Endothelial Progenitor Cells as a Biomarker for Transitional Phenotypes in Hypertension

Hypertension is a cardiovascular disease associated with elevated blood pressure (BP). The transition from the normotensive state to the disease state phenotype(s) of hypertension displays various intermediate phenotypes. The term “prehypertension” is such an intermediate phenotype characterized by levels of one biomarker of hypertension, ie, a systemic arterial BP between 120/80 mm Hg and 139/89 mm Hg.1 There are approximately 69 million individuals in the United States with this phenotype.2 Some individuals with BP in this range, particularly those with comorbidities such as diabetes mellitus, actually have hypertension and are at increased risk for cardiovascular events, particularly stroke, and progressive increase in BP over time.3-5 In the April issue of this Journal, Yang and colleagues6 investigated yet another potential biomarker in prehypertension––circulating CD34+ endothelial progenitor cells (EPCs). EPCs are necessary for repair and continued function of the vascular endothelium.6 It is known that the initial phases of (pre)hypertension may involve endothelial dysfunction as measured by reduced flow-mediated vasodilation (FMD) measured by changes in forearm blood flow.7 Prehypertension is associated with increased arterial stiffness, as indicated by increased augmentation index (AI) and increased arterial pulse wave velocity.6 Reduced endothelial nitric oxide (NO) production is thought to be part of the pathophysiology of both reduced FMD and indices of increased arterial stiffness.8 Thus, it is interesting that these investigators found that premenopausal women have an increased number and activity of circulating CD34+ EPCs when compared with men, and this was correlated with enhanced NO levels in plasma and culture medium. However, there was no difference in the number and activity of circulating EPCs and NO level and levels of vascular endothelial growth factors (VEGFs) and granulocyte-macrophage colony-stimulating factor (GM-CSF) between the normotensive and prehypertensive premenopausal women. The authors postulate that the sex differences in EPCs in prehypertension may be related to the mechanism(s) underlying vascular protection in premenopausal women in general. Data such as these reported here are of great importance in further refining the transitional phenotypes of hypertension. However, the interpretation of the data also illustrates the difficulty in analyzing such data. It is curious why one group of women was prehypertensive if no differences existed in circulating EPC number and activity, as well as levels of NO, VEGF, and GM-CSF, between the normotensive and prehypertensive women. However, the cardiovascular event rate in individuals with high-normal BP (130–139/80–85 mm Hg) is greater in men than women. Crude event rates per 1000 person-years in patients with high-normal BP who were 65 years or older were 19.5 in women and 28.1 in men. The crude event rates per 1000 person years in patients with high-normal BP who were younger than 65 years were 4.7 in women and 9.2 in men.9 Thus, the findings from the present study would seem to indicate that factors other than circulating EPC number and activity and NO, VEGF, and GM-CSF levels modulate the increase in BP from normotensive to prehypertensive. Perhaps the preservation of these factors in women relative to men may have greater long-term importance in preserving endothelial structure than in controlling BP. The BPs used to define the prehypertension phenotype in this study were recorded from the brachial artery. Yet, it is known that differences exist between peripheral systolic BP (pSBP) and central systolic BP (cSBP) as well as vascular stiffness as recorded from men and women. There are also significantly different characteristics of arterial wave reflection in women and men. Relative to men, women have larger reflected waves, indicating an earlier return of the reflected wave,10 and slower left ventricular ejection than men,11 as well as a smaller end-diastolic left ventricular diastolic diameter, stroke volume, and aortic distention and compliance10––all of which represent factors that might explain why women have a relatively higher cSBP relative to men.12 In addition, the different wave reflections and shape of arterial waves appear to affect how women and men correlate between different measuring devices. Women have a stronger correlation than men for cSBP, but men have a stronger correlation than women for peripheral AI.13 Peripheral AI measures backward-traveling arterial pressure waves and reflection. Because of the high level of resistance encountered as arterial diameters narrow, an increased AI should reflect an augmented reflection wave and therefore explain why an increase in stiffness would increase cSBP.14 Higher AI values are observed with adverse cardiovascular events15, 16 and left ventricular hypertrophy.17 Aortic pressure waveforms alter dramatically during lifetime, as return of reflected pressure wave to central aorta occurs earlier in the cardiac cycle as aging occurs. Young adults will have a pulse pressure that is higher in the periphery compared with the central aorta because of reflected pressure wave arriving centrally during diastole, but middle-aged adults have reflected pressure wave to the central aorta during systole. This will augment cSBP and central pulse pressure and reduce peripheral amplification. Our group has reported that women have significantly higher cSBP for the same level of pSBP than do men.18 This was true for both black and white women and independent of age. Thus, it appears that pSBP underestimates cSBP compared with men. Importantly, while the women in this study had a mean pSBP of 115±14.5 mm Hg, a level characterized as “ideal,” their corresponding cSBP, 123.7±16.6 mm Hg, was in a range consistent with prehypertension as detected by an applanation tonometric device. cSBP is a more potent predictor of target organ damage than is brachial blood pressure.19 These findings suggest a scenario wherein pSBP underestimates cSBP in women relative to men, and therefore underestimates risk of hypertensive target organ damage in women but not men. It is now also apparent that better phenotypic characterization occurs when ambulatory BP monitoring is used. Thus, at least 20% of individuals classified as having prehypertension do not actually have BP in the prehypertensive range.20 It is possible that the discrepancy between cellular markers and BP in normotensive as opposed to prehypertensive women may be related to measurement of BP. Finally, the more we learn about EPCs the better we will be able to utilize data from studies such as this to further refine phenotypic designations. For example, EPCs that express CD133+ in addition to CD34+ may be better at promoting new vessel growth and repair. Such molecular biomarkers will need to be correlated with physiological markers that reflect vascular stiffness. Further studies will be necessary to understand differing mechanisms of cardiovascular risk between men and women and the biomarkers that will help to define these mechanisms. Studies such as the one reported by Yang and his collaborators must be interpreted cautiously but certainly stimulate us to continue to explore the true nature of the disease hypertension.