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Epidemiology and pathophysiology of hypertension 

Epidemiology and pathophysiology of hypertension
Chapter:
Epidemiology and pathophysiology of hypertension
Author(s):

Stefano Taddei

, Rosa Maria Bruno

, Stefano Masi

, and Anna Solini

DOI:
10.1093/med/9780198784906.003.0563_update_001

Update:

Multiple new references provided.

Prevalence and temporal trends of hypertension in Europe extensively updated.

Updates throughout.

Updated on 23 April 2020. The previous version of this content can be found here.
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date: 28 June 2022

This chapter provides the background information and detailed discussion of the data for the following current ESC Guidelines on: Epidemiology and pathophysiology of hypertension management of arterial hypertension - https://academic.oup.com/eurheartj/article/39/33/3021/5079119#133825458

Summary

Hypertension remains the leading cause of morbidity and mortality worldwide and significantly impacts the risk of all major cardiovascular events, including stroke, sudden cardiac death, coronary heart disease, heart failure, abdominal aortic aneurysm, and peripheral vascular disease. Important advances in our understanding of its pathophysiology contributed to clarifying the complex origins of the disease, involving dysregulation of multiple homeostatic systems influencing not only blood pressure but also the progression of end-organ damage related to hypertension. Growing evidence suggests that the pathophysiology of hypertension results from complex interactions between environmental and genetic factors, resulting in different risks and age of onset of the disease within the general population. This chapter reviews the recent statistics of hypertension with a specific emphasis on its prevalence and temporal trends in Europe. Also, it provides a comprehensive overview of the mechanisms involved in the aetiopathogenesis of hypertension, highlighting their relative importance in different forms of hypertension.

Epidemiology

Prevalence and temporal trends of hypertension in Europe

Epidemiology and pathophysiology of hypertension Hypertension remains the leading risk factor for death at the global level.1 Its definition varies depending on guidelines, as the latest American guidelines have reduced the thresholds for diagnosis of arterial hypertension to values of systolic blood pressure (SBP) of at least 130 mmHg and/or diastolic blood pressure (DBP) of at least 80 mmHg,2 while the 2018 European guidelines left the old thresholds of 140/90 mmHg. Hypertension-related deaths occur most commonly as a result of ischaemic heart disease, haemorrhagic stroke, and ischaemic stroke, which are estimated to account for 4.9, 2.0, and 1.5 million deaths, respectively.3 Beyond its impact on mortality, raised SBP is the largest contributor to global disability, accounting for 218 million (95% uncertainty interval 198–237 million) global disability-adjusted life years (DALYs) for both sexes.4 Data also show an increasing burden of hypertension-related cardiovascular disease (CVD) that accounts for a significant increase in the number of DALYs. Between 2007 and 2017 the number of DALYs due to hypertensive heart disease increased by 31%.4 Thus, reliable estimations of hypertension prevalence and its trends are essential to calculate the burden of future events and costs of intervention policies. However, the prevalence of hypertension is difficult to estimate as limited comparable data are available, due to different methods used to apply these criteria in practice, and the population being examined.5 For example, several surveys used to assess the prevalence of hypertension across different countries have identified the hypertension burden based on measurements obtained from a single evaluation, and it is now well established that the use of this approach carries a substantial risk of a false-positive diagnosis.

Due to the difficulty of obtaining comparable results among countries, the World Health Organization Global Health Observatory represents an important source of data on the prevalence of hypertension and the mean SBP values among 51 European national populations. The first striking feature of these data is the similarity of the pattern of the association between blood pressure (BP) and age as well as between BP and sex in different countries. SBP progressively increases throughout life, with a difference of 20–30 mmHg between early and late adulthood.6,7 DBP increases to a lower extent until the fifth decade, and then average DBP tends to remain constant or, more frequently, to decline slightly.6,8 For both SBP and DBP, the mean levels are higher in men than in women in early adulthood, although this difference narrows progressively and is either non-existent or reversed by the sixth or seventh decade.9,10

The most recent estimates suggest that, across both European Union and non-European Union member states, the prevalence of hypertension is around 40% and tends to be highest in Central and Eastern European countries and lowest in Northern and Southern countries.11 Mean levels of SBP can vary up to 10 mmHg across different European Union countries (136 mmHg in Portugal vs 125.7 mmHg in France) and show similar regional variation as the prevalence of hypertension, with higher levels generally found in Central and Eastern European countries and lower levels in Southern, Western, and Northern European countries (Figure 44.1.1).11 Mean SBP and mean DBP are highly correlated across European countries.1 However, men and women in countries in Central and Eastern Europe have higher DBPs than expected based on their SBPs and the association between SBP and DBP.1

Figure 44.1.1 Prevalence of raised blood pressure in Europe in 2014. (a) In males aged over 18 years; (b) in females aged over 18 years.

Figure 44.1.1 Prevalence of raised blood pressure in Europe in 2014. (a) In males aged over 18 years; (b) in females aged over 18 years.

Adapted from11 with permission.

Temporal trends of hypertension show that its age-standardized prevalence declined from 2010 to 2014 in most European countries.1 Similar favourable trends are observed for the mean SBP in many European countries between 1975 and 2015, with a particularly sharp decrease since about 2008 in both sexes.1 The greatest decreases seem to have occurred in Northern and Western European countries, while the levels in many Eastern European countries have remained more stable or even show increasing trends (i.e. Slovenia, Serbia, and Romania).1 Values of mean DBP between 1975 and 2015 showed similar trends, although to a lesser extent, than mean SBP and are more evident in females than males. Independently from these temporal trends, high SBP is the only risk factor which remained ranked among the leading three contributors to the global burden of loss of DALYs in the period between 1990 and 2015.4

Epidemiology and pathophysiology of hypertension Hypertension treatment also differs among different European countries and between Europe and other geographic regions. Statistics elaborated from data collected infive major European countries (Sweden, Italy, England, Spain, and Germany) suggest that the use of antihypertensive treatment is lower in Europe (England 25%, Germany 26%, Spain 27%, and Italy 32%) than in the United States (53%) and Canada (36%). The percentage of subjects treated for hypertension varies with sex and age. Women in all countries are more likely to be treated than men and, while the proportion of hypertensives receiving treatment was reasonably constant across the age range in the United States, younger subjects have lower levels of treatment than older age groups in Europe.12

Epidemiology and pathophysiology of hypertension Despite the improvement in the number and efficacy of antihypertensive medications, a large proportion of patients with arterial hypertension remain uncontrolled while on treatment. The European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA) study documented a 51.6% prevalence of uncontrolled hypertension in Europe, ranging from 38.6% in Greece to 59.7% in Turkey.13 Similar values had previously been reported.14,15 Control is more common in women compared with men in some European countries (Spain, Italy), Canada, and the United States.

Blood pressure-related risk of cardiovascular disease

Several studies documented that the relationship between BP values and cardiovascular (CV) morbid and fatal events is continuous16,17,18 and extends to relatively low values of SBP (90–114 mmHg) and DBP (60–74 mmHg).17 This evidence has generated an intense debate about whether patients with prehypertension (i.e. SBP 120–139 mmHg, DBP 80–89 mmHg) or with BP values greater than 110/74 mmHg should receive antihypertensive treatment to reduce their CV risk (the ‘lower the better’ hypothesis). If the prehypertension thresholds or the theoretical minimal cardiovascular disease (CVD) risk exposure level of SBP (≥110 mmHg) are applied to the general population, the number of subjects who should be followed up for hypertension would increase significantly. For example, data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 show that approximately 3.5 billion people aged 25 years and older have SBPs of at least 110 mmHg (an 11% increase between 1980 and 2015), compared to 0.9 billion who have SBPs of 140 mmHg or higher (an 18% increase between 1980 and 2015). These prevalence estimates might translate into a 49% increase in the number of annual deaths due to a SBP of 110 mmHg or higher and a 51% increase due to a SBP of 140 mmHg or higher in 2015.19

Masked hypertension might account for a proportion of the increased CVD morbidity and mortality observed in subjects with a BP level below the cut-off values for a diagnosis of hypertension. The term masked hypertension is used to define people who have a normal seated clinic BP but an elevated out-of-office BP, as determined by ambulatory BP monitoring or home BP monitoring. Masked hypertension is associated with an increased risk of subclinical end-organ damage, including left ventricular hypertrophy, increased pulse wave velocity, and carotid intima–media thickness.20,21,22 Most importantly, patients with masked hypertension, diagnosed by home or ambulatory BP monitoring, have an increased risk of CV morbidity and mortality compared with persons with sustained normotension.23,24,25 The prevalence of masked hypertension varies from 10% to 30% of patients with normal BP values. The risk of masked hypertension is higher in males than females and increases gradually with increasing values of BP within the normal range (from 6.6% among persons with optimal BP (<120/80 mmHg), to 29.7% among those with prehypertension (≥130/85 mmHg and <140/90 mmHg)) and with ageing.26,27 The lifestyle and metabolic risk profile of patients with masked hypertension resemble that of sustained hypertensive patients.24,28,29,30 Therefore, screening for masked hypertension is particularly recommended in elderly, male subjects with prehypertension and with multiple CVD risk factors.

A striking feature of the association between BP and the risk of CVD is that it spans all major CV events, including stroke and other forms of cerebrovascular disease, sudden cardiac death, coronary heart disease, heart failure, abdominal aortic aneurysm, and peripheral vascular disease. The risk associated with higher BP is similar for different CVD conditions. Using data from linked healthcare records of 1.25 million patients in England registered with their primary care doctors between 1997 and 2010, the CArdiovascular research using LInked Bespoke studies and Electronic health Records (CALIBER) project reported that a 20 mmHg rise in SBP has stronger associations with stable angina (hazard ratio (HR) 1.41; 95% confidence interval (CI) 1.36–1.46), subarachnoid haemorrhage (HR 1.43; 95% CI 1.25–1.63), and intracerebral haemorrhage (HR 1.44; 95% CI 1.32–1.58) than with total CVD (HR 1.26; 95% CI 1.25–1.28).17 Compared with SBP, DBP has weaker associations with stable angina, peripheral arterial disease, myocardial infarction, and with the total CVD. The CALIBER project also confirmed previous data from the large Prospective Studies Collaboration (PSC) and Asian Pacific Cohort Studies Collaboration (APCSC)16,31 that the strength of the association of SBP with CVD attenuates significantly in older age groups. For example, in the age group of 30–59 years, 20 mmHg higher SBP was associated with a HR of 0.62 (95% CI 0.58–0.66) for stable angina, but was associated with a HR of 0.78 (95% CI 0.68–0.88) in the age group of greater than 80 years. Similarly, for ischaemic stroke, 20 mmHg lower SBP was associated with a HR of 0.64 (95% CI 0.56–0.72) in the age group of 30–59 years but a HR of 0.86 (95% CI 0.77–0.96) in the age group of greater than 80 years.

Epidemiology and pathophysiology of hypertension The relationship between BP values and CV events is independent of other CVD risk factors. However, due to the well-documented risk factor clustering that is seen in hypertensive individuals, guidelines on the management of raised BP recommend assessment of total (or global) CVD risk in this population, as only a small fraction of the hypertensive population has an elevation of BP alone.32 In the Framingham Heart Study, for example, more than 80% of hypertensive individuals had one or more coexisting risk factors, and 55% had two or more risk factors.33,34 When hypertension coexists with other CV risk factors, the total CV risk increases exponentially rather than resulting from the sum of its components. This is true also for relatively low values of BP. For example, prehypertension leads to a 10% increase in the 10-year absolute risk of CVD for middle-age adults without diabetes, which rises to 40% in the presence of diabetes and/or established CVD.35 Similar results are available for patients with established hypertension. In the INTERHEART study, the presence of a single risk factor (smoking, hypertension, dyslipidaemia, or diabetes) was associated with atwo- to threefold increase in the risk of acute myocardial infraction, while when hypertension coexists with the other three risk factors was related to a 20-fold increase in the same risk.36 A combination of antihypertensive drugs with other therapies is often necessary to obtain adequate control of BP values in individuals with multiple CV risk factors, to maximize cost-effectiveness of the management of hypertension.

Several multivariate risk models have been developed for estimating the global risk of future CV events in apparently healthy, asymptomatic individuals with raised BP. Many of these risk models provide an estimation of the 10-year risk of fatal CVD event. Among those available, the guidelines on BP management published by the European Society of Cardiology in 201837 suggest the use of the Systematic COronary Risk Evaluation (SCORE), developed from data on more than 200,000 patients pooled from cohort studies in 12 European countries.38 SCORE differs from the other risk prediction models (i.e. the Framingham score) in two important ways: it estimates the 10-year risk of any first fatal atherosclerotic event (e.g. stroke or ruptured abdominal aneurysm), not just coronary heart disease-related deaths, and it estimates CVD mortality based on age, sex, smoking habits, total cholesterol, and SBP.32 The SCORE model allows calibration of the charts for individual countries, which has been done in numerous European countries. At the international level, two sets of charts are provided: one for high-risk and one for low-risk countries. While the SCORE model represents a considerable step forward compared to previous risk prediction models, it is now increasingly recognized that models based on 10-year risk estimates have significant limitations, primarily due to overestimation of the contribution of age and sex in the assessment of the individual CVD risk.39 Thus, younger adults (particularly women) are unlikely to reach high-risk levels even when they have more than one major risk factor and a clear increase in relative risk.40,41 By contrast, many older adults reach a high total risk level while being at very little increased risk relative to their peers. The consequences are that most resources are concentrated in the oldest segments of the general population, where reduction of BP values is unlikely to provide significant benefits according to the age-stratified analyses of the CALIBER, PSC, and APCS data.16,17,31 Novel models based on lifetime risk estimates of CVD have been developed to overcome these issues.

Lifetime risk estimates, which represent the risk of the disease of interest and adjust for competing risk of death from other causes, provide a simple conceptual basis for estimating the absolute risk of developing a disease during the remainder of an individual’s life.42 Using these models, it is possible to identify a new group of people in the general population who are at low short-term but high long-term risk. In those younger than 50 years, around half of those in the low short-term risk category fall into this group.40 The contribution of hypertension to lifetime risk prediction models for CVD remains substantial. The CALIBER study documented that the lifetime risk of total CVD at 30 years of age is 17.2% higher in people with hypertension than in those with a healthy BP, corresponding to a mean of 5 CVD-free life years lost associated with hypertension.17 Afterwards, hypertension shows a reducing impact on mean number of CVD-free life years lost, becoming 3.4 years from 60 years, and 1.6 years from 80 years of age. The specific CV event accounting for the largest proportions of lifetime risk of total CVD due to hypertension differed by ages. Stable angina (22%), unstable angina (21%), and myocardial infarction (15%) accounted for the largest proportion of CVD-free years of life lost at age 30. At 80 years of age, heart failure (19%), unstable angina (15%), myocardial infarction (12%), and ischaemic stroke (10%) become the leading contributors. At 30 years of age, the lifetime risk associated with hypertension was higher in males than females for most CV outcomes, apart from subarachnoid haemorrhage, intracerebral haemorrhage, heart failure, ischaemic stroke, and transient ischaemic attack. Isolated systolic and combined systolic and diastolic hypertension accounted for the largest proportion of CVD-free years of life lost, with a negligible contribution from isolated diastolic hypertension, even in those aged 30–59 years, in whom the prevalence of isolated diastolic hypertension was highest (Figure 44.1.2). These data highlight the importance of early rather than late interventions in people with mild elevation of BP to maximize CVD prevention.

Figure 44.1.2 Example of lifetime cardiovascular disease risk estimation model related to hypertension. Years of life lost to cardiovascular disease up to 95 years of age associated with hypertension at index ages 30, 60, and 80 years in the CALIBER registry. Data are adjusted for sex, smoking, diabetes, and total and high-density lipoprotein cholesterol.

Figure 44.1.2 Example of lifetime cardiovascular disease risk estimation model related to hypertension. Years of life lost to cardiovascular disease up to 95 years of age associated with hypertension at index ages 30, 60, and 80 years in the CALIBER registry. Data are adjusted for sex, smoking, diabetes, and total and high-density lipoprotein cholesterol.

Reproduced from17 with permission.

Conclusion

In summary, current epidemiological data suggests that:

  1. 1. Although temporal trends show that the prevalence of hypertension is declining in most European countries, it remains the leading cause of CVD morbidity and mortality in Europe.

  2. 2. The prevalence of hypertension varies considerably among different European countries, with Eastern European regions needing an urgent implementation of public health strategies to reduce their considerable burden of hypertension.

  3. 3. The relationship between BP and increased risk of CVD is continuous and extends to values of BP below the thresholds recommended for diagnosis of hypertension by most influential guidelines.

  4. Epidemiology and pathophysiology of hypertension4. A large proportion of patients with arterial hypertension do not reach the treatment targets despite significant improvement in the number and efficacy of blood pressure-lowering medications.

  5. 5. Raised BP is a risk factor for all major manifestations of CVD.

  6. 6. The association between BP and risk of CVD weakens with age. Lifetime rather than 10-year risk prediction models are more likely to capture the risk related to raised BP, particularly in the youngest populations.

Pathophysiology

Maintenance of a normal BP is dependent on the balance between the cardiac output and peripheral vascular resistance. It follows that patients with arterial hypertension may have an increase in cardiac output, an increase in systemic vascular resistance, or both. While this conceptual framework is used to understand the final physiological alterations leading to elevated BP, it is now well established that multiple renal, neural, endocrine, and CV control systems can affect cardiac and vascular homeostasis, making the pathophysiology of hypertension extremely complex. The contribution of each of these factors to elevated BP values is defined by gene–environment interactions and varies among different individuals.43 In this section, the role of the main BP regulation systems in the pathogenesis of essential hypertension are reviewed.

Renal mechanisms

The kidney is an important regulator of BP, and impaired renal function, irrespective of its cause, is almost invariably associated with the development of hypertension. Besides the numerous renal parenchymal causes of hypertension (summarized in Box 44.1.1), the most important mechanisms by which the kidney controls BP homeostasis are by regulating the pressure–natriuresis relationship and the activity of the renin–angiotensin (RAS) system. Also, perturbation of the renal physiology induced by an impaired renal blood flow and an elevation of renal inflammation and oxidative stress burdens stimulate adaptive changes that could lead, if sustained, to increased BP.

Pressure–natriuresis relationship: the BP responsiveness to variations in salt intake, defined as salt sensitivity, is critically dependent on renal salt handling. More than 60 years ago, Strauss and colleagues showed that, during a saline load, 5 days were required before the rate of renal sodium excretion became equal to the rate of sodium intake (i.e. until sodium balance was achieved). Based on this evidence, they hypothesized that hypertension might result from a relative inability of the kidney to excrete salt efficiently. Guyton and colleagues further developed this hypothesis, postulating that the long-term control of BP was strictly dependent on the ability of the kidney to respond with an appropriate natriuresis at normal BP.44,45 It was also hypothesized that the ability of the kidney to excrete sodium would provide a compensatory system to counterbalance processes tending to raise BP, including an increased peripheral vascular resistance.44

Salt sensitivity and the renin–angiotensin system: under normal conditions, BP and Na+ excretion are primarily regulated by the RAS. In physiological conditions, the RAS is activated by reduced salt intake, stimulating renal sodium reabsorption and preserving body fluid volumes and BP. In contrast, an increased salt intake leads to suppression of the RAS, facilitating natriuresis.46 Consequently, the RAS is a powerful modulator of the pressure–natriuresis relationship, shaping the features of BP regulation in healthy and diseased individuals. Pathological conditions leading to a chronic elevation of angiotensin II (Ang II) cause a shift of the pressure–natriuresis curve to the right, with higher BP values required to excrete an equivalent sodium load. Administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, in contrast, shifts the curve to the left, reducing the BP values necessary to obtain an effective natriuresis.

Salt-sensitive hypertension is related to an excessive sodium and volume retention, often associated with a residual plasma renin activity,47,48 which is thought to be related to a dysregulation of the intrarenal RAS.49,50 Indeed, intrarenal Ang II levels are elevated in salt-sensitive hypertension, even in the presence of plasma volume expansion. Also, while plasma aldosterone levels are reduced or even suppressed in these patients, it has been documented that a hyperactivation of the mineralocorticoid receptor may persist in the kidney, leading to inappropriate renal sodium retention. Other alterations described in these patients that might contribute to salt-sensitive hypertension are an upregulation of the angiotensin-converting enzyme-2 activity resulting in increased Ang II formation and renal vascular resistance and BP,51 as well as an altered sodium appetite.52

Role of the Na+/K+ balance: renal sodium and potassium excretion in the distal renal tubule is regulated by neurohormonal control, with the participation of corticosteroids, vasopressin, Ang II, catecholamines, and insulin. The distal tubule is divided into several segments, including the thick ascending limbs of Henle’s loop, the distal convoluted tubules, the connecting tubules, and cortical and medullary collecting ducts. Different cells in these segments express different electrolyte transporters, including Na–K–Cl cotransporter 2, Na–Cl cotransporter, and epithelial sodium channel. Loss- or gain-of-function mutations in genes encoding such transporters may cause genetic disorders of salt-losing hypotension or salt-sensitive hypertension.52,53

When dietary sodium intake is high and potassium intake is low, a large proportion of the aldosterone-regulated sodium and potassium transport would occur in the distal convoluted tubule and in the connecting tubule, collectively identified as the ‘aldosterone-sensitive distal nephron’. The activity of aldosterone at this level is regulated by mineralocorticoid receptors (mainly expressed in the distal nephron and collecting duct), the glucocorticoid receptors (ubiquitously distributed across the entire nephron), and the enzyme 11-beta-dehydrogenase isozyme 2 (that inactivates cortisol or corticosterone to prevent the occupation of the mineralocorticoid receptors by circulating glucocorticoids).54

The role of aldosterone and mineralocorticoid receptor activation in the pathophysiology of essential hypertension is a topic of increased interest, as hyperaldosteronism is now considered more common than previously believed, especially in patients improperly classified as having resistant hypertension. The overall effects of aldosterone on natriuresis are similar to those observed for Ang II: low sodium intake stimulates aldosterone secretion, preventing sodium loss and sustaining BP. By contrast, during high sodium intake, suppression of aldosterone secretion avoids excessive sodium retention and attenuates the potential increase in BP.54 An inadequate suppression of circulating aldosterone and elevated activation of receptors in conditions of high salt intake reduces the natriuresis and contributes to volume expansion, leading to a phenotype similar to salt-sensitive hypertension.55 Dysregulation of the aldosterone secretion is thought to underline several cases of resistant hypertension. Indeed, mineralocorticoid receptor antagonism may provide an important therapeutic tool for reducing BP in these conditions, with the efficacy of the treatment predicted by baseline aldosterone levels.56

Volume depletion leads to increased aldosterone activity in the distal nephron, ultimately resulting in a Na+ retaining state. In this condition, while reabsorption of salt is increased, K+ secretion remains unchanged. Thus salt is retained without losing K+. On the other hand, if plasma K+ is increased, aldosterone is also released, favouring K+ secretion in the distal nephron, without affecting the salt reabsorption rate. Thus K+ is lost without retaining salt. This phenomenon is commonly referred to as the aldosterone paradox.57

In conclusion, paracrine regulation of ion transport and cross-talk in the different nephron segments play a key role in the regulation of sodium/potassium and BP homeostasis. An impaired activation of ion transport leads to the development of salt-sensitive hypertension.

Impaired renal blood flow: impaired microvascular function leading to a decrease in glomerular blood flow might result in the release of substances (such as renin) that raise BP. As a result, renal perfusion pressure increases, reducing the risk of parenchymal ischaemia. In this condition, the slope of the pressure–natriuresis relationship is normal, a characteristic of salt-resistant hypertension. If heterogeneous vascular lesions are present, a rise in systemic BP and renal perfusion pressure might result in over-perfusion of some regions of the kidney and under-perfusion of others. The local ischaemia in underperfused regions might induce a greater BP variability in response to high and low salt intakes, as reported in animal models and humans.58,59 While changes in the microvascular blood flow regulation might initially be related to changes in arteriolar function, the prolonged exposure to high BP will progressively induce microvascular remodelling and arterioles will become fibrotic. This will compromise the autoregulatory capacity of the renal flow, leading to greater pressure transmitted to the glomerulus and faster propagation of the parenchymal kidney damage.60

Kidney inflammation: inflammation is involved in the regulation of sodium retention related to local Ang II activity. Suppression of renal inflammation blocks the local increase in Ang II and subsequent salt-sensitive hypertension.60,61,62 Different immunosuppressive agents and anti-inflammatory strategies prevent, correct, or ameliorate BP values, by blocking the interstitial inflammatory response in the kidney.63 Among the various inflammatory cells and pathways, recent studies suggest that T cells might have a crucial role in mediating the potential effect of renal inflammation on BP. These cells produce not only Ang II, but also respond to local Ang II via the Ang II type 1 receptor, limiting their inflammatory activity.63,64

Vascular mechanisms

Structural and functional vascular abnormalities either in the micro- or macrocirculation are involved in the pathophysiology of hypertension, leading to increased total peripheral resistance and arterial stiffening, respectively (Figure 44.1.3). Though the specific contribution of each mechanism involved in the pathogenesis of hypertension can be hardly quantified, accumulating evidence shows that vascular abnormalities play a role which is equally important as renal vascular volume control.

Figure 44.1.3 Main mechanisms involved in the pathophysiology of essential hypertension. DBP, diastolic blood pressure; MBP, mean blood pressure; PP, pulse pressure; RAS, renin–angiotensin system; SBP, systolic blood pressure.

Figure 44.1.3 Main mechanisms involved in the pathophysiology of essential hypertension. DBP, diastolic blood pressure; MBP, mean blood pressure; PP, pulse pressure; RAS, renin–angiotensin system; SBP, systolic blood pressure.

Microcirculation: microcirculatory alterations are considered both a cause and consequence of hypertension, particularly in the diastolic and systo-diastolic forms, which are caused by either volume overload (mostly related to renal mechanisms, as highlighted in the dedicated session) and/or total peripheral resistance increase. Peripheral vascular resistance is controlled mainly at the level of small arteries and arterioles. Their vascular tone is regulated by many factors, including the sympathetic nervous system (SNS), humoral factors (mostly endothelium derived), and local autoregulation.

Arteriolar and capillary rarefaction, as well as small artery remodelling, are early hallmarks of hypertension and account for most of the end-organ damage related to the disease. Microvascular alterations are part of a vicious cycle that initiates, maintains, and amplifies high BP.65,66

  • Endothelium-derived factors: the endothelium has emerged as the key regulator of vascular homeostasis, as it has not merely a barrier function but also acts as an active signal transducer for circulating influences that modify the vessel wall phenotype. Alterations in endothelial function precede the development of morphological microvascular changes and can also contribute to lesion development in large vessels and later clinical complications. The endothelium can respond to physical and chemical signals by the production of a wide range of factors that regulate vascular tone, cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation.67 These factors include nitric oxide (NO), reactive oxygen species, endothelin 1, Ang II, bradykinin, and several other growth factors. Endothelial NO production by the endothelial isoform of NO synthase (eNOS) is controlled by receptor-mediated mechanisms (acetylcholine, bradykinin, serotonin, substance P, adenosine diphosphate) and mechanical stimuli (such as shear stress). Endothelial dysfunction is characterized by a reduced NO availability due to an altered balance between production and degradation of NO.68,69 Various enzymatic and non-enzymatic sources of reactive oxygen species have been described to be activated in endothelial cells, smooth muscle cells, and inflammatory cells within the arterial wall of hypertensive patients, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, cyclooxygenase, xanthine oxidase, and uncoupled eNOS.69 In the attempt to compensate for NO deficiency, endothelium-dependent vasodilation is partially maintained by the production of endothelium-derived vasodilators other than NO, such as prostanoids and other endothelium-derived hyperpolarizing factors. Endothelin 1, by contrast, is a potent vasoconstrictor and mitogenic peptide produced by endothelial cells.70 Essential hypertension is characterized by a relative increase of endothelin-1 vasoconstrictor tone compared to the vasodilatory effect of NO.71 Beyond the direct control of BP mediated by its renal actions, the RAS is also involved in the microcirculatory dysfunction and remodelling characterizing hypertension. In systemic arterioles and small vessels, hyperactivation of the RAS induces an increased vasoconstrictor tone, potentiates SNS-mediated vasoconstriction, induces increased reactive oxygen species production by NADPH oxidase, and promotes smooth muscle cell proliferation and collagen deposition in the vascular wall. In summary, endothelial dysfunction is a key player in microvascular dysfunction and remodelling observed in hypertension.

  • Immunity and inflammation: recent evidence suggests that both the innate and the adaptive immune systems contribute to the pathogenesis of hypertension and end-organ damage. Involvement of immune mechanisms in cardiac, vascular, and renal changes in hypertension have been demonstrated in many experimental models.72 Inflammation has been shown to downregulate eNOS activity and increase reactive oxygen species production, thus inducing endothelial dysfunction. A dysfunctional endothelium, in turn, loses its anti-inflammatory properties, such as inhibition of leucocyte adhesion, thus exacerbating the inflammatory process in a vicious circle.73 The impact of inflammation on the pathogenesis of hypertension might also be independent of its influence on endothelial function. A study combining genetic information and a small randomized clinical trial have documented a potential causal link between a chronic inflammatory disease of the gingival tissues (periodontitis) and elevated blood pressure, which was independent of the presence of endothelial dysfunction.74 Vascular and perivascular infiltration of T cells and macrophages promote increased oxidative stress in vascular smooth muscle cells: reactive oxygen species-induced vascular smooth muscle cell senescence and metalloproteinase production favours extracellular matrix degradation and induces perivascular fibrosis.75 As such, the vascular alterations induced by inflammation are similar to those observed in ageing.

  • Local autoregulation and arteriolar remodelling: myogenic tone is an intrinsic property of vascular smooth muscle cells. An increased transmural wall pressure induces stretching and contraction of vascular wall smooth muscle cells, independent of neural or humoral influences. This response protects the distal capillaries against deleterious BP elevations but also causes an increase of total peripheral resistance, which sustains elevation of systemic BP values.76 Initially, microvascular adaptations are functional, but prolonged exposure to elevated BP induces rearrangement of smooth muscle cells and extracellular matrix at constant cell number and mass. These structural alterations, known as eutrophic inward remodelling, induce luminal narrowing and increase wall-to-lumen ratio, representing the earliest form of hypertensive target organ damage.77

  • Microvascular rarefaction: a reduced spatial density of microvascular networks has been described in both experimental models and human hypertension. A reduced capillary density was found in borderline hypertensive subjects as well as in normotensive offspring of hypertensive patients. Microvascular rarefaction appears to be an extreme consequence of the functional microcirculatory alterations: marked vasoconstriction causes a reversible closure of arterioles (functional rarefaction), followed by their anatomic disappearance. A reduced NO availability observed in patients with hypertension is considered one of the most important triggers of functional and structural capillary rarefaction. Evidence suggests that NO deficiency could alter the response to vascular growth factors (including vascular endothelial growth factor) and reduce maturation and mobilization of endothelial progenitor cells in the bone marrow. These alterations might impair angiogenesis and contribute to microvascular rarefaction.76

  • Large arteries: the ageing process is characterized by a profound remodelling of large artery walls, associated with structural changes such as increased collagen deposition and rupture of elastin fibres.78,79 The consequent loss of the reservoir function of the aorta, as well as early wave reflection, are responsible for the physiological changes of BP values with ageing. These include a decline in DBP and increase in SBP, ultimately leading to isolated systolic hypertension and widening pulse pressure. The molecular pathways underpinning macrovascular remodelling might largely overlap with those involved in small vessel remodelling and include a reduced endothelial NO availability, increased vascular oxidative stress, and inflammation. For many years, cardiovascular risk factors have been considered keytriggers in the activation of pathways involved in macrovascular remodelling. Novel factors associated with an increased large artery stiffness such asgut microbiome diversity have been described recently, although the mechanisms accounting for this association remain largely unknown.80

Hypertension, and particularly elevated pulse pressure, might accelerate the age-related process of vascular stiffening, amplifying the damage to elastin lamellae and substitutions with collagen fibres. Building on these pathophysiological concepts, increased large artery stiffness assessed by pulse wave velocity has long been considered a consequence of hypertension. However, recent studies showed that increased pulse wave velocity is not invariably associated with pulse pressure widening, suggesting that it might precede and contribute to the pathogenesis of the disease, rather than being its consequence.81

Independently from its temporal relationship with hypertension, increased stiffness of the large arteries leads to transmission of excessive pulsatile energy to small resistance arteries and capillaries, causing an arterial wall barotrauma and irreversible damage. The accumulation of microvascular damage accounts for the progression of the end-organ damage in hypertension, particularly in low-resistance organs such as the brain and the kidney.82 Since most of the antihypertensive drugs target peripheral vascular resistance or cardiac output, with minimal influence on large artery stiffness, isolated systolic hypertension remains the most common cause of treatment-resistant hypertension.83

Neural mechanisms

The SNS is known to play a central role in CV homeostasis.84 Sympathetic activity plays a key role in both short- and long-term BP control, conferring to the SNS an important role in the pathophysiology of hypertension.85,86,87,88 The increasing appreciation of the role of the SNS in the pathogenesis of hypertension is highlighted by the development of novel, non-pharmacological antihypertensive approaches targeting the SNS in patients with resistant hypertension, such as renal denervation and baroreceptor-activating therapy.

Sympathetic activation induces sustained BP increases by several mechanisms, including peripheral vasoconstriction, potentiation of cardiac contraction, reduction of venous capacitance, and modulation of the renal sodium and water excretion.85,86,87 An increased sympathetic tone is associated with obesity/weight gain, hyperinsulinaemia/altered glucose metabolism, and obstructive sleep apnoea, all conditions associated with hypertension development and with resistant hypertension.88

Several reports suggest that increased sympathetic discharge in hypertension origins from the central nervous system. The underlying mechanisms remain to be fully elucidated. However, a baroreflex ‘resetting’ to avoid its saturation,88 an impaired carotid baroreflex sensitivity secondary to large artery stiffness,89 a dysregulation of the renal autonomic system resulting in hyperactivation of renal autonomic afferents,90 and an increase in inflammation and oxidative stress in cardioregulatory brain centres are common alterations detected in experimental models and human hypertension.

The relationship between central SNS and peripheral organs controlling BP is often bidirectional. For example, central sympathetic discharge regulates renal vascular resistance, renal blood flow, and renin release, while renal afferents convey sympathoexcitatory stimuli towards autonomic regulatory nuclei in the central nervous system.90 Similarly, while inflammation might activate the central SNS, adrenergic overactivity characterizing hypertension might interfere with recruitment and mobilization of immune cells from bone marrow and lymphoid organs, as these are densely innervated by sympathetic fibres.91

Environmental and genetic factors

Essential hypertension is a complex trait resulting from the interactions of multiple environmental and genetic factors. People living in non-industrialized societies rarely develop hypertension or age-related increases in systolic and mean pressures, confirming the importance of environmental exposure in defining the risk of hypertension. Similarly, familial aggregation of hypertension is well recognized, and a family history of hypertension has been associated with an increased risk and earlier onset of hypertension in the offspring, highlighting the importance of genetic factors in hypertension.

Environmental factors: traditional environmental and lifestyle factors associated with an increased risk of hypertension are obesity, physical inactivity, and excess sodium intake. Over the last few years, low birth weight, exposure to air and noise pollution, as well as chronic stress have emerged as other potentially important factors influencing the risk of hypertension.

  • Epidemiology and pathophysiology of hypertension Obesity: the prevalence of obesity has risen dramatically in the past decades and is now the most important public health problem in many industrialized countries. Population studies show that the relationship between body mass index and SBP and DBP is nearly linear among different countries. Weight loss is effective in reducing the risk of developing hypertension and, in subjects where the disease is already established, in promoting a better BP control. Although the co-morbidities associated with obesity, including diabetes mellitus, dyslipidaemias, and sleep apnoea syndrome have been considered for many years major factors accounting for the increased incidence of hypertension in obesity, new evidence suggests that, independently from the role of cardiovascular risk factors, obesity might causally increase the risk of cardiovascular and cerebrovascular events.92 Obesity is associated with extracellular fluid volume expansion, increased tissue blood flow and cardiac output, increased sympathetic traffic directed to the kidneys, RAS activation, impaired pressure natriuresis and greater renal tubular sodium reabsorption, and low-grade inflammation. All these alterations play a major role in initiating the rise in BP associated with elevated weight. Furthermore, physical compression of the kidneys by surrounding fat accumulation and by increased abdominal pressure is considered another crucial kidney-related mechanism leading to obesity-related hypertension.43

  • Excess sodium intake: in human evolution, a strong increment in sodium and a reduction in potassium intake occurred. The daily average salt global consumption is estimated as 9.8 g.93 The differences in the BP response to salt intake might distinguish salt-sensitive subjects (with an exaggerated BP variation in response to salt loading or restriction) from salt-resistant subjects (with BP relatively resistant to changes in salt intake). A reduced ability of the kidney to adapt to changes in salt intake (impaired pressure–natriuresis response) is commonly observed in ageing94 and has been attributed to (1) a reduced number of sodium carriers (thick ascending limb of the loop of Henle), (2) reduction of urea channels (distal tubule), and (3) altered aldosterone resistance in the distal nephron (reduced distal sodium reabsorption).95 This condition has been associated with an increased number of CV events.96,97

    Salt sensitivity is more frequent in African Americans,98 and is characterized by the loss of BP dipping at night and by an increased urinary albumin excretion rate.99 Salt sensitivity and hypertension also increase in women after menopause, suggesting an important role for oestrogens in modulating the pressure–natriuresis balance.100

    In contrast to the deleterious effects of a high-salt diet, low dietary salt consumption is associated with relatively low BP values and incidence of CVDs. This is confirmed by several lines of epidemiological evidence. For example, the population of Yanomamo Indians in the Brazilian rainforest consume a limited amount of salt in their diet, and this is associated with very low values of arterial pressure (102/62 mmHg), as well as an extremely low prevalence of arterial hypertension (0.6–3.0%); in addition, there is no BP increase with ageing in these individuals.101 Similar findings were reported in African and Australian populations.102,103 Aborigines, by contrast, have a higher prevalence of obesity, metabolic syndrome, and salt-sensitive hypertension.104 These differences are likely due to the different expression of genes that are important for Na+ handling by the kidney, and whose expression is altered by the composition of various diets, supporting the hypothesis that high dietary Na+ intake is a major contributor to essential hypertension.

    Elevated dietary salt intake induced several cellular and physiological changes that contribute not only to increasing BP but also to evolution of target organ damage. At the renal level, an increased expression of proinflammatory cytokines, increased synthesis of extracellular matrix components, endothelial dysfunction, and a reduced ability of cells to survive and differentiate were observed.105,106 Increased salt intake also enhances proliferation of myoblasts, stimulates hypertrophy of vascular smooth muscle cells, increases expression of Ang II type 1 receptors, activates nuclear factor kappa B in renal proximal tubule cells, increases central sympathetic activity, and increases transforming growth factor-beta in the renal cortex, reducing the expression of vascular endothelial growth factor receptor.107,108,109 Other, BP-independent effects of increased dietary salt intake include hypertrophy of the left ventricle, microalbuminuria,109 an increased occurrence of nephrolithiasis, and osteoporosis, with the most plausible mechanism of these effects being an increased calcium loss due to natriuresis.

  • Low birth weight: fetal adaptation to adverse intrauterine conditions, aimed at increasing the chances of survival, may permanently influence physiology and metabolism, causing increased disease susceptibility in extrauterine life, including a higher risk of hypertension.110 An increasing amount of evidence from different age groups supports a relationship between low birth weight and high BP values, though the magnitude of this effect is likely to be marginal (approximately 2 mmHg greater SBP per 1 kg reduction in birth weight).111,112 Some putative mechanisms have been hypothesized. An adverse fetal environment may have a significant impact on angiogenesis and vascular function in the long term. Microcirculatory rarefaction has been reported in the kidneys, as well as in the skin and retina of low-birth-weight children, offering a possible additive mechanism for the increased risk of hypertension. A reduced nephron number was also observed in individuals with low birth weight, leading to diminished filtration surface area, sodium retention, and, ultimately, increased BP values. Impaired endothelial function in both microvasculature and large arteries has been observed in individuals with low birth weight. It remains unclear, however, if the risk of hypertension in these subjects is defined by the absolute weight at birth or by the amount of weight gain in the first weeks after birth (catch-up growth). A rapid weight gain sustained by enhanced neonatal nutrition is more common in low-birth-weight children and might create a disproportion between genetic programming and the burden of environmental exposure in people with limited adaptive capacities.113

  • Air and noise pollution: environmental factors are a major cause of poor health worldwide. The most solid evidence is for air pollution, which is the fifth leading risk for both sexes, largely contributing to increasing DALYs related to CV and circulatory diseases.114 Mechanistic evidence illustrates plausible pathways by which acute and chronic exposures to air pollutants might disrupt the haemodynamic balance favouring vasoconstriction and thus inducing BP elevations, including autonomic imbalance and augmented release of various pro-oxidative, inflammatory, and/or haemodynamically active mediators. Exposure to noise has been also associated with hypertension in several settings. However, the largest effect on BP appears to be related to nocturnal aircraft noise. Underlying mechanisms include chronic activation of pathways related to stress, sleep deprivation, and fragmentation. From the pathophysiological point of view, in the presence of night-time noise exposure, the hormonal, inflammatory, and autonomic pathways are activated not only by chronic stress but also by sleep fragmentation and deprivation, which are per se associated with hypertension. Repeated nocturnal autonomic arousals may prevent BP dipping and contribute to the risk of developing hypertension in those chronically exposed to relevant levels of environmental noise.115

  • Acute and chronic stress: it is well known that the classical response to acute stress, including neural and hormonal mechanisms, is a physiological process crucial for maintaining biological homoeostasis during environmental or physiological challenges. In the short term, these alterations aim at restoring homeostasis and increase the individual chances of surviving. However, the parallel increase in BP, as well as the development of insulin resistance and endothelial dysfunction, is potentially harmful to the CV system.116 Indeed, some authors suggest that increased autonomic stress reactivity, and in particular impaired CV recovery after acute mental stress, is associated with an increased incidence of hypertension.117 An increase in muscle sympathetic nerve activation after mental stress in young, borderline hypertensive men has also been demonstrated.118 Large acute increases in BP caused by stress-induced SNS activation could cause small injuries to target tissues, especially the kidneys, which accumulate over time and lead to chronic hypertension. The evidence is accumulating in support of the hypothesis that chronic stress might induce a chronic SNS activation, as well as activation of the hypothalamic–pituitary axis and the RAS and inflammatory pathways, thus leading to sustained BP elevations and arterial hypertension, but data are still contradictory.116,119

Genetic factors: hypertension is a complex disease resulting from environmental exposures superimposed on an inherited predisposition.120 Gene variants and regulation of gene expression by epigenetic modifications have an important influence on the risk of hypertension.121 Since the Human Genome Project was completed,122 multiple genetic analyses have uncovered a number of common variants of modest effect as well as low-frequency variants that contribute to BP variation (Table 44.1.1).123 Some of these large-scale genome-wide association studies have coupled the genetic information with biological insights into gene function, identifying variants at multiple loci associated with genes involved in BP homeostasis.124 In the future, screening for these genetic variants might refine patient risk stratification and guide the selection of specific classes of antihypertensive agents for individual patients, depending on the pathway more likely to contribute to the disease. Despite considerable advances in the identification of genetic variants associated with a greater risk of hypertension, it has been estimated that genetic risk scores obtained from a combination of multiple genetic variants associated with the risk of hypertension account for 3.5% of the trait variance.125 Although it is expected that many more as yet undiscovered loci will contribute to explain a larger variation of BP within the general population, it is likely that a large proportion of the residual BP variability at a population level could be related to environmental factors. Unfortunately, environmental factors are difficult to quantify or even identify. Analysis of the products of interactions between the genome and the environment in tissues relevant to the disease could be highly valuable in overcoming these limitations. Epigenomics is the study of epigenetic marks on a genome or near-genome scale. Epigenomes capture the biological influence of environmental and lifestyle factors in a quantifiable and analysable molecular form. Epigenetic dysregulation has emerged as a hallmark of several complex pathologies, including hypertension. A recent genome-wide association and replication study of BP phenotypes among 320,251 individuals of East Asian, European, and South Asian ancestry revealed that single nucleotide polymorphisms influencing BP associate strongly with methylation at multiple local CpG sites,126 suggesting the presence of possible interactions between genomic and epigenomic regulation of BP.

Table 44.1.1 Validated genetic loci/nearest mapped genes for blood pressure traits identified through genome-wide association studies

2q36.3

CMIP

HIPK2

OSR1

SETBP1

7q32.1

COL21A1

HIVEP3

PABPC4

SF3A3

ABHD17C

COX14

HM13-AS1-ID1

PALLD

SH2B3

ABLIM3,SH3TC2

CPEB4

HNF4G-ZFHX4-AS1

PAX2

SLC14A2

ABO

CR1L-CD46

HOMEZ-PPP1R3E

PDE10A

SLC20A2

AC016735.1

CRACR2B

HOXA3

PDE1A

SLC22A7

ACE

CREB5

HOXB7

PDE3A

SLC24A3

ACOX1

CRK

HOXC4

PDE5A

SLC35F1

ACTRT1-SMARCA1

CRYAA-SIK1

HRCT1

PHACTR1

SLC39A8

ADAMTS7

CSNK1G3

HRH1-ATG7

PHIP

SLC4A7

ADAMTS8

CXCL12-TMEM72

HSD52-MIR4711

PIK3CG

SLC7A1

ADAMTS9

CYP17A1-NT5C2

IGFBP1-IGFBP3

PKHD1

SLC8A1

ADCY3

CYP1A1-ULK3

INSR

PLCB1

SMOC2-THBS2

ADM

CYP46A1-EML1

JAG1

PLCD3

SNX31

ADO

DNM3

JPH2

PLCE1

SOX6

ADRB1

DOT1L

KANSL1

PLEKHA7

SSPN

AGT

DPEP1

KCNH4-HSD17B1

PLEKHG1

ST7L-CAPZA1-MOV10

ARHGAP12

EBF1

KCNK3

PNPT1

SUGCT

ARHGAP24

EHBP1L1

KCNN2-TRIM36

POC5-SV2C

SULT1C3

ARNTL

ENPEP

KIAA0753

PPAP2B

SVEP1

ARVCF

ESR1

KIAA1462

PPL

SWAP70

ATP1B3

EXOC6B-SPR

LHFPL2

PPP2R5E

SYT4-SETBP1

ATP2B1

FAF1

LMO1

PPP6C

TBC1D1-FLJ13197

BDNF

FAM108C1

LOC144486-MIR5700

PRDM11

TBX2

BLK-GATA4

FAM176C

LRRC10B

PRDM16

TBX5-TBX3

C10orf107

FAM186B

LRRTM3-CTNNA3

PRDM6

TCF7L1

C2CD4B-MGC15885

FAM208A

LSP1-TNNT3

PREX1

TCF7L2

C2orf43

FBLN5

MAP4

PRKAG1

TEX41

C3orf38-EPHA3

FBN1

MCF2L

PRKAG2

TFAP2D

C5orf56

FBN2

MDM4

PRKCE

THBS2

CACNA2D2

FBXL19

MECOM

PRKD3

TM6SF1

CACNB2

FERMT2

METTL21A-AC079767.3

PRKRIR-C11orf30

TMEM161B

CAMKV–ACTBP13

FGD5

MIR1263

PROCR

TMEM194B-NAB1

CASC15

FGGY

MKLN1

PSMD5

TNRC6A

CASZ1

FIGN-GRB14

MRC2

PYY

TNRC6B

CCDC141

FLJ32810-TMEM133

MTAP

RABGAP1-GPR21

TNS1

CCDC41

FN1

MTCH2-AGBL2

RAPSN, PSMC3, SLC39A13

TP53-SLC2A4

CCNE1

FNDC1

MTF1

RBM47

TRAPPC9

CD34

FOSL2

MTHFR-NPPB

RGL3

TRIM36

CDC42BPA

FURIN-FES

MYEOV

RNF207

TSHZ3-THEG5

CDH13

FUT9-UFL1

MYH6

RP11-273G15.2

ULK4

CDH17

GATA2

NADK–CPSF3L

RP11-321F6.1

UMOD

CDK6

GDF7-C2orf43

NFAT5

RP11-439C8.2

VAC14

CELA2A

GJA1

NME7

RP11-61O1.1

VCL

CEP164

GOSR2

NOS3

RP4-710M16.1–PPAP2B

VMP1

CEP68

GPAT2-FAHD2CP

NOTCH3

RPL6-ALDH1

WNT3A

CERS5

GPATCH2

NOV

RRAS

XRCC6

CFDP1

GPR20

NOX4

RSPO3

ZBTB38

CHIC2

GS-EDN3

NPNT

RYK

ZC3HC1

chr15mb95

GTF2B

NPR1

SARNP

ZFAT

chr1mb25

GUCY1A3-GUCY1B3

NPR3-C5orf23

SBNO1

ZNF101

chr1mb9

GYPA-HHIP-AS1

NUCB2

SCAI

ZNF438-ZEB1-AS1

chr4mb174

HAAO-ZFP36L2

OBFC1

SCARNA7-ARL14

ZNF638

CHST12-LFNG

HDAC9

OR4A47-TRIM51GP

SDCCAG8-MIR4677

ZNF652

CHST12-MIR4648

HFE

OR5B12

SENP2

ZNRF3

Source data from Patel RS, Masi S, Taddei S (2017). Understanding the role of genetics in hypertension. Eur Heart J 38: 2309–2312.

Collectively, genomic information is shaping a new attractive prospective in the approach to hypertension, providing the physician with strong instruments for (1) early identification of subjects at risk before development of the phenotype, (2) implementation of aggressive and perhaps targeted lifestyle interventions, and (3) a more rational and targeted selection of CV drugs that are likely to be effective and safe for that individual. As such, genomic studies of hypertension might provide a significant step forward towards the application of precision medicine to hypertension, ensuring that the right patient gets the right treatment at the right time.

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Further reading

Dominiczak A, Delles C, Padmanabhan S. Genomics and precision medicine for clinicians and scientists in hypertension. Hypertension 2017;69:e10–13.Find this resource:

GBD 2013 Risk Factors Collaborators, Forouzanfar MH, Alexander L, Anderson HR, Bachman VF, Biryukov S, Brauer M, Burnett R, Casey D, Coates MM, Cohen A, Delwiche K, Estep K, Frostad JJ, Astha KC, Kyu HH, Moradi-Lakeh M, Ng M, Slepak EL, Thomas BA, Wagner J, et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;386:2287–323.Find this resource:

Laurent S, Agabiti-Rosei E. The cross-talk between the macro- and the microcirculation. In: Nilsson P, Olsen MH, Laurent S, eds. Early Vascular Aging (EVA): New Directions in Cardiovascular Protection. London: Elsevier; 2015; pp 105–18.Find this resource:

Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res 2014;114:1804–14.Find this resource:

Masi S, Johnse A, Charackida M, O'Neill F, D'Aiuto F, Virdis A, Taddei S, Deanfield JE, Ghiadoni L. Blood pressure and vascular alterations with growth in childhood. Curr Pharm Des 211;17:3045–61.Find this resource:

Munzel T, Gori T, Bruno RM, Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 2010;31:2741–8.Find this resource:

Rapsomaniki E, Timmis A, George J, Pujades-Rodriguez M, Shah AD, Denaxas S, White IR, Caulfield MJ, Deanfield JE, Smeeth L, Williams B, Hingorani A, Hemingway H. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet 2014;383:1899–911.Find this resource:

Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol 2009;157:527–36.Find this resource: