One in seventeen adults below the age of 40 years are hypertensive with higher rates in those with particular predispositions such as a familial history or developmental exposures to pregnancy hypertension or preterm birth. Hypertension in early life significantly increases the risk of stroke and cardiovascular disease before the age of 50 years and, to reduce this disease burden, interventions that target the distinct physiological mediators of blood pressure control in young people are required. This review highlights recent studies that have used a deep phenotyping approach to characterize the key phenotypic differences in vascular structure and physiology in young people that may be amenable to intervention.
Hypertension and the young adult
Recent randomized trials have demonstrated that there is a benefit for stricter control of blood pressures and that the lower the level the better the risk reduction,1 an observation supported by recent meta-analyses.2 As a result, the concept that the risk associated with high blood pressure is a continuum is increasingly recognized and current trends are for guidelines to encourage lower levels for diagnosis of hypertension, while aiming for tighter control.3 This changing practice is of particular relevance to younger individuals who are being diagnosed as hypertensive at younger ages and who will need appropriate advice on blood pressure management over many decades.4,5 Current guidelines for diagnosis of hypertension propose systolic blood pressures greater than 140 mmHg and/or diastolic pressures greater than 90 mmHg based on repeated clinic readings.3 Home or ambulatory monitoring has lower thresholds for diagnosis of stage 1 hypertension of a daytime average greater than 135 mmHg systolic or 85 mmHg diastolic.3,6 Based on these criteria it has been estimated that 1 in 17 young adults below the age of 40 years have blood pressures that exceed the diagnostic thresholds with this number rising to 1 in 5 if there are specific predisposing factors, such as a family or developmental history.7
Traditionally, awareness of blood pressure levels in young people has been suboptimal due to lower levels of interaction with health services and reduced opportunities for blood pressure management.8 When diagnosed there has been a tendency to manage the higher levels suboptimally because it is not considered relevant to the immediate health concerns of the individual or because it is felt it can be well managed with lifestyle changes.5,9 However, recent systematic review demonstrates that lifestyle interventions are effective when initially introduced but fail to sustain benefits for blood pressure reduction beyond a few months.5 The net effect of these problems is that there is a proportion of young people with poorly controlled blood pressure with a substantial lifetime risk for cardiovascular disease and stroke when older.4 However, there are also immediate health concerns for these young people, particularly women, who will be more likely to have complications and hypertension during their pregnancies,10 with resultant relevance to the long term health of their offspring.11 Research on optimal management of this age group is hampered by an under-representation of young people in clinical studies of hypertension so that there is a lack of evidence base with regard the nature of the hypertension in this young population or in relation to the most effective lifestyle or therapeutic interventions.12
Deep phenotyping to study development of hypertension in young adult life
Our approach to understand disease development in early life, identify key pathways of interest in predisposition to hypertension and develop specific preventive approaches has been to use multi-modality imaging to capture information on cardiovascular structure and function ‘from heart to capillary’. With this approach it becomes possible to model the interrelationship between features of the cardiovascular system and, with longitudinal data, study the progression of disease across vessel and heart.13 By extending the data collection to other organs such as brain and liver, a holistic view of disease development can be captured.14 Such multi-modality, multi-organ imaging provides unprecedented insight into disease development, which is recognized through its use within several landmark epidemiological studies, such as UK Biobank15 and guidance on future, disease-specific research strategies.16
Figure 1 demonstrates the range of measures that can be performed with appropriate equipment and infrastructure in young people for observational studies or clinical trials.13,17 Such investigations, in experienced hands, can be performed within a few hours, or split over a couple of days, making them acceptable for the majority of participants. Typically, to assess cardiac structure and function, cardiovascular magnetic resonance allows for the most robust, and detailed measures of left and right ventricular mass and geometry. Combined with echocardiography the imaging protocol allows a comprehensive study of systolic and diastolic function as well as valvular function.18,19 During the magnetic resonance scan it is also possible to image the aorta directly to measure aortic size, geometry and function, in the form of distensibility or pulse wave velocity.20,21 The ability to undertake regional assessment allows more specific study of the differential impact of variables, such as ageing, gender,22,23 or risk factor such as cholesterol levels24 on structure of different parts of the aorta. This is of importance as the structure of the aorta and composition of collagen differs significantly from ascending aorta to bifurcation so that it can function as a conduit for pulsatile cardiac flow.
Other arterial stiffness parameters can capture information on broader vascular beds including conduit vessels. These include tonometer and cuff-based measures of pulse arrival time at peripheral vessels such as the carotid, femoral, or radial artery.25 In addition, measures that use the peripheral waveform and transform this to extract interpretations of features of pulse wave analysis can provide additional information.26 Cardiac ankle vascular index (CAVI) provides an additional global measure of arterial pathophysiology. Figure 2 demonstrates how the device uses both a microphone to identify the time of aortic valve closure and limb cuffs to identify the timing and character of the pulse wave.27,28 The calculation used to derive the index means it is independent of blood pressure at time of measurement.28 Imaging also allows assessment of a further, vascular bed important in determining blood pressure levels, the smaller vessels that extend from resistance arterioles to the capillary bed.29 Techniques exist to study density of small vessels within tissue including the skin30,31or at accessible visible beds such as the retina.31 Functional differences in these vascular beds can also be measured based on responses to different stimuli and stimuli-induced measures incorporate those that study conduit function such as flow mediated dilatation32 and reactive hyperaemic flowmetry measures along with tests of microvessel oxygenation or perfusion.29
There are limitations to this deep phenotyping approach. Only a limited number of centres have the complex infrastructure required to support multiple modalities from cardiovascular magnetic resonance through to microvascular assessment, alongside the individual technical expertise across modalities to maintain and process the imaging data to a high standard. As a result, a deep phenotyping approach, although potentially of value in selected patients, is unlikely to form part of population-based clinical care. Rather, its value lies in investigation of currently poorly defined areas of cardiovascular diseases to refine understanding and to help focus future studies and clinical trials into pathways of specific interest; akin to an -omics-style investigation with an ‘imaging probe’. Once the infrastructure is established in a centre, the per participant cost for a combination of investigations is in the order of £500–£1000, with larger studies introducing economies of scale. The cost of logistical organization and time required for identification and recruitment of participants for observational studies is significant and, therefore, the investment in deep phenotyping ensures maximum scientific value is obtained from these studies. The costs associated with clinical trial failure due to inappropriate selection of a limited set of endpoints are also substantial and could be mitigated by collection of a more detailed cardiovascular evaluation.
CAVI as tool to investigate cardiovascular pathophysiology
Previous studies have shown that associations between cardiac and vascular measures differ between younger people and older individuals.23,33,34 This may be relevant to how cardiovascular changes emerge during adolescence. What have studies that incorporate a broad range of measures told us about cardiovascular predispositions to hypertension in young people? The number of studies with a comprehensive assessment of the cardiovascular system ‘from heart to capillary’ are limited. However, some of our examples are presented below to highlight the potential value of this approach.
Longitudinal studies that have followed individuals from adolescence to adulthood with multiple vascular measures have shown that vascular measures during adolescence can predict both cardiovascular phenotype in young adulthood and changes in blood pressure. Interestingly, those individuals with reduced endothelial responses in adolescence, independent of other risk factors such as their body size, cholesterol level or smoking history, tended to have an accelerated increase in their blood pressure over the next 5 years.35 Furthermore, they had greater cardiac mass in young adulthood than their contemporaries with better endothelial function during adolescence.35 These findings raise the possibility that there may be value in specific interventions to protect vascular responses during early life to reduce more widespread adverse changes in cardiovascular growth and development.36
The use of multimodality measures have also proved of value for developing insights into variation in cardiovascular pathology related to early life exposures and risk markers, for example, links between a family history of hypertension and the emergence of hypertension in the offspring. Those at risk are most easily identifiable early in life in families where the stress of pregnancy induces hypertension in the mother17 or the pregnancy results in preterm birth. The offspring of such pregnancies are known to be more likely to be hypertensive in later life with 1 in 5 born to more complicated hypertensive pregnancies being hypertensive by the age of 20 years.7 We have undertaken detailed cardiovascular phenotyping of these individuals to define the cardiovascular changes evident in the early stages of hypertension. Using a multimodality approach, we showed that a range of early life exposures can be associated with long term variation in vascular function. In preterm infants who had received antenatal steroids37 or were fed with intravenous lipids24 differences in aortic stiffness were evident 20 years later. However, these investigations also showed the overall impact of preterm birth was relatively small.13 Previous studies had suggested all preterm infants may have stiffer arteries but interpretation of these results has been complicated by the fact those born preterm have higher blood pressure. CAVI provided information on global changes in arterial function independent of blood pressure at time of measurement that supported our observations from other imaging modalities that, in general, those born preterm have very similar arterial stiffness to those born at term. The exclusion of significant effects of arterial stiffness then allowed us to, highlight the importance of differences in the microvasculature to the phenotype observed in those born preterm38 CAVI provided a key validation step in defining the essential phenotypes relevant to disease in these populations.
More recently we have been studying, using deep phenotyping, contributions of the cardiovascular system to blood pressure variability in young adults. Blood pressure variability is known to be an independent determinant of cerebrovascular and cardiovascular risk39 but little has been known about factors that determine blood pressure variability early in life. Through use of multi-modality measures we have been able to establish that the major vascular determinant of blood pressure variability in young adults is central aortic stiffness, as opposed to more global or peripheral arterial stiffness changes.40 This was highlighted with cardiovascular magnetic resonance measures of central aortic stiffness and confirmed using CAVI, which also captures central aortic stiffness within its calculation and, in young people, closely relates to the cardiovascular magnetic resonance measures.40
Future work has the potential to study how CAVI varies in relation to changes in other organs such as the brain and liver so that we can understand whether changes in CAVI may provide additional prognostic information in young people. However, an important consideration in all these studies is that the current datasets are largely observational and therefore the evidence base for causality, and its direction, will remain limited until randomized trials targeted at phenotypes are completed. We currently have trials in progress to study the impact of interventions on the cardiac and vascular system in young adults to understand the holistic impact of cardiovascular preventive treatments.
Future directions for hypertension management and research in the young
Clinically relevant hypertension is not restricted to older populations but can be present at any age, from infancy to childhood to young adulthood. There is a notable lack of studies that have tested in randomized controlled trials effective treatment options for younger individuals. There is also a lack of detailed observational studies that have sought to define the underlying pathophysiological basis for the variation in blood pressure in young people. Deep phenotyping studies have started to unravel the heterogeneity in cardiac and vascular changes that are present in young people with higher blood pressure.33–35 New observations challenge a repeated dogma that high blood pressure in young people is predominantly due to increased stroke volume and sympathetic hyperactivity. Whereas someone with established cardiovascular disease might be expected to have a consistent reduction in arterial stiffness, endothelial response, microvascular structure and function as well as altered cardiac morphology,41 associations between different vascular components appear to differ with type of risk factor exposure in younger people.34 As a result, opportunities for targeted interventions either to ameliorate the dysfunctional features of the cardiovascular system or to protect the normally functioning elements may have particular benefit.36
By using a multi-modality imaging protocol, that incorporates a range of cardiovascular measures including cardiovascular magnetic resonance, ultrasound, microscopy and more unique indices, such as CAVI, we have been able to gain insights into some of the background changes related to specific risk groups in young adulthood. Our initial phase of findings has demonstrated that no single measure provides a complete assessment of cardiovascular risk phenotype in younger people but that changes in specific vascular beds can be identified and characterized. Further work is needed to identify those young individuals who have specific impairments in CAVI and thereby understand the risk and lifestyle features that directly impact on the arterial wall. However, changes in larger artery pathophysiology are likely to be relevant to blood pressure control, including central blood pressure and blood pressure variability. Based on these findings trials of treatments, whether lifestyle or pharmacological, will then be possible to start to establish how an altered CAVI in early life might be targeted to reduce risk of cardiovascular disease.
Acknowledgements and disclosures
PL is supported by the British Heart Foundation (FS/06/024 and FS/11/65/28865), the National Institute for Health Research Oxford Biomedical Research Centre and Oxford British Heart Foundation Centre for Research Excellence.
Conflict of interest: P.L. has previously received an unrestricted research grant and honoraria from Fukuda Denshi who manufacture the VaSera.