44.4 Secondary causes of hypertension

Secondary hypertension may be defined as a type of hypertension (i.e. blood pressure >140/90 mmHg) with an underlying, potentially correctable cause. Secondary hypertension should be particularly considered in (1) young patients without a family history of arterial hypertension, (2) patients with resistant hypertension, and (3) late onset of hypertension. In addition to the medical history, a secondary aetiology may be suspected in the presence of symptoms (e.g. flushing and sweating suggestive of phaeochromocytoma), clinical findings (e.g. a renal bruit suggestive of renal artery stenosis), or laboratory abnormalities (e.g. hypokalaemia suggestive of hyperaldosteronism). Approximately 5% of adults with hypertension have a secondary cause. The prevalence of secondary hypertension and the most common aetiologies vary by age group. This chapter aims to summarize the principal causes of secondary hypertension, how these may be diagnosed and their specific treatments.

Arterial hypertension is a major cardiovascular risk factor that affects between 10% and 40% of the general population in an age- and population-dependent manner (see also Chapter 44.1). The sympathetic nervous^1,2 and renin–angiotensin–aldosterone systems³ regulate blood pressure, fluid volume, and the vascular response to injury and inflammation (see also Chapter 5.1 and 5.3). Depending on the population, in up to 5% of individuals, high blood pressure is caused by an underlying disease of the vasculature or the endocrine system. If that is the case, the condition is termed secondary hypertension. The incidence of secondary hypertension differs widely among different patient populations. It is also subject to referral bias with much lower frequencies in first care centres and much higher in referral hypertension units. As secondary hypertension has potentially correctable causes, diagnosing this type of hypertension is of particular clinical importance. Thus, whenever a patient is diagnosed with hypertension, it must be the aim of the initial assessment (i.e. history, physical examination, and basic laboratory testing) to exclude or suspect possible secondary causes of high blood pressure (Table 44.4.1).

The secondary forms of hypertension are generally infrequent and thus easy to miss in clinical practice. Central elements to raise the suspicion for secondary hypertension are age below 30 years at the onset of hypertension, absence of family history for hypertension or overweight, as well as a sudden deterioration of blood pressure control in patients with previously well-controlled values. Moreover, secondary hypertension should also be considered in patients with resistant hypertension.

As a general approach, the physician should first confirm that the patient’s blood pressure has been accurately measured according to the guidelines⁴ (see also Chapter 44.2) using an appropriately sized cuff. Ambulatory blood pressure monitoring can be useful to rule out white coat hypertension. Moreover, it is also important to review the patient’s diet and medication use for other potential causes of elevated blood pressure. Indeed, excessive consumption of sodium, liquorice, or alcohol is known to increase blood pressure.⁵ Many drugs, in particular non-steroidal anti-inflammatory medications, affect blood pressure (Table 44.4.2).⁶ Hence, a trial wash-out of potentially blood pressure-raising medications may be all that is needed to reduce blood pressure. If these causes of elevated blood pressure have been excluded and a suspicion of secondary hypertension remains, the physician should investigate potential causes.

In this chapter, we aim to summarize the clinical characteristics, which may induce suspicion of a secondary cause of hypertension and the diagnostic steps, that are required for the diagnosis of the most common diseases causing arterial hypertension.

Coarctation of the aorta is the second most common cause of hypertension in children (Figure 44.4.1a). Rarely, coarctation may be found in adults with high blood pressure. Discrepancies between bilateral brachial, or brachial and femoral blood pressures suggest the presence of a coarctation.⁷ In younger patients, chest radiography may be non-specific, whereas in adults, the classic sign of rib notching may be present Figure 44.4.1b).⁸ Transthoracic echocardiography with Doppler blood velocity measurement in the descending aorta is sufficient for diagnosis in children, while magnetic resonance imaging is increasingly becoming the preferred imaging tool in adults.⁹

Renal parenchymal disease is the most common cause of secondary hypertension in children¹⁰ and the second most common cause in adults.¹¹ Indeed, the kidney plays a central role in blood pressure regulation and is also one of the first organs to become a target of hypertension with impaired renal function as an end result^3,12,13 (see also Chapter 21.1).

Possible causes of renal hypertension are an intrinsic kidney disease such as glomerular (e.g. glomerulonephritis) or tubulointerstitial processes (e.g. polycystic kidney disease) as well as microvascular kidney damage. Moreover, some rare form of kidney cancer (e.g. reninoma) may be associated with increases in blood pressure and/or stable arterial hypertension.⁵

The diagnosis of renal hypertension is established by clinical data and typical laboratory findings such as increased creatinine plasma levels with a reduced glomerular filtration rate, an abnormal urine sediment, albuminuria/proteinuria (i.e. an increased urine albumin/creatinine ratio), and abnormalities in the imaging of the kidney and/or its blood vessels.⁴

The treatment of such patients depends on the aetiology, but is mainly conservative in nature with blood pressure control and possibly anti-inflammatory drugs, if appropriate⁴ (see also Chapter 21.5).

Activation of the renin–angiotensin–aldosterone system occurs with both unilateral and bilateral renal hypoperfusion.¹⁴ This leads to increases in angiotensin II levels and secondary hyperaldosteronism with in turn sodium and water retention, and vasoconstriction, all of which contribute to an increase in blood pressure.

In patients with unilateral renal artery stenosis, the ischaemic kidney starts to secrete renin, which leads to an increased level of angiotensin and eventually also aldosterone secretion and in turn increased blood pressure^15,16 (Figure 44.4.2). As blood pressure rises, sodium excretion by the normal contralateral kidney increases; therefore, there is no sodium retention or subsequent volume overload under these conditions. In patients with bilateral renal artery stenosis, the lack of compensatory sodium excretion by the contralateral kidney leads to fluid retention, reduction of kidney function, and increased risk of developing heart failure with flashing pulmonary oedema in some patients.¹⁷

The dominant cause, in at least 85% of patients, of renovascular hypertension in Western countries is atherosclerotic renal artery stenosis.¹⁸ The rest of the cases are due to fibromuscular dysplasia (FMD), renal trauma, and renal artery occlusion due to dissection, embolism, and/or thrombosis.^{19,  20}

Clinical features of patients with renovascular hypertension are an early or late onset hypertension (<30–40 years in females with FMD or >50 years in those with atherosclerotic lesions), an acceleration of a previously well-treated essential hypertension, deterioration of renal function or acute kidney injury in treated essential hypertension, flash pulmonary oedema, therapy-resistant hypertension, or refractory congestive cardiac failure.

FMD is a non-atherosclerotic, non-inflammatory vascular disease.²¹ Under this category, a variety of histologically distinct forms of FMDs, such as medial fibroplasia, perimedial fibroplasia, intimal fibroplasia, and medial hyperplasia are summarized. Not all FMDs are associated with arterial hypertension, provided that they do not impair renal blood flow. Indeed, some FMD forms not causing renal ischaemia may be detected incidentally in up to 3% of normotensive men or women presenting as potential kidney donors.²²

The classical patient with FMD is a young, slim female without risk factors for hypertension. Because of this sex predominance, it has been suggested that hormonal factors might modulate the progression of this disorder and its clinical phenotype.²² FMD may be found in any vessel, mostly it affects the renal, intestinal, femoral, and carotid arteries.²³ The typical changes of the renal artery (chain-of-beads appearance; Figure 44.4.3a) are usually found distally and in the renal artery branches. In around 60% of the patients FMD occurs bilaterally.^23,24 The preferred diagnostic tool for the diagnosis of a FMD is Doppler sonography of the kidney and renal artery, followed by a renal artery angiogram (by computed tomography, magnetic resonance imaging, or angiography with pressure wire measurements).²² A captopril test or a renal scintigram are no longer considered as routine tests.^{4,  22}

This kind of renal artery stenosis it is most commonly seen in patients over 65 years of age and often develops as part of systemic atherosclerotic disease affecting multiple vascular beds, including coronary, cerebral, peripheral vessels and particularly the aorta.²⁵

The possible clinical presentations are a worsening of a previously well-controlled hypertension (e.g. renovascular hypertension on top of essential hypertension), an acute hypertensive crisis with a typical flash pulmonary oedema, or even recurrent ‘angina-like symptoms’.¹⁷ Marked blood pressure increases are suggestive for unilateral renal artery stenosis.²⁵

Sometimes a relevant difference in kidney size (>1.5 cm) or atherosclerotic changes or calcifications of the renal artery may be observed during a routine abdominal ultrasound.²⁵ In over 40% of patients with peripheral arterial occlusive disease and over 10% of patients undergoing coronary angiography or coronary artery bypass grafting, a renal artery stenosis may be found. ^{26,  27}

The most widely used screening modality is Doppler sonography of the renal arteries, which provides both structural and functional information.²² In contrast to FMD, atherosclerotic stenosis typically is located in the proximal segment of the renal arteries²⁴ (Figure 44.4.3b). The typical finding is an increase in peak systolic velocity, which allows for the diagnosis of an atherosclerotic renal artery stenosis with good specificity (92%) and a sensitivity (85%).²⁸ The resistance index, defined as the ratio of the difference between peak systolic velocity and peak end-diastolic flow rate divided by peak systolic velocity, provides information on the blood flow to the renal tissue. An increased resistance index is a sign of a diminished parenchymal blood flow.²⁸

In the last decades, the management of renovascular hypertension has undergone radical paradigm shifts.²⁹ Although renal artery stenosis still remains a prototype for reversible causes of secondary hypertension, and restoring vessel patency and perfusion pressures can decrease blood pressure to normal levels in certain patients, current practice favours primarily medical management. Revascularization is particularly applicable to younger individuals, such as women with FMD, whose hypertension often regresses completely with technically successful renal artery angioplasty (Figure 44.4.4).²⁹ In contrast, older individuals with widespread atherosclerotic vascular disease and pre-existing hypertension are likely to require ongoing medical antihypertensive therapy regardless of the success of revascularization.²⁹ Since the introduction of blockers of the renin–angiotensin system, target blood pressures can be reached in more than 80%, although multiple agents may be required.^30,31 Patients with renovascular hypertension treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have a long-term mortality benefit compared with those without such treatment.³² Importantly, recent prospective, randomized trials³³ failed to show that renal revascularization procedures are associated with substantial additional benefit for patients who can be controlled with effective antihypertensive drugs.

Accordingly, management of atherosclerotic renovascular hypertension should begin with optimizing medical therapy, which necessarily includes withholding tobacco use, introduction of statins, glucose control, and effective antihypertensive drugs, most often including either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (see also Chapter 5.1). If this approach achieves normalization of blood pressure and stable renal function, no further action may be required, other than surveillance for disease progression. In older patients with pre-existing hypertension, the likelihood of a cure for hypertension is small. However, some patients may still benefit from a revascularization therapy. Restoration of blood flow to the kidney beyond a stenotic lesion remains an obvious approach to improving renovascular hypertension and halting progressive vascular occlusive injury. Although complications are extremely uncommon in experienced hands, they can be catastrophic, including atheroembolic disease and aortic dissection.

Experience since the 1980s indicates greater than 94% technical success rates of percutaneous angioplasty in these patients.³⁴ However, approximately 10–15% of patients may develop restenosis, for which repeat procedures may be required. Appropriate blood pressure control in observational outcome studies reached 65–75% of patients.³⁵

Cure of hypertension, defined as sustained blood pressure reduction to less than 140/90 mmHg with no antihypertensive medication, is achieved in 35–50% of patients.³⁶ Predictors of cure, that is, normal arterial pressures without medication beyond 6 months after angioplasty, include lower systolic blood pressures, young age, and short duration of hypertension.

Percutaneous transluminal renal angioplasty alone commonly fails to maintain patency for proximal or ostial atherosclerotic lesions, in part because of extensive recoil of the plaque extending into the main portion of the aorta and restenosis. Therefore, endovascular stents provide an indisputable advantage. Several observational studies suggest that patients with bilateral atherosclerotic renal stenosis disease are at high risk of renal failure and accelerated cardiovascular disease leading to a reduced long-term survival. Thus, progression of renal failure attributed to ischaemic nephropathy may be reduced by an endovascular procedure.³⁷ Based on these data, several prospective randomized controlled trials have focused on the role of renal revascularization on top of medical therapy in patients with atherosclerotic renal artery stenosis. Three early trials were using percutaneous transluminal renal angioplasty without stenting compared with medical therapy.³⁸ Crossover rates for failure of medical therapy ranged from 22% to 44%, suggesting a role for percutaneous transluminal renal angioplasty in refractory hypertension, although the overall intention-to-treat analyses were negative (which obviously is not very enlightening under these circumstances).³⁸ Greater blood pressure benefit after percutaneous transluminal renal angioplasty was described in patients with bilateral renal artery stenosis.³⁹

More recent prospective trials^30,40,41,42 investigating the effects of stent placement on top of blood pressure and lipid-lowering therapy on prevention of progression of renal dysfunction caused by atherosclerotic ostial renal artery stenosis reported slightly improved blood pressure control and/or reduced drug requirements, but the differences were minor. No definitive benefits regarding recovery of renal function, blood pressure control, or reduction of serious co-morbid vascular events have been identified in any of these trials over an observation period of 3–5 years.^30,40,41,42 These negative results have dampened the enthusiasm for early vascular intervention in atherosclerotic renovascular disease. However, substantial limitations of these trials need to be highlighted, as patients with progressive renal insufficiency, therapy-resistant hypertension, and/or episodic pulmonary oedema have been excluded.^30,40,41,42 As such, these trials under-represented high-risk disease, which were included in registries and observational reports.⁴¹

Elevated blood pressure resulting from endocrine disorders (endocrine hypertension) accounts for a relevant proportion of cases of secondary hypertension. Although some features may be suggestive, many cases of endocrine hypertension remain silent until worked up for the disease. A majority of cases result from primary aldosteronism. Other rare conditions include congenital adrenal hyperplasia, Liddle syndrome, phaeochromocytomas, Cushing’s syndrome, acromegaly, thyroid diseases, primary hyperparathyroidism, and iatrogenic hormone manipulation. Early identification and treatment of endocrine hypertension may help to reduce morbidity and mortality related to these disorders. This section gives a comprehensive and practical approach to the diagnosis and management of endocrine hypertension.

Endogenous hypercortisolism, also called Cushing’s syndrome, is characterized by typical clinical signs/symptoms that in its overt form are usually not missed. The diagnosis of Cushing’s syndrome involves hormonal assessments, including a non-suppressible serum cortisol after application of 1 mg of dexamethasone overnight, elevation of urinary free cortisol in a 24 h urine collection, or demonstration of a flattened circadian cortisol rhythm indicated by elevated (salivary) midnight cortisol levels. The localization (i.e. central vs adrenal) is guided by assessment of baseline adrenocorticotropic hormone levels. Further differential diagnosis will likely require other functional tests (such as high-dose dexamethasone suppression test and corticotropin-releasing hormone stimulation testing), targeted imaging procedures, and sometimes invasive procedures such as sinus petrosus venous sampling.^43,44 While glucocorticoid excess does play a role in blood pressure regulation, arterial hypertension is only rarely the leading clinical feature in patients with Cushing’s syndrome. Considering the rarity of the condition, it is therefore prudent to restrict screening procedure in hypertensive patients to those suggested by current guidelines⁴⁵:

Primary aldosteronism is the most common form of secondary hypertension in adults with an estimated prevalence of around 10% in referral centres and 4% in a primary care setting. Despite its relatively high prevalence until recently, insights into the genetic and molecular basis of the disease had remained largely obscure.

Initially, primary aldosteronism was described by Conn in 1955. He described the characteristics of the syndrome such as autonomous production of aldosterone by a tumour of the adrenal cortex (Figure 44.4.5) and the secondary suppression of renin with development of hypertension with hypokalaemic alkalosis.^46,47 Conn also recognized that normokalaemic forms of the syndrome exist which masquerade as essential hypertension. As a consequence, normokalaemic primary aldosteronism is often overlooked. The advent of a simple screening test, the aldosterone–renin ratio, led to a better recognition of such patients.

Accordingly, in a significant proportion of patients who are resistant to combined antihypertensive medical treatment (i.e. between 11% and 20%), primary aldosteronism may be the underlying cause.⁴⁸ Given the detrimental cardiovascular adverse effects of aldosterone excess that are in part independent of high blood pressure,⁴⁹ early detection of primary aldosteronism has an important impact on clinical outcome and survival. The two predominant causes of autonomous aldosterone secretion are aldosterone-producing adenomas, treated commonly by unilateral adrenalectomy, and idiopathic hyperaldosteronism due to bilateral adrenal hyperplasia, currently managed by chronic mineralocorticoid antagonist therapy (i.e. spironolactone, eplerenone; see Chapter 5.2). Despite progress in the management of primary aldosteronism, critical issues related to diagnosis, subtype differentiation, and treatment of not surgically correctable forms still persist. To date, the definitive diagnosis of primary aldosteronism is a multistep procedure requiring expert knowledge (Figure 44.4.6).^{50,  51}

For example, while adrenal venous sampling is recommended to assess whether aldosterone hypersecretion is lateralized in patients with primary aldosteronism, this procedure is invasive, poorly standardized, and not widely available.^52,53,54

Overall, compared with its importance as the major secondary cause of hypertension, the currently available tools for diagnosis and treatment of primary aldosteronism are quite inefficient. These shortcomings relate in part to the heterogeneity of Conn’s syndrome. In epidemiological terms, there appears to be a continuous spectrum from low renin hypertension, normokalaemic Conn’s syndrome to hypokalaemic primary aldosteronism that makes cut-offs used for screening somewhat arbitrary. Likewise, based on histopathology of adrenal tissues resected during adrenalectomy, heterogeneity exists at multiple levels as aldosterone excess may be caused by micro- or macronodular hyperplasia or by a typical adrenal adenoma; the adjacent adrenal cortex may be atrophic, diffuse hyperplastic, or nodular hyperplastic.⁵⁵

In appreciation of the overall high prevalence and the complexity of the endocrine work-up, current guidelines support a relatively broad screening policy (Table 44.4.3) as well as a liberal treatment trial with mineraloreceptor antagonists despite incomplete differential diagnosis⁵¹. Candidates with a particular high cure rate following a surgical procedure are females, younger patients, and those with a short history of hypertension⁵⁶. Therefore, in these patients, completion of the whole diagnostic procedure should be aimed for.

Tumours secreting excessive amounts of catecholamines are termed ‘phaeochromocytomas’ or ‘paraganglioma’ in accordance to their anatomical location.

Lesions producing excess catecholamines may be located in the adrenal glands (phaeochromocytomas, around 90% of the diagnosis) or in sympathetic ganglia, which are present along the entire sympathetic chain (paragangliomas or extra-adrenal phaeochromocytomas, around 10%). Although the sympathetic chain extends throughout the body, most extra-adrenal phaeochromocytomas are located in the abdomen; less common locations for these lesions include the neck, chest, and urinary bladder. The majority of head and neck paraganglioma are not hormonally active.

Both phaeochromocytoma and paraganglioma are uncommon tumours that account for less than 0.1% all hypertensive cases (Figure 44.4.7).⁵⁷

The clinical presentation of phaeochromocytomas is quite variable, ranging from severe, causing emergencies and sudden death, to those cases with minimal or no symptoms. In the latter, the diagnosis is often initiated following abdominal imaging with an incidental finding of an adrenal tumour. Commonly described symptoms are headache, flushing, palpitations, anxiety, chest pain, dyspnoea, abdominal pain, diarrhoea, blurred vision, dizziness, weakness and fatigue, anorexia and weight loss, polyuria, and polydipsia; clinical signs include arterial hypertension (stable or hypertensive crisis), tachycardia, orthostatic hypotension, and heart failure.⁵⁸ Phaeochromocytoma/paraganglioma have a strong genetic background and in more than 30% of cases a mutation in one of many identified susceptibility genes can be found. Therefore, genetic testing has been advocated for in all affected patients. The diagnosis of a pheochromocytoma⁵⁹ requires confirmation of inappropriate catecholamine production. This is achieved by measurement of normetanephrine, metanephrines, and methoxytyramine in plasma and/or 24 h urine which provides a high sensitivity and specificity, while determination of vanillylmandelic acid in the 24 h urine is no longer recommended.^57,60,61,62 Screening is recommended in patients with typical signs and symptoms, in those with a family history or earlier diagnosis of a phaeochromocytoma/paraganglioma, and in all patients with an adrenal incidentaloma. Similar to the situation for Cushing’s syndrome the low pretest probability renders a general screening of the hypertensive population as inappropriate.

Deregulation of thyroid and parathyroid function are reversible causes of secondary hypertension.⁶³ Thyroid disorders induce several haemodynamic changes leading to elevated blood pressure as a consequence of their interaction with endothelial function, vascular reactivity, renal haemodynamics, and renin–angiotensin system. However, in thyroid disorders, the regulation of blood pressure and the development and maintenance of variable forms of arterial hypertension are different.^64,65 Hyperthyroidism results in an increased endothelium-dependent responsiveness secondary to the shear stress induced by the hyperdynamic circulation, and contributes to reduce vascular resistance. Conversely, hypothyroidism is accompanied by a marked decrease in sensitivity to sympathetic agonists with an increase of peripheral vascular resistance and arterial stiffness.^66,67,68 Furthermore, in animal models, hypothyroidism reduces the endothelium-dependent and nitric oxide-dependent vasodilatation.⁶⁹ Increased blood pressure due to thyroid disorders is usually reversible with achievement of euthyroidism, but in some cases pharmacological treatment for blood pressure control is required. In hyperthyroidism, beta blockers are the first-choice treatment to control blood pressure, but when they are contraindicated or not tolerated, angiotensin-converting enzyme inhibitors or calcium channel blockers are recommended. Hypothyroidism is a typical low-renin hypertension responding particularly well to calcium antagonists and diuretics; indeed, in hypothyroidism a low-sodium diet seems to improve blood pressure control further. Randomized clinical trials to compare the efficacy on blood pressure control of the antihypertensive treatment in thyroid disorders are needed.

Sporadic primary hyperparathyroidism is an endocrine disorder usually characterized by persistent fasting hypercalcaemia attributable to autonomous overproduction of parathyroid hormone by parathyroid adenoma or hyperplasia (hypercalcaemic primary hyperparathyroidism).⁷⁰ However, a proportion of patients with primary hyperparathyroidism (20%) show normal total and ionized serum calcium levels in the presence of persistently elevated parathyroid hormone concentrations.⁷⁰

Primary hyperparathyroidism is associated with an increased risk of arterial hypertension.⁷¹ Recent investigations have reported high blood pressure in 40–65% of patients with primary hyperparathyroidism.⁷² Despite variations in published data due to different patient selection criteria, the prevalence of hypertension in patients with primary hyperparathyroidism is higher than in the general population regardless of age.⁷² However, elevated parathyroid hormone levels have also been reported in a subgroup of patients with primary (essential) hypertension.⁷² Proposed mechanisms linking hypertension and primary hyperparathyroidism include abnormalities in major endocrine pressor factors, such as the sympathetic nervous system⁷³ and/or the renin–angiotensin–aldosterone axis⁷⁴, dysfunction or structural changes of resistance vessels documented either by an altered vasodilatory response, and/or an enhanced vascular constriction to pressor hormones.^{75,  76}

Adherence to antihypertensive therapy is critical to achieving adequate blood pressure control.^77,78 Of note, 30–50% of hypertensive patients do not take their drugs as prescribed⁷⁹ and physicians often underestimate this issue, particularly in their own patients. Non-adherence has important public health implications and, moreover, it results in increased morbidity and mortality rates.⁸⁰ The causes of poor adherence are both patient and therapy related.^{78,81,82,83,84,85,86,87,88,89,90,91} Reducing the number of drugs which need to be taken daily by prescribing fixed-dose combination drugs and regular visits⁸⁶ as well as biochemical screening⁹² have been shown to improve adherence.

Currently, multiple, different direct and indirect methods to measure therapeutic adherence are available, but in clinical practice there is no cost-effective and simple tool. Therapeutic drug monitoring, characterized by drug (or metabolite) concentration measurement in body fluids (blood or urine), is a cost-effective direct method to assess therapeutic adherence.⁹² Despite some limitations, therapeutic drug monitoring may decrease health costs, by reducing the number of visits and by identifying those patients who would undergo unnecessary further diagnostic and/or interventional procedures and would rather need more intensive counselling. Moreover, therapeutic drug monitoring is useful to identify patients with true resistant hypertension, rather than those with poor compliance. Other possibilities include urine testing with fluorescent drugs, pill counting, among others.

Obstructive sleep-disordered breathing is characterized by recurrent episodes of partial or complete upper airway obstruction during sleep.⁹³ Obstructive sleep apnoea has been newly recognized as a secondary cause of hypertension (see chapter 23.1).^93,94

Indeed, obstructive sleep-disordered breathing is accepted as an important independent risk factor for cardiovascular diseases in general, and in particular for hypertension. It is an important part of both the European and American guidelines as an identifiable and treatable cause of secondary hypertension.^4,93 Moderate or severe obstructive sleep-disordered breathing can be detected in a third or more of patients with primary hypertension and in up to 80% of individuals with drug-resistant hypertension.

It is difficult to tease out confounding variables and to infer a direct causal relationship between obstructive sleep apnoea and hypertension. Nevertheless, a large body of evidence suggests a link, after adjusting for confounders. Importantly, treating obstructive sleep-disordered breathing may improve hypertension and may translate into an improved CV risk profile and patient outcomes. Obstructive sleep-disordered breathing is seen in 70% of patients with resistant hypertension, but only in 38% of those with controlled hypertension.⁹⁵ The mechanisms by which obstructive sleep-disordered breathing is thought to elicit hypertension include sympathetic activation^96,97 (Figure 44.4.8), endothelial dysfunction,⁹⁸ increased endothelin release,⁹⁹ reduced nitric oxide production, and systemic inflammation.⁹⁴ A sustained effect of obstructive sleep-disordered breathing on muscle sympathetic nerve activity has been documented during wakefulness in subjects with normal and impaired left ventricular systolic function.¹⁰⁰ Of note, Grassi and colleagues¹⁰¹ recorded daytime muscle sympathetic nerve activity in four otherwise similar lean and obese cohorts with and without severe obstructive sleep-disordered breathing (Apnea–Hypopnea Index averaging at least 40 events per hour). Muscle sympathetic nerve activity burst incidence was significantly greater in lean and in obese subjects with obstructive sleep-disordered breathing as compared to controls, indicating that these neural disturbances are not due to confounding effects of obesity. They also documented significantly greater daytime muscle sympathetic nerve activity in individuals characterized as having ‘non-dipping’ or ‘reverse dipping’ nocturnal ambulatory blood pressures, a clue to the presence of obstructive sleep apnoea, compared with individuals who are normotensive during the day and night.¹⁰²

Of note is the fact that an increased incidence of hypertension has also been associated with restless legs syndrome^103,104 and reduced sleep duration,^{105,106,107,108,109} independently of the presence of obstructive sleep-disordered breathing. Furthermore, obstructive sleep-disordered breathing has also been linked to diabetes, metabolic syndrome, heart failure, arrhythmia, depression, and erectile dysfunction.¹¹⁰

In patients with obstructive sleep-disordered breathing, several meta-analyses and randomized trials demonstrate improved blood pressure control with the use of positive airway pressure (continuous or bi-level).^{111,112,113,114,115,116} A meta-analysis of 32 randomized trials pooled 1948 patients and showed a mean net reduction in blood pressure of 2.5 mmHg.¹¹⁷ Including studies involving patients with resistant hypertension and obstructive sleep apnea and measuring blood pressure changes by ambulatory blood pressure monitoring only, Iftikhar and colleagues found a mean change in 24 h systolic blood pressure of −7.21 mmHg and in 24 h diastolic blood pressure of −4.99 mmHg.¹¹⁸ Blood pressure-lowering effects are especially evident in those with more severe obstructive sleep-disordered breathing. Even a modest blood pressure reduction is of relevance at the population level when considered in the context of the 10/5 mmHg reduction in systolic/diastolic blood pressure, which may reduce the risk of stroke, major cardiovascular events, and death between 20% to 25%.¹¹⁹ Randomized trials suggest that treatment of obstructive sleep-disordered breathing with mandibular devices can also lower blood pressure.¹²⁰

Whether other beneficial effects of obstructive sleep-disordered breathing therapy, such as attenuation of nocturnal hypoxaemia, sympathetic activation, and systemic inflammation, confer further benefit beyond blood pressure reduction remains to be determined. Currently, no class of antihypertensive drugs is best suited to treat hypertension related to obstructive sleep-disordered breathing. Aldosterone antagonists may be beneficial in those with resistant hypertension and obstructive sleep-disordered breathing,¹²¹ but randomized data are at the present time not available. Aldosterone has emerged as a key factor linking obstructive sleep-disordered breathing, dietary sodium intake, renal sympathetic activation, fluid retention, and hypertension.^{122,123,124,125} Any fluid retention resulting from increased renal- and aldosterone-mediated sodium retention will shift fluids at night from the legs to the neck. The resultant peripharyngeal oedema and increase in neck circumference will increase upper airway resistance and the severity of obstructive sleep-disordered breathing^{122,123,124,125} and in turn leads to an increase in blood pressure.

This positive feedback loop might be exacerbated by antihypertensive therapies associated with peripheral oedema (i.e. calcium antagonists). Conversely, combining the mineralocorticoid receptor antagonist spironolactone with conventional antihypertensive therapy significantly reduces the Apnoea–Hypopnea Index, nocturnal desaturation, and ambulatory blood pressure.¹²⁶

A recent meta-analysis suggests renal denervation may prove to be beneficial as an adjunct for patients with obstructive sleep-disordered breathing and hypertension (see also Chapter 44.8).¹²⁷ Efferent renal sympathetic nerve stimulation elicits increases in renin release from juxtaglomerular cells, renal sodium and water reabsorption, and renal vascular resistance. Thus, if obstructive sleep-disordered breathing activates efferent renal sympathetic nerve discharge in parallel with muscle sympathetic nerve activity, this could increase blood pressure acutely via sympathetically mediated vasoconstriction and sustain hypertension chronically by engaging sodium and water retention in addition to entraining and resetting the sympathetic nervous system.^127,128,129

A variety of therapeutic agents or chemical substances may increase blood pressure.⁶ Therefore, a comprehensive history including use of medications, over-the-counter agents, and illegal substances should be elicited in every hypertensive individual. A recent review of the therapeutic agents and chemical substances that may elevate blood pressure listed anticancer agents, analgesics, anti-inflammatory and psychiatric drugs, steroids and mineralocorticoids, recombinant human erythropoietin, highly active antiretroviral therapy, antiemetic drugs, herbal products, alcohol, cocaine, caffeine, taurine, liquorice, and sexual hormones (Table 44.4.2).