Challenges of premature CAD Richard J. Katz, MD

Premature coronary artery disease (CAD) earlier than 40 years is rare; however, it remains a significant and potentially devastating example of the ongoing epidemic of atherosclerosis in men and women. Many studies have examined the risk factors associated with early-onset CAD and its prognosis in young adults. Smoking, familial hyperlipidemia, and diabetes are strongly associated with premature CAD, but these traditional risk factors identify only a subset of cases. Early and intermediate outcomes for young patients with CAD are favorable compared with older patients; however, long-term follow-up has been lacking.1 A better understanding is needed regarding the pathophysiology of this aggressive form of CAD and the modifiable risk factors for primary and secondary prevention.

The report by Cole and Miller (page 39) adds insight to the risks and prognosis of early-onset CAD. These investigators describe a large cohort of patients with the longest reported follow-up to date. Using the Emory Cardiac Database, 834 patients younger than 40 years were identified with clinical CAD. Patient variables were obtained at baseline, and outcomes were observed over 15 years. The study population represented 2% of Emory patients with acute myocardial infarction (MI). Overall mortality was 30% (2% per year). Risk assessment in the Emory study focused on traditional factors. Baseline predictors of increased mortality included smoking, diabetes mellitus, previous MI, and low ejection fraction or evidence of congestive heart failure.

Importance of smoking and diabetes in conferring risk

Similar to the Framingham Heart Study, the Emory database found smoking and diabetes mellitus to be major risk factors for early CAD. Two thirds of young CAD men and women in the Emory database were former or active smokers. Long-term mortality was increased for active smokers (hazard ratio, 1.59). The 15-year event rates for former and nonsmokers were similar, emphasizing the long-term benefit of smoking cessation.

Diabetes mellitus, a well-known potent risk factor for premature CAD, carried a 65% 15-year (4% per year) mortality rate in the Emory study. Only 10% of all patients had the diagnosis of diabetes at baseline. In young women, however, diabetes appeared to be a particularly potent risk factor for early CAD; 30% of the young women in the Emory study were diabetic compared with only 9% of men with early CAD. Nearly all of the diabetic patients in the Emory study had type 1 diabetes mellitus. Insulin was used to manage diabetes in 93% of the women and in 72% of the men. It is likely the Emory database underestimated

the importance of diabetes as a risk factor in the pathophysiology and long-term outcomes of premature CAD. Although only 10% of patients had diabetes at baseline, many of the patients in the nondiabetic category (90%) may have had unrecognized prediabetes. It has been reported that clinical atherosclerosis often precedes overt diabetes.2 Therefore, many individuals in this cohort could be expected to develop overt type 2 diabetes mellitus during follow-up. Screening for impaired glucose tolerance may be helpful in nondiabetics with premature CAD.

Improved understanding

of pathophysiology

In recent years, our understanding of the pathophysiology of CAD has grown beyond the characteristics included in the Emory database. Analysis of nontraditional CAD

risk factors should enhance the identification of high-risk patients and improve prevention strategies for premature CAD. Among these, the metabolic syndrome, homocysteine levels, lipid subclasses, and inflammatory markers have been partially studied in young CAD patients.

The metabolic syndrome, which includes obesity, insulin resistance, and impaired glucose tolerance, is increasingly common across all ages. This syndrome is associated with dyslipidemia, pro-oxidant stress, endothelial dysfunction, and prothrombotic factors. Several components of the metabolic syndrome have been identified as risk factors in young CAD patients. These include impaired glucose tolerance, low high-density lipoprotein cho-lesterol, elevated triglycerides, increased small, dense, low-density lipoprotein cholesterol, and high plasminogen activator inhibitor-1 levels.3

Homocysteine and lipoprotein(a) also have been associated with increased CAD risk in young men and women.4 Further studies of lipid subclasses and inflammatory markers, such as C-reactive protein, may add to the understanding of the high risk of premature CAD.

Genetic factors likely determine the effects of risk factors and expression of premature CAD. Familial hyperlipidemia, although rare, is

a disease with genetic links. The Emory database study is remarkable for the high incidence of family history of premature CAD. Two thirds of men and women had a first-degree relative with CAD who was younger than 50 years. A positive family history of premature CAD was found in 81% of the nonsmokers. New gene mapping techniques should allow determination of specific genetic markers of CAD risk.

Conclusion

With improved screening of patients at high risk for premature CAD, we can apply the lessons

from clinical trials that provide evidence-based treatment strategies

for disease prevention. The Heart Outcomes Prevention Evaluation (HOPE) trial provided evidence that we can prevent diabetes and CAD in high-risk patients using angiotensin-converting enzyme inhibitors.5 The Heart Protection Study showed benefit from statin treatment irrespective of baseline low-density lipoprotein cholesterol.6 The Diabetes Prevention Program demonstrated diabetes prevention using lifestyle and metformin therapy.