Response

Frick, Alber, and Weidinger raise several important questions about our investigation of flow-mediated dilation (FMD) in the Framingham Heart Study Offspring cohort.¹ They note that FMD in our Framingham participants was substantially lower than FMD in prior reports from our group. Even the participants in the lowest Framingham Risk Score quintile had lower FMD% (women 4.1±0.2%, men 2.7±0.2%; mean± SE) than a previously reported group of predominantly male patients with established coronary artery disease (6.7±0.8%),² who would be expected to have worse endothelial function. As suggested by Frick and colleagues, we believe that the most likely explanation for this apparent discrepancy relates to differences in the position of the occlusion cuff used to produce reactive hyperemia. We used a below-elbow cuff position in our current study. It is well recognized that the below-elbow cuff position produces less hyperemia and a lower FMD compared with the above-elbow position.^3,4 When designing the vascular function station at Framingham, we decided to use this cuff position because of a prevailing concern that local ischemia produced by an above-elbow position would confound our results. More recent consensus suggests that either position is acceptable.⁴

Frick and colleagues also raise the interesting possibility that risk factor burden plays a greater role as a determinant of FMD than prevalent cardiovascular disease (CVD). At their suggestion, we compared the mean FMD% values between low-risk individuals without CVD and those with prevalent CVD. Accordingly, we found that participants without CVD and with low risk factor burden have higher mean FMD% than individuals with higher risk factor burden and participants with prevalent CVD. The age-adjusted FMD% for women and men, respectively, was 3.9±0.1% and 2.7±0.1% for those without CVD and with low risk factor burden (quintiles 1 to 2; n=621 women, 545 men), 2.9±0.1% and 2.2±0.1% for those without CVD and with high risk factor burden (quintiles 3 to 5; n=777 women, 563 men), and 2.5±0.2% and 2.2±0.2% for those with prevalent CVD (n=127 women, 249 men).

In age-adjusted models, CVD was estimated to significantly lower FMD% by 0.36 (P=0.02). However, CVD was no longer significantly associated with FMD% after adjusting for other risk factors associated with FMD%, including sex, age, systolic blood pressure, body mass index, heart rate, walk test, lipid-lowering medication, and smoking within 6 hours before the test. Hence, we agree that the data are consistent with the hypothesis that in the community, FMD is more indicative of risk factor burden than underlying CVD.