Once normal coronary arteries, always normal coronary arteries?

Coronary artery disease (CAD) is the leading cause of mortality worldwide [1]. While numerous studies quantified the importance of comorbidities on the risk of cardiovascular events, the pathogenesis of CAD remains incompletely understood. Studies investigating the incidence and progression of early stages of atherosclerosis are sparse. Rowe and coworkers report in the current issue on a retrospective cohort of patients originally found to have normal coronary arteries and undergoing repeat coronary angiography after a median time interval of more than 4 years. Among 97 patients with initially angiographically normal coronary arteries at a median age of 60 years, about 10% had developed CAD at the time they were referred for repeat angiography. The lifetime risk of CAD decreases with advancing age free of CAD [2]. In the absence of a history, symptoms, or signs of CAD, the lifetime risk at age 40 years was estimated at one in two for men and one in three for women in the Framingham cohort [2]. At age 70, the risk decreased to one in three for men and about one in four for women. Absence of clinical manifestations can, however, not be mistaken for absence of CAD. Acute myocardial infarction may originate from mild to moderate stenoses. The majority of these patients do not manifest with clinical symptoms prior to the event [3]. In the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, events attributable to nonculprit lesions represented nearly half of all repeat events at 3 years. Approximately, one-third of the nonculprit lesions eventually causing an event were angiographically inconspicuous at baseline [4]. The present study takes the hypothesis to the next level by taking absence of angiographically documented disease as the reference rather than absence of symptoms. While CAD may manifest in previously asymptomatic patients with progression of subclinical disease, the prognostic importance of angiographic absence of disease has not been determined to date. The study suggests a low incidence of new onset CAD in middle-age patients and implies that repeat angiographies in patients with previously angiographically normal coronary arteries may be unnecessary. The study is confounded by a selection bias of patients referred for angiography not once but twice for suspicious symptoms or cardiac comorbidities. Furthermore, the study is limited by a small sample size and a relatively short duration of follow-up. The estimated incidence of new CAD is hence not representative. On the other side, the observational study corroborates the importance of established cardiovascular risk factors such as age, hypercholesterolemia, and smoking status. Regrettably, the protective factor alcohol is not addressed. The study does not reveal a specific risk pattern for late onset of disease, and it remains to be determined, whether there may be a differential in timing of the importance of particular cardiovascular risk factors. What are the clinical implications of the presented findings on secondary prevention among patients with an established risk profile but angiographic absence of