Hypertension is the medical word for high blood pressure. Hypertension is persistently raised blood pressure (the pressure of blood in the main arteries). Blood pressure goes up temporarily as a normal response to stress and physical activity, and it rises naturally with increasing age and weight. A person with hypertension, however, has persistently high blood pressure even when at rest. Because the condition itself causes no symptoms, a large number of people have hypertension without realizing it; however, because hypertension causes the risk of developing serious cardio-vascular disorders to increase, regular medical checks are advised in order to detect the condition at an early stage.
Hypertension is very common, particularly in men, and its incidence is highest in the middle-aged and elderly. Blood pressure is measured as two values, each expressed as millimetres (mm) of mercury (chemical symbol Hg) or mmHg. The systolic value (the higher value) is the pressure when blood surges into the aorta from the heart; the diastolic value is the pressure when the ventricles (lower chambers of the heart) relax between beats. A blood pressure consistently exceeding about 140 mmHg (systolic) and 90 mmHg (diastolic) at rest is defined as hypertension.
Symptoms and complications
Hypertension is usually symptomless, and generally goes undiscovered until detected during a routine physical examination. However, if it is severe or accelerated (known as malignant hypertension) it may cause headaches, breathlessness, and visual disturbances. The condition puts considerable strain on the heart and blood vessels, increasing the risk of stroke, coronary artery disease, and heart failure. Hypertension may eventually lead to kidney damage and retinopathy (damage to the retina at the back of the eye).
In many cases, there is no obvious cause, in which case the condition is called essential hypertension. Genetic factors are important, although hypertension is not attributed to a specific gene. Other factors that are associated with hypertension include high alcohol intake, a high-salt diet, obesity, diabetes mellitus, a sedentary lifestyle, and smoking. There is also evidence that low birth weight increases the risk of developing hypertension in later life. If hypertension results from a specific disorder, the condition is known as secondary hypertension. Causes include various kidney disorders; certain disorders of the adrenal glands; pre-eclampsia (a complication of pregnancy); coarctation of the aorta (a congenital heart defect); and the use of certain drugs. Taking the combined contraceptive pill can lead to hypertension in susceptible women.
The patient’s blood pressure is measured at rest on several occasions in order to make a diagnosis. If there is any doubt, an ambulatory blood pressure device is fitted to monitor blood pressure over a 24 hour period. This may detect a condition known as white coat hypertension, in which blood pressure is raised during a test by a doctor, but it is otherwise normal and does not require treatment. The eyes may also be examined for evidence of long-standing hypertension. If secondary hypertension is suspected,blood tests, X-rays, and other appropriate tests are carried out to exclude any potential causes.
With mild to moderate hypertension, if no underlying cause is found, lifestyle changes are recommended as the first line of treatment. For example, smokers should give up their habit and drinkers should reduce their consumption of alcohol. Any overweight person with hypertension should try to lose weight by modifying the diet and introducing gradually increasing amounts of exercise into the daily routine. Biofeedback training and relaxation techniques can also help to reduce blood pressure. If self-help measures have no effect, or if hypertension is severe, anti-hypertensive drugs may be given. There is a large range of drug treatments available and the treatment chosen depends on the presence of other disorders, such as diabetes mellitus. The response of the condition to treatment, as well as any side effects it has provoked, may prompt a change of treatment. Usually, the patient is monitored by having regular blood pressure checks, so that adjustments to drug type or dosage can be made if necessary. It may be possible for the patient to monitor his or her own blood pressure at home, but the individual’s machine should be checked regularly and calibrated against the doctor’s machine. In many cases, drug treatment must continue for life, but this may help to extend life expectancy significantly.
Series of easy to read articles about high blood pressure:
What are those two numbers your doctor gives you after measuring your blood pressure? In this part, we answer that question and describe the correct technique for taking blood pressure at home or in your doctor’s office. We also discuss who is most at risk for developing high blood pressure and what you need to know about secondary high blood pressure.
- 1. High blood pressure - an introduction
- 2. How to diagnose high blood pressure
- 3. Determining your risk of high blood pressure
- 4. Dealing with secondary high blood pressure
Three major organs of the body suffer when high blood pressure isn’t controlled: the heart, the kidneys, and the brain. In this part, we explain exactly how high blood pressure affects each of these organs and how the sooner any damage is diagnosed, the better the chances are of reversing the damage. We also address ways to deal with organ damage that already exists. Although we separate these three major organs into separate chapters, uncontrolled high blood pressure doesn’t pick and choose. Instead, uncontrolled high blood pressure tends to damage all these organs and within the same time frame.
- 5. Protect the heart from high blood pressure
- 6. Protect the kidneys from high blood pressure
- 7. Protect the brain from high blood pressure
Fortunately, you can treat (or prevent) high blood pressure in multiple ways so it never damages you. Starting with lifestyle changes and ending with drugs (only if absolutely necessary), this part gives you all the necessary tools. No one need ever suffer a heart attack, a brain attack, or kidney failure as a result of high blood pressure.
- 8. Developing a successful treatment plan for high blood pressure
- 9. Diet to lower high blood pressure - the DASH diet
- 10. Keeping salt out of your diet
- 11. Avoiding tobacco, alcohol and caffeine
- 12. Lowering blood pressure with exercise
remainder of articles coming soon
Series of technical detailed articles about hypertension:
- Essential hypertension - definition, epidemiology and pathophysiology in more detail - technical - on this page below
- Diagnosis, assessment and treatment of essential hypertension
- Secondary hypertension
- Mendelian disorders causing hypertension
Essential hypertension - definition, epidemiology and pathophysiology in more detail - technical
Essential hypertension’ is high blood pressure for which there is no clearly defined aetiology. From a practical perspective, it is best defined as that level of blood pressure at which treatment to lower blood pressure results in significant clinical benefit—a level which will vary from patient to patient depending on their absolute cardiovascular risk.
Most guidelines define ‘hypertension’ as an office blood pressure greater than or equal to 140/90 mmHg. When using 24-h ambulatory blood pressure or home blood pressure averages to define hypertension, the diagnostic thresholds are lower than those used with office measurement.
Isolated diastolic hypertension (systolic blood pressure (SBP) < 140 mmHg, dialstolic blood pressure (DBP) > 90 mmHg) is more common in younger people, and isolated systolic hypertension (SBP > 140 mmHg, DBP < 90 mmHg) is the most common form of hypertension in older people.
Recent American guidelines have recently included a new category of ‘prehypertension’ (SBP 120–139 mmHg and/or diastolic blood pressure, DBP 80–89 mmHg), the reason for this being that blood pressure in this range is associated with both adverse cardiovascular outcome and a high rate of progression to hypertension.
In 2000, it was estimated 25% of the world’s adult population were hypertensive, and predicted that this would rise to 29% by 2025. By the age of 60, more than one-half of adults in most regions of the world will be hypertensive.
There is a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as 115/75 mmHg.The relationship is steeper for stroke than it is for coronary heart disease, and is magnified by age. There is a doubling in risk of stroke and ischaemic heart disease mortality for every 20/10 mmHg increase in blood pressure.
Most people with hypertension are over the age of 50 years, and in these systolic blood pressure is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension.
Pathogenesis and pathophysiology
The pathogenesis of essential hypertension is a complex interplay between (1) genetic predisposition, (2) lifestyle and environmental influences, and (3) disturbances in vascular structure and neurohumoral control mechanisms.
Genetic predisposition—blood pressure runs in families, with a remarkably consistent level of correlation of around 0.2 between first-degree relatives found in many studies. This means that if the blood pressure of one member of the family deviates from the norm by + 10 mmHg, the first-degree relative will deviate by + 2 mmHg on average. Variants in a large number of genes, involving virtually all of the main physiological systems affecting blood pressure, have shown association with blood pressure in one or more studies, but the effect of any individual variant is likely to be modest.
Lifestyle and environmental influences—the exploding prevalence of hypertension in economically developing regions reflects lifestyle changes, so-called ‘Westernization’, more than anything else, with the most important influences on blood pressure being sodium intake, obesity, and alcohol intake.
Pathophysiology—a characteristic finding in essential hypertension is an inappropriate increase in peripheral vascular resistance relative to the cardiac output. This is due to remodelling of small arteries (arterioles), which is characterized by an increase in their media/lumen ratio, but it is not clear whether these changes are a consequence or a cause of raised blood pressure. The functional integrity of large conduit arteries, i.e. the aorta, which becomes stiffer, also influences the development of hypertension—especially systolic hypertension. Endothelial dysfunction and decreased nitric oxide production are found in hypertension, but are more likely a consequence than a cause of elevated blood pressure. The specific role of the renin–angiotensin–aldosterone system in the development of essential hypertension remains unclear, but therapeutic agents that inhibit this system have proved to be very effective treatments. The sympathetic nervous system is involved in the acute and chronic regulation of blood pressure, but whether disturbances in it play a major role in the initiation and maintenance of chronic essential hypertension remains unknown.
The hypertensive phenotype and target-organ damage
Although blood pressure measurement is used to define hypertension, hypertension is more than just blood pressure. Essential hypertension is commonly associated with metabolic disturbances (the ‘insulin-resistance phenotype’) and multisystem structural damage that conspire to enhance cardiovascular risk beyond that which can be attributed to blood pressure alone.
Left ventricular hypertrophy is a classic feature of untreated or inadequately treated long-standing hypertension, and is a very potent predictor of premature cardiovascular disease and death. Inhibition of the renin–angiotensin–aldosterone system is particularly effective at regressing left ventricular hypertrophy, which is associated with dramatically improved prognosis for people with hypertension.
Hypertension is the single most important risk factor for stroke, and is increasingly recognized as a major factor contributing to the rate of cognitive decline in later life. Patients with renal disease often have hypertension, people with hypertension can develop renal disease, and the age-related decline in GFR is more rapid in people with essential hypertension, but renal function is usually well preserved throughout life in patients with mild to moderate essential hypertension.
Implications of the evolution of hypertensive injury
The process of hypertensive injury to target organs evolves silently over many years. Current treatment guidelines have been developed from an evidence base relating to changes in hard clinical endpoints derived from studies in very elderly patients at the end of the hypertensive disease process. Future treatment strategies must surely focus on preventing the evolution of the silent disease process, rather than simply battling with its consequences.
Hypertension - definition, epidemiology and pathophysiology - in great detail
Defintions of hypertension
The commonest form of hypertension has been termed ‘essential hypertension’, i.e. hypertension for which there is no clearly defined aetiology. Blood pressure is normally distributed within populations and thus the definition of ‘hypertension’ is a moving target. From a practical perspective it is best defined as that level of blood pressure at which treatment to lower blood pressure results in significant clinical benefit, which will change as new evidence from clinical trials emerges. This statement also highlights the conundrum in definition of ‘hypertension’ because the risk associated with blood pressure is a continuum and the level of pressure at which treatment results in ‘significant clinical benefit’ for any individual will depend on their absolute cardiovascular risk.
There is substantial evidence that treating systolic pressure (SBP) above 160 mmHg and/or a diastolic pressure (DBP) above 100 mmHg is beneficial; there is also evidence that treating pressures above 140/90 mmHg is worthwhile, especially in higher-risk patients. Most guidelines therefore define ‘hypertension’ as an office blood pressure ≥140/90 mmHg. Various grades of hypertension are also specified. See table below:
|Table 1 Classification of hypertension. Grades 1–3 replace the old terminology of ‘mild’, ‘moderate’, and ‘severe’. The ‘high normal’ blood pressure range corresponds to ‘prehypertension’ in the United States guideline|
|Grade 1 hypertension||140–159||and/or||90–99|
|Grade 2 hypertension||160–179||and/or||100–109|
|Grade 3 hypertension||>180||and/or||>110|
|Isolated systolic hypertension||>140||and||<90|
Reproduced from Giuseppe Mancia, Guy De Backer, Anna Dominiczak, et al, 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension, Journal of Hypertension, 2007, 25:1751–1762.
The hypertension guidelines in the United States of America have recently included a new category of ‘prehypertension’ (SBP 120–139 mmHg and/or DBP 80–89 mmHg).
It is important to note that the diagnostic thresholds for hypertension vary according to the method of measurement. The aforementioned blood pressure thresholds for diagnosis have been defined according to seated blood pressure measurements, so-called ‘office blood pressures’. When using 24-h ambulatory blood pressure or home blood pressure averages to define hypertension, the diagnostic thresholds are lower than these office blood pressures.
Subtypes of hypertension
Various categories of blood pressure can be identified in populations, with isolated diastolic hypertension (IDH) (SBP <140 mmHg, DBP >90 mmHg) being more common in younger people and isolated systolic hypertension (ISH) (SBP >140 mmHg, DBP <90 mmHg) being the most common form of hypertension in older people, with systolic/diastolic hypertension (SDH) (SBP>140 mmHg and DBP >90 mmHg) bridging the two extremes of age.
Although traditionally DBP was considered to carry the greatest prognostic significance, it is now clear that this is no longer the case. Most people with hypertension are over the age of 50 years, and in them SBP is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension. The different patterns of blood pressure and the relative importance of DBP and SBP with regard to prognosis reflect progression of the underlying pathology. The pathogenesis of hypertension in younger people is characterized by an increased peripheral vascular resistance. This results in an increased diastolic pressure, with any associated rise in systolic pressure ‘cushioned’ by a compliant aorta, hence the commonly observed IDH. With ageing there is progressive stiffening of the aorta, a consequent reduction in large-artery compliance, and a reduced capacity to sustain diastolic pressure and to cushion systolic pressure. The result is an age-related widening of pulse pressure as diastolic pressure falls alongside a progressive rise in SBP, hence the emergence of ISH.
The global prevalence of hypertension when defined either as a blood pressure of ≥140/90 mmHg, or the use of antihypertensive medication, was estimated to be 972 million in the year 2000, representing about 25% of the world’s adult population. The global prevalence of hypertension is expected to rise dramatically by about 60% by 2025, representing 29% of the world’s adult population and affecting 1.6 billion people (Fig. 188.8.131.52). Most of this increase in the worldwide burden of hypertension is expected to result from an increase in the number of people with hypertension in economically developing regions, hence almost 75% of the world’s hypertensive populations will be in economically developing regions by 2025.
The prevalence of hypertension in almost all regions of the world increases with age and more steeply in women. By the age of 60, more than one-half of adults in most regions of the world will be hypertensive. India and Asia have and will most likely continue have the lowest rates of hypertension, whereas the highest rates are likely to remain in Latin America, the Caribbean, former Socialist Republics, and sub-Saharan Africa. Consequently, hypertension is set to remain the single most important preventable cause of premature death worldwide over the next two decades, with the World Health Organization estimating that about 7.1 million deaths per year may be attributable to hypertension, and that suboptimal blood pressure (SBP ≥115 mmHg by their definition) is responsible for 62% of cerebrovascular disease and 49% of ischaemic heart disease worldwide, with little variation by sex.
The prevalence of hypertension increases with age, affecting over one-half of those aged 60 to 69 years and over three-quarters of those aged over 70 years in the United States of America and most developed countries. As indicated above, almost all of the age-related rise in the prevalence of hypertension is due to a progressive rise in SBP. The lifetime probability of developing hypertension is about 90% for men and women who were not hypertensive at 55 or 65 years old and survived to age 80 to 85.
Cardiovascular morbidity and mortality associated with hypertension
Elevated blood pressure increases the risk of cardiovascular morbidity and mortality. Data from observational studies of over 1 million people has indicated a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as 115/75 mmHg. The relationship is steeper for stroke than it is for coronary heart disease and is magnified by age. For every 20/10 mmHg increase in blood pressure, there is a doubling in risk of stroke and ischaemic heart disease mortality. Hypertension also increases the risk of congestive cardiac failure, endstage renal disease, and dementia. Moreover, data from the Framingham Heart Study also indicates that there is a doubling of risk of cardiovascular complications in patients with blood pressure levels above normal but not yet classified as having overt hypertension. This was the basis for the American guidelines introducing the term ‘prehypertension’ (SBP 120–139 mmHg and/or DBP 80–89 mmHg) to emphasize that this level of blood pressure (1) is not benign, (2) is associated with an elevated cardiovascular disease risk, and (3) predicts with a high degree of certainty that blood pressure is on an upward trajectory and that affected people are almost certain to develop more severe hypertension, unless there is intervention with effective in lifestyle changes and/or drug therapy.
Systolic blood pressure as the main risk factor
For many years DBP was considered the main denominator for defining the threshold and treatment targets for hypertension. This is no longer the case. As indicated above, there is a progressive rise in DBP up to about the age of 50 years and thereafter it usually falls. By contrast, SBP begins to rise relentlessly from the age of around 40 years. Thus, at the age of peak prevalence of hypertension, i.e. older than 60 years, SBP is the major contributor to the diagnosis of the condition and its associated risk. Below the age of 50 years, DBP is also important. but there is a shift in the major risk burden attributable to hypertension, from DBP to SBP, at about the age of 50 years. However, because most hypertension, i.e. >75%, occurs over the age of 50 years, SBP rather than DBP is by far the most important contributor to the huge global cardiovascular risk burden attributable to hypertension. SBP is also the most difficult to treat, which has led some to argue that for patients over the age of 50 years the attention of doctors should be focused solely on the SBP.
Pathogenesis and pathophysiology of hypertension
The pathogenesis of essential hypertension has remained something of an enigma, in part reflecting the fact that the basis for the diagnosis, i.e. an elevated blood pressure, has so many potential causes. From a physiological perspective, the pressure in the circulation is the product of the cardiac output (CO) and impedance to flow, i.e. peripheral resistance (PR):
Blood pressure = cardiac output (CO) x peripheral resistance (PR)
Both CO and PR can be influenced by a number of control mechanisms, including activity of the renin–angiotensin–aldosterone system, activity of the sympathetic nervous system, and other factors influencing salt and water homeostasis. In addition, vascular structural changes associated with hypertension play a role in accentuating its severity and conferring resistance to treatment. These structural changes include small-artery remodelling that results in a reduced media/lumen ratio (which increases peripheral resistance) and large-artery stiffening (which changes pulse wave characteristics and reduces the compliance of the circulation). Recent reports suggest that a reduced diameter of the proximal aorta may also be a factor contributing to the development of hypertension. Whether structural changes precede and predispose to the onset of hypertension, or follow it, or both, remains a subject of considerable debate.
In some cases (probably <10%) a discrete cause for hypertension will be identified (see Chapter 16.17.3). In most other circumstances the pathogenesis of essential hypertension, i.e. hypertension that is not due to a recognized secondary cause, is a complex interplay between (1) genetic predisposition (2) lifestyle and environmental influences, and (3) disturbances in structure and the aforementioned control mechanisms. These are in turn compounded by the effects of ageing on the cardiovascular and renal systems.
The history of the genetics of hypertension is marked by a celebrated debate in the 1950s and 1960s between Platt and Pickering, two doyens of British medicine. On the basis of a finding of a bimodal distribution of blood pressures in some families of patients with hypertension, and evidence of hypertension transmitted over three generations in a few pedigrees, Platt argued that hypertension was a distinct genetic disorder with a likely autosomal dominant mode of inheritance. By contrast, Pickering and colleagues showed that in the general population there was no obvious discontinuity of blood pressure distribution and that the familial resemblance of blood pressure spanned the whole range of blood pressures, and was not different for those with hypertension. Thus, Pickering argued that blood pressure, like height and weight, was a quantitative trait, and that although there was a significant genetic contribution, this was polygenic and that hypertension represented one extreme of the trait but was not a distinct disorder, except perhaps for rare monogenetic forms embedded in the blood pressure distribution curve. Today, the overwhelming mass of evidence supports the Pickering concept, although several mendelian disorders that predispose to hypertension have been described.
Genetic epidemiology of blood pressure and hypertension
The extent of familial aggregation of blood pressure has been studied in diverse ethnic groups living in distinct places, ranging from Polynesians to Middle Americans. A remarkably consistent level of correlation of around 0.2 between first-degree relatives has been found, meaning that if the blood pressure of one member of the family deviates from the norm by +10 mmHg, the first degree relative will deviate by +2 mmHg on average. Studies in children and infants suggest that the familial resemblance in blood pressure starts very early and is maintained throughout life.
Attempts to partition the familial resemblance of blood pressure between shared genes and shared environment have been made through studies of adoptees and twins. In the Montreal Adoption Study, correlations between natural siblings compared with adoptive siblings, and between parents and natural children compared with parents and adopted children, were at least twice as great. Similarly, several studies have documented much higher correlations in blood pressure between monozygotic twins (0.55 to 0.85) compared with dizygotic twins (0.25 to 0.50), although the results from twin studies have to be viewed with caution as there is substantial evidence of excess sharing of sociocultural environments by twin pairs, especially monozygotic.
However, taken altogether the epidemiological data suggest that genetic factors account for about 40 to 45% of the population variability of blood pressure, common household environment for about 10 to 15%, and nonfamilial factors for the remaining 40 to 45%.
Although determination of familial correlations of blood pressure provides an overall view of the impact of heredity in determining blood pressure, a more relevant measure of the importance of genetic factors in determining susceptibility to hypertension is relative risk. This is the ratio of the risk of an individual developing the condition given its presence in a first-degree relative compared with the overall population risk. For relatively rare monogenetic conditions such as cystic fibrosis, relative risk is as high as 500. For common and complex polygenic disorders, relative risk tends to be much lower. For hypertension, relative risk estimates vary between 2 and 5 depending on the criteria used to define family history. Values are highest when both parents have hypertension before the age of 55 years.
Genes involved in ‘essential hypertension’
Given the importance of hypertension as a risk factor for several cardiovascular diseases, a huge effort has been made in the last 20 years to identify genes where variants affect blood pressure and increase risk of hypertension or hypertension-related end-organ damage. Most of the studies have involved association analyses of so-called candidate genes whose products are known, or suspected to, be involved in regulation of blood pressure. A smaller number have used linkage analyses in collections of affected sib pairs to identify genetic loci in a systematic manner. Variants in a large number of genes, involving virtually all the main physiological systems affecting blood pressure such as the renin–angiotensin–aldosterone system and the sympathetic system have shown association with blood pressure in one or more studies. See table below:
|Table 2 Some genes with evidence for common variants influencing blood pressure or risk of hypertension|
|Angiotensinogen||Substrate for renin|
|Angiotensin converting enzyme||Converts angiotensin 1 to angiotensin I|
|Angiotensin receptor (type 1)||Main vascular receptor for angiotensin II|
|Aldosterone synthase||Promotes synthesis of aldosterone|
|α-Adducin||Cytoskeletal protein involved in sodium homeostasis|
|G protein β3 subunit||Involved in G-protein signalling|
From Cusi D et al. (1997). Polymorphisms of α-adducin and salt sensitivity in patients with essential hypertension. Lancet, 349, 1353–7
The findings to date suggest that the effect of any individual variant is likely to be modest. For example, a meta-analysis of 32 case–control studies (corresponding to 13 760 patients) of the methionine to threonine (M235T) polymorphism in the angiotensinogen gene, one of the most studied variants, found that the TT genotype conferred a 31% increased risk of hypertension compared with the MM genotype. There is evidence that variants may act in an additive or epistatic fashion. For example, one prospective study of 678 initially normotensive subjects found that combined carriage of the angiotensin-converting enzyme DD genotype (at the insertion (I)/deletion (D) polymorphism in the gene), the tryptophane (Trp) allele at codon 460 in the α-adducin gene, and the CC genotype at the –344C/T promoter polymorphism in aldosterone synthase CC genotype, increased the risk of developing hypertension by 252% over a median follow-up of 9.1 years compared with other genotypes.
The Trp allele of α-adducin, part of a ubiquitous α/β heterodimeric cytoskeletal protein which affects sodium absorption in the kidney, has also been associated with greater blood-pressure-lowering response to thiazide diuretics, and in one study of hypertensive subjects diuretic therapy was associated with a lower risk of combined myocardial infarction or stroke than other antihypertensive therapies in carriers of this adducin variant. Such findings raise the prospect of better prediction and individually tailored treatment for hypertension. However, inconsistent findings between studies reflecting, at least in part, poorly understood gene–gene and gene–environment interactions have hampered progress and significant clinical application so far.
While genetic dissection of essential hypertension has proved challenging, the genetic basis of several monogenic forms of hypertension has been elucidated during the same period. The findings have provided novel and illuminating insights into the molecular regulation of blood pressure and particularly the role of the kidney and sodium homeostasis.
Environmental and lifestyle influences on the development of hypertension
The prevalence of hypertension can be powerfully influenced by local lifestyles and customs. There are a number of lines of evidence that support this conclusion, including studies of migrant populations, comparisons between different communities, prospective population studies, and randomized trials of lifestyle interventions. There is little doubt that the exploding prevalence of hypertension in economically developing regions reflects lifestyle changes, so-called ‘Westernistation’, more than anything else.
Migration studies have provided powerful evidence to illustrate the importance of the local environment and lifestyle on the level of blood pressure and the prevalence of hypertension. Studies of migration from rural to urban areas of Africa and Australia typically report marked increases in migrant blood pressure, body weight, and sodium intake, coincident with the adoption of more sedentary lifestyles, usually within months of migration. This latter point is important because it helps discriminate between powerful lifestyle factors and genetics—i.e. the changes in blood pressure are more nurture than nature.
Studies of specific populations are often very informative. Populations in specific regions of the world, e.g. primitive rural populations such as the Yanamamo Indians of Brazil, do not show much evidence of an age-related rise in blood pressure, suggesting that the progressive rise in systolic blood pressure seen in urban populations is not inevitable. This could reflect genetic differences in vascular structure in discrete populations, but most likely reflects influence of the local environment, and customs. Evidence in support of this conclusion comes from a classic study which compared Italian nuns with a control group of women from the same town. In the control group, blood pressure typically rose with age, whereas the nuns, from a similar genetic background, showed no such rise in blood pressure over 20 years of follow-up. Thus, essential hypertension is undoubtedly a ‘disease of urbanization’, reflecting the impact of a number of specific lifestyle factors.
Specific lifestyle influences on blood pressure
The most important lifestyle/environmental influences on blood pressure are sodium intake, obesity, and alcohol intake. Early nutritional deficiency may be important, and recent evidence suggests that psychosocial factors are likely to play some role in the development of essential hypertension. A small socioeconomic gradient of blood pressure has also been observed. Interestingly, this gradient is negative for developed countries and positive for developing countries, which probably reflects the higher prevalence of obesity and higher intakes of alcohol and salt among those of higher socioeconomic status in developing countries, compared to the reverse in more economically developed regions of the world. With regard to dietary influences on blood pressure, recent evidence (discussed later) suggests that diets rich in fruit and vegetables with low total and saturated fats may protect against hypertension. Low calcium intake, although associated with hypertension in population studies, is now considered to play no part in pathogenesis.
There has been vigorous debate about the role of dietary salt in the genesis of hypertension. It is clear that sodium balance is a key factor determining the blood pressure of an individual. Moreover, it is intriguing that the various monogenic forms of hypertension that have been characterized by genetic studies all involve disturbances to renal sodium handling. Review of the evidence from population-based studies and studies of dietary intervention support the hypothesis that dietary sodium intake has an important impact on blood pressure, and recent studies have also highlighted the importance of salt intake in the genesis of hypertension in children and the effectiveness of sodium restriction at reducing blood pressure. That said, there will clearly be some patients whose blood pressure will be more sensitive to dietary sodium intake than others. Dietary sodium restriction forms part of the lifestyle interventions recommended by all guidelines as part of the treatment strategy for hypertension, and to delay the development of hypertension in people with prehypertension.
A related but different question is whether dietary sodium restriction could influence not only blood pressure, but also cardiovascular disease outcomes. Recent studies suggest that this is likely to be the case. People allocated to a sodium restricted diet experienced a 30% lower incidence of cardiovascular events in the next 10–15 years, irrespective of sex, ethnic origin, age, body mass, and blood pressure. As the people randomized into these studies were not hypertensive (blood pressure c.125/85 mmHg) it is conceivable that the benefits, impressive as they are, might have been even greater in a hypertensive population. These findings support current guideline recommendations and underscore the importance of education and national health policies to reduce dietary sodium intake.
Fat people generally have higher blood pressures than lean people. Fat arms can lead to overestimation of blood pressure when small cuffs are used, but the relation between body weight and blood pressure persists after correcting for arm circumference. Although body mass index (BMI) is often used to define obesity, visceral adiposity seems to be more important in defining the relationship between blood pressure and obesity. Visceral obesity also increases the likelihood of coexisting ‘metabolic syndrome’ (see below) in people with hypertension. In untreated hypertensive people, fat tends to preferentially accumulate intra-abdominally and intrathoracically, and the magnitude of the visceral adiposity is quantitatively related to the blood pressure. Importantly, the adiposity–blood pressure link is observable from early childhood and a key predictor of the likelihood of developing overt hypertension.
Recent analysis of longitudinal data from the Bogalusa Heart Study tracked the association between obesity in childhood and the risk of developing hypertension. Excess adiposity was present in one-fifth of those with normal blood pressure, one-third of those with prehypertension and more than one-half of those with hypertension. Moreover, these associations were evident in people as young as 4 to 11 years, suggesting that the avoidance of obesity could markedly reduce the prevalence of hypertension in middle-aged adults. In support of the strength of the association between BMI and the risk of developing hypertension, in a study of 36 424 Israel Defense Forces employees (mean age c.35 years), BMI was the strongest predictor of prehypertension, with a 10 to 15% increase in risk for every 1 kg/m2 increase in BMI. The strong cause and effect relationship between obesity and hypertension has been confirmed by intervention studies showing that weight reduction results in a fall in blood pressure.
Epidemiological data have consistently shown an association between alcohol intake and blood pressure, and intervention trials confirm that blood pressure falls when alcohol is withdrawn from heavy drinkers. Analysis of data from the National Health and Nutrition Examination Survey (NHANES) (1999–2000) showed that an alcohol intake of up to two drinks per day had no effect on blood pressure, which is consistent with previous reports that moderate drinking (2–3 units daily) does not appear to exert a pressor effect. Heavier alcohol intakes, patterns of alcohol consumption, and the types of alcohol consumed can also influence blood pressure. Binge drinking can exert a pressor effect, but the mechanism accounting for the pressor effects of alcohol remain undefined. However, whatever the mechanism, data from the WHO Global Burden of Disease survey in 2000 attributed 16% of all hypertensive disease to alcohol.
There has been controversy about whether moderate alcohol consumption might actually reduce cardiovascular disease risk. For example, in a prospective study of almost half a million men and women in the United States of America, the relative risk of death from cardiovascular disease in moderate drinkers compared with nondrinkers was 0.7 for men and 0.6 for women. However, it is important to emphasize that these kind of analyses run the risk of confounding by an unmeasured disease effect modifier that tracks with different patterns of alcohol consumption.
Blood pressure characteristically falls during sleep. A recent longitudinal analysis of the first NHANES (n = 4810) examined the impact of sleep duration on the risk of developing hypertension. This risk was increased by about twofold in adults in middle age who sleep for less than 5 h each night. Even after adjusting for obesity and diabetes (the risk of which also increase with sleep deprivation), the risk remained around 1.6-fold. There are a number of mechanisms that might account for this relationship: it may simply reflect a longer duration of sympathetic nervous system activation as a consequence of less time asleep and hence a higher 24-h average blood pressure load, giving rise to a higher risk of longer-term cardiovascular structural damage and hence to sustained hypertension.
There is also a clear association between obstructive sleep apnoea and hypertension. An apnoea–hypopnoea index of ≥15 (i.e. breathing decreases or stops ≥15 times per hour of sleep) is associated with a threefold increase in the risk of developing hypertension. Moreover, in such patients continuous positive airway pressure can be effective in lowering both night-time and, to a lesser extent, daytime blood pressure. Doctors should therefore consider sleep deprivation and obstructive sleep apnoea in their assessment of people developing hypertension.
Blood pressure elevation is a well-recognized acute stress response, and the act of taking the blood pressure can increase the systolic by up to 75 mmHg in some patients. However, the role of chronic stress in the pathogenesis of hypertension has been difficult to assess, (1) because of individual variability in the response to stress, (2) because it is difficult to objectively measure chronic stress, and (3) because stress can induce behavioural and lifestyle choices that could influence blood pressure independently of stress per se.
One measure of stress that does appear to be robust in predicting blood pressure is an individual’s perception of control in their employment. Using ambulatory blood pressure monitoring it has been shown that in men—but not in women—job strain is associated with an elevated blood pressure, both at work and also while at home and during sleep. Job strain in this context was defined as having a highly demanding job, but with the individual having little control over it. By contrast, people employed in equally demanding jobs, but where they have an element of control over their work, have less stress and less elevation of blood pressure. This effect of job strain on blood pressure is independent of other environmental and lifestyle influences, and is as strong as the impact of obesity.
Early origins of hypertension—impact of fetal and infant growth
An associated between low birth weight and risk of developing hypertension and premature cardiovascular disease has been recognized in many epidemiological studies. A large family-based study recently explored the mechanisms underlying the associations of birth weight and gestational age with systolic blood pressure measured at 17 to 19 years of age. This suggested that the inverse associations of birth weight and gestational age with systolic blood pressure are not explained by confounding resulting from a family’s socioeconomic status, or other factors that are shared by siblings. Variations in maternal metabolic or vascular health during pregnancy or placental implantation and function may explain these associations. Other studies have suggested that this relationship may relate to fetal programming of increased risk for hypertension via a reduction in nephron number, thereby increasing salt sensitivity. For further discussion of the impact of fetal growth on cardiovascular disease.
Another hypothesis has suggested that increased nutritional support to promote ‘catch-up growth’ in the immediate postnatal period for babies who are small for gestational age could ameliorate the risk for developing hypertension. This hypothesis was tested in a cohort of small for gestational age babies who had been fed with either a standard or nutrient-enriched (28% more protein than standard) formula after birth. The enriched feed promoted faster postnatal weight gain and was associated with higher (not lower) blood pressure in later childhood, which does not support the promotion of faster weight gain in infants born small for gestational age.
Prehypertension predicts hypertension
The presence of mild elevation in blood pressure for age predicts the likelihood of developing hypertension. In a study of patients with prehypertension (SBP 120–139 mmHg and/or DBP 80–89 mmHg) the annual rate of progression to hypertension (≥140/90 mmHg) was greater than 15% per year despite lifestyle advice. In addition to an elevated blood pressure, people with prehypertension often also have the characteristic metabolic phenotype associated with hypertension (see below) and evidence of endothelial dysfunction and cardiovascular structural damage. This may explain why an analysis of data from the Women’s Health Study in the United States of America, involving over 60,000 women followed for 7 years, showed that the presence of prehypertension was associated with an almost doubling in risk of any cardiovascular event—including death, myocardial infarction, stroke, or hospitalization for heart failure—when compared to those with normal blood pressure. Prehypertension was also more common in people with diabetes, when it was associated with an almost fourfold increase in risk of cardiovascular disease when compared to people without diabetes and normal blood pressure.
Kidney, vascular structure, and neurohumoral control systems and the development of hypertension
The maintenance of an adequate mean arterial pressure is fundamental to life, hence there are many homeostatic mechanisms designed to achieve this despite fluctuations in posture, volume status, exercise and other metabolic demands. There is considerable redundancy within these control systems, such that inhibition of one system is compensated for by increased activity of another, which is important when considering the design of effective strategies to lower blood pressure.
The kidney is important for blood pressure regulation via two key mechanisms (1) the regulation of sodium and volume homeostasis, and (2) the regulation of the activity of the renin–angiotensin–aldosterone system. The transplantation of a kidney from a genetically hypertensive rat into a normotensive control rat results in the development of hypertension in the recipient, and the converse is also true. In humans, significant renal impairment is invariably associated with hypertension, which in large part relates to disturbances in sodium handling, and as stated previously almost all of the single gene defects resulting in the development of hypertension involve disturbances in the renal tubular handling of sodium.
The kidney is also intimately involved with sensing and setting of blood pressure via the activity of the renin–angiotensin–aldosterone system. Reduced renal perfusion pressure (e.g. in renal artery stenosis) results in activation of the renin–angiotensin–aldosterone system, which in turn elevates blood pressure to try and restore renal perfusion pressure via a number of mechanisms (see below).
Structure of small arteries
A characteristic finding in essential hypertension is an inappropriate increase in peripheral vascular resistance relative to the cardiac output. The main site of this resistance is small arteries (arterioles), which undergo inward eutrophic remodelling that is characterized by an increase in their media/lumen ratio. These changes result from vascular remodelling, i.e. rearrangement of existing material in the vascular media around a smaller lumen, and there is often also evidence of some hypertrophy and/or hyperplasia of the resident myocytes.
There has been much debate about whether these changes in small artery structure antedate and thus contribute to the development of hypertension, and/or whether they are the consequence of an elevated blood pressure and the trophic effects of neurohumoral activation (i.e. sympathetic nervous system and the renin–angiotensin–aldosterone system) in people with hypertension. Whatever the mechanism, recent studies of small arteries isolated from biopsies in humans, or retinal vascular structural changes (especially narrowing), suggest that the magnitude of structural changes of the small arteries is strongly predictive of future cardiovascular events. It is also predictive of the likelihood and magnitude of structural changes elsewhere, i.e. left ventricular hypertrophy.
Structure of large arteries
The functional integrity of large conduit arteries, i.e. the aorta, also influences the development of hypertension, especially systolic hypertension. The pulsatile nature of blood flow exerts chronic cyclical stress on the walls of these arteries, and over time this results in deterioration in their elastic properties as a consequence of thinning, splitting, and fragmentation of the elastin fibres within the media. This process is accelerated in people with hypertension, resulting in progressive dilatation in aortic root diameter and arterial stiffening. In turn, this reduction in arterial compliance increases pulse wave velocity, increases systolic pressure and central aortic pulse pressure, and reduces diastolic pressure. This explains the very high prevalence of systolic hypertension with advancing age and the progressive age-related disappearance of diastolic hypertension.
The process of age-related stiffening of the aorta is accelerated by post-translational modification of vascular wall proteins such as collagen by the formation of advanced glycation end products (AGEs). AGE formation is accelerated in people with diabetes, thereby explaining the earlier onset of isolated systolic hypertension in patients with this condition. It is conceivable that if aortic function and especially its elasticity were genetically determined, then accelerated degeneration of aortic elastic function could also be a factor in the development of systolic hypertension in younger people. Aside from aortic function, there is current debate about whether the diameter of the aortic root is causally related to the likelihood of developing hypertension. This has been prompted by recent observations that central aortic pulse pressure appears to be inversely related to aortic root diameter, prompting speculation that a smaller effective root diameter might also contribute to the development of hypertension.
The endothelium plays a key role in the regulation of vascular tone. Endothelial cells form nitric oxide (NO) from L-arginine via the activity of nitric oxide synthase (eNOS), which is tonically activated by shear stress and relaxes vascular tone. NO also inhibits platelet aggregation and inhibits vascular smooth muscle cell proliferation. Hypertension, even in its earliest stages, has been associated with ‘endothelial dysfunction’, usually by demonstrating a reduction in forearm blood flow in response to agents that promote NO release such as acetyl choline or its mimetics. NO production has also been shown to be decreased in people with hypertension.
It is not clear whether endothelial dysfunction and decreased NO production are a cause or consequence of an elevated blood pressure, but the latter seems most likely. Whatever the mechanism, a reduction in NO production would be expected to increase vascular tone and may also contribute to vascular proliferation and remodelling (see above). NO-donors such as glyeryl trinitrate (GTN) are very effective at lowering blood pressure in the acute setting, and are especially effective at reducing central aortic pressure. However, the use of NO-donors to lower blood pressure outside of the acute setting has been bedevilled by their short duration of action and the fact that tolerance to them develops rapidly. The actions of some commonly used antihypertensive drugs, i.e. ACE inhibitors and angiotensin receptor blockers (ARBs), have in part been attributed to their local potentiation of NO.
The endothelium also produces a powerful vascoconstrictor, endothelin. This seems less important in the chronic regulation of blood pressure, even though inhibitors of endothelin have been shown to lower it. The biology and actions of NO and endothelin are discussed in greater detail elsewhere.
Numerous studies in experimental animals and humans have indicated that hypertension is associated with markers of increased systemic oxidative stress, i.e. the increased production of oxygen free radicals such as superoxide and hydrogen peroxide. These are short-lived reactive species that have the potential to cause cellular damage via oxidation of proteins, lipids and DNA. They also react with and inactivate NO, thereby providing a mechanism for reduced NO levels and increased vascular tone. The mechanism for increased oxidative stress in hypertension is not known, but studies have suggested that this may in part relate to activation of NADH/NADPH oxidase within vascular cells. Of interest, this vascular oxidase is activated by angiotensin II, which provides a link between the renin–angiotensin–aldosterone system and endothelial dysfunction and may contribute to the pressor effect of angiotensin II.
The renin–angiotensin–aldosterone system, whose main effector molecules are angiotensin II and aldosterone, plays an important role in the regulation of blood pressure via a number of mechanisms. Angiotensin II is produced by an enzymatic cascade. Renin—the rate-limiting step for the production of angiotensin II—may be synthesized in a number of tissues apart from the kidney, including the adrenal, heart, the blood vessel wall, and brain. In the kidney it is produced by the juxtaglomerular apparatus in response to falls in renal perfusion pressure, sodium depletion, and increased sympathetic nerve activity. However, the renin–angiotensin–aldosterone system is active both in the circulation and locally within tissues.
The two principle angiotensin receptors are AT1 and AT2. The major actions of angiotensin II are via the AT1 receptor, which is the target for the ARB class of blood-pressure-lowering agents. The AT2 receptor is less ubiquitously expressed than the AT1 receptor, is markedly up-regulated during tissue repair, and its activation produces effects that appear to oppose those of AT1 activation, suggesting that the two receptors may operate a Yin–Yang relationship.
Angiotensin II elevates blood pressure by a number of different mechanisms: (1) it is a direct pressor agent promoting vasoconstriction, and it also increases superoxide production by the endothelium, which reduces NO availability (see above); (2) it increases sodium reabsorption by the kidney via direct tubular effects and via simulation of aldosterone release from the adrenal cortex; (3) it can have trophic effects on vascular cell growth and has been implicated in the small artery remodelling process that results in increased peripheral vascular resistance; (4) it acts centrally on AT1 receptors in the nucleus tractus solitaris to desensitize the afferent component of the baroreceptor reflex.
In addition to these pressor actions, angiotensin II has also been implicated in the development of end-organ damage through (1) trophic effects on the myocardium, resulting in left ventricular hypertrophy; (2) the development of glomerular hypertension, albuminuria and interstitial fibrosis, leading to chronic renal disease; (3) pro-oxidant effects, contributing to the development of atherosclerosis. Consequently, the renin–angiotensin–aldosterone system has become a popular target for drug therapy to lower blood pressure and limit its cardiovascular consequences.
Aldosterone is the other effector molecule of the renin–angiotensin–aldosterone system. It is produced by the adrenal cortex in response to many stimuli, including sodium and volume depletion, angiotensin II, excess potassium intake, trauma and stress. It acts on the distal tubule of the kidney to promote sodium absorption in exchange for potassium. An inappropriate increase in production of aldosterone can lead to the development of hypertension (e.g. Conn’s syndrome and adrenal hyperplasia).
The specific role of the renin–angiotensin–aldosterone system in the development of essential hypertension remains unclear, although therapeutic agents that inhibit this system have proved to be very effective treatments. Plasma renin levels vary widely in essential hypertension, from low (30%), to normal (50%), to high (20%): they are inversely related to sodium loading and tend to decline with ageing. Thus patients with low renin levels are generally older and have volume-dependent hypertension. Hypertensive patients with higher renin levels are generally younger, and their increased renin may reflect increased levels of sympathetic nervous system activity (see below). Blacks at any age have a high prevalence of low renin hypertension, suggesting a primary role for sodium retention in the pathogenesis of their hypertension. Although the baseline renin level is rarely measured in routine clinical practice, age has been used as a surrogate in the recent hypertension guidelines in the United Kingdom for predicting the most effective initial therapy in people with essential hypertension. If plasma renin levels are measured, it is important to recognize that they can be affected by concomitant blood-pressure-lowering therapy, with almost all commonly used classes of antihypertensive drugs increasing plasma renin, the main exception being β-blockers which suppress plasma renin.
Sympathetic nervous system
The sympathetic nervous system is involved in the acute and chronic regulation of blood pressure. It is known to be involved in the regulation of arteriolar resistance, cardiac output and volume regulation, renin release by the kidney, and catecholamine and mineralocorticoid release by the adrenal gland. It is by necessity a complex system that involves (1) vasomotor control centres within the brain; (2) the peripheral nervous system providing efferent and afferent signals, and (3) the adrenal medulla. Several nuclei within the central nervous system are involved in the regulation of blood pressure, with control integrated in the rostral ventrolateral nucleus of the medulla oblongata—the vasomotor centre—that is particularly influenced by the nucleus tractus solitarius (NTS) which receives its input from peripheral afferents such as baroreceptor activation in the aortic arch, carotid sinus, and cardiac ventricles and atria. The NTS also receives excitatory and inhibitory inputs from other regions of the brain, i.e. the brain stem and cortex, and its outputs to the vasomotor centre tend to inhibit sympathetic outflow and thus buffer acute rises in blood pressure—the baroreceptor reflex arc. Another important influence on the rostral ventrolateral nucleus–NTS complex is the action of angiotensin II. The area postrema in the floor of the IV ventricle does not have a blood–brain barrier, which allows circulating angiotensin II to blunt the inhibitory effect of the NTS on the rostral ventrolateral nucleus, thereby increasing central sympathetic outflow.
Environmental and behavioural impacts on blood pressure are primarily coordinated via the hypothalamus. The posterolateral hypothalamus is responsible for the classical ‘flight or flight’ response, and lesions in this area reduce blood pressure. By contrast, lesions in the anterior hypothalamus can substantially increase blood pressure.
The peripheral vascular α-adrenergic system (α1 receptors) is also important in maintaining enhanced vascular resistance in hypertension, with some studies suggesting that peripheral α-adrenergic responsiveness might be especially enhanced in blacks with hypertension.
The importance of the sympathetic nervous system in the regulation of blood pressure is beyond question, but a key unanswered question is whether disturbances to the regulation of the sympathetic nervous system play a major role in the initiation and maintenance of chronic essential hypertension. Most surveys of younger people with prehypertension or stage 1 hypertension indicate the presence of an elevated heart rate, indicative of sympathetic nervous system activation. Other studies have reported elevated circulating catecholamine levels in young patients with prehypertension, and that such elevations predict the risk of developing hypertension. Further studies have used radiolabelled norepinephrine to demonstrate enhanced ‘spillover’ indicative of enhanced sympathetic nervous system activity, or microneurography to demonstrate increased sympathetic nervous system activity in young hypertensives. It must be emphasized, however, that simple demonstration of enhanced activity of a particular system at a single snap shot in time cannot be taken as evidence of a direct causal role—the critical question is whether the level of activity is appropriate or inappropriate in the context of the overall integrated physiological regulation of blood pressure. In this regard, a full understanding of the role of the sympathetic nervous system in the genesis of essential hypertension in humans has been hindered by the complexity of the system under study and the rather crude instruments used to evaluate the system in vivo. Some remain to be convinced of the importance of the sympathetic nervous system in the genesis of essential hypertension, while others argue that given the importance of the sympathetic nervous system in regulating blood pressure, then—even if essential hypertension has an unrelated aetiology—abnormal activity of the sympathetic nervous system must be permissive in maintaining blood pressure elevation.
Sympathetic nervous system, obesity, and the metabolic syndrome
Obesity is associated with increased muscle sympathetic nerve activity, and increased sympathetic nervous system activity has been implicated in the pathogenesis of obesity-related hypertension. Hypertension is often associated with features of a metabolic syndrome (see below) characterized by insulin resistance, dyslipidaemia, and impaired glucose tolerance. Increased sympathetic nervous system activity has also been implicated in the development of this syndrome, and drugs therapies that reduce central sympathetic outflow or block α1 adrenergic receptors improve insulin sensitivity and features of the metabolic syndrome.
The natriuretic peptide system—including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP)—is an endocrine system that is involved in the regulation of salt and water homeostasis. ANP is secreted primarily by the right atrium in response to atrial wall stretch. BNP was initially identified in the brain (hence the name), but is predominantly produced in the ventricles in response to stretch. CNP is produced by vascular endothelial cells and in the kidney. These natriuretic peptides bind to specific cell membrane receptors on target tissues and induce natriuresis and diuresis; they also decrease renin secretion and aldosterone, and induce vasodilatation and a modest fall in blood pressure. These physiological actions suggested a potential role for reduced natriuretic peptide levels or action in the pathogenesis of hypertension, hence these have been measured in patients with essential hypertension. The results have been conflicting, with no clear pattern emerging. This in part reflects the fact that levels of natriuretic peptides, especially BNP, will be elevated in people with early or established left ventricular dysfunction and other hypertension related complications, but it does not preclude a future role for drugs that augment the activity of natriuretic peptides in the clinical management of hypertension.
The hypertensive phenotype and target organ damage in hypertension
Although blood pressure measurement is used to define hypertension, hypertension is more than just blood pressure. Essential hypertension is commonly associated with metabolic disturbances and multisystem structural damage that conspire to enhance cardiovascular risk beyond that which can be attributed to blood pressure alone.
Hypertension and the metabolic syndrome
Few people with essential hypertension simply have an elevated blood pressure: many also have associated disturbances in metabolism which are typical of the ‘insulin resistance phenotype’, notably predisposition to impaired glucose tolerance, elevated triglyceride levels, reduced HDL-cholesterol values, and hyperuricaemia. These metabolic disturbances appear to precede and may even predict the likelihood of developing hypertension: in large prospective population studies in the United States of America and Europe the development of hypertension could be predicted by a person’s initial metabolic profile. Even in those with optimal initial blood pressure levels (<120/80 mmHg), increasing obesity and the aforementioned abnormal lipid profile were major predictors of the development of hypertension.
With regard to obesity, the accumulation of visceral fat (i.e. abdominal obesity) is most strongly associated with hypertension and attendant metabolic disturbances. Indeed, the link between visceral fat content and indices of insulin resistance and metabolic syndrome is demonstrable even in lean patients when MRI is used to quantify visceral fat. Moreover, the link between visceral adiposity and blood pressure is present from early childhood and explains the approximately two-fold increase in risk of developing type 2 diabetes in patients with essential hypertension.
The frequent coexistence of obesity with other features of metabolic syndrome in patients with hypertension underscores the need to view hypertension as more than just blood pressure in the context of cardiovascular disease risk management, and it points to the importance of early lifestyle interventions as the foundation for prevention and treatment.
Vascular structural changes and atherosclerosis
Aorta and large arteries
The arterial system is designed to convert the pulsatile flow generated by cardiac contraction into steady flow in the capillary bed. Thus the aorta is both a conduit and an elastic reservoir designed to buffer pulsatile blood flow. Over time, recurrent pulsatile stress produces uncoiling, disruption and calcification of elastic fibres within the aortic wall. At the same time, relatively inelastic collagen is increased and made more rigid by post translational modification by the accumulation of advanced glcycation end products (AGEs). Such age-related processes cause loss of the normal elastic reservoir function of the aorta and other large arteries. These changes are accelerated by the presence of high blood pressure and hence occur at an earlier age in hypertensive patients.
In addition to these structural changes, elevation in pressure itself contributes to a loss of large artery compliance and buffering because, as pressure increases, the elastic fibres become fully stretched, thereby transferring load-bearing function to the relatively inelastic collagen fibres. As a result of these changes, the pressure wave generated by left ventricular contraction is no longer buffered by the aorta and proximal large arteries, but instead is transmitted into the arterial tree with greater amplitude. This is manifested clinically as increased brachial pulse pressure, with higher systolic and lower diastolic pressures. More importantly, the resulting increase in pulse wave velocity and changes in arterial haemodynamics contribute to an elevation in central aortic systolic and pulse pressures and an increase in ventricular loading conditions—changes that cannot always be appreciated by measurement of the brachial blood pressure alone.
Increased large artery stiffening and reduced compliance also reduces the sensitivity of the carotid and aortic baroceptors to stretch, which blunts the normal rapid buffering of changes in blood pressure. As a result, blood pressure becomes more labile and the circulatory adaptation to acute changes, i.e. postural, may become impaired, producing symptoms of postural dizziness in older people.
The characteristic structural change in the smaller arteries and arterioles of hypertensive patients is an increase in wall/lumen ratio, the characteristics and pathogenesis of which have been discussed above. These changes have important functional consequences. The vessels can still dilate in response to stimuli such as warmth or drugs, but maximal vasodilatation is reduced. The converse is also true; responsiveness to pressor agents or stimuli becomes enhanced. These structural changes in resistance vessels also contribute to the characteristic increase in vascular resistance in hypertension, and they render vital organs more susceptible to ischaemic damage at the small vessel level, e.g. small vessel ischaemic brain damage.
Atheroma in hypertension
Hypertension is associated with an increased risk of generalized atherosclerotic disease. This is likely to result from an interplay of many factors, including pressure and haemodynamic stress, metabolic disturbances, inflammatory and oxidative stresses, endothelial disturbances, neurohumoral activation, and many other factors.
The overwhelming importance of haemodynamic factors and pressure is illustrated by (1) the predilection for atheroma to develop at sites of increased haemodynamic stress within the circulation, i.e. arterial bifurcations; and (2) the fact that atheroma is rarely observed in a low pressure circulation, i.e. the pulmonary circulation or venous system (unless pulmonary hypertension develops, or veins are grafted into the arterial circulation). Two recent studies have been important in establishing a direct link between pressure and the development and/or regression of atherosclerosis. Using a mouse genetically prone to develop atheroma, the placement of a suprarenal clip was used to generate aortic constriction (a high renin state) and hypertension. Atheromatous plaque area was greatly increased by the presence of hypertension and was not obviously ameliorated by administration of angiotensin receptor blockade. This study therefore suggested that pressure and not activation of the renin–angiotensin–aldosterone system was the main cause of accelerated atheroma in this model. Further data from a human study that used intravascular ultrasonography to quantify changes in coronary atheroma suggested that the patients’ in-trial blood pressure determined whether there was progression, stabilization or regression of atheromatous plaque over a 2-year period. Thus, a large body of evidence supports the hypothesis that blood pressure plays a key role in the initiation and progression of atheroma in humans. It is also likely that haemodynamic stress plays an important role in the process of plaque rupture, as well as the plaque burden.
The heart in hypertension
Left ventricular hypertrophy is a classic feature of untreated, or inadequately treated, long-standing hypertension. In this regard it can be considered the hypertensive equivalent of the glycated HbA1c for patients with diabetes: it is an index of the prevailing blood pressure load. Left ventricular hypertrophy is demonstrable in about 50% of untreated hypertensive patients using echocardiography, but only 5 to 10% when using conventional ECG criteria (Sokolov–Lyon or Cornell duration product). Pressure load on the left ventricle is unquestionably the most important pathogenic factor, with ambulatory monitoring blood pressure measurements much better correlated with left ventricular hypertrophy than clinic measurements of pressure. Pressure load is compounded by stiffening of the aorta with ageing, but neurohumoral factors, including the activity of the sympathetic nervous system and renin–angiotensin–aldosterone system, also appear to be important.
Left ventricular hypertrophy is a very potent predictor of premature cardiovascular disease and death. Its presence on the ECG, especially when associated with a characteristic ‘strain pattern’, is associated with a two- to threefold increase in risk of cardiovascular disease morbidity and mortality, including a marked increased risk of stroke and heart failure. Using echocardiography to characterize left ventricular hypertrophy, recent studies suggest that concentric hypertrophy carries a worse prognosis that eccentric hypertrophy.
There are two pathological features of the cardiac changes in hypertension that culminate in the development of left ventricular hypertrophy: an increase in size of cardiomyocytes, which increases the muscular mass of the left ventricle, and an increase in extracellular matrix deposition within the ventricle, which contributes to an increase in wall stiffness. The increase in left ventricular mass and stiffness manifests initially as impaired relaxation during diastole, which is often detectable on echocardiography in hypertensive patients at diagnosis, even before the left ventricular mass is sufficiently increased to be classified as indicating hypertrophy. Over time, in untreated or poorly treated patients, cardiac changes will progress to impaired systolic function and ultimately overt heart failure.
In addition to impaired cardiac diastolic and systolic function, the hypertensive heart is also predisposed to myocardial ischaemia because of (1) increased myocardial oxygen consumption due to increased cardiac afterload, (2) impaired endocardial blood flow due to the structural and functional changes in small arteries described above, (3) an increase in the systolic time interval and reduced diastolic filling time and pressures due to large artery stiffening and impaired ventricular–vascular coupling, and (4) increased risk of coronary atheroma in people with hypertension.
The aforementioned structural and ischaemic changes also predispose to an increased prevalence of simple and complex ventricular arrhythmias in people with hypertensive left ventricular hypertrophy. In addition, it has recently become recognized that atrial fibrillation is much commoner in older people with hypertension. Moreover, in hypertensive patients with left ventricular hypertrophy the risk of developing atrial fibrillation is at least twofold greater, and increases further as a function of advancing age, increased systolic pressure, increased left ventricular mass, and increased left atrial diameter. The combination of these latter two cardiac features is a particularly potent predictor of the risk of developing atrial fibrillation in hypertensive patients.
Regression of left ventricular hypertrophy
Recent clinical studies suggest that inhibition of the renin–angiotensin–aldosterone system is particularly effective at regressing left ventricular hypertrophy. This is important, because there is now clear evidence that regression of the ECG manifestations of left ventricular hypertrophy is associated with dramatically improved prognosis for people with hypertension (50% reduction in risk of cardiovascular death over 5 years). Moreover, blockade of the renin–angiotensin–aldosterone system may be particularly effective at reducing the risk of developing atrial fibrillation in people with hypertensive left ventricular hypertrophy. Consensus in guidelines is that blood pressure lowering is of paramount importance for patients with left ventricular hypertrophy, but that effective renin–angiotensin–aldosterone system blockade should also be part of the treatment strategy.
The brain and hypertension
Hypertension is the single most important risk factor for stroke and is increasingly recognized as a major factor contributing to the rate of cognitive decline in later life. All categories of stroke—ischaemic (large and small vessel), haemorrhagic, and embolic—are increased in hypertensive patients.
Cerebral (atherothrombotic) infarction
Infarction accounts for about 80% of the strokes suffered by patients with hypertension. It is usually attributable to atheroma of one of the larger cerebral arteries (usually the middle cerebral artery), or to small vessel (lacunar) infarction. Although poorly characterized, it is likely that embolic stroke is also more common in people with hypertension, especially those with left ventricular hypertrophy, because of the increased likelihood of paroxysmal or sustained atrial fibrillation on a background of increased left atrial size.
This accounts for 10 to 15% of strokes in patients with hypertension and is usually the result of rupture of a small intracerebral degenerative microaneurysm (Charcot–Bouchard aneurysm). These lesions develop in the small (<200 µm diameter) perforating arteries in the region of the basal ganglia, thalamus, and internal capsule. Hyaline degeneration (lipohyalinosis) occurs in the aneurysmal wall, with a defect in the media at the neck of the aneurysm. The incidence of Charcot–Bouchard aneurysms is closely correlated with age and blood pressure, the two factors acting additively so that lesions are rarely if ever seen in younger normotensive people. The relationship between blood pressure and haemorrhagic stroke appears to be steeper in people of Chinese Asian origin.
The remaining strokes in hypertensive patients are due to subarachnoid haemorrhage. Transient ischaemic attacks due to disease of extracranial vessels are also more frequent in hypertensive subjects.
Hypertension and cognitive function
Hypertension is increasingly recognized as an important cause of dementia, with increased blood pressure in mid life associated with an increased risk of dementia in later life. Cognitive decline is related to diffuse small vessel cerebrovascular disease in untreated hypertension and in older patients. Functional imaging studies have shown relative reductions in blood flow in parietal and forebrain areas in hypertensive patients during memory tasks and areas of cortical and subcortical hypometabolism. More advanced vascular disease gives rise to multiple, punctate, hyperintense white matter lesions on MRI scanning. These are due to focal ischaemia, either as a result of lipohyalinosis or microatheromatous disease, tortuosity, and narrowing of the perforating arteries. All degrees of impairment of cognitive performance may occur as a result of these lesions, ranging from effects only detectable with sensitive psychometric testing, to lacunar strokes and Binswanger’s disease.
The brain is protected from wide fluctuations in blood pressure by blood flow autoregulation, i.e. the intrinsic capacity of the cerebral vessels to constrict in the face of increased pressure and dilate in the face of decreased pressure to maintain a constant flow. Resistance vessel remodelling and hypertrophy may enhance protection against higher perfusion pressures, thereby extending the upper limits of the autoregulatory range in long-standing hypertension. However, such remodelling may also impair the autoregulation of blood flow when faced with decreased pressure because of impaired capacity of hypertrophied resistance vessels to dilate, thereby predisposing to small vessel ischaemia. In severe hypertension focal areas of vasodilatation can develop if blood pressure rises above the autoregulatory range, resulting in localized perivascular oedema and fibrinoid necrosis. Focal haemorrhages, ischaemia, and infarction may result, giving rise to the clinical picture of encephalopathy.
The kidney in hypertension
Patients with renal disease often have hypertension, and people with hypertension can develop renal disease. The age-related decline in GFR is more rapid in people with essential hypertension. However, GFR is usually well preserved throughout life in patients with mild to moderate essential hypertension, hence the development of endstage renal disease in such patients is unusual in the absence of any other renal lesions. The decline in GFR, when it does occur, is due to progressive glomerulosclerosis, most likely driven by raised intraglomerular capillary pressures, which also explain the increased urinary albumin excretion rates in these patients. Increased urinary albumin excretion rate has in turn been linked to increased likelihood of more widespread endothelial/vascular dysfunction and an increased risk of premature cardiovascular disease and death, hence the kidney—and urinary albumin excretion rate in particular—has been proposed as the earliest clinical indicator of significant pressure mediated vascular injury.
Significant hypertension-induced glomerulosclerosis is much more likely in two settings (1) severe and accelerated hypertension, resulting in so-called hypertensive nephropathy; and (2) in the presence of intrinsic renal disease, i.e. due to diabetes or glomerulonephritis. Effective control of blood pressure is of substantial importance in retarding the progression of renal impairment in these settings.
Another important association between hypertension and renal disease is atheromatous renal vascular disease. In these patients, hypertension is usually moderate to severe, and the condition is characteristically associated with a progressive ischaemic nephropathy due either to proximal renal artery (often ostial) disease and/or smaller branch artery disease. It may be associated with small vessel cholesterol embolization, the affected patients usually being older, with evidence of widespread atheromatous disease.
The eye in hypertension
The findings in the retina of patients with hypertension range from mild generalized retinal–arteriolar narrowing, through to the development of more significant changes of flame-shaped or blot-shaped haemorrhages, cottonwool spots, hard exudates, microaneurysms, or a combination of all of these factors. Swelling of the optic disc can also be seen.
The evolution of hypertensive injury—from physiology to philosophy
The process of hypertensive injury to target organs evolves silently over many years, the magnitude and rate of progression determined largely by the level of blood pressure, but also by individual susceptibility. In the prehypertensive phase, patients may already have disturbances in blood pressure regulation, i.e. responses to pressor stimuli, visceral obesity, and subtle features of the metabolic syndrome. The injurious process and metabolic disturbances then progress though a silent phase, often lasting many years, during which there is subtle damage to many target organs as cited above, i.e. vascular wall, myocardium, brain, kidney, and eye. This subtle early damage is potentially preventable and/or reversible, but progresses if untreated to more sinister markers of more advanced damage—the so-called intermediate or surrogate disease markers that can be detected in many cases by simple tests such as the ECG, or urinalysis for albumin or protein. Untreated or poorly treated, this progressive hypertension-mediated damage culminates in overt cardiovascular, renal, and cerebrovascular disease and clinical events—the so-called ‘hard clinical endpoints’ that form the evidence base for treatment guidelines. Alongside, the metabolic syndrome is evolving, increasing the risk of developing diabetes and magnifying the cardiovascular risk burden associated with the blood pressure elevation. Along the way, the conduit arteries are stiffening with damage and age, and the systolic pressure is rising and becoming more difficult to treat.
Current treatment guidelines have been developed from an evidence base relating to changes in hard clinical endpoints derived from studies in very elderly patients at the end of the hypertensive disease process. Somehow, we have to try to translate that evidence into strategies for treating younger patients at the start of the disease process when their risk of clinical events is low. Future treatment strategies must surely focus on preventing the evolution of the silent disease process, rather than simply battling with its consequences. To meet that challenge, we need more and better studies of younger patients with hypertension to better characterize the impact of treatments on the evolution of hypertensive disease, and to determine the robustness of the associated intermediate or surrogate disease markers at predicting treatment benefit.