Hypertension is the leading cause of morbidity and mortality worldwide. The individual and public health effects of hypertension are devastating. Due to the simplicity of diagnosing hypertension and the effectiveness of antihypertensive treatments, targeting hypertension is the single most effective public health measure available (Ezzati et al, Lim et al). Approximately 90–95% of individuals with hypertension have essential hypertension, also referred to as primary hypertension. Essential hypertension is defined as hypertension without an identifiable underlying cause. Researchers previously believed that this form of hypertension was a physiological reaction that was necessary to maintain normal hemodynamics, hence the term essential. However, a growing body of science suggests that essential hypertension is a multifactorial disease caused by a complex interplay between genes and environment. Industrialization and a Western lifestyle are strongly related to the development of hypertension. Developing and non-Western countries rarely display the blood pressure trajectories and high prevalence of hypertension that is ubiquitous in high-income Western countries. Fortunately, modern antihypertensive therapy enables most patients to return to normal blood pressure (normotension). Combination therapy with multiple antihypertensives is often necessary to normalize blood pressure. Management of hypertension requires careful consideration of other cardiovascular risk factors and coexisting conditions. Therapy must be tailored to each patient.

Optimal blood pressure

Optimal blood pressure is 115 mm Hg systolic and 75 mm Hg diastolic (115/75 mm Hg). Thus, optimal blood pressure is significantly lower than the current threshold for hypertension, and the current treatment target levels for patients with and without diabetes. The threshold for hypertension is currently 140 mm Hg systolic or 90 mm Hg diastolic (140/90 mm Hg). The discordance between optimal blood pressure and the definition of hypertension is explained by a cost-benefit equation. The benefits of interventions for hypertension exceeds the risks and costs at 140/90 mm Hg. However, it may be argued that this cutoff is somewhat arbitrary and there may be individual benefits of initiating treatment at lower blood pressure levels.

KEY POINTS
• The risk of cardiovascular disease increases gradually at blood pressure levels above 115/75 mm Hg.
• A rise in blood pressure of 20 mm Hg systolic or 10 mm Hg diastolic leads to a doubling of the risk of stroke and acute myocardial infarction.
• The threshold for diagnosing hypertension is systolic blood pressure 140 mm Hg or diastolic blood pressure 80 mm Hg or higher.
• Approximately 50% of all cardiovascular events attributable to hypertension occur in individual with blood pressure below the cutoff for hypertension (Lewington et al, Lawes et al, Pulter et al).

Epidemiology of hypertension

  • Blood pressure is normally distributed in the population. Individual blood pressure increases gradually during the life course (Balijepalli et al).
  • Blood pressure is positively correlated with societal economic development, age, alcohol intake, body weight, male sex and salt intake. Population blood pressure increases in parallel with economic development and industrialization.
  • The increasing prevalence of obesity, diabetes, sedentary lifestyle, the rapid economic development and ageing of most populations is driving the rapid increase in the global prevalence of hypertension.
  • It is estimated that between 15% and 37% of the global population have hypertension and the prevalence is increasing rapidly (Pulter et al, Lim et al). Thus, the current and impending burden of disease caused by hypertension is inapprehensible.

KEY POINT: >1 billion individuals worldwide have hypertension.

Symptoms of hypertension

Hypertension is most often asymptomatic. The high prevalence and asymptomatic nature of the disease motivates liberal screening among adults, in order to detect disease before complications arise.

Non-specific symptoms of hypertension include the following:

  • Headache
  • Reduced exercise capacity
  • Tiredness, fatigue
  • Dyspnea
  • Nosebleeds
  • Flushing
  • Vertigo (dizziness)
  • Chest discomfort (chest pain)
  • Hematuria (blood in urine)

These symptoms are non-specific and (among individuals with hypertension) it is difficult to determine whether these symptoms are due to elevated blood pressure or other causes.

Other signs of hypertension are related to complications, e.g coronary artery disease (angina pectoris) acute myocardial infarction (acute chest pain), stroke, heart failure (dyspnea, edema, tachycardia), renal failure.

Physiological regulation of blood pressure

Blood pressure is the pressure in larger arteries. Systolic blood pressure is the pressure in the arteries during systole (i.e the highest pressure during the cardiac cycle). Diastolic blood pressure is the pressure in the arteries during diastole (i.e the lowest pressure during the cardiac cycle). The average (mean) blood pressure in the arteries (MAP, mean arterial pressure) is the product of cardiac output and total peripheral resistance:

MAP = TPR × CO

Systolic and diastolic blood pressure are easier to measure than total peripheral resistance and cardiac output. Moreover, MAP can be estimated using systolic and diastolic pressure, according to the following formula:

MAP = [SBP + (DBP×2)] / 3
SBP = systolic blood pressure; DBP = diastolic blood pressure.

Neurohormonal mechanisms

Multiple physiological mechanisms interact to control blood pressure by influencing cardiac output and and total peripheral resistance. The renin–angiotensin–aldosterone system (RAAS) has a fundamental role in regulating blood pressure. RAAS includes several effector molecules that control vascular tone and fluid balance. Activation of RAAS leads to fluid retention, increased vascular tone (vasoconstriction) and unfavorable changes in the myocardium, kidneys and blood vessels. Inhibition of RAAS results in fluid excretion and reduced vascular tone (vasodilation); it also alleviates the unfavorable cellular changes in the myocardium, kidneys and endothelium.

Left ventricular function

Left ventricular function is crucial for the ability to generate systolic pressure and maintain diastolic pressure. Impaired systolic function or diastolic function leads to heart failure, reduced cardiac output, and ultimately a reduction in blood pressure. Heart failure is always associated with increased atrial and ventricular filling pressure, which results in secretion of natriuretic peptides (BNP and NT-proBNP). These peptides increase diuresis and exert vasodilating effects.

Blood vessels and the autonomous nervous system

Blood vessels have a fundamental role in regulating blood pressure. An array of hormones (including RAAS effectors), neurotransmitters (autonomic nervous system) and local signal substances (e.g nitric oxide [NO]) interact to continuously regulate vascular tone. The autonomic nervous system also regulates blood pressure via stretch receptors (baroreceptors) the carotid body (carotid sinus in the common carotid artery). High systolic blood pressure leads to distention of the carotid sinus, which stimulates baroreceptors to increase signalling to hypothalamus. This prompts hypothalamus to decrease sympathetic output in order to lower blood pressure. People with high blood pressure typically have higher activity in the sympathetic nervous system, as compared to normotensive individuals.

Intake of salt (sodium) and potassium

Salt balance is strongly correlated with fluid balance and, consequently, blood pressure. Reducing the intake of salt (sodium) can lower blood pressure. In contrast, increased intake of potassium results in lowering of blood pressure (refer to Treatment of hypertension below).

Fluid intake

Fluid intake is likewise an important factor. High fluid intake elevates blood pressure, at least transiently. Dehydration results in lower blood pressure, at least transiently. The transient effect of is explained by activation of several neurohormonal (e.g RAAS) systems that counteract the effect of excess fluid intake or dehydration.

Renal function

Kidney function is also important for blood pressure regulation. Renal failure results in fluid retention, disturbance of RAAS, and electrolyte disturbances. Aldosterone exerts its effects in the kidneys by increasing fluid retention, in addition to its vasoconstricting effects.

Definition of hypertension

The threshold for diagnosing hypertension is systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg. The relation between blood pressure and risk of cardiovascular disease is continuous, such that the risk of cardiovascular events and complications increases gradually as blood pressure rises above the optimal level, i.e 115/75 mm Hg.

Although optimal blood pressure is considered to be 115/75 mm Hg, the threshold for hypertension is ≥140 mm Hg systolic and ≥90 mm Hg diastolic. There is consensus that the level 140/90 mm Hg represents the threshold where the benefit of interventions outweighs the risks and costs.

Degrees of hypertension

Hypertension is graded from I to III (Table 1). Most studies indicate that systolic blood pressure is a stronger predictor (i.e risk factor) of cardiovascular events and long-term complications, as compared with diastolic blood pressure. Whether this difference reflects a true causal differences remains elusive. (It is mathematically difficult to disentangle variables that are strongly correlated, regardless of whether regression methods or machine learning methods are used).

The risk of cardiovascular disease increases when systolic blood pressure exceeds 115 mm Hg or when diastolic blood pressure exceeds 75 mm Hg. That means the risk of cardiovascular complications increases already below the threshold for hypertension.

TABLE 1. CLASSIFICATION OF HYPERTENSION.

ClassificationSystolic pressure (mm Hg)Diastolic pressure
(mm Hg)
Optimal115 (<120)and75 (<80)
Normal120–129and/or80–84
High normal130–139and/or85–89
Grade I
hypertension
140–159and/or90–99
Grade II
hypertension
160–179and/or100–109
Grade III
hypertension
≥180and/or≥110
Isolated systolic hypertension≥140and<90
CLASSIFICATION OF HYPERTENSION.

Blood pressure variability

The cumulative (total) risk conferred by a cardiovascular risk factor can be assessed in terms of area under the curve, where the x-axis represents time and y-axis represents the value for that specific risk factor. The area under the curve represents the overall burden that the risk factor brings over time. For LDL cholesterol the area under the curve is simply the total amount of LDL cholesterol that the vascular tree is exposed to over time. Individuals with high LDL cholesterol are exposed to more LDL cholesterol over time, as compared with individuals with lower LDL levels during the same time period. Temporary fluctuations in LDL cholesterol have no significant effect on cardiovascular risk; it is the total amount that determines risk. The same concept can be applied to blood pressure. However, with regards to blood pressure, the following must be noted:

  • Blood pressure variability is defined as episodic and pronounced increases in blood pressure. Such variations are associated with increased risk of cardiovascular events, notably stroke (Pulter et al).
  • A very large increase in blood pressure (hypertensive crisis) may immediately cause hemorrhagic stroke or aortic dissection.

Hence, with regards to blood pressure, early diagnosis and continuous monitoring is important to reduce cardiovascular risk.

Measuring blood pressure

Routine office measurement of blood pressure:

  1. The patient should sit relaxed for 5 minutes before measuring blood pressure.
  2. Measurement is done with the cuff placed at the level of the heart.
  3. The cuff is inflated until the palpable pulse in the radial artery cannot be felt.
  4. The cuff is deflated slowly, while listening in the stethoscope.
    • The first sound (Korotkoff sound 1) is heard when blood pressure is equivalent to systolic blood pressure.
    • When the pulsating sound disappears, the pressure is equivalent to diastolic pressure.
  5. Repeat the measurement 2 or 3 times and calculate the mean of the measurements. The documented blood pressure is the mean value.

If the pressure is above the threshold for hypertension (140/90 mm Hg), then a second measurement should be performed after a few days. If the pressure remains elevated on the second measurement, a diagnosis of hypertension is made. Occasionally, three measurements are needed.

When hypertension is confirmed, the pressure in both arms should be compared. A pressure difference greater than 15 mm Hg should prompt careful investigation for atherosclerotic disease and, in young individuals, aortic coarctation. A pressure difference larger than 15 mm Hg is common in individuals with severe atherosclerosis.

Measuring blood pressure with automatic blood pressure monitor yields a few units (mercury) lower blood pressure, as compared with manual measurement. Table 2 presents thresholds for hypertension with different methods for measurement.

TABLE 2. THRESHOLDS FOR HYPERTENSION WITH DIFFERENT METHODS

MethodTimeSystolic pressure (mm Hg)Diastolic pressure (mm Hg)
Office / clinic blood pressure≥140≥90
Ambulatory blood pressureDaytime≥135≥85
Night-time≥120≥70
24 h mean≥130≥80
Home blood pressure≥135≥85
Hypertension: ESC, European Society of Cardiology; ESH, European Society of Hypertension

When investigating suspected hypertension, two to three measurements are usually made at the primary care or outpatient clinic. However, 24-hour ambulatory blood pressure has the highest sensitivity and specificity for hypertension. Cost analysis suggests that ambulatory blood pressure measurement is cost-effective and excludes 25% of all cases of white coat hypertension (UK NICE Guidelines).

Masked hypertension

Masked hypertension means that office measurements of blood pressure are normal, but ambulatory measurements confirms that the patient is hypertensive. Masked hypertension is a topic under intensive research. Given that masked hypertension may be common, it is justifiable to encourage patients to monitor their blood pressure at home using blood pressure monitors available to consumers.

White coat hypertension

Up to 25% of people with hypertension on office measurements have normal blood pressure when repeating measurements at home. This condition, in which blood pressure is temporarily elevated while in the clinic, is referred to as white coat hypertension. In case of suspicion of white coat hypertension, a 24-hour ambulatory measurement should be performed.

Risk factors for hypertension

  • Heredity
  • High age
  • High alcohol intake
  • Metabolic syndrome
  • Physical inactivity
  • Smoking
  • Diabetes
  • Obesity
  • High calorie intake
  • High salt intake
  • Psychosocial stress
  • Sleep apnea
  • Atherosclerotic vascular disease.

Complications of hypertension

Essential hypertension

  • Constitutes 90–95% of all cases of hypertension.
  • Typically middle-aged and elderly individuals.
  • Pathophysiology unknown. Strong association with industrialization, sedentary lifestyle, increasing age, alcohol, salt intake and genetic predisposition (heredity). It is believed that 30% of the risk is attributable to genetics. Over 100 genetic loci have been identified. The individual effect of each locus is very small.

Secondary hypertension

Secondary hypertension is defined as hypertension caused by an identifiable disease, e.g endocrine disorder, kidney disease, drug side effect. Common causes of secondary hypertension are as follows:

  • Conn’s disease
  • Cushing syndrome: overweight, polyuria, polydipsia, diabetes, Cushing phenotype, moon face, buffalo-hump, striae, hirsutism.
  • Renal artery stenosis: renal impairment (declining eGFR, increasing creatinine), abdominal murmur on auscultation.
  • Pheochromocytoma: headache, sudden sweating and pallor (flush), palpitations, sudden increases in blood pressure.
  • Chronic kidney disease (CKD): CKD causes hypertension.
  • Liddle syndrome: genetic (monogenic) disease that causes hypertension.

Secondary hypertension tends to debut earlier in life. Secondary hypertension should be suspected if antihypertensive has insufficient effect, despite combination therapy and adequate dose titration.

Routine examinations in patients with hypertension

  • Medical history, with emphasis on cardiovascular disease.
  • Physical examination, with emphasis on cardiovascular disease.
  • Heredity for hypertension?
  • Specific questions: Tobacco habits, dietary habits, licorice consumption, physical activity, salt intake, potassium intake, medications.
  • Blood tests: glucose (HbA1c), sodium, potassium, TSH, T3, T4, ALT, AST, gamma-GT, lipids (total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol), creatinine, eGFR.
    • Specific blood tests if suspicion of secondary hypertension.
  • Consider referral to echocardiography in case of cardiac murmur.
  • Consider analysing natriuretic peptides (BNP, NT-proBNP) if signs or symptoms of heart failure.
  • Consider referral for CTCA*, myocardial perfusion scintigraphy or stress echocardiography if signs or symptoms of coronary artery disease.
  • Consider primary prevention with statins if high 10-year risk of vascular events.

*CTCA = Computerized tomography or coronary arteries

Treatment of hypertension

Diet and lifestyle treatments

  • Reduce intake of salt to <5 g/ day. This is recommended despite the fact that there is data questioning the effect of this. Presumably, the effect of reducing intake of salt is greater among people with hypertension, compared to people with normal blood pressure. In high-income countries, the average daily salt intake is about 10 g.
  • Increase intake of potassium. Low intake of potassium can raise blood pressure and vice versa. Recommended intake is 3.5-5.0 g/day. Do not recommend increased intake of potassium in patients with renal failure.
  • Increase physical activity. All forms of exercise lower blood pressure. It is recommended that all patients exercise 30 to 60 minutes three times per week. This can lower systolic blood pressure by 11 mm Hg and diastolic blood pressure by 5 mm Hg (Borjesson et al).
  • Weight loss. Losing weight results in lowering of both systolic and diastolic blood pressure.
  • Limit intake of alcohol to 1 standard glass for women and 2 standard glasses for men (daily). This can be expected to lower blood pressure by approximately 3 mm Hg.
  • Recommend the DASH (Dietary Approaches to Stop Hypertension) diet. DASH diet can lower systolic blood pressure by 8–14 mm Hg.

Antihypertensive medications

  • Although monotherapy (one drug) may be sufficient for grade I hypertension, combination therapy (2 or 3 drugs) is more effective and may cause fewer side effects (combination therapy allows for lower doses of individual drugs).
  • Avoid combining ACE inhibitors and ARBs as these act on the same system (RAAS) and the risk of side effects, as well as the need to repeatedly measure electrolytes and kidney function, increases significantly.
  • The treatment strategy is equal for men and women.
  • The higher the blood pressure, the more important to lower blood pressure rapidly and substantially.

TABLE 3. ANTIHYPERTENSIVE DRUGS

DiureticsFirst-line option
Calcium channel inhibitors (antagonists)First-line option
ACE inhibitorsFirst-line option
Angiotensin receptor blockers (ARB)First-line option
Beta blockers– Secondary option in individuals without cardiovascular disease.

– First-line option in individuals with heart failure, ischemic heart disease, ventricular tachyarrhythmias, atrial tachyarrythmias or left ventricular dysfunction
Alfa blockersSecondary option.
Typically used in resistant hypertension.
Aldosterone blockersSecondary option.
Typically used in resistant hypertension or in patients with heart failure.

Proposed treatment algorithm

  1. Initiate treatment with one of the following:
    • ACE inhibitors: enalapril 10–20 mg × 1 or ramipril 5–10 mg × 1.
    • ARB: losartan 50–100 mg × 1 or candesartan 8–32 mg × 1.
    • Calcium antagonist: amlodipine 5–10 mg × 1 or felodipine 2.5–5 mg × 1.
    • Thiazide: hydrochlorothiazide 12.5–25 mg × 1 or bendroflumethiazide 2.5–5 mg × 1.
  2. If treatment effect is insufficient, add another drug from the list above and increase doses.
  3. If treatment effect remains insufficient, add a third drug.
    • Consider adding beta-blockers (metoprolol depot 50–100 mg × 1 or bisoprolol 2.5–10 mg × 1).
  4. Alpha-blockers and aldosterone antagonists are used in resistant hypertension.

Beta blockers for hypertension

Beta-blockers are no longer a first-line option for patients with hypertension. Beta-blockers, however, should be preferred in patients with coronary heart disease (ischemic heart disease), previous myocardial infarction, heart failure, atrial fibrillation (supraventricular tachyarrhythmias), ventricular tachyarrhythmias or left ventricular dysfunction. Beta-blockers generally have a smaller effect on blood pressure than other antihypertensives.

Diuretics for hypertension

  • First-line option.
  • Can be considered to anyone with hypertension.
  • Especially suitable for patients with heart failure.
  • Electrolytes should be assessed after initiation of therapy.
  • Thiazide diuretics (thiazides) are well documented and well-tolerated by elderly.
  • Potassium-sparing diuretics (amiloride) can be used in patients with hypokalemia.
  • Loop diuretics (furosemide) represent an alternative.

Calcium antagonists for hypertension

  • First-line option.
  • Amlodipine and felodipine are effective and can be considered to anyone with hypertension.
  • Verapamil and diltiazem have negative inotropic and chronotropic effects, and are therefore contraindicated in heart failure, AV Block II and AV Block III.

ACE inhibitors for hypertension

  • First-line option.
  • Preferred in cases with heart failure.
  • Monitor electrolytes, creatinine, eGFR before and after initiation.
  • Side effects: angioedema (rare), dry cough (10–20%), impaired renal function.
  • Contraindicated in pregnant women.
  • Full effect emerge after 3 to 4 weeks.

ARB (angiotensin receptor blockers) for hypertension

  • First-line option.
  • Preferred in cases with heart failure.
  • Not combined with ACE inhibitors.
  • ARBs can replace ACE inhibitors if the latter causes unbearable cough.
  • Contraindicated in pregnant women.
  • Caution in renal impairment.
  • Full effect emerge after 3 to 4 weeks.

Alpha blockers for hypertension

  • Doxazosin may be considered if blood pressure target level is not achieved despite the use of 2 or 3 blood pressure medications.

Aldosterone antagonists for hypertension

  • Preferred in cases with heart failure.
  • For other patients, spironolactone may be given if hypertension is treatment resistant.
  • Side effects: hyperkalemia, gynecomastia.

Special Patient Groups

Ischemic heart disease (coronary heart disease): Beta blockers are preferred, although the evidence for beta-blockers is weak in patients with normal left ventricular function. Beta blockers reduce angina pectoris.

Ventricular or supraventricular arrhythmias: Beta blockers should be preferred in patients with tachyarrhythmias. Early data shows that beta-blockers reduce the risk of ventricular tachyarrhythmias (reduction of ventricular extrasystoles and ventricular tachycardia). Beta blockers do not have anti-arrhythmic effects, but reduces ventricular rate in atrial fibrillation, atrial flutter and atrial tachycardia.

Type 1 diabetes, type 2 diabetes: ACE inhibitors and ARBs preserve renal function in diabetics and are therefore preferred.

Chronic kidney disease (renal failure): ACE inhibitors and ARBs can preserve renal function and should be preferred. Consult a nephrologist if creatinine rises >30% or eGFR drops rapidly after initiation of therapy with ACE or ARBs.

Renal denervation

The sympathetic fibers to the kidneys can be disrupted by means of radiofrequency ablation. This procedure is referred to as renal denervation. Several studies showed that renal denervation may cure resistant hypertension. However, these studies were flawed (lacking a sham control group) and subsequent studies, with rigorous methodology, showed that renal denervation had no significant effect (Bhatt et al).

References

Balijepalli et al: Percentile distribution of blood pressure readings in 35683 men and women aged 18 to 99 years. Journal of Human Hypertension volume 28, pages193–200(2014).

Lawes et al: Blood pressure and the global burden of disease 2000. Part II: estimates of attributable burden. J Hypertens 2006; 24: 423–30.

Oparil et al: Hypertension. Nature Reviews. doi:10.1038/nrdp.2018.14

Pulter et al: Hypertension. Lancet 2015; 386: 801–12.

Lim et al: A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60.

Williams et al: 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). European Heart Journal, (2018).

Lewington et al: Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).

NICE. 2011 Guidelines for Hypertension: Clinical Management of Primary Hypertension in Adults. http://publications.nice.org.uk/ hypertension-cg127 (accessed Jan 8, 2015).

Luft et al. Twins in cardiovascular genetic research. Hypertension 37, 350–356 (2001).

Fagard et al. Heritability of conventional and ambulatory blood pressures: a study in twins. Hypertension 26, 919–924 (1995).

Borjesson et al: Physical activity and exercise lower blood pressure in individuals with hypertension: narrative review of 27 RCTs. Br. J. Sports Med. 50, 356–361 (2016).

Kristina Bengtsson Bostrom et al. Hypertoni. Lakemedelsboken (2016).

Bhatt et al: A Controlled Trial of Renal Denervation for Resistant Hypertension. New England Journal of Medicine (2014).

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