The JNC-7 guidelines defined prehypertensive individuals as those having systolic BP: 120-139 mm Hg or diastolic BP 80-89 mm Hg and advised health-promoting lifestyle modifications in prehypertension to prevent the progressive rise in blood pressure and CVD (104). It is acknowledged that more recent JNC-8 guidelines do not define hypertension and prehypertension but instead define thresholds for pharmacologic treatment (105). Prehypertension is associated
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with increased stiffness of large to middle-sized arteries which is then associated with hypertension and increased risk of CVD. Tomiyama et al. compared arterial stiffness (measured by brachial-ankle PWV) in 1349 Prehypertensive and 984 normotensive people, reporting arterial stiffness to be increased in
prehypertensives. This was the case even after adjustment for potentially confounding variables, including age, sex and mean BP (106). Similarly a review of seven longitudinal studies showed that measures of arterial stiffness are independent risk factors for the development of hypertension (106). In another prospective study, 777 middle-aged Japanese men with prehypertension were successfully followed up for 3 years for the development of hypertension (107). Despite evidence of “tracking” (i.e. subjects with higher BP at the start of the follow-up period also had higher BP at the end of the follow-up period), higher brachial-ankle PWV values at baseline were independently associated with the risk of new onset of hypertension even after adjustment for major confounders and baseline BP(107).
Apart from prehypertensives, Najjar et al. (65) demonstrated that higher carotid-femoral PWV (arterial stiffness) was also an independent risk factor for new-onset hypertension in normotensive subjects. Increased arterial stiffness has also been reported in hypertensive children (108). Tomiyama et al. evaluated change in arterial stiffness in normotensive and prehypertensive people over a follow up period of 5-6 years (109): they found that change in brachial-ankle PWV during the study period was higher in prehypertensive subjects (n=550) than in those with persistent normal blood pressure (n= 612) (109).
Thus, prehypertension is a risk factor for arterial stiffness, while increased arterial stiffness contributes to elevation of BP. Some more mechanistic detail is given below.
1.3.7.1 Mechanism of increased arterial stiffness contribution to the development of hypertension
The medial layer of the aorta is enriched with elastic fibres which are
responsible for its elasticity. With each cardiac contraction, the systolic pressure of blood is dampened by the aorta due to its elasticity. This cushioning effect of
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the aorta attenuates the pressure wave (energy) as it is propagated to the peripheral organs (110-113). Increased arterial stiffness reduces this
“cushioning” effect and exaggerates the propagated pressure energy wave to peripheral vessels causing microvascular damage, especially in blood-flow-rich organs, such as the brain and kidney (110-113). Tomiyama et al. demonstrated in a middle aged cohort, that over six years of follow up, increased stiffness of large arteries as measured by brachial-ankle PWV was an independent risk factor for progression of the renal function impairment (estimated glomerular filtration rate- eGFR). In addition to this renal dysfunction, increased arterial stiffness also predicted increased peripheral vascular resistance and increase in BP (114). Thus, arterial stiffness related microvascular alteration increases peripheral vascular resistance, which may lead to development of hypertension (see Section 1.3.3).
1.3.7.2 Mechanism of prehypertension contribution to arterial stiffness
The changes associated with increased tensile stress on the vascular wall
include, VSMC hypertrophy, fatigue and degradation of elastic fibres, increase in the collagen content and increase in inflammation (115;116). In turn, these changes induce medial layer hypertrophy along with neointima formation in the arterial wall. Cumulatively, all these changes decrease elasticity and/or increase arterial stiffness (see Section 1.3.6) (115;116). The increase in BP in
prehypertension also augments the age-associated increase in arterial stiffness (109), and is also associated with increased arterial stiffness in old age (109).
Antihypertensive medications reduce arterial stiffness along with reduction in BP; especially, drugs blocking the RAAS. The TROPHY study was a landmark trial showing the importance of controlling BP in prehypertension range. It
demonstrated that a two year treatment of prehypertension with Candesartan (an angiotensin receptor blocker-ARB) reduced the risk of development of hypertension over an additional two years (117). Another provocative finding from TROPHY trial was that the rate of development of hypertension was 13.6% in candesartan group and 40.4% in placebo group after 2 years. Candesartan treatment was stopped after two years, and at the end of four years, the rate of incident hypertension was less in Candesartan group (53.2% vs placebo 63%) (117). This can be taken to show the importance of controlling or maintaining BP
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in prehypertension range as it has the potential to rapidly progress to hypertension.
As mentioned earlier (Section 1.3.7.1), elevated BP and arterial stiffness may aggravate each other, establishing a positive feedback loop; conversely, improving one abnormality may prove beneficial for the other (Figure 1.1).
1.3.7.3 Barker hypothesis
Low birth weight is a recognized risk factor for the development of hypertension and also CVD (118;119). Low birth weight is associated with structural and
functional changes in the vasculature, which are then implicated in the
development of CVD in adult life. Low birth weight is associated with reduced renal mass, and some studies have also shown its association with a reduced capillary network in peripheral organs (118;119). Both reduced renal mass and reduced capillary network may act to elevate BP. Mori et al. also showed increased aortic stiffness in new-born infants that were born small for
gestational age (120). In addition low birth weight is also associated with raised fasting plasma cortisol concentration in adult life and suggests involvement of hypothalamic-pituitary-adrenal axis as the link between low birth weight and raised BP in adult life (121). In summary both hypertension and increased arterial stiffness are more likely to occur in low birth weight infants.
Another possible mechanism in relation to birth weight is the changes in microcirculation. The primary evidence comes from the work of Barker et al. who found that BP and the risk of hypertension among middle aged
(approximately 50 years) men and women was predicted by a combination of their birth weight and placental weight (122). The highest BP levels were found among people who had been small babies with large placentas, and they
suggested that reduced blood flow in the trunk of a foetus that is small in relation to its placenta could lead to reduced microcirculatory growth (122). Another proposition is that a primary deficit in the development of the
microcirculation could have led to impaired growth of the foetus. The reduced microcirculatory growth in a foetus due to any mechanism may predispose the person to the development hypertension in later life.
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Similarly examination of men and women in different UK populations which had low growth rates up to the age of one year; were associated with increased prevalence of known risk factors for CVD, including BP, blood glucose, insulin, fibrinogen, factor VII, apolipoprotein B; along with increased death rates from CVD (123).
1.3.7.4 A “vicious cycle” in hypertension
The microvascular abnormalities have been shown to both result from and contribute to hypertension. A “vicious cycle” may exist in which the
microcirculation maintains or even exaggerates an initial increase in BP. Delano et al. described the pressure changes from central to peripheral circulation and have indicated that as much as 70% to 90% of the systemic pressure is delivered to the microcirculation in many skeletal muscles (124). Moreover Pries et al (125) showed that almost all the contribution in decreasing intravascular pressure before delivery to peripheral tissues was by micro vessels with a diameter of 100µm or less. An increase in BP might raise microvascular resistance which may lead to a further elevation of BP. Pries and colleagues (125;126) used computer simulation techniques to study the long term effects of increased BP and blood flow on the resistance and structural adaptation of microvascular circulation. They showed that a small increase in pressure can lead to larger structural increases in pressure and flow resistance by a
mechanism involving the tendency of vessels to reduce their luminal diameter in response to increased intraluminal pressure (125;126).
On the other hand, microvascular abnormalities might initiate the pathogenic sequence in primary hypertension by increasing peripheral vascular resistance. Increased peripheral resistance to blood flow raises central pressure in the aorta and large arteries, ultimately increasing vascular stiffness in large vessels as they are exposed to higher pressure. From this perspective primary hypertension may be seen as a developmental abnormality of the microcirculation.
Microvascular rarefaction reduces the vessel surface area available for oxygen delivery and also increases the diffusional distance between vessels and their target cells. If there is progression in rarefaction, it will result in tissue ischaemia which may be responsible for much of the end organ damage associated with hypertension (77).
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