Early life determinants of blood pressure patterns in young adults

1. Background

1.1 The importance of blood pressure

Globally, elevated blood pressure is one of the most important risk factors for cardiovascular disease, accounting for two thirds of all stroke and a half of all coronary heart disease (CHD)1 . Blood pressure tracks throughout the lifecourse: hypertensive adults are likely to have higher than average blood pressure in youth, with the strongest tracking correlation being observed with the period of late adolescence2. Evidence that adult blood pressure is determined by factors operating in early life is strong3. These include maternal influences, such as smoking, blood pressure and breast feeding, and factors operating in childhood including salt intake and growth trajectories from birth. This latter appears to be a particularly strong determinant of subsequent adiposity, blood pressure and cardiovascular disease (CVD) risk4-10.

1.2 Early growth patterns and blood pressure

Developmentally, three critical post-natal periods have been identified: 1) the perinatal period, 2) the period of adiposity rebound and 3) puberty/adolescence. These represent periods when homeostatic set-points may be determined and when transient environmental exposures can exert long lasting effects11. The consequences of weight gain during development are complex. For example, weight gain during infancy appears to be beneficial in terms of adult risk of diabetes and CHD12-14. In contrast, adiposity rebound in childhood, particularly in low birthweight babies14 (so called accelerated growth or centile crossing) leads to an elevated risk of adult obesity, type 2 diabetes and elevated blood pressure5;10;13-18. Further, there is evidence that the earlier in childhood that this 'rebound' occurs, the greater the risk of subsequent CVD14;18. One mechanistic explanation for these observations is that rapid weight gain in childhood may result in persistently greater fat to lean mass ratio and central adiposity in adulthood19. This suggestion is of particular importance in view of the burgeoning epidemic of obesity and obesity-related disease in children in the developed world.

1.3 Limitations of brachial blood pressure

While there have been a number of longitudinal and cross sectional studies of blood pressure (BP) in childhood and adolescence20-22; all of these studies have been based on measurements of brachial blood pressure at rest. Although brachial blood pressure clearly predicts CVD in adults23, it is an imperfect measure, and has limitations as a measure of the BP experienced by the heart and cerebral circulation24 for a number of reasons. These are discussed below.

1.3.1 Brachial versus central blood pressure

Central (aortic) pressure appears to be a better predictor of CHD than brachial pressure25-27. On average BP measured in the brachial artery exceeds aortic or 'central' blood pressure by ~10mmHg 28, however the magnitude of difference between brachial and central BP is highly variable and is actually greater in young, fit individuals29-31. Sometimes this difference in brachial and central BP is so extreme that it results in a spurious diagnosis of hypertension in youth31-33. These observations suggest that brachial measurement of BP in young people may significantly underestimate relationships between early life events and central BP as a result of confounding by spurious augmentation of brachial BP. Consistent with this, one study of children aged 7-18 years attending paediatric outpatients34 reported that low birth weight was associated with increased central blood pressure and increased central augmentation index (AIx; a indicator of wave reflection). Increased AIx was associated with low birth weight independently of age, gender, diastolic BP, heart rate and current height, but the influence of current weight was not examined and relationships to measures of growth trajectory were not assessed.

1.3.2 Resting versus ambulatory blood pressure

Ambulatory blood pressure over a 24 hour period provides a more comprehensive assessment of blood pressure burden, and is generally a stronger predictor of cardiovascular outcomes than clinic measures, even in the general population35. Further, nocturnal blood pressure may be more informative in predicting risk, in part as loss or reversal of nocturnal blood pressure dipping is associated with an adverse CVD risk factor profile 36,37, and with increased arterial stiffness38. More recently, exaggerated blood pressure variability, particularly at night (assessed as the standard deviation of blood pressure), has also been shown to increase CVD risk, independently of absolute nighttime pressure39. Many of these phenomena have also been observed in youth; ambulatory blood pressure is superior to clinic measures in detecting disordered blood pressure patterns and associated measures of target organ damage 40,41. However, determinants of these altered 24 hour patterns have been less well studied and are conflicting. For example, whilst some studies shown an association between loss of nocturnal blood pressure dipping and obesity42, others do not43. Similarly, reports of associations between blood pressure variability and birthweight are inconsistent 44,45. As above, detailed assessment of growth trajectory, and other early life influences have not been comprehensively studied in association with blood pressure patterns in youth, but may account for the discrepancies observed.

1.3.3 Static versus dynamic blood pressure measurements

An exaggerated BP rise in response to exercise or dynamic pressor tests predicts the development of hypertension46-49, and stroke risk, independently of resting BP50. These independent associations may be due to impaired exercise induced vasodilation, as a consequence of arterial wall remodelling resulting in increased peripheral vascular resistance51;52 or endothelial dysfunction53, but early life determinants of dynamic blood pressure responses, and their associations with large artery structure and function, have not been studied.

1.4 The impact of blood pressure on the vasculature

Chronic elevated blood pressure is associated with increased pulse wave velocity (PWV; an indicator of arterial stiffness) and increased intima-media thickness (IMT) of large blood vessels, such as the carotid or femoral artery. These changes have been associated with subsequent cardiovascular risk, independent of other risk factors, including blood pressure itself, and have therefore acquired the status of surrogate CVD endpoints54-58. Obesity in youth and elevated blood pressure have been associated with increased thickness of the carotid artery wall in adolescence and early adulthood59-60. However associations between risk factors (e.g. maternal blood pressure and childhood growth) and arterial stiffness in youth have been inconsistent, with some studies showing the anticipated inverse relationship with, for example birthweight7 61, while others have shown no relation or counter-intuitive relationships with growth or maternal blood pressure 62, 6364. No study has explored the association between detailed early growth patterns, blood pressure and arterial wall thickness and stiffening, which may help to account for some of the inconsistent previous findings, and help to determine how these parameters influence structure and function of the large vessels.

In summary, elevated blood pressure in adolescence, tracks to adult blood pressure and subsequent CVD risk. Key determinants of blood pressure operate in early life, in particular growth trajectories, but the exact role of these determinants is unclear, and their relations with structural and functional aspects of the large vessels inconsistent. In part, previous studies may have been confounded by marked differences between brachial and central BP that are common in youth and failure to capture the full complexity of blood pressure patterns, including circadian patterns of BP, the inherent variability of BP and response to stressors. In addition, previous studies have not had a comprehensive assessment of maternal and early life influences in a sufficiently large study sample. We propose to measure such detailed aspects of BP, including central BP, wave reflection, arterial stiffness, ambulatory BP, ambulatory arterial stiffness index (AASI) 65 and dynamic BP responsiveness and relate these to key determinants such as early life influences, particularly post-natal growth trajectories and current obesity, and with surrogate CVD outcomes (i.e. carotid IMT, PWV) in the ALSPAC cohort.