A number of prospective studies including MESA8, 15, 18
have shown that impaired FMD, a measure of NO bioavailability, predicts CVD events, independent of traditional risk factors. Given the important role of NO in blood pressure regulation and vascular function, a reduction in NO bioavailability, mediated by an increased generation of reactive oxygen species,19, 20
may be a mechanism underlying chronic blood pressure elevation and hypertension onset. Several studies have demonstrated a consistent cross-sectional relation between impaired FMD and hypertension.6-10
However, it remains unclear whether endothelial dysfunction predicts progression to hypertension.
In the current study, reduced FMD was associated with an increased prevalence of hypertension at baseline, and this relation was independent of several other possible explanatory factors. This finding is consistent with previous cross-sectional studies6-10
that have examined the relation between FMD and hypertension. Although reduced FMD was associated with incident hypertension in unadjusted analyses, this relationship was attenuated and not statistically significant in adjusted models. A European of Society Working Group21
proposed in 2005 that impaired endothelial function is unlikely to be a direct causal mechanism of hypertension initiation and maintenance. Our results provide longitudinal evidence in support of this hypothesis.
At least one previous longitudinal study has examined the relation between impaired FMD and incident hypertension.11
A total of 952 normotensive post-menopausal women, recruited from an outpatient center in Italy had FMD assessed and were followed for hypertension incidence over a mean period of 3.6 years. Participants were excluded if they had a history of overt cardiovascular disease or a history of traditional risk factors such as hyperlipidemia, smoking, diabetes, and obesity. Lower FMD levels predicted incident hypertension, even after adjusting for age, family history of hypertension, baseline blood pressure levels, body mass index, waist circumference, duration of menopausal period, years of education, alcohol use, and physical activity. The association between reduced FMD and incident hypertension was large in magnitude. Compared to the highest quartile of FMD (≥ 5.5%), the multivariable-adjusted relative risks (95% CI) associated with decreasing FMD quartiles (4.3 - 5.4%; 3.6 - 4.2%; and ≤ 3.5%) were 1.92 (1.62 – 3.55), 3.00 (2.43– 4.29), and 5.77 (4.34 – 8.10) respectively.
The contrary findings of our study may be explained by differences in the characteristics of the study population. Our study utilized a large multi-ethnic, community-based sample that included an equivalent number of men and women drawn from several geographically diverse communities. Participants in MESA were also not excluded on the basis of traditional CVD risk factors. Further, the quartile-stratified incident hypertension rates (per 1000 person-years), as shown in , were substantially greater than those observed in the study conducted by Rossi et al. (10.4 for Q4, 20.9 for Q3, 40.8 for Q3, 61.1 for Q1).11
However, the cumulative incidence of hypertension in the current study (31.3% over a median of 4.8 years) is comparable to the proportions observed in other population-based studies including the Framingham Heart Study.22-24
Overall, the results of our study strongly suggest that endothelial dysfunction is not an independent predictor of hypertension in the general population. One explanation for this finding is that endothelial dysfunction may have influenced other risk factors for hypertension that were included in the multivariable-adjusted models. However, the relationship between lower FMD levels and incident hypertension became weaker and non-significant after adjustment for demographics and MESA site, which are factors that FMD could not have directly influenced. A more likely explanation is that endothelial dysfunction is a consequence of hypertension. In the Cardiovascular Risk in Young Finns Study,25
FMD was assessed in adults aged 24 to 39 years, and the relation of blood pressure levels measured in childhood and adolescence with subsequent FMD levels was examined. In male participants, systolic blood pressure levels in adolescence predicted lower FMD levels in adulthood, independent of traditional risk factors. These findings suggest that blood pressure elevations, at least in adolescent males, may adversely affect the biological processes underlying endothelial function such as NO bioavailability in early adulthood. Therefore, a chronic increase in blood pressure may induce endothelial damage over time, thereby contributing to atherosclerosis development and CVD event onset.4
There are several limitations to our study. The follow-up period was relatively short. However, hypertension incidence during follow-up was relatively common even among those in the highest FMD quartile. It is therefore possible that the relation between reduced FMD and hypertension onset may become even weaker over a longer follow-up period, as the incident hypertension rates between the highest and lowest FMD quartiles narrowed. Although non-significant, the adjusted relative risks of incident hypertension associated with lower FMD quartiles were not entirely negligible. Thus, despite our study being the largest to date (N=1,869) to examine the relation between FMD and incident hypertension, it is possible that an even larger sample size might have led to a statistically significant association between lower FMD quartile levels and incident hypertension. However, no clear association with incident hypertension was present when examining FMD as a continuous variable (adjusted relative risk of 1.00, p=0.935, Model 3, ). Further, even if the results in the fully adjusted model (Model 3, ) were to become statistically significant in a larger sample, the relative risk (95% CI) of 1.14 (0.93 – 1.38), comparing Q1 vs. Q4, is substantially weaker in magnitude than the relative risk of 5.77 (4.34 – 8.10) observed in the smaller study (N=952) by Rossi et al.11
Endothelium-independent vasodilation, typically assessed by exogenous nitrate administration, was not assessed in this study. Thus, we cannot definitely exclude the possibility that reduced FMD was additionally explained by smooth muscle dysfunction. Similar to other large population-based studies,8
we did not include this measure, because of limited feasibility in conducting this measure in a large number of participants. Blood pressures measured in the clinic environment are known to be variable. Therefore, it is possible that we included participants with hypertension at baseline in the analysis of FMD and incident hypertension. However, the results were not different when excluding those participants with baseline blood pressures in the prehypertensive range (systolic/diastolic blood pressure: 120-139/80-89 mmHg;26
data not shown). The classification of hypertension at follow-up could also be affected by misclassification, but analyses defining the outcome as incident hypertension across consecutive visits (i.e., incident sustained hypertension) did not produce different results.
Strengths of the current study include the use of a large multi-ethnic cohort that was drawn from several communities in the United States, the longitudinal study design, and the careful and standardized assessment of cardiovascular risk factors including blood pressure readings across time. As limited data exist on the longitudinal relation between FMD and the subsequent risk of hypertension, the current study provides valuable new information.