Hypertension is a costly public health problem with a large burden of disease complications, including cardiovascular disease, chronic kidney disease, and increased mortality (22
). However, the pathogenesis of essential hypertension is not known. In these analyses, we found that structural measures (higher common carotid intima-media thickness by ultrasound) and functional measures, lower aortic distensibility by MRI, and lower large and small arterial elasticity by pulse contour analysis are independent predictors of incident hypertension. Most importantly, we found that the strength of these associations varied significantly by vessel caliber, with the strongest associations observed for the index relating to the pool of small arteries. These findings suggest that subclinical vascular abnormalities present before the onset of hypertension may be important in the pathway of development of hypertension.
Our findings confirm prior findings that subclinical measures of central stiffness predict incident hypertension (7
). Increased pulse wave velocity (a measure of central stiffness) predicted hypertension among only those participants followed up for more than 4 years in the Baltimore Longitudinal Study of Aging. Dernellis and Panaretou (23
) found that aortic stiffness, measured by echocardiography, was associated with incident hypertension in a Greek cohort. Moreover, Liao et al. (24
) found that arterial stiffness measured by ultrasound of the left common carotid artery was associated with hypertension defined as >160/95 mm Hg, which already represents stage II hypertension (22
), or the use of an antihypertensive medication. Our study extends these findings to both structural and functional measures of subclinical vascular disease in a large multiethnic cohort.
It is noteworthy that, in our study, the strength of the associations varied by vessel caliber. Even small changes in small arterial elasticity (the second quintile) were independently associated with hypertension, whereas only the highest quintiles of large arterial elasticity and aortic distensibility had independent associations. It is possible that the small arteries, which represent the oscillatory compliance of the vascular tree, are uniquely important in the development and initiation of hypertension, relative to the vascular stiffness and atherosclerotic plaque deposition of the larger vessels.
The fact that increased coronary artery calcification was not associated with incident hypertension after adjustment for comorbidities and inflammation suggests that deposition of calcium may play a less important, independent role in the incidence of hypertension than do other changes in the endothelium that affect function or structure of arteries. However, it is also possible that vascular calcium is an important contributor to hypertension only at much higher levels than those observed in MESA.
Our study is novel in that it includes different techniques to measure subclinical cardiovascular disease (ultrasound, MRI, and pulse contour analysis), which significantly strengthens our conclusions and reduces the bias that may occur from using only one technique. Moreover, these measures have been associated with adverse events. For example, common carotid intima-media thickness has been shown to predict adverse cardiovascular events (18
), and lower arterial elasticity has been found to be associated with cardiovascular risk factors in healthy adults (26
), with early kidney dysfunction (20
), and with cardiovascular disease (27
). In addition, this large, multiethnic cohort is fairly representative of the US population, free of cardiovascular disease at baseline. To minimize noise from those close to the threshold, we also included only those participants with blood pressures of <130/80 mm Hg.
Our study has certain limitations. We did not have invasive measures of endothelial function. We used pulse contour analysis to estimate large and small arterial elasticity. This method makes certain assumptions about the arterial tree when using the modified Windkessel model of circulation. Although some studies have suggested low reliability of the estimates, which may reduce the validity of the methodology (28
), this method has been shown to correlate with invasive measures of arterial compliance, and it has high reproducibility (10
). Moreover, lower elasticity by this measure has been associated with higher prevalence of cardiovascular risk factors among young adults (26
), with early kidney dysfunction (20
) and reported adverse cardiovascular events in one US cohort (27
). We ascertained some cases by the use of a newly prescribed antihypertensive medication, which may result in misclassification due to other indications for some of these medicines, including the report of subclinical abnormalities to treating physicians. Misclassification may also have occurred if a participant started and then stopped using a medication before a follow-up visit. However, our sensitivity analyses reclassifying diabetics, those with kidney disease, or those who had an adverse cardiovascular event during follow-up showed similar results.
In summary, we found that structural and functional measures of subclinical vascular disease are independent predictors of incident hypertension in a multiethnic cohort and that small arterial elasticity is the earliest predictor. Our findings are an important step in elucidating possible pathways for the development of idiopathic hypertension. Future studies should focus on elucidating whether these measures may be cost-effective in identifying persons at risk of hypertension and who may benefit from earlier treatment.