Chapter 4: Special blood-pressure phenotypes

Sustained hypertension and true normotension

Home and ambulatory measurements identify blood-pressure phenotypes that cannot be recognised when assessment is limited to office readings. Sustained hypertension means that pressure is elevated both in and outside the clinic. True normotension means that pressure is normal in both settings.

These phenotypes can describe untreated and treated people. In treated people they indicate either control in both settings or lack of control in both. Studies have defined out-of-office normality or hypertension using either HBPM or ABPM. The PAMELA population study from northern Italy is unusual in having office, ambulatory and home measurements for every participant, although its home-measurement protocol was restricted. Compared with true normotension, sustained hypertension was associated with a clearly higher prevalence of cardiovascular disease and cardiovascular mortality. Differences were also observed when one, two or all three measurement methods were elevated, suggesting that more complex blood-pressure phenotypes may have clinical relevance.

White-coat hypertension (WCH)

WCH describes untreated people whose office pressure is elevated but whose ABPM, HBPM or both are normal. The white-coat effect is the difference between a higher office value and a lower ambulatory or home value and is thought to reflect an alerting pressor response triggered by measurement by a doctor or nurse. Other factors probably contribute, as shown by the weak correlation between office–out-of-office differences and the white-coat effect measured by repeated recordings.

Although prevalence varies between studies, WCH may occur in about 30% of people attending hypertension clinics and in 30–40% of those with elevated office pressure. It is more common with increasing age—above 50% in very old patients—among women and non-smokers. Prevalence is lower when office pressure is based on repeated readings or when the treating clinician is not present during measurement. A large white-coat effect can occur at every grade of hypertension, including true resistant hypertension, but WCH is most common in grade 1 hypertension.

WCH is not automatically benign. HMOD is less prevalent than in sustained hypertension, and many studies show lower cardiovascular risk. Compared with true normotension, however, people with WCH may have increased adrenergic activity, more metabolic risk factors and more HMOD, often without symptoms. In PAMELA, asymptomatic cardiac or renal HMOD was found in roughly one in three people with WCH compared with about one in ten people who were normotensive both in and outside the clinic.

Compared with people with established hypertension, WCH has also been associated with a higher long-term risk of new-onset diabetes, progression to sustained hypertension and cardiovascular death. Increased cardiovascular risk or mortality has been reported when WCH was identified using both HBPM and ABPM, even without HMOD at baseline, and in isolated systolic hypertension and older patients. Possible explanations include a higher prevalence of night-time hypertension and slightly higher, although technically normal, 24-hour pressure than in people without a white-coat phenotype.

Because WCH has limited reproducibility, it should be confirmed with repeated office and out-of-office measurements. Ideally both ABPM and HBPM should be used because they can disagree: one may be normal while the other is elevated. Cardiovascular risk appears lowest—closer to true normotension—when both are normal. A comprehensive assessment of cardiovascular risk factors and HMOD is recommended. Management should include lifestyle changes and closer follow-up than for true normotension.

Antihypertensive drugs reliably lower office pressure, but their effect on out-of-office pressure is small and variable. Whether all people with WCH should receive medication remains unanswered. Although people with WCH made up a substantial proportion of many trials demonstrating treatment benefit, no outcome trial was specifically designed for WCH. Medication may be considered when HMOD or cardiovascular risk is high.

Masked hypertension (MH)

MH describes untreated people whose office pressure is normal but whose HBPM or ABPM is elevated. Approximately 10–20% of people attending hypertension clinics have MH when out-of-office pressure is assessed, and substantial prevalence has also been found in population studies, particularly among Asian and African-American populations.

Prevalence differs according to whether daytime, night-time or 24-hour ABPM is used. The best strategy for detecting MH has not been established, and screening everybody with a normal office pressure is impractical. High-normal office pressure is associated with a greater likelihood of MH. It is more common in younger people, men, smokers and people with higher physical activity, alcohol intake, anxiety or work stress. Obesity, diabetes, low HDL cholesterol, CKD and a family history of hypertension are also associated with increased prevalence.

An exaggerated blood-pressure response to exercise or standing can predict MH. A risk-based approach has therefore been proposed, reserving out-of-office testing for people with multiple risk factors. MH is associated with HMOD, including impaired kidney function, left-ventricular hypertrophy, increased carotid intima-media thickness and large-artery stiffness.

People with MH have more metabolic disorders and diabetes, higher sympathetic activity and a risk profile that may approach that of sustained hypertension. Meta-analyses and recent studies show substantially more cardiovascular events than in true normotension. Both ABPM-defined and HBPM-defined MH have been independently associated with cardiovascular events and mortality. Cardiovascular and kidney risk is particularly concerning in people with diabetes when pressure rises at night.

Systematic reviews suggest that the reproducibility of MH is low to moderate and may be better with ABPM than HBPM. A diagnosis should therefore be confirmed with at least a second set of office and out-of-office measurements. No randomised outcome trial has tested treatment specifically for MH, so the treatment effect is unknown. Given the adverse prognostic significance of out-of-office elevation, intensive lifestyle modification and closer follow-up are reasonable after confirmation. Medication can be considered when cardiovascular risk is especially high or HMOD is present.

Uncontrolled white-coat hypertension (WUCH) and masked uncontrolled hypertension (MUCH)

WCH and MH were originally described in untreated people but also occur during treatment. WUCH means that treatment controls pressure outside the clinic but not in the clinic. MUCH means that office pressure appears controlled while out-of-office pressure remains elevated.

Although WUCH has been associated with greater arterial stiffness than controlled hypertension, many studies found no major difference in cardiovascular risk compared with people controlled both in and outside the clinic. In IDACO, WCH was associated with increased cardiovascular risk only in untreated people. Large pooled analyses likewise found no clear excess risk with WUCH compared with sustained control.

Masked hypertension is more common among treated than untreated people. In the large IDACO database, ambulatory MH occurred in about 31.9% of treated people compared with 19.2% of untreated people. Similar findings were reported in the Jackson Heart Study. Among SPRINT participants with controlled office pressure, MUCH occurred in 62% of the intensive-treatment group and 56% of the standard-treatment group. MUCH was associated with a worse metabolic profile, more HMOD and poorer clinical outcomes, regardless of whether ABPM or HBPM was used.

Observational meta-analysis found that many people with MUCH had more cardiovascular events than those controlled in both settings and event rates similar to people uncontrolled in both settings. A limitation is that WUCH and MUCH were often assigned from a single set of measurements; subsequent trial analyses show that both phenotypes are highly unstable. In ELSA, only about 5% of people with either phenotype remained in the same category throughout four years. They may therefore be intermittent rather than persistent phenotypes.

As with MH, MUCH is more common with smoking, alcohol, excess weight, exaggerated responses to exercise and psychological stress, and some comorbidities. The contribution of non-adherence is uncertain. Increased sympathetic activity during daily life may partly explain the cardiovascular risk. Repeated office and out-of-office measurements should be used to identify WUCH and MUCH. Given the limitations of the evidence, it is reasonable to consider intensifying treatment in either phenotype if well tolerated, while avoiding pressure above generally recommended treatment targets.

Isolated systolic hypertension in the young (ISHY)

ISHY is defined as systolic pressure at least 140 mmHg with diastolic pressure below 90 mmHg in young people and adolescents, not only in older adults. It is more common in males and can occur in children and teenagers, often in association with overweight or obesity.

Its clinical significance is debated because ISHY has several possible mechanisms. Increased cardiac output, heart rate and stroke volume are common haemodynamic features and may explain a high peripheral pulse pressure. ISHY is more common in athletes than in sedentary people. However, around 20% of affected people have a normal stroke volume with increased pulse-wave velocity, suggesting early aortic stiffening.

NHANES and other studies linked ISHY with obesity, male sex, high salt intake and smoking. Other investigations identified a lower-risk subgroup, often tall, non-smoking and physically active men, in whom pulse-pressure amplification occurred despite normal central pressure. This pattern is called spurious systolic hypertension. In multi-ethnic populations, people with ISHY had lower central systolic pressure and pulse-wave velocity than people with isolated diastolic or combined systolic–diastolic hypertension and were similar in some respects to people with high-normal pressure. These conflicting findings indicate that ISHY is highly heterogeneous.

Central pressure may identify people with lower risk and a favourable long-term prognosis, but recent studies have also linked ISHY with higher cardiovascular risk, in some reports mainly among men and in others among women. Sex comparisons are difficult because all studies show a clear male predominance. WCH should be considered because a marked white-coat effect is one of the strongest determinants of pulse pressure in this setting.

All young people with ISHY should therefore undergo out-of-office assessment. If ISHY is confirmed, central pressure, other central haemodynamic parameters and arterial compliance may provide additional information, although validated cut-offs separating normal from high central pressure are lacking. Young people should receive lifestyle advice, especially smoking cessation, sodium restriction and calorie reduction when overweight, and should have close follow-up because some develop sustained combined hypertension. Drug treatment may be considered when out-of-office pressure, central pressure or other cardiovascular risk factors are abnormal.

Isolated systolic hypertension in older adults

With ageing, endothelial dysfunction, vascular remodelling and fibrosis increase stiffness of the large elastic arteries. A larger forward pressure wave and earlier return of reflected waves from peripheral arteries raise systolic pressure and pulse pressure. Systolic pressure rises steadily with age, while diastolic pressure plateaus around 50–60 years and then declines. The increased arterial load promotes further vascular stiffening and left-ventricular hypertrophy, eventually contributing to coronary disease, cerebrovascular disease and heart failure.

After age 50, isolated systolic hypertension (systolic pressure at least 140 mmHg and diastolic pressure below 90 mmHg) becomes the commonest phenotype and is present in most hypertensive people over 70. It is also more common in women and people with excess weight. Systolic pressure has a stronger relationship with outcomes than diastolic pressure after age 50. ISH assessed by office measurement or ABPM is associated with high cardiovascular risk and mortality, including grade 1 ISH with systolic values of 140–159 mmHg. Risk is particularly high when ISH is accompanied by orthostatic hypertension.

Diagnosis is challenging because pressure varies greatly and pronounced WCH is common in older people. Repeated office visits or out-of-office measurement are recommended. Central pressure may help identify people whose aortic pressure is less elevated than their peripheral pressure.

Randomised trials demonstrate benefit from treating ISH, including in older adults. An individual-participant meta-analysis in older patients with ISH found that active treatment reduced all-cause mortality by 13%, cardiovascular mortality by 18% and all cardiovascular outcomes by 26%. Pulse pressure was inversely associated with total mortality in that analysis, highlighting its role as a risk marker. Benefit was greater in men, people over 70 and people with previous cardiac complications. Across the cited studies, earlier rather than delayed treatment consistently provided greater cardiac protection.

Overall evidence favours calcium-channel blockers and thiazide-like diuretics for ISH. ACE inhibitors and ARBs may be less effective for this phenotype, but remain first-line options when there is a compelling indication such as heart failure, coronary disease, CKD, metabolic syndrome or diabetes. Because monotherapy often fails to control ISH, initial two-drug combination therapy may also be appropriate in older people who are not frail.

Target systolic and diastolic pressures in older adults remain debated. In trials dedicated to ISH, on-treatment systolic pressure generally remained between 140 and 150 mmHg. Recent RCT meta-analysis supports an initial systolic target of 140–150 mmHg. Other trials in older adults achieved cardiovascular benefit by reducing systolic pressure below 140 mmHg; a meta-analysis of 23 RCTs with a mean baseline diastolic pressure below 90 mmHg found benefit when systolic pressure was reduced below 140 mmHg. A further reduction toward 130–140 mmHg may therefore be attempted if well tolerated and if diastolic pressure does not become too low. In VALISH, systolic pressure below 140 mmHg appeared safe, although dedicated ISH trials provided little information about treated diastolic pressure and outcomes.

Excessive diastolic reduction should nevertheless be avoided. The benefit from lowering systolic pressure may be offset by low diastolic pressure, as suggested by SPRINT, and intensive treatment may be particularly hazardous in severe large-artery stenosis. Diastolic pressure should generally not be reduced below 70 mmHg with medication, although this can be difficult because many people with ISH already have a diastolic pressure below 70 or between 70 and 80 mmHg.

In population studies, very low diastolic pressure in ISH was associated with high cardiovascular disease prevalence. The explanation may be not only impaired organ perfusion but also marked arterial stiffness reflected by a very high pulse pressure. Treatment is challenging because systolic reduction often lowers diastolic pressure at the same time. Clinicians should balance the greatest tolerated systolic reduction against a diastolic pressure that does not suggest impaired organ perfusion or compromise treatment tolerance. Systolic control remains the primary goal, including in people with low diastolic pressure when treatment is well tolerated. In SHEP, treatment-related systolic reduction lowered major cardiovascular events even though mean diastolic pressure fell to 68 mmHg.

Isolated diastolic hypertension (IDH)

IDH is defined as systolic pressure below 140 mmHg with diastolic pressure above 90 mmHg. In adults its prevalence is approximately 2.5–7.8%, peaks at 30–39 years, falls during the fifth and sixth decades and is almost absent above 70 years. It is more common in men. Awareness and treatment can be very low: in PEACE, only 10.3% of untreated people knew they had IDH and 86.1% had received no treatment.

IDH is associated with overweight, central obesity and other components of metabolic syndrome. Compared with other phenotypes, affected people are generally younger, male, more likely to consume alcohol and tobacco and more often have diabetes. Longitudinal studies show a greater likelihood of progressing to combined hypertension, and large Asian, American and European cohorts found higher long-term cardiovascular risk than in normotension, particularly in people under 50–60 years.

A cohort of 107,599 people found that the relationship between cardiovascular events and systolic pressure was age-independent, whereas the relationship with diastolic pressure was important mainly below age 50. A meta-analysis of 15 studies involving 489,814 participants and IDACO data based on ABPM supported the conclusion that IDH is primarily a cardiovascular risk factor in younger adults.

The evidence does not establish whether younger adults with IDH require antihypertensive drugs. Early trials enrolled people largely on the basis of diastolic pressure, but treatment lowered both systolic and diastolic pressure, so the independent effect of lowering either component could not be separated. There is no direct evidence of outcome benefit from medication specifically for IDH. Blood pressure should nevertheless be reassessed regularly, lifestyle modification should begin in all patients, and medication may be considered in people under 50 or in anyone at high cardiovascular risk. In older adults, the low prevalence and uncertain association with events support lifestyle intervention and close follow-up unless overall risk is high.

Night-time hypertension and dipping

Night-time hypertension is usually defined as a sleep-time ABPM average above 120/70 mmHg. Dedicated home devices that measure during sleep may provide a practical alternative to ABPM. Studies using three upper-arm or wrist readings during sleep suggest reasonable agreement with ABPM, with mean systolic and diastolic differences of approximately 1.4 and −0.2 mmHg.

Night-time pressure is often a stronger predictor of cardiovascular events and mortality than daytime or even 24-hour pressure. It is associated with structural changes in the heart and carotid artery. Isolated night-time hypertension—night-time elevation despite normal office and daytime pressure—occurs in approximately 9.2–12.9% of adults and is more common in men with high-normal pressure, people at high cardiovascular risk, African-Americans, older adults, obesity, diabetes and CKD.

Night-time pressure rises and nocturnal dipping decreases with age. Risk increases not only with high night-time pressure but also with reduced dipping, independent of the absolute night-time value. A night-to-day ratio below 0.9, or a fall of more than 10% from daytime pressure, defines a dipper pattern; a ratio above 0.9 or a fall below 10% defines non-dipping. Reverse dippers, whose night-time pressure is equal to or higher than daytime pressure, have particularly high risk. In people aged 70 or older, a U-shaped relationship has been reported, with extreme dipping above 20% also associated with risk.

In younger adults the relationship may be more linear. Night-time phenotypes are not highly reproducible in treated or untreated people, so classification should be based on repeated ABPM rather than a single recording. Mechanisms include increased sympathetic activity, autonomic dysfunction, impaired baroreflex sensitivity, salt sensitivity, expanded plasma volume, increased renin–angiotensin-system activity, OSA and other sleep disorders, stress and kidney failure.

There is no established selective treatment for night-time hypertension and no strong evidence that deliberately increasing nocturnal lowering improves outcomes in non-dippers or reverse dippers. Proposed strategies include bedtime dosing, salt restriction, treatment of sleep disorders, renal denervation and selected drug classes. Some studies have been criticised for quality, and excessive night-time lowering may be harmful. A recent large blinded-endpoint trial found no cardiovascular outcome difference between bedtime and morning dosing; morning dosing had better adherence despite somewhat greater morning pressure reduction. For single-pill treatment, morning or evening administration can be chosen according to patient preference. With several medicines, splitting doses between morning and bedtime may smooth 24-hour control, but diuretics are usually unsuitable at bedtime.

Orthostatic blood-pressure elevation and hypotension

Standing blood pressure should be measured at the first visit and regularly in older adults, people receiving antihypertensive treatment, people with diabetes and people with factors or symptoms suggesting orthostatic hypotension. Take at least two readings after one and three minutes of standing. Orthostatic hypotension is a fall in systolic pressure of at least 20 mmHg or diastolic pressure of at least 10 mmHg within three minutes. It is associated with mortality, cardiovascular events, clinically important hypotension and falls, particularly when vasodilators are used.

An exaggerated rise or orthostatic hypertension is also associated with adverse outcomes in younger and older people. Smoking, heavy coffee intake and alcohol may contribute. The standing response can help identify MH. Neurohumoral overshoot appears to be the main mechanism in young adults, while vascular stiffening may dominate in older people. There is no universally accepted definition; some describe a sustained diastolic rise of at least 20 mmHg from lying to standing, while others require a standing systolic pressure of at least 140 mmHg with an exaggerated response.

Baroreflex failure and efferent autonomic failure

Arterial baroreceptors sense changes in vascular stretch caused by fluctuations in pressure. Afferent nerves carry this information to the brainstem, which produces counter-regulatory changes in sympathetic and parasympathetic outflow to stabilise pressure. Damage to the afferent limb, integrating brainstem centres or efferent limb can cause severe blood-pressure disorders. Baroreflex failure may occur after bilateral injury to the carotid baroreceptors or afferent nerves despite an anatomically intact aortic reflex arc.

Efferent baroreflex injury is usually part of autonomic failure. The two conditions differ in their clinical presentations, and neither blood-pressure treatment nor general treatment has been supported by trials with clinical endpoints. Baroreflex failure is characterised by extreme pressure variability, abrupt hypertensive surges, hypotensive episodes and, in some but not all patients, orthostatic hypotension.

Causes include neck surgery or radiotherapy, bilateral removal of carotid-body paragangliomas, familial autonomic dysfunction such as hereditary sensory autonomic neuropathy type 3, and very rarely brainstem lesions. The diagnosis should be confirmed by pharmacological baroreflex testing. Because hypertensive surges are mediated by unrestrained sympathetic activation and worsened by psychological or physiological stress, long-acting central sympatholytic agents are the main treatment. Vasodilators and diuretics can cause marked hypotension and should be avoided whenever possible. Hypotensive episodes are usually treated non-pharmacologically; parasympathetic bradycardia may require a pacemaker.

Autonomic failure produces a range of posture-related disorders, including orthostatic hypotension and, in many patients, supine hypertension. Treatable causes, such as autoimmune autonomic ganglionopathy, should be distinguished. Severe symptomatic orthostatic hypotension usually requires supportive treatment. First try compression garments, increased salt intake and adequate hydration, and stop medicines that worsen the condition whenever possible. Alpha-agonist drugs may be required when symptoms persist.

All current pressor drugs, especially long-acting mineralocorticoids, can worsen supine hypertension. Supine hypertension increases nocturnal urine production and can worsen orthostatic hypotension the following morning; cardiovascular-risk data are limited. Sleeping with the head of the bed elevated may reduce night-time pressure and morning orthostatic symptoms. Bedtime antihypertensive treatment can be considered in selected patients, balancing possible long-term cardiovascular benefit against falls and the prognosis of the underlying autonomic disorder.