This is the first study to examine the severity of inducible ischemia in an asymptomatic population of individuals with a sibling family history of premature CAD. We demonstrate that the presence and the severity of inducible ischemia at the time of screening are strongly and independently associated with long-term prognosis and the development of ACS. The prevalence of inducible ischemia was notably high in male siblings, including >30% after 50 years of age. Most siblings with reversible perfusion abnormalities had only minimal or mild severity ischemia but that still conveyed significant excess risk of subsequent ACS events. The presence and the severity of ischemia were particularly significant in predicting ACS events in siblings at intermediate risk by traditional risk factor assessment.
Very little is known about ischemia severity and CAD outcomes in asymptomatic populations. Few studies have been constituted entirely of asymptomatic persons who were not referred for testing based on risk assessment. Khandaker et al7
retrospectively evaluated 260 asymptomatic patients who were referred for nuclear perfusion imaging without known CAD but with an increased index of suspicion; all were at intermediate Framingham risk. Low and severe risk scans were defined by corresponding percent summed stress score as <5.5% and ≥14.0%, respectively, as per the Cedars-Sinai criteria.6
The prevalence of low, moderate, and severe ischemia was 22%, 20%, and 13%, respectively. Over 10 years of follow-up, little difference was seen in annual mortality in absent, low, and moderate severity ischemia but high severity subjects had an annual mortality rate ≥3%. Recently, Zellweger et al3
retrospectively examined an asymptomatic population referred for exercise treadmill stress myocardial perfusion imaging. High severity ischemia (≥7.5%) was significantly predictive for MI or cardiac death (annual event rate ≥3.0%). For other ischemia severity groups, the rate of incident CAD was very low, 0.4%. Thus, in a referred population, ischemia severity was not really predictive of CAD events, likely because the group was relatively homogenous for CAD events a priori. In contrast, our study did not select subjects based on any a priori suspicion or concern about possible CAD, except for family history. Fleg et al2
found the prevalence of ischemia by stress thallium perfusion imaging to be <5% in apparently healthy individuals 40 to 60 years of age in the Baltimore Longitudinal Study of Aging (BLSA), in contrast to the higher prevalence observed in our higher risk population with a family history of CAD. Annual ACS event rates were lower than seen in our study.
Recent position statements by the American College of Cardiology/American Heart Association28
and the American Society of Nuclear Cardiology29
indicate that myocardial perfusion imaging may be considered in asymptomatic adults with a strong family history of CAD, although there are no prior studies that support this and no guidelines currently exist. Our findings indicate that stress myocardial perfusion imaging in asymptomatic persons with a sibling history of premature CAD further risk stratifies persons in the Framingham intermediate risk category.
Other noninvasive imaging modalities exist for identifying occult coronary atherosclerosis. Coronary artery calcification (CAC) as determined by electron beam computed tomography or multidetector helical computed tomography (MDCT) is a popular and rapid means of detection of subclinical CAD. Higher coronary calcium scores offer incremental predictive value for CAD events over the Framingham Risk Score, especially among those at intermediate Framingham risk.30
However, CAC is an indirect measurement of anatomical CAD and does not necessarily reflect the severity of CAD stenoses,31
or more dynamic functional ischemic abnormalities on perfusion imaging.12,32
Some investigators have suggested that CAC could be used as a first-step screening tool in asymptomatic subjects to identify individuals with a higher pretest likelihood of hemodynamically significant CAD on stress perfusion testing.33,34
However, the specificity of CAC is very low in young persons, especially those <50 years of age.35
We have previously demonstrated discordance between CAC on MDCT and inducible ischemia on exercise thallium tomography.12
Recent advances in MDCT angiography now enable direct anatomical quantification of plaque severity and composition but the technique does not routinely detect perfusion abnormalities, and true utility for risk prediction in asymptomatic populations has yet to be determined.36
Thus, perfusion imaging may improve CAD risk prediction in this population with a strong family history of premature CAD by possibly capturing the early dynamic vascular pathophysiology of subclinical CAD.37
It is also possible that a tiered or hybrid approach for CAD detection using a combination of stress perfusion imaging with helical CT for CAC or MDCT angiography could provide improved prognostic assessment in higher risk asymptomatic populations, as has been suggested by some investigators for patients with known or suspected CAD.38