve that diverged from nondiabetic patients by year 2. Analysis of other subgroups demonstrated increased mortality for the 451 patients with prior MI, starting at six years and further increasing over the 15 years (Fig. 2). Although the number of individuals with an EF <30% was low, their mortality was 72% at 11 years (Fig. 3). Thus, in our analysis, diabetic patients had a long-term survival comparable to the group with an EF <30%.



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  		Figure 1 Survival in diabetic and nondiabetic patients. The increase in diabetic mortality starts in the first year after angiography and continues over the 15 years of follow-up (p < 0.0001). After 15 years only 35% of the diabetic patients had survived.

 


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  		Figure 2 Survival for patients with a prior myocardial infarction (MI) versus no prior MI. A significant increase in mortality is seen starting after the second year for the individuals with a prior MI, and they had 45% mortality at 15 years (p < 0.0001).

 


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  		Figure 3 Fifteen-year survival for patients categorized by ejection fractions (EFs) <30%, 30%–49%, and >50%. Patients with an EF <30% had a dramatic mortality increase during the first year of follow-up, and only 17% were alive at 15 years (p < 0.0001 for differences across the three groups of therapy).

 
Next, outcomes were analyzed on the basis on initial treatment strategy. Figure 4 shows that freedom from a new MI was equivalent for the three treatment groups until year 8, when 23% of the CABG patients had an MI, a value that increased to 33% by year 10. The angioplasty group had the lowest number of second infarcts, with 27% having an event at 15 years versus 33% in the medical group (p < 0.0001) and 40% in the CABG group (p < 0.0001). Also, 26% of the medically treated patients eventually required CABG by six years compared with 12% of the angioplasty group (p = 0.09).



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  		Figure 4 Freedom from myocardial infarction (MI) based on initial therapy. The coronary bypass patients had the highest rates of MI starting around year 8, reflecting the time of expected vein graft loss (p = 0.04 for differences in survival across three initial therapy groups).

 
Cox proportional hazard model
In order to evaluate individual hazards of long-term mortality, a Cox proportional hazard model was developed for long-term mortality, with results detailed in Table 4. The initial model included all presenting clinical characteristics as potential covariates of mortality, and the strongest predictors of long-term mortality were active tobacco use (HR 1.59; 95% CI 1.14 to 2.21) and New York Heart Association class II heart failure (HR 1.75; 95% CI 1.03 to 2.97). As anticipated, diabetic patients also had a significantly worse prognosis (HR 1.41; 95% CI 1.04 to 1.90). Worsening EF was also correlated with poor prognosis (HR 1.3; 95% CI 1.19 to 1.43, for each 10% drop in EF). Importantly, age, gender, hypertension, angina class, and number of diseased vessels were not statistically significant predictors of long-term mortality. Next, choice of initial therapy was added to the model, and patients undergoing either revascularization option had a substantially lower mortality compared to medical therapy (two-way comparisons: angioplasty vs. medical therapy, HR 0.51; 95% CI 0.32 to 0.81, and CABG vs. medical therapy, HR 0.68; 95% CI 0.50 to 0.94). Hazard ratios for other covariates were little changed.


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  		Table 4 Correlates of Long-Term Mortality for All Patients

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The study of CAD in young individuals is important in the current era of preventive cardiology. The 823 patients detailed here represent the largest described series of documented patients with CAD under the age of 40. The large sample size allows new insights into the dramatic mortality of this group and identifies specific risk factors that predict individuals at a higher mortality risk. We also provide long-term follow-up data on three large treatment groups.

Some have identified current tobacco use as the most common risk factor in young MI patients. These studies reported that between 76% and 90% of young patients with MI are smokers compared with 40% of older patients with MI (10,11). Others have reported that only 8% of MI patients under the age of 45 did not smoke (12). Also, smoking is a notable risk factor for the development of fatty streaks in the aortas and coronary arteries of young autopsy patients (13). In our study, active and former smokers represented 65% of the patients. Smoking was not only a prevalent risk factor, but its presence was an important predictor of long-term mortality regardless of treatment strategy. Importantly, former smokers did not have a significant increase in their long-term mortality compared with those who had never smoked. Our data provide strong epidemiologic support to findings that show a decline in mortality with smoking cessation.

As would be expected on the basis of smaller observational studies, diabetes, which was present in 10% of our patients, was a significant marker for mortality risk. Interestingly, a much higher percentage of the women were diabetic. Most of the diabetic patients required insulin, and they also had greater cardiovascular morbidity, including Q-wave infarction and heart failure. Although in-hospital mortality rates were low, diabetes was a significant negative predictor of survival, as the diabetic patients had an unadjusted mortality of 65% at 15 years. Also, mode of treatment did not change their risk. This information confirms the importance of diabetes as a predictor of cardiac mortality, something that has been shown both in primary (18) and secondary prevention patients (19,20).

Ejection fraction is another well-known predictor of cardiovascular mortality (21–24). Our analysis confirms this point in young adults as well. Even though the average EF in our study was between 55% and 57%, for every 10% drop in EF, there was a substantial mortality increase. Furthermore, because of the inclusion criteria for our dataset, our analysis is relatively specific to ischemic cardiomyopathy. Of our patients with an EF <40%, only one did not have a prior MI. Although medical therapy has changed since the time of initial data inclusion, the mortality for the young patients with an ischemic cardiomyopathy was tremendous. Smaller studies have shown that patients with lower EFs and residual myocardial ischemia benefit from revascularization (25–27); however, the inclusion of mode of therapy as a covariate does not eliminate the profound hazard associated with low EF: an uncorrected 10-year mortality of 80%.

Our study provides 15 years of observational follow-up on three large treatment groups. Revascularization in young patients has been examined in small patient populations with varying results. Kofflard reported that angioplasty patients under the age of 35 had low infarct rates and excellent graft patency, but higher rates of repeat revascularization (28). Also, young patients undergoing CABG have been shown to have excellent short-term survival (29). One study of 125 patients under the age of 40 reported a mortality rate of 5.2% at 4.5 years (30). However, others have disputed this finding (31), and another showed patients to have a 75% and 50% survival at 10 and 15 years, respectively (32). In our large cohort, the angioplasty and CABG patients had a much lower long-term mortality (HR 0.51 and 0.68, respectively) than the medically treated group. During the first year after admission, the angioplasty patients had the highest rates of repeat revascularization, likely reflecting the high degree of restenosis in the pre-stent era. Also, medically treated patients were more likely to undergo CABG if revascularization were required. The CABG group had the highest rate of recurrent MI around the time of expected graft loss (year 8), yet they still had the lowest long-term mortality. Although selection bias cannot be overcome in the absence of randomization, our data illustrate that young individuals can benefit from revascularization.

The most striking finding of our study is the overall poor prognosis of individuals with premature CAD. Although only one patient in each treatment group died during the initial hospitalization, there was a 15-year mortality of 30%. Even considering differences in study design and patient characteristics, our analysis differs significantly with prior reports. In GISSI-2, an analysis of patients under age 50 showed them to have a low in-hospital and short-term mortality (33). Other studies also note low mortalities in follow-up of six months (2.7%) and longer to seven years (16%) (10,11). We demonstrate a mortality increase after the time period defined in other studies (8,10,32). Also, even though other studies required an MI as admission criteria, not all patients underwent angiography. Of note, data show that 20% of young adults may have non-atherosclerotic infarctions (34) and have a more favorable prognosis than individuals with arteriosclerosis (35). Finally, it is also important to recognize that our study reflects a tertiary referral center patient population.

Limitations of our investigation reflect a lack of understanding about the vascular biology of atherosclerosis at the time of initial data collection. Unfortunately, the importance of cholesterol as a coronary risk factor was not fully appreciated into the mid-1980s, and we do not have data on patient lipid levels. We also do not have documentation of specific medication therapy. Angiotensin-converting enzyme inhibitors, beta-blockers, and anti-lipemic medications have all been accepted into the treatment regimen of these patients since our cohort was first identified. It would also be ideal if there were documentation of other risk factors, such as cocaine abuse, but this information is not available. Many of our patients had a family history of CAD, and this is a prominent risk factor documented in other studies (2,29,32,36). It would be ideal to obtain follow-up on these patients’ children, as there are emerging data regarding the genetics of atherosclerosis. Recent data show that even healthy individuals with a family history of premature CAD have abnormal endothelial function reflecting early arterial pathology (37). In the future, we may find that atherosclerosis manifesting in young patients reflects a different disease process than in older individuals. Further investigation incorporating a modern understanding of oxidative stress, endothelial dysfunction, inflammatory markers, and lipid subtypes may better define the vascular biology and additional markers of future risk.

For now, however, clinicians must focus on the modification of known risk factors for CAD, and our study demonstrates the importance of these risk factors—particularly cigarette smoking and diabetes—in young adults. Finally, when a physician sees a young patient with documented CAD, the mortality demonstrated in our cohort gives a particular sense of urgency to treatment decisions, along with a possible bias toward revascularization if clinically appropriate. Our data also provide strong motivation for more continued aggressive study into the pathophysiology of CAD in this patient group.


   Acknowledgments
 
The authors thank Debbie Canup, Dee Anderson, and Marianne Hitchcock from the Emory Cardiac Databank for their assistance in maintenance and follow-up of the data for this paper.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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