Older age is a major risk factor for developing hypertension and a strong confounder of its independent risk for CV and renal events. Above the age of 40 years, younger individuals have higher risk for death for any given BP increase ( Fig. 46.1 ). The prevalence of hypertension increases with age and according to the latest NHANES data from 2017–2020; when BP is defined as SBP ≥140/90 mm Hg; the prevalence of hypertension in adults aged 65 to 74 years was 64% and in adults aged 75 years or older was 74.5% ( Table 46.2 ) A meta-analysis of more than 1 million adults demonstrated that risk increases in all age groups with SBP >115 mm Hg or DBP >75 mm Hg with a doubling of the risk of death from heart disease or stroke for every 20 mm Hg higher SBP and 10 mm Hg higher DBP. SBP and pulse pressure are more potent predictors of risk in patients older than the age of 50 to 60 years, whereas DBP is a better predictor of mortality in individuals younger than 50 years of age. When SBP is <130 mm Hg, regardless of age, DBP does not associate with CV risk. ^, The absolute risk of CV disease is dependent on older age and other CV risk factors in addition to the level of BP. Antihypertensive drug therapy, however, reduces the risk for CV events across the full age spectrum and has its greatest absolute benefit in older persons including those older than the age of 80 years.

Coronary heart disease mortality according to systolic blood pressure and age.

Reprinted with permission from Elsevier, from Lewington S, Clarke R, Qizilbash N, 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. 2002;360:1903–1913.

Hypertension in children and adolescents also contributes to premature atherosclerosis and early development of CV disease as adults. The diagnosis of hypertension in children and adolescents is becoming more prevalent due to the epidemic of obesity in young Americans. Current U.S. guidelines suggest diagnosing hypertension in children younger than 13 years based on new normative pediatric blood BP tables based on normal-weight children as opposed to children with overweight/obesity (those with a BMI ≥85th percentile). In adolescents ≥13 years of age, diagnosis of hypertension has been simplified and aligns with the AHA/ACC adult BP guidelines. There is also a more limited recommendation to perform screening BP measurements only at annual preventive care visits; however, BP should be checked at every health care encounter for persons with obesity, those taking medications known to increase BP, with kidney disease, a history of aortic arch obstruction or coarctation, or diabetes. Trained health care professionals in the office setting should make a diagnosis of HTN if a child or adolescent has auscultatory confirmed BP readings ≥95th percentile at three different visits, and guidelines encourage an expanded role for ambulatory BP monitoring (ABPM) in the diagnosis and management of pediatric hypertension.

Hypertension is a major problem for both men and women, but men tend to develop it at an earlier age ( Table 46.2 ), which is also true of the adverse clinical consequences of hypertension. Among individuals older than 70 years, women are more likely to have hypertension ^, and to have a CV event rate comparable with men. Age and body mass index have been much stronger predictors of incident hypertension than sex in epidemiologic studies. Drug treatment of hypertension yields roughly the same benefits for women and men. ^,

The NHANES survey from 2017–2020 demonstrated, similar to previous surveys, a higher prevalence of hypertension in non-Hispanic Blacks (46.6%) than in non-Hispanic Whites (30.7%) ( Table 46.2 ). The prevalence was unchanged in non-Hispanic Whites but increased as compared with NHANES 2013-2016 in non-Hispanic Blacks (from 44.1%–46.6%) and to a greater extent in non-Hispanic Asians (from 28.9%–33.5%) and Hispanics (from 30 to 33.2%). Although the prevalence of hypertension has increased in non-Hispanic Asians and Hispanics, non-Hispanic Blacks still have the highest overall prevalence of hypertension in the United States. The prevalence of hypertension is geographically heterogeneous, with the highest prevalence in Blacks and Whites in the southeastern United States (“the Stroke Belt”). Perhaps because of the persistent historical difference in BP control rates, the adverse long-term consequences of hypertension are still more common in Blacks than Whites, but disparities have decreased in the past decade. In 2014, the age-adjusted death rate from heart disease was 24% higher in Blacks, as was stroke (by 41%) and hypertension or hypertensive renal disease (by 111%). In 2021, the prevalence of ESKD among Black individuals was more than four times that of White individuals. The prevalence among Hispanic and Native American individuals was more than twice as high as among White individuals. Although diuretics or calcium channel blockers (CCBs) may have an advantage as initial therapy for reducing CV events in Blacks, an angiotensin-converting enzyme (ACE) inhibitor (ACEI) was better than either a CCB or a β-blocker in preventing the decline of kidney function in African Americans with hypertensive nephrosclerosis. ^{, ,} Most current hypertension guidelines therefore recommend controlling BP with multidrug regimens in all racial/ethnic groups.

Through observations by multiple groups and experiments performed by physiologists including Guyton, the role of dietary sodium intake plays a major role in the pathogenesis of hypertension. Dahl’s hypothesis articulated in 1963 suggested that higher dietary sodium intake within a population was associated with a higher prevalence of hypertension. Several groups have also made this association even when comparing groups with differences in dietary sodium that have few other confounders that could modulate BP. ^, In populations with low dietary sodium intake, BP does not increase with age, but in modern society with ubiquitously high dietary sodium, hypertension is increasingly common and prevalence rises sharply with aging.

Humans have the ability to match sodium excretion to relatively large swings (40–100×) in sodium intake such that BP is only modestly altered by a few mm Hg. Initially, acute rises in dietary sodium increase BP in healthy individuals, but both renal and extrarenal compensatory processes result in a modest rise in BP. ^, One example of chronic adaptation to hypertension is the renin-angiotensin-aldosterone system, described as follows.

Guyton summarized the work of several investigators as to the mechanism of how an increase in sodium intake leads to hypertension. Although an increase in volume is the initiating event, the rise in CO is transient, as the excess sodium is excreted. However, that short-term rise in CO leads to a rise in BP that is sustained through a rise in peripheral vascular resistance via autoregulation. Thus a volume-driven event leads to hypertension, but after a few days of physiologic adaptation, the signature of that hypertension is an increase in total peripheral resistance. The higher BP will remain until the sodium intake returns to normal. Thus Guyton added a critical nuance to Dahl’s hypothesis. In healthy controls, sodium intake does not increase BP, but in those with a “volume factor” (i.e., a rise in sodium intake, in the presence of a “kidney factor” to diminish sodium excretion), higher sodium intake does increase BP ( Fig. 46.2 ).

Pressure-natriuresis curves in dogs at different levels of sodium intake (reflected in urinary salt output, y-axis).

In the normal state, massive fluctuations in sodium intake produce minimal changes in blood pressure (BP). In states of high angiotensin II (Ang II) levels (Ang II infusion in this model), BP increases significantly, even with modest increases in sodium intake. Conversely, in states where Ang II is absent or low (administration of captopril in this model), the increased sodium results in increased BP only at low BP levels; once BP becomes normal, the relationship is similar to that of normal kidneys. Values in parentheses are the relative estimated concentrations of Ang II (1 being the reference).

From Guyton AC, Coleman TG, Young DB, et al. Salt balance and long-term blood pressure control. Annu Rev Med. 1980;31:15–27.

Salt sensitivity is defined by the change in BP with a change in sodium intake. The characteristic of salt sensitivity is not binary (i.e., salt-sensitive vs. salt-resistant) but as a continuum. An extension of Guyton’s work is that salt sensitivity implies a “kidney factor” to raise BP. Each of these factors can be considered to shift the long-term kidney function curve to the right. Several mechanisms are known to increase salt sensitivity including CKD, genetic or acquired gain-of-function changes in the machinery for sodium reabsorption in different nephron segments, and many other factors (i.e., intrinsic to the kidney or external factors acting on the kidney, such as neural, vascular, or hormonal) that deserve their own categories as clinically relevant, pathophysiologic mechanisms of hypertension. Some of these factors by historical convention fall under the heading of secondary causes of hypertension (e.g., primary aldosteronism and renovascular hypertension), while others are considered causes or exacerbating factors for primary/idiopathic/essential hypertension (e.g., obesity).

The interplay between renal sodium retention and hypertension involves changes in sodium handling throughout the nephron. A theory with substantial experimental support proposes that increased renal vasoconstriction due to a variety of possible mechanisms (e.g., increased levels of angiotensin II, catecholamines, or uric acid, and progressive aging) induces a preglomerular (afferent) arteriolopathy that results in impaired sodium filtration. ^, In addition, renal vasoconstriction results in tubular ischemia, another mediator of sodium avidity. Several studies have also shown that Blacks have higher salt sensitivity due to several factors, in part due to higher effective response to aldosterone. ^,

A key factor in regulation of BP is the phenomenon of pressure natriuresis. Pressure natriuresis is defined as the increase in renal sodium excretion because of mild increases in BP, typically due to extracellular fluid volume expansion, allowing BP to remain in the normal range. This concept is essential to the understanding of the sustainability of hypertension. If one understands the “set-point BP” as the BP at the point when extracellular volume and pressure natriuresis are in equilibrium, it necessarily follows that a change in BP can only be sustained if pressure natriuresis is abnormal. Pressure natriuresis occurs over hours to days and is modulated by both biophysical and humoral factors.

In the normal state, increased sodium intake causes an increase in extracellular volume and BP. Because of the steep relationship between volume and pressure, small increases in BP produce natriuresis that restores sodium balance and returns BP to normal ( Fig. 46.2 ). Expansion of extracellular fluid volume and increased BP result in a rise in blood flow through the vasa recta, which stimulates the production of paracrine factors such as nitric oxide (NO) and ATP, which can inhibit tubular sodium reabsorption at multiple sites of the nephron. Nitric oxide also blunts the myogenic response of arteriolar autoregulation, thus allowing increased blood flow that is necessary to increase renal blood flow and interstitial pressure (see later). ^,

The pressure-natriuresis process is also mediated by biophysical factors. Increased renal interstitial hydrostatic pressure is an important factor. Sodium-loading results in increased pressure in the vasa recta, which has noticeably poor autoregulation, while pressure in cortical peritubular capillaries remains normal. ^, Vasa recta blood flow approximates 10% of total renal blood flow. This increase in interstitial pressure inhibits sodium transport largely by increasing 20-hydroxyeicosatetraenoic acid, an inhibitor of sodium-potassium adenosine triphosphatase (Na ⁺ -K ⁺ -ATPase), whose inhibition causes decreased activity of the Na ⁺ -H ⁺ -exchanger isoform 3 (NHE3). In addition, increased interstitial pressure limits proximal tubular paracellular pathways, thus maximizing natriuresis.

Because abnormalities in pressure-sodium relationships are essential to maintaining chronic elevations in BP, they represent a fundamental step in the pathogenesis of any type of hypertension in both the primary and maintenance phases of most secondary causes, such as renal and renovascular hypertension, hyperaldosteronism, glucocorticoid excess, coarctation of the aorta, and pheochromocytoma.

Hypertension clusters in families; an individual with a family history of hypertension has a fourfold greater chance of developing hypertension. It is estimated that the heritability of hypertension ranges from 27% to 68%. Genome-wide association studies (GWAS) in several multinational cohorts have identified a large number of single-nucleotide polymorphisms (SNPs) associated with hypertension. ^, However, these individual SNPs (>900 identified by 2023) are responsible for only minor BP effects (0.5–1 mm Hg), and the overall impact of these identified SNPs on the overall BP variance is only approximately 1% to 2%. The shortcomings of GWAS and other large population approaches are multiple. The SNP platforms used for testing are not hypothesis driven; they simply include common genetic variants for exploratory analyses that might provide clues for molecular pathways leading to better understanding of disease or new targets for therapy. To advance progress toward personalized medicine in hypertension, a GWAS based on the large U.K. Biobank Study cohort also performed functional and transcript expression analyses of candidate genes in target tissues in vitro (vascular smooth muscle cells, aortic fibroblasts, and endothelial cells) with the goal of identifying potential therapeutic targets. The study also developed and validated an unbiased genetic risk score that included clinical and genotype information including data on a total of 107 independent risk loci to generate estimates of risk of hypertension and risk of specific hypertension-related outcomes (stroke, coronary disease, and any cardiovascular outcome). These analyses showed a sex-adjusted systolic BP difference of 9.3 mm Hg between the lowest and highest risk quintile (higher in the high-risk group, which also had 2.32-fold greater odds of hypertension and a 1.35-fold increase in the odds of adverse cardiovascular events. These results indicate the potential value for genetic risk–based clinical scoring.

BP measurement is another important concern, as it is not uniform in these large, population-based GWASs. In addition, large numbers of patients are receiving treatment at the time of testing, thus limiting the strength of any associations. Finally, hypertensive phenotypes are not well defined, so patients with very different phenotypes (e.g., isolated diastolic hypertension and isolated systolic hypertension of the young, isolated systolic hypertension of older adults) are all lumped together. We now understand that each of these phenotypes likely has different underlying pathophysiologic mechanisms and that even within each group there is substantial variability in hemodynamic profile. ^,

With the improvement in techniques that allow expeditious, cheaper whole-exome or whole-genome analyses and the expansion of precision medicine, it is possible that greater mechanistic insights into the genetics of hypertension will become available. Unfortunately, however, the heavy influence of lifestyle and environmental factors in hypertension makes it unlikely that the simple analysis of genome sequence will yield groundbreaking discoveries.. Instead, the systematic evaluation of epigenetic modification associated with detailed functional phenotyping should allow us to advance understanding of the complex interplay of lifestyle and environmental factors in patients with hypertension, particularly among patients with primary or “essential” hypertension. ^,

Whereas the attempts at using GWAS to understand essential hypertension have not been particularly fruitful, the study of monogenic causes of hypertension, although rare, has provided substantial insight into the pathogenesis of hypertension. Whether as yet uncharacterized variants in genes known to cause hypertension play a key role in essential hypertension will require further whole exome and whole-genome studies. Coupled with family-based studies, the use of diverse racial/ethnic cohorts to enable inherited or de novo rare variant detection aids the discovery of genetic causes of most chronic diseases including hypertension. ^, For example, the prevalence of Liddle syndrome or a Liddle phenotype with low renin, low aldosterone is more common in Blacks. Of the monogenic forms of hypertension with well-described molecular mechanisms in adrenal cortex or the distal nephron, many share one thing in common: a defect in renal sodium handling. This commonality is consistent with the Guytonian hypothesis and highlights the importance of the kidney in regulating BP by way of sodium balance.

In Liddle syndrome, mutations in subunits of the epithelial sodium channel (ENaC)( SCNN1A, SCNN1B, SCNN1G ) lead to increased ENaC expression and decreased removal from the luminal membrane, both of which contribute to persistent channel activation leading to sodium avidity, volume expansion, hypertension, hypokalemia, and metabolic alkalosis with suppressed plasma renin activity and aldosterone.

In Gordon syndrome (pseudohypoaldosteronism type 2), various mutations have been described, leading to activation of the thiazide-sensitive sodium-chloride cotransporter (NCC, SLC12A3 ). These mutations were initially mapped to the with-no-lysine (WNK) kinases 1 and 4, which stimulate NCC phosphorylation and activity. Mutations in two E3 ubiquitin ligase complex proteins (kelch-like 3 and cullin 3) were discovered later. Collectively, these mutations are responsible for most cases of the syndrome. The shared mechanism is related to reduced degradation of kelch-like 3 and cullin 3 targets, WNK1, and WNK4 and therefore higher phosphorylation of NCC leading to the clinical phenotype of hypertension, hyperkalemia, and metabolic acidosis.

Mutations in mineralocorticoid receptor activation can also produce hypertensive syndromes, such as hypertension exacerbated by pregnancy (Geller syndrome), in which there is constitutive activity of the receptor in addition to marked sensitivity to progesterone, leading to hypertension during pregnancy in addition to chronic, severe hypertension with hypokalemia. Likewise, increases in aldosterone production are due to a chimeric gene crossover of the promoter for 11β-hydroxylase and the aldosterone synthase gene CYP11B2. Adrenocorticotropic hormone (ACTH) stimulates this promoter and hence aldosterone synthase expression independent of angiotensin II or plasma potassium. Such patients have hyperaldosteronism that is blunted by glucocorticoid-induced ACTH suppression, thus the term glucocorticoid-remediable hyperaldosteronism .

Other patients may have “apparent mineralocorticoid excess” due to mutations in the 11β-hydroxysteroid dehydrogenase type 2 gene. This enzyme is responsible for the conversion of cortisol to the inactive cortisone in target epithelia, including renal tubular epithelial cells of the distal nephron. Extracellular cortisol is typically ∼1000× fold more abundant than aldosterone. Thus mutations in this gene permit cortisol to almost constitutively activate the mineralocorticoid receptor leading to a state of apparent mineralocorticoid excess (salt-sensitive hypertension, hypokalemia, metabolic alkalosis) with suppressed plasma renin activity and aldosterone.

Similarly, patients with congenital adrenal hyperplasia due to 11β-hydroxylase or 17α-hydroxylase deficiency have an excess production of 21-hydroxylated steroids such as deoxycorticosterone and corticosterone, which are potent activators of the mineralocorticoid receptor, thus also producing the syndrome of apparent mineralocorticoid excess in addition to the well-known sexual developmental abnormalities of the syndromes.

In addition to hypertension-causing mutations that stimulate renal sodium reabsorption, human genetics has revealed inactivating mutations in sodium transporters, sodium channels, or their regulatory machinery that lower BP. These include but are not limited to Bartter syndrome (mutations in SLC12A1, KCNJ1, CLCNKB, BSND, CASR, MAGED2 ), Gitelman syndrome (SLC12A3), and pseudohypoaldosteronism type 1 (SCNN1A, SCNN1B, SCNN1G), which impair NKCC2, NCC, or ENaC, respectively. Taken together, these findings provide strong evidence for the role of renal sodium handling in the genesis of hypertension.

As discussed further later, endothelial and vascular smooth muscle cells also help to determine BP. The elucidation of the molecular genetics of the rare syndrome of autosomal hypertension with brachydactyly points to a vascular etiology that does not involve sodium reabsorption within the kidney. This is a monogenic form of salt-resistant hypertension transmitted via gain-of-function mutations in the phosphodiesterase 3A gene (PDE3A), which results in increased protein kinase A–mediated PDE3A phosphorylation and increased cAMP-hydrolytic activity. These cellular actions result in enhanced cell proliferation in vascular smooth muscle and dysregulated parathyroid hormone-related peptide physiology, accounting for the hypertensive and skeletal phenotypes.

The paradigm of sodium balance described earlier assumes that sodium and its accompanying anion are osmotically active and therefore retained isosmotically with water. However, this paradigm cannot explain the observation that acute sodium loading in humans and animals results in positive sodium balance without the expected water (weight) gain. Consequently, sodium may accumulate without water, most prominently in the skin, where negatively charged glycosaminoglycans bind sodium. This system of interstitial sodium buffering adds to the classical Guytonian approach wherein nonosmotic accumulation occurs acutely and is presumably followed by increased removal from skin (via an enhanced lymphatic network) for ultimate renal excretion.

The mechanisms explaining isosmotic sodium storage are under intense investigation. Mice and rats receiving a high-salt diet develop hypertonicity of the skin interstitium, which triggers a series of mechanisms to keep interstitial volume constant. The hypertonic sodium content activates the tonicity-responsive enhancer–binding protein (TonEBP) present in mononuclear cells infiltrating the skin. Consequently, these skin macrophages act as “local osmosensors” and secrete vascular endothelial growth factor type C, resulting in increased density and hyperplasia of the skin lymphocapillary network and increased endothelial nitric oxide synthase (eNOS). If these responses are blocked, skin sodium accumulates and salt-sensitive hypertension develops. ^, These studies were primarily performed in preclinical models, but studies in patients treated with vascular endothelial growth factor receptor inhibition showed consistent results. Moreover, clinical conditions associated with sodium-sensitive hypertension also display higher amounts of skin sodium. ^, These findings link the mononuclear phagocyte system to extracellular fluid volume control.

The implications of these findings were addressed in a study evaluating sodium balance in cosmonauts undergoing prolonged training (up to 205 days) in a facility simulating life in space. By carefully monitoring water and electrolyte intake and excretion, as well as factors regulating sodium balance, individuals exhibited a large variability in sodium excretion on a day-to-day basis despite relatively stable diets. In the long term, approximately 95% (70% to 103%) of ingested sodium was recovered, but daily sodium excretion during stable sodium intake varied considerably and was independent of BP and sodium intake. Instead, urine sodium excretion varied as a function of circaseptan fluctuations (6–9 days in this case) in levels of aldosterone and cortisol/cortisone. Moreover, total body sodium stores had even longer infradian fluctuations (averaging several weeks).

The factors regulating these intriguing changes are still unknown. These observations have clinical implications for the use of urine sodium excretion to assess sodium intake because they suggest wide day-to-day variations that cannot be captured in a single 24-hour urine collection. Moreover, these findings help to inform potential causes (e.g., immune-mediated) for salt-sensitive hypertension.

The RAAS has wide-ranging effects on BP regulation. Fig. 46.3 summarizes the most relevant elements of the RAAS and its role in the pathogenesis of hypertension and its complications. The different elements of the RAAS have key roles in mediating sodium retention, pressure natriuresis, salt sensitivity, vasoconstriction, endothelium dysfunction, and vascular injury. RAAS inhibitors are highly effective in treating hypertension; these classes are recommended among several first-line antihypertensive agents. Taken together, the RAAS has an important role in the pathogenesis of hypertension. However, there are some still unanswered issues. For example, in a large GWAS of 2.5 million genotyped or imputed SNPs in 69,395 individuals of European ancestry from 29 studies, the meta-analysis failed to show any significant RAAS-related SNPs associated with this analysis. Another meta-analysis evaluating the relations among polymorphisms in key RAAS genes ( ACE, AGT, and CYP11B2 ) and salt sensitivity also found no significant associations. Despite these genetic inconsistencies, there is a wealth of experimental evidence linking the RAAS to hypertension.

Key elements of the renin-angiotensin-aldosterone system.

ACE, Angiotensin-converting enzyme; ACE2, Angiotensin-converting enzyme type 2; Ang, angiotensin; AGT, angiotensinogen; AT1R, Ang II type 1 receptor; AT2R, Ang II type 2 receptor; MasR, Mas receptor; NEP, neutral endopeptidase.

Angiotensinogen is the precursor of all components of the RAAS. Angiotensinogen is made primarily in the liver, although can be produced in other tissues (e.g., adipocytes), and its regulation is distinct from that of renin and aldosterone. Angiotensinogen is the rate-limiting factor in the production of angiotensin II, and higher copy number of the angiotensinogen gene, AGT, and higher plasma levels of angiotensinogen are associated with higher BP. ^, Although research into the effects of global RAAS inhibition (via inhibition of angiotensinogen) has been delayed due to the lack of available pharmacologic inhibitors, its significance beyond downstream therapeutics has become clinically relevant with the development of RNA interference therapeutics that target translation of angiotensinogen mRNA. Intriguing effects such as nonredundant benefits of angiotensinogen knockdown on BP despite the angiotensin receptor blocker irbesartan may elucidate additional aspects of systemic versus tissue-specific blockade of RAAS.

Renin and prorenin are synthesized and stored in the juxtaglomerular cell apparatus and released in response to decreased renal afferent perfusion pressure, decreased sodium delivery to the macula densa, activation of renal nerves (via β ₁ -adrenergic receptor stimulation), and a variety of metabolic products including prostaglandin E ₂ and several others. Renin’s main function is to cleave angiotensinogen into angiotensin I. Prorenin, previously viewed as an inactive substrate for renin production, stimulates the (pro)renin receptor (PRR). This receptor leads to more efficient cleavage of angiotensinogen and activates downstream intracellular signaling through the mitogen-activated protein (MAP) kinases extracellular signal–regulated kinases 1 and 2 (ERK1/2) pathways that have been associated with profibrotic effects in some, but not all, experimental models. ^, It is still uncertain if the PRR is involved in the genesis or complications of hypertension in a manner independent of the effects of angiotensin II; however, deletion of PRR from principal cells of the collecting duct lowers BP and sodium reabsorption. ^{, ,}

Angiotensin II, formed by the cleavage of angiotensin I by ACE, is at the center of the pathogenetic role of RAAS in hypertension. Primarily through its actions mediated by the angiotensin II type 1 receptor (AT ₁ R), angiotensin II is a potent vasoconstrictor of vascular smooth muscle, causing systemic vasoconstriction, as well as increased renovascular resistance and decreased medullary flow, the latter a mediator of salt sensitivity. Angiotensin II leads to increased sodium reabsorption in the proximal tubule by increasing the activity of NHE3, the sodium-bicarbonate exchanger, and Na ⁺ -K ⁺ -ATPase and by inducing aldosterone synthesis and release from the adrenal zona glomerulosa. In addition, angiotensin II is associated with endothelial cell dysfunction and produces extensive profibrotic and proinflammatory changes, largely mediated by increased oxidative stress, resulting in renal, cardiac, and vascular injury, thus providing a strong link between angiotensin II and target-organ injury in hypertension. Conversely, stimulation of the angiotensin II type 2 receptor (AT ₂ R) is associated with opposite effects, resulting in vasodilation, natriuresis, and antiproliferative effects.

Tissue expression of different elements of the RAAS is important, including the protection of animals from the development of hypertension after targeted elimination of renal ACE activity. Because angiotensin II is necessary for normal renal development, experimental manipulation of the intrarenal RAAS demands the presence of some level of activity in the system. In experiments where the ACE gene was knocked out systemically and then reintroduced in myelomonocytic cells, there was no demonstrable renal ACE activity, but systemic levels generated from the myelomonocytic cells were enough to allow for normal renal development. Animals with absent renal ACE activity have markedly blunted hypertensive responses to the infusion of angiotensin II or L-NAME (low renin, angiotensin II-independent model of hypertension). At face value, this indicates that the absence of renal ACE protects against hypertension irrespective of plasma angiotensin II concentrations, an unexpected finding given the traditional view of the RAAS, in which an infusion of angiotensin II bypasses ACE and produces sustained hypertension regardless of ACE activity but well in line with growing evidence for the importance of ACE-induced intrarenal tubular generation of angiotensin II in the mediation of hypertension. However, because ACE was not expressed in other organs, either, it is also possible that the hypotensive effects of the absence of ACE activity were the result of absence of an effect in other locations, such as the vasculature. ^, This question remains unanswered while developments continue to occur in the understanding of the function of tissue RAAS (especially intrarenal), a system that has different regulators from the systemic RAAS and that, distinct from the endocrine RAAS, has feedforward mechanisms that generate further augmentation of local responses upon activation by the circulating RAAS.

The relative importance of the renal and vascular effects of angiotensin II was evaluated in classic cross-transplantation studies using both wild-type mice and mice lacking the AT ₁ R. ^, By cross-transplanting kidneys of wild-type mice into AT ₁ R knockout mice and vice versa, investigators were able to generate animals that were selective renal AT ₁ R knockouts or selective systemic (nonrenal) AT ₁ R knockouts. In physiologic conditions, renal, systemic, and total knockout mice had lower BP than wild-type mice, indicating a role of both renal and extrarenal AT ₁ R in BP regulation. Gain- and loss-of-function studies of proximal tubular AT1R are also consistent with a role for angiotensin II signaling in the kidney. The systemic absence of AT ₁ R was associated with approximately 50% lower plasma aldosterone, but the lower BP observed in this group was independent of this lower aldosterone production, as BP remained low despite aldosterone infusions to supraphysiologic levels following adrenalectomy in the systemic knockout mice. In addition, the BP reduction in kidney knockout mice occurred despite normal aldosterone excretion, again confirming the independence of renal angiotensin II effects from aldosterone.

In the hypertensive environment, it is the presence of renal AT ₁ R that mediates both hypertension and organ injury ( Fig. 46.4 ). When animals were infused with angiotensin II for 4 weeks, animals lacking renal AT ₁ R did not develop sustained hypertension, whereas wild-type and systemic knockout mice had a significant increase in BP. Additionally, only animals with elevated BP developed cardiac hypertrophy and fibrosis. This indicates that cardiac injury is largely dependent on hypertension and not on the presence of AT ₁ R in the heart, as the (hypertensive) systemic knockout mice developed significant cardiac abnormalities despite the absence of AT ₁ R in the heart. In summary, these experiments indicate that both systemic and renal actions of angiotensin II are relevant to physiologic BP regulation, but in hypertension, the detrimental effects of angiotensin II are mediated via its renal effects.

Effects of angiotensin II (Ang II) infusion on blood pressure (A), urinary sodium excretion (B), body weight (C), and cardiac hypertrophy (photos) according to renal and extrarenal presence of Ang II type 1 receptor.

See text for details. KO, Knockout; MAP, mean arterial pressure.

From Crowley SD, Gurley SB, Herrera MJ, et al. Ang II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci U S A. 2006;103:17985–17990.

Aldosterone, the adrenocortical hormone synthesized in the zona glomerulosa, plays a critical role in hypertension through its well-known effects on sodium reabsorption that are largely mediated by genomic effects through the mineralocorticoid receptor leading to increased expression of ENaC. An extensive body of literature has identified other genomic and nongenomic effects of aldosterone with relevance to hypertension. Extensive nonepithelial effects include vascular smooth muscle cell proliferation, vascular extracellular matrix deposition, vascular remodeling, and fibrosis, and increased oxidative stress leading to endothelial dysfunction and vasoconstriction.

Several other elements of the RAAS, including ACE2 and angiotensin (1-7), have been identified as having potential roles in BP regulation and angiotensin II–associated target-organ injury. ACE2 is expressed largely in heart, kidney, and endothelium; it has partial homology to ACE and is unaffected directly by ACEIs. ACE2 has a variety of substrates, but its most important action is the conversion of angiotensin II to angiotensin-(1-7). Angiotensin-(1-7) is formed primarily through the hydrolysis of angiotensin II by ACE2, and its actions are opposite to those of angiotensin II, including vasodilatory and antiproliferative properties that are mediated by the Mas receptor, a G-protein coupled receptor that, upon activation, forms complexes with the AT ₁ R, antagonizing the effects of angiotensin II. The vasodilatory effects are mediated by increased cyclic guanosine monophosphate, decreased norepinephrine release, and amplification of bradykinin effects. Studies have identified ACE2 and angiotensin-(1-7) as protective factors in the development of atherosclerosis and cardiac and kidney injury, ^, and administration of recombinant ACE2 or its activator, xanthenone, has resulted in improved endothelial function, decreased BP, and diminished renal, cardiac, and perivascular fibrosis in hypertensive animals. However, a phase 1 study of recombinant ACE2 in healthy humans did not show BP-lowering effects despite appropriate modulation of the RAAS, including a sustained increase in angiotensin (1-7) levels. The SARS-CoV-2 virus, the etiology of the COVID-19 pandemic, led to studies targeting the ACE2-Ang-(1-7) pathway. Using a synthetic angiotensin (1-7) (TXA-127) to augment the Ang-(1-7) pathway or an angiotensin II type 1 receptor–biased ligand (TRV-027) to block the angiotensin II pathway did not improve oxygen-free days or in-hospital mortality. Whether investigation of these compounds or other therapeutics accelerated by the pandemic have the potential value in the landscape of hypertension treatment remains unknown.

The sympathetic nervous system (SNS) is activated consistently in patients with hypertension compared with normotensive individuals, particularly in the obese ( Fig. 46.5 ). Many patients with hypertension are in a state of autonomic imbalance that encompasses increased sympathetic and decreased parasympathetic activity. ^, SNS hyperactivity is relevant to both the generation and maintenance of hypertension and is observed in human hypertension from early stages. For example, studies in humans have identified markers of sympathetic overactivity in normotensive individuals with a family history of hypertension. Among patients with hypertension, increasing severity of hypertension is associated with increasing levels of sympathetic activity measured by microneurography. ^, In human hypertension, plasma catecholamine levels, microneurographic recordings, and systemic catecholamine spillover studies have shown consistent elevation of these markers in obesity, metabolic syndrome, and hypertension complicated by heart failure or kidney disease. In addition, SNS hyperactivity is observed in most hypertensive subgroups, though it appears more pronounced in men than in women, and in younger than in older patients.

Causes and consequences of sympathetic nervous system activation in the pathogenesis of hypertension.

OSA, Obstructive sleep apnea; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; VSM, vascular smooth muscle.

Several experimental models have outlined the importance of the SNS in generating hypertension. Different models of obesity-related hypertension indicate that the SNS is activated early in the development of increased adiposity, and the key factor in the maintenance of sustained obesity-related hypertension is increased renal sympathetic nerve activity and its attendant sodium avidity.

SNS-mediated induction of salt sensitivity is a key element to sustaining high BP in other models of hypertension as well. For instance, rats receiving daily infusions of phenylephrine for 8 weeks developed hypertension during the infusions, but BP normalized under a low-salt diet after discontinuation of phenylephrine. However, once exposed to a high-salt diet, the animals again became hypertensive. The degree of BP elevation on a high-salt diet was directly related to the degree of renal tubulointerstitial fibrosis and decrement of GFR. These findings can be interpreted within the paradigm that catecholamine-induced hypertension causes renal interstitial injury that associates with a salt-sensitive phenotype even after sympathetic overactivity is no longer present. In addition, enhanced SNS activity results in α ₁ -receptor–mediated endothelial dysfunction, vasoconstriction, vascular smooth muscle proliferation, and arterial stiffness, all of which contribute to the development of hypertension.

Renalase is a flavoprotein highly expressed in kidney and heart that metabolizes catecholamines and catecholamine-like substances to aminochrome. Tissue and plasma renalase is decreased in experimental models with renal mass reduction, and renalase knockout mice have increased BP and elevated circulating catecholamine levels. This phenotype is reversed by administration of recombinant renalase. Also of relevance to catecholamine metabolism is catestatin, a product of the proteolysis of the neuroendocrine peptide chromogranin A. Catestatin acts at nicotinic cholinergic receptors in adrenal chromaffin cells as an inhibitor of catecholamine release. Chromogranin A knockout mice are hypertensive and have elevated catecholamine levels, both of which are normalized by administration of catestatin. Moreover, serum catestatin levels are decreased in patients with hypertension and their normotensive offspring, raising the possibility of a regulatory role in the development of hypertension. The role of renalase and catestatin in the modulation of SNS-mediated hypertension, as well as their possible value in the treatment of hypertension in humans remain uncertain.

Because increased SNS activity is associated with vascular smooth muscle proliferation, LVH, large artery stiffness, myocardial ischemia, and arrhythmogenesis, there is also a mechanistic role for SNS in the complications of hypertension. In support of this concept, there are several cohort studies reporting an association between physiologic or biochemical markers of SNS activation and adverse outcomes in heart failure, stroke, and end-stage kidney disease. ^, However, there are no such studies among patients with hypertension, and the indirect evaluation of the impact of treatment-induced heart rate reduction in hypertension has yielded paradoxical results.

In a meta-analysis of hypertension trials, heart rate reduction during treatment with β-blockers was associated with increased risk for death and CV events in patients with hypertension. In contrast, in a large ( n = 10,000) patient outcome trial, a post hoc analysis of heart rate at baseline demonstrated that those with a resting heart rate above 80 beats per minute even with a BP below 140/90 mm Hg had a higher mortality rate. Therefore while apparent that SNS activation is deleterious to patients with CV disease, and presumably with hypertension, a cause for the overactivity should be sought and an attempt made to inhibit that mechanism.

Although the role of the SNS has been known for decades, targeted treatment of this mechanism has not been a common treatment for essential hypertension. β-adrenergic receptor blockers can target β1ARs and inhibit renin release by the SNS. α-1 adrenergic receptor blockers (e.g., doxazosin, terazosin, and prazosin) are second-line antihypertensive agents utilized in states of refractory hypertension, concomitant benign prostatic hypertrophy in men, and α-2 adrenergic receptor agonists (e.g., clonidine, guanfacine, and α methyl dopa) may be useful in labile hypertension or individuals with baroreceptor dysfunction. However, procedures that ablate afferent and/or efferent renal nerves (i.e., renal denervation) may reduce medication burden and have shown modest success in lowering BP in randomized, blinded, sham-controlled clinical trials with a wide, interindividual range of efficacy. These approaches are now approved for treatment of uncontrolled hypertension in the United States. Whether these nonpharmacologic, irreversible approaches become a more common form of treatment around the world is yet unknown.

Approximately 60% to 70% of essential hypertension can be attributed to obesity. Moreover, in large-scale epidemiologic studies such as the INTERSALT study, body mass index, a proxy for obesity, is directly associated with the degree of hypertension. Moreover, in longitudinal observational analyses, each 10 kg of weight loss is associated with a–3.0/–2.2 mm Hg reduction in BP. Obesity-related hypertension is characterized primarily by impaired sodium excretion and endothelial dysfunction, both of which are dependent on SNS overactivity, activation of the RAAS, and increased oxidative stress. ^, Fat tissue in obesity is hypertrophied and marked by increased macrophage infiltration. As it is now well described, adipose tissue is not inert and secretes a wide range of cytokines and chemokines whose profile is abnormal in obesity, marked by increased levels of leptin, resistin, interleukin-6, and tumor necrosis factor-α secretion, elevated free fatty acid release, and reduced serum adiponectin concentrations. Decreased serum adiponectin concentrations contribute to insulin resistance, decreased induction of eNOS, and possibly increased sympathetic activity.

Resistin, an adipokine that promotes insulin resistance, impairs nitric oxide (NO) synthesis (eNOS inhibition), and enhances endothelin-1 (ET-1) production, shifts the vasodilation/vasoconstriction balance toward vasoconstriction. Hyperleptinemia directly stimulates the SNS through complex mechanisms that involve central leptin receptors, as well as activation of the pro-opiomelanocortin system (via the melanocortin 4 receptor).

Lastly, visceral adipocyte mass is directly correlated with aldosterone secretion by the zona glomerulosa, a process mediated by angiotensinogen production by adipocytes, as well as increased secretion of Wnt signaling molecules that modulate steroidogenesis. In addition (despite a lack of clarity regarding mechanism[s]), obese individuals tend to have lower natriuretic peptides than lean individuals, and this relative deficiency is amplified in patients with obesity and hypertension. All of these factors compound the tendency toward sodium retention and shifting the pressure-natriuresis curve to the right in obese individuals. Activation of these same systems leads to a proinflammatory state related to increased reactive oxygen species, factors directly associated with endothelial dysfunction and vascular proliferation. Obesity is also associated with higher rates of obstructive sleep apnea, which can contribute to elevated BP. Therefore multiple mechanisms contribute to the development and maintenance of hypertension in obese individuals.

Natriuretic peptides (atrial [ANP], brain [BNP], and urodilatin) also contribute to hypertension, as well as to salt sensitivity and heart failure. These peptides have important natriuretic and vasodilatory properties that allow maintenance of sodium balance and BP during sodium loading. Upon administration of a sodium load, atrial and ventricular stretch lead to release of atrial natriuretic peptide (ANP) and BNP, respectively, which result in immediate BP lowering due to systemic vasodilation and decreased plasma volume, the latter caused by fluid shifts from the intravascular to the interstitial compartment.

All natriuretic peptides increase GFR, which in volume-expanded states is mediated by an increase in efferent arteriolar tone. They also inhibit renal sodium reabsorption through both direct and indirect effects. Direct effects include decreased activity of Na ⁺ -ATPase and ENaC in the distal nephron. The inhibitory effects of natriuretic peptides on renin and aldosterone release mediate indirect effects on BP as well. Unfortunately, understanding the contribution of natriuretic peptides to the development of hypertension in humans is complicated by the elevation of their levels in association with increased BP (due to increased afterload) and hypertensive heart disease.

Some studies have tested whether polymorphisms in ANP or BNP genes resulting in higher levels of these peptides would associate with lower BP; results of these studies have been inconsistent and show small effect sizes. There are no published studies evaluating sequential changes in natriuretic peptides and risk for incident hypertension.

There are several unanswered issues about the relation between natriuretic peptides and BP. For example, in a large GWAS of 2.5 million genotyped or imputed SNPs in 69,395 individuals of European ancestry briefly described earlier, the majority of SNPs were directly or indirectly related to abnormalities in natriuretic peptides.

Attention has been given to corin, the serine protease that is largely expressed in the heart and converts pro-ANP and pro-BNP to their active forms. Genetic variants and defects of the enzyme that activates corin have been found in persons with hypertension, heart failure, and preeclampsia. Corin interacts with natriuretic peptides, and hence impaired intracellular trafficking, cell surface expression, and zymogen activation of corin will result in fluid retention. ^, Experiments suggest that states of corin deficiency are associated with sodium overload, heart failure, and salt-sensitive hypertension, ^, and several clinical studies have observed an association between lower serum corin concentrations and increased risk of adverse cardiovascular outcomes in patients with coronary disease, heart failure, and stroke.

The endothelium is a major regulator of vascular tone and thus plays a key role in BP regulation. Endothelial cells produce a host of vasoactive substances, of which nitric oxide (NO) is the most relevant to BP regulation. Nitric oxide is continuously released by endothelial cells in response to flow-induced shear stress, leading to vascular smooth muscle relaxation through activation of guanylate cyclase and generation of intracellular cyclic guanosine monophosphate (cGMP). Interruption of the production of cGMP via inhibition of the constitutively expressed endothelial NO synthase (eNOS) causes BP elevation and development of hypertension in both animals and humans. Using brachial artery flow-mediated vasodilation and measurement of urinary excretion of NO metabolites as methods to evaluate NO activity in humans, several studies have demonstrated decreased whole-body production of NO in patients with hypertension compared with normotensive controls.

Several elements are responsible for endothelial dysfunction in hypertension. Normotensive offspring of patients with hypertension have impaired endothelium-dependent vasodilation despite normal endothelium-independent responses, thus suggesting a genetic component to the development of endothelial dysfunction. Besides direct pressure-induced injury in the setting of chronically elevated BP, a mechanism of major importance is increased oxidative stress. Reactive oxygen species are generated from enhanced activity of several enzyme systems; reduced nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase), xanthine oxidase, and cyclo-oxygenase in particular; and decreased activity of the detoxifying enzyme superoxide dismutase. ^, Excess availability of superoxide anions leads to their binding to NO, leading to decreased NO bioavailability, in addition to generating the oxidant, proinflammatory peroxynitrite. It is the decreased NO bioavailability that links oxidative stress to endothelial dysfunction and hypertension. Angiotensin II is a major enhancer of NADPH-oxidase activity and plays a central role in the generation of oxidative stress in hypertension, although several other factors are also involved including cyclic vascular stretch, ET-1, uric acid, systemic inflammation, norepinephrine, free fatty acids, and tobacco smoking.

ET-1 is the endothelial cell product that counteracts NO to maintain balance between vasodilation and vasoconstriction. ET-1 expression is increased by shear stress, catecholamines, angiotensin II, hypoxia, and several proinflammatory cytokines such as tumor necrosis factor-α, interleukins 1 and 2, and transforming growth factor-β. ET-1 is a potent vasoconstrictor through stimulation of ET-A receptors in vascular smooth muscle. In hypertension, increased ET-1 levels are not consistently observed. However, there is a trend of increased sensitivity to the vasoconstrictor effects of ET-1. ET-1 therefore is considered a relevant mediator of BP elevation, as ET-A and ET-B receptor antagonists attenuate or abolish hypertension in several experimental models of hypertension (angiotensin II–mediated models, deoxycorticosterone acetate–salt hypertension, and Dahl salt-sensitive rats) and are effective in lowering BP in humans. Endothelin receptor antagonists are utilized in the treatment of pulmonary hypertension and IgA nephropathy. Moreover, a dual endothelin receptor antagonist has shown efficacy to lower BP in patients with treatment-resistant hypertension. Therefore an alternative and more direct treatment of the endothelium may soon provide an additional pathway to target hypertension in patients.

Endothelial cells also secrete a variety of other vasoregulatory substances. These include the vasodilating prostaglandin prostacyclin and several vasodilating endothelium-derived hyperpolarizing factors, the identity of which remains uncertain. In addition to ET-1, there are also endothelium-derived contracting factors, such as locally generated angiotensin II and vasoconstricting prostanoids such as thromboxane A ₂ and prostaglandin A ₂ . The balance of these factors, along with NO and ET-1, determine the final impact of the endothelium on vascular tone.

Other non–endothelium-derived factors may be of relevance to the genesis of hypertension via endothelium dysfunction. Much attention is given to uric acid, which can induce endothelial dysfunction and produce salt-sensitive hypertension through mechanisms that involve renal microvascular injury. ^, These changes can be abrogated by therapies that lower serum urate in animals and may be of value in lowering BP and limiting kidney injury in humans with hyperuricemia. Current evidence from randomized trials, however, only supports a modest BP-lowering effect of allopurinol in hyperuricemic hypertensive adolescents, with no observable effect of allopurinol or probenecid on flow-mediated vasodilatation in obese nonhypertensive adults with mild hyperuricemia. These findings suggest an age-dependent effect or an effect of duration of the exposure to hyperuricemia, even if mild. Also of relevance is the possible role of high dietary fructose consumption in intracellular adenosine triphosphate depletion, increased oxidative stress, increased uric acid production, and endothelial dysfunction. ^,

Nitric oxide is not the only gasotransmitter relevant to vascular biology. Hydrogen sulfide (H ₂ S) is another compound that has received attention due to potential treatment relevance. H ₂ S is a vasodilating gas produced from sulfated amino acids by action of one of two key enzymes, cystathionine γ-lyase (CSE) and cystathionine β-synthase. CSE homozygous knockout mice have ∼80% decreased H ₂ S expression in heart and aorta and ∼60% reduction in serum and both homozygous and heterozygous animals demonstrate impaired endothelial function and develop age-dependent hypertension. The mechanisms underlying the BP effects of H ₂ S are multiple, including enhanced NO-mediated vasodilation, activation of potassium-ATP channels, activation of protein kinase G1α, inhibition of phosphodiesterase type 5, and inhibition of SNS activity. Modulation of serum H ₂ S concentrations with the administration of gaseous H ₂ S or H ₂ S donors (sodium hydrosulfide or sodium thiosulfate) results in lower BP and decreased cardiovascular and renal injury in several experimental models. If delivery systems permit and successful oral use of these agents are developed, it is possible that H ₂ S may become a therapeutic target in hypertension and vascular disease.

Taken together, the net result observed in patients with hypertension is one of endothelial dysfunction. In cross-sectional analyses, the lesser the degree of forearm flow-mediated vasodilation, the greater the prevalence of hypertension. ^, Prospective cohort studies have used flow-mediated vasodilation as a measure of endothelial dysfunction (regardless of specific mechanism) to evaluate its relation with hypertension and test whether endothelial dysfunction is cause or consequence of hypertension, or both. These studies have shown conflicting results, but the larger of them were unable to demonstrate an association between endothelial dysfunction and incident hypertension among 3500 patients followed for a median of 4.8 years.

Furthermore, endothelial dysfunction carries a genetic predisposition that is independent of BP and may be improved by agents that have little or no impact on BP (e.g., some antioxidants). Therefore as it currently stands, the evidence is stronger for endothelial dysfunction as a consequence, not a cause, of hypertension. ^,

Arterial stiffness is clearly associated with hypertension, particularly the syndromes of isolated systolic hypertension and hypertension with widened pulse pressure. Arterial stiffness develops as a result of structural changes in large arteries, particularly elastic arteries. These include loss of elastic fibers and substitution with less distensible collagen fibers. Factors strongly associated with arterial stiffening include aging, hypertension, diabetes mellitus, CKD, smoking, and high sodium intake.

The most commonly used measure to assess arterial stiffness in humans is carotid-femoral pulse wave velocity (cf-PWV). The traditional view linking arterial stiffness (measured as increased cf-PWV) to hypertension is that faster PWV produces faster reflection of the incident pulse wave, which results in an earlier reflected wave that returned to the central circulation before the end of systole, resulting in increased systolic BP. While these mechanisms still hold true, newer data have highlighted the relevance of two other factors: increased amplitude of the forward wave and increased characteristic impedance of the proximal aorta. When these specific factors are taken into account, the relative contribution of wave reflection to the observed age-dependent change in pulse pressure is only 4% to 11%.

Arterial stiffness was previously thought to be a consequence of hypertension. Cyclical pulsatile load is associated with fracture of elastin fibers and wall stiffening, and increased distending pressure demands recruitment of the less distensible collagen fibers, thus making vessels stiffer. Evidence from several studies, however, indicates that arterial stiffness may precede and predispose to hypertension. For example, in the Framingham Heart Study, markers of arterial stiffness (cf-PWV and amplitude of the forward pressure wave) were associated with a 30% to 60% increased risk for incident hypertension (per standard deviation of each variable) during 7 years of follow-up in a cohort with baseline mean age of 60 years. Conversely, baseline BP did not associate with future changes in arterial stiffness. Other studies corroborate these findings, but other studies also suggest a bidirectional relation such that arterial stiffness is also a consequence of chronic hypertension. Conversely, a cohort study of younger adults (baseline age 36 years) indicated that higher BP was associated with more severe large artery stiffness, not the opposite. These differences in results between younger and older adult populations may indicate that earlier in life, hypertension is mediated by factors that are largely independent of large vessel stiffness, whereas later in life, arterial stiffness is more likely to contribute to the development of hypertension.

Arterial stiffening is relevant to target-organ damage in hypertension. Increased PWV is associated with mortality and an increased risk of CV events, as well as with a variety of subclinical CV injury markers including coronary calcification, cerebral white matter lesions, ankle-brachial index, and albuminuria. The relation between PWV and cardiovascular complications is easily grasped: Increased impedance to left ventricular ejection results in LVH, diastolic dysfunction, and subendocardial myocardial ischemia.

The relations among PWV, brain complications, and kidney complications are more complex. It is apparent that the mechanism of damage of these organs, which are characterized by vasculature with high flow and low impedance, is mediated by increased transmission of increased pulsatile pressure to the brain and kidney parenchymata. The reason for this is related to the abnormal process of “impedance matching.” For individuals with normal vessels, the elastic arteries are much less stiff than muscular arteries, thus creating an impedance mismatch. This mismatch provokes wave reflection, thus protecting the tissue located distally to the reflection point from injury caused by traveling pulse wave. In states of increased arterial stiffness, the stiffening of elastic arteries approximates the stiffness of muscular arteries, thus eliminating the protective impedance mismatch. Once impedances become matched, there is less reflection and potential for more severe tissue injury, as supported by a growing body of clinical and experimental literature.

Immune responses, both innate and adaptive, participate in several of the mechanisms discussed earlier, including the generation of reactive oxygen species, mediation of the afferent arteriolopathy thought important to maintain salt sensitivity, activation by storage of skin sodium, and participation in the inflammatory changes noted in the kidneys, vessels, and brain in hypertension. Innate responses, especially those mediated by macrophages, have been linked to hypertension induced by angiotensin II, aldosterone, and NO antagonism.

Macrophages play opposing but important roles in the regulation of BP. As noted in the section on “Nonosmotic Sodium Storage” earlier, macrophages in the skin interstitial sodium levels, and depletion of macrophages and consequent TonEBP/VEGFC signaling, causes hypertension. ^, Conversely, macrophages in the kidney and vasculature contribute to hypertension. Reductions in macrophage infiltration of the kidney or the periadventitial space of the aorta and medium-sized vessels lead to improvements in BP and salt sensitivity in several experimental models. ^,

Adaptive responses via T cells have been linked to the genesis and complications of hypertension. T cells express AT ₁ R and mediate angiotensin II-dependent hypertension, as demonstrated by the observations that adoptive transfer of T cells restored the hypertensive phenotype in response to angiotensin II infusion that was absent in mice without lymphocytes. Abnormalities in both proinflammatory T cells and regulatory T cells alike are implicated in complications of hypertension, as they appear to regulate vascular and renal inflammation that underlies target-organ injury. Suppression of these inflammatory responses can improve BP control. ^{, , ,} T helper 17 cells that produce interleukin-17 are critical for sustained angiotensin II-dependent hypertension in mice. Serum interleukin-17 concentrations are higher in patients with hypertension, and interleukin 17 has been shown to independently cause hypertension and kidney disease. The pleiotropic actions of interleukin-17 are reviewed elsewhere in the text but include a number of mechanisms addressed here including increased renal sodium retention, endothelial dysfunction, and arterial stiffness.

How are these T cells activated? High sodium, whether by high dietary sodium or more specifically, by increased interstitial sodium, is known to activate/polarize immune cells including T helper 17 cells to a proinflammatory and high-producing interleukin-17 state. ^, Dendritic cells are sensors for high dietary sodium by activation of serum-and-glucocorticoid kinase 1 (SGK1) that, in turn, stimulates ENaC expression on the surface of dendritic cells to promote sodium entry and isoketal (isolevuglandin) formation and isoketal adducts on intracellular proteins in mice. These adducts promote activation of T cells and cytokines including the aforementioned interleukin-17. These dendritic cells are also activated by hypertension, establishing a positive feedback loop. Isoketal production and proinflammatory cytokines are also elevated in patients with hypertension versus controls.

B lymphocytes may also play a causative role in hypertension, as suggested by reports of several autoantibodies including agonistic antibodies against adrenergic receptors, vascular calcium channels, and AT ₁ R, and antibodies against endothelial cells causing endothelial dysfunction, or heat shock proteins (hsp70) causing salt-sensitive hypertension. Further research will determine if manipulation of immune targets is of value in the prevention and treatment of human hypertension.

Several vasodilating substances act as compensatory vasodilators to balance the heavily provasoconstrictive milieu in hypertension. Some of these vasodilators act primarily through an increase in NO release from endothelial cells, such as calcitonin gene–related peptide, adrenomedullin, and substance P. The glucose-regulating, gut hormone glucagon-like peptide-1 (GLP-1) has vasodilating properties, and its administration to Dahl salt-sensitive rats improves endothelial function, induces natriuresis, and lowers BP. Additionally, a meta-analysis of GLP-1 receptor agonists to treat obesity in humans demonstrated a modest but significant BP reduction (–3.4/–1.1 mm Hg) compared with placebo.

The gut microbiome may be related to several humoral and hemodynamic aspects of hypertension, including neuroimmunologic aspects of BP regulation including regulation of the RAAS and activation of the SNS. Bacteria that produce short-chain fatty acids (SCFAs) (especially acetate, propionate, and butyrate) are seen as favorable to produce an environment of lower BP. A proof-of-concept study demonstrated that an unfavorable gut microbiome profile (i.e., one that leads to less available SCFAs) is seen in spontaneously hypertensive rats as compared with normotensive Wistar Kyoto rates and is observed in animals exposed to angiotensin II infusions. In addition, analyses of stool samples of 10 normotensive and 7 hypertensive patients showed a similar pattern. Germ-free mice compared with controls with a presumably conventional microbiome exhibit lower BP in response to angiotensin II and lower vascular fibrosis. Although the role of microbiome dysbiosis in hypertension has been shown in multiple species, the precise molecular mechanisms are not clear. There are multiple SCFAs; each can act through multiple G-protein coupled olfactory receptors; each of these receptors has multiple SCFA ligands; and these receptors are expressed in multiple tissues including endothelial cells, immune cells, and juxtaglomerular cells. ^, There may also be regulatory networks in the microbiome and the host that alter the levels of each of these components. For example, in a study of 70 patients, the intestinal production of SCFAs and the expression level of cognate G-protein coupled receptors on immune cells differed between normotensive patients and those with hypertension, raising the possibility that shifts in microbial gene pathways may alter responses to BP-regulatory metabolites.

High dietary sodium can also alter the bacterial components of the microbiome (dysbiosis) in mice. Moreover, fecal transplant of microbiome from high sodium-fed mice induces isoketal protein adducts, proinflammatory T cells, interleukin-17, and elevated BP. The mechanism of how dietary sodium altered the microbiome in this study is unknown.

The use of probiotics, typically as yogurt or other dairy products, is the most commonly used approach to alter the gut microbiome. A meta-analysis of nine randomized clinical trials investigating the use of probiotics to lower BP showed an average BP reduction of 3.6/2.4 mm Hg. Only one study included hypertensive patients (average BP reduction 9.7/4.4 mm Hg), but an analysis of BP lowering according to baseline BP above or below 130/85 mm Hg showed no differences in systolic BP and a small difference in diastolic BP reduction (2.7 vs. 0.9 mm Hg).

These early results indicate that modification of the gut microbiome may alter hemodynamics and that the use of probiotics, presumably through such microbiome changes, may have salutary effects on BP, though the magnitude and clinical relevance of this effect remain to be determined. Further research to target specific ligands and/or receptors may be useful to better understand the role of the microbiome in hypertension.

The medical history and physical examination are essential to uncovering possible secondary causes of hypertension, identifying signs and symptoms suggestive of hypertensive target-organ damage, and diagnosing comorbid conditions that may affect treatment decisions. While the focus is traditionally on the CV, central nervous system, and kidneys, a complete review of systems is indicated when the patient is first evaluated, as some patients will present with hypertension because of sleep apnea (snoring, witnessed apneas/gasping), hyperthyroidism or hypothyroidism (each with their litany of possible symptoms), hyperparathyroidism (symptoms of hypercalcemia), Cushing syndrome (symptoms of cortisol excess), pheochromocytoma or paraganglioma (symptoms of catecholamine excess), or acromegaly with its distinctive physical findings. These conditions are discussed in detail later in this chapter.

High BP is typically asymptomatic, but some symptoms are common among patients with very high BP levels, such as headaches, epistaxis, dyspnea, chest pain, and faintness, all of which were present in more than 10% of patients presenting with diastolic BP levels above 120 mm Hg. Other common symptoms are nocturia and unsteady gait, whereas treated patients often complain of fatigue in addition to symptoms of overtreatment and those related to specific side effects of medications.

When searching for target-organ damage, one looks for signs and symptoms to suggest a previous stroke or transient ischemic attack, previous or ongoing coronary ischemia, heart failure, peripheral arterial disease, or a history of kidney disease or current symptoms such as hematuria or flank pain.

Obtaining a detailed family history as it pertains to hypertension is important. Focus should be on the development of hypertension at a young age or clustering of endocrine (pheochromocytoma, multiple endocrine neoplasia, primary aldosteronism) or kidney problems (autosomal dominant polycystic kidney disease or other inherited forms of kidney disease). The young patient with hypertension and a family history of hypertension poses a particular challenge and should be evaluated in detail. Table 46.3 provides a guide to possible causes to be entertained.

Knowledge of several conditions with potential relevance to treatment is important. For example, issues related to CV risk management such as diabetes mellitus, hypercholesterolemia, and tobacco use need to be evaluated. Patients with established CV disease will need some treatments for both their hypertension and their underlying disorder (e.g., β-blockers for angina pectoris), so knowledge of specific CV diagnoses is essential. Lastly, some non-CV conditions may have an impact on treatment options. For example, patients with reactive airway disease (asthma) probably should not receive β-blockers, patients with prostatic hyperplasia may benefit from a regimen that includes an α-blocker, and patients with attention-deficit/hyperactivity disorder or anxiety may benefit from a central sympatholytic (e.g., guanfacine), whereas those with major depression should probably not be treated with this drug class.

It is also important to recognize that it is during the history that the clinician has the opportunity to explore issues related to lifestyle, cultural beliefs, and patient preferences that will be essential in designing an effective treatment plan. It is important to define dietary and physical activity patterns and, when problems are identified, to determine if the patient is willing and/or able to modify them. Cultural beliefs related to the treatment of hypertension, health literacy, and mistrust in physicians and the pharmaceutical industry are several of the items that can affect the relationship with the patient and that should be openly raised. It is only then that patients will be able to participate in shared decision making about their treatment, an essential tenet of patient-centered care.

The physical examination is designed to complement items discussed in the history. One should pay attention to syndromic features of cortisol excess (moon face, central obesity, frontal balding, cervical and supraclavicular fat deposits, skin thinning, abdominal striae), hyperthyroidism (tachycardia, anxiety, lid lag/proptosis, hypertelorism, pretibial myxedema), hypothyroidism (bradycardia, coarse facial features, macroglossia, myxedema, hyporeflexia), acromegaly (frontal bossing, widened nose, enlarged jaw, dental separation, acral enlargement), neurofibromatosis (neurofibromas, café au lait spots, as neurofibromatosis is associated with pheochromocytoma and renal artery stenosis), or tuberous sclerosis (hypopigmented ash leaf patches, facial angiofibromas, as tuberous sclerosis is associated with renal hypertension, usually related to angiomyolipomas). Other even rarer associations exist but fall beyond the scope of this chapter.

In younger patients or in patients with unexplained, difficult-to-treat hypertension, it is worth exploring the possibility of coarctation of the aorta by measurement of BP in both arms and in one thigh. If present, there will be a significantly lower BP in the thigh (typically by >30 mm Hg). Sometimes, in case of a lesion proximal to the left subclavian, there may be a significant interarm difference, lower on the left. In addition, there is significant decrease in intensity of the femoral pulses and a palpable radial-femoral pulse delay.

Funduscopic examination is valuable in many patients, particularly those with severe hypertension (BP ≥180/110 mm Hg). The retinal changes are associated with severity of both acute and chronic BP elevation. Acute changes can happen quite abruptly (hours to days) and range from arteriolar spasm in most patients with uncontrolled BP to retinal infarcts (exudates) and microvascular rupture (flame hemorrhages), to papilledema once the protection afforded by vasoconstriction is overcome. Chronic changes take much longer to develop and include vascular tortuosity (arteriovenous nicking) due to perivascular fibrosis, followed by progressive arteriolar wall thickening that prevents visualization of the blood column, thus leading to the appearance of copper wiring, then silver wiring. Several studies have demonstrated a relationship between severity of hypertensive retinopathy and risk for LVH and stroke. Smartphone-based technology allows the use of a condensing lens coupled with the smartphone’s own camera for video and photography of the retina (undilated pupil) in place of a conventional ophthalmoscope. ^, These devices can be used even by inexperienced operators, and the images can be shared for more precise diagnosis.

The CV examination focuses on the identification of volume overload (jugular venous distension, lung crackles, peripheral edema), cardiac enlargement (deviated cardiac impulse), and the presence of a third or fourth heart sound as markers of impaired left ventricular compliance. We routinely look for bruits over the carotid arteries, as the prevalence of carotid atherosclerosis is increased in patients with hypertension, as well as in the abdomen, primarily looking for renal arterial bruits heard over the epigastrium and/or flanks. These bruits are of greater significance if occurring on both systole and diastole. Finally, detailed palpation of the peripheral pulses of the arms and legs is important to look for signs of peripheral arterial disease.

To wrap up the examination, a focused neurologic examination looks for obvious cranial nerve abnormalities, motor deficits, or speech or gait abnormalities. Any further testing is based on specific symptoms or on focal findings on the screening examination.

Because treatment decisions are based largely on BP levels, accurate BP measurement is essential. Cuff-based brachial BP is the most used method to measure BP, typically in the office setting. However, the use of 24-hour ABPM and home BP monitoring has become part of routine hypertension care in many parts of the world, as we discuss later. Finally, there has been extensive interest in the development of cuffless BP measurement devices using technologies based on pulse-wave analysis through photoplethysmography, tonometry, or bioimpedance. These are exciting technologies that will ultimately allow nonintrusive continuous or semicontinuous BP measurement and monitoring. We welcome these developments, but there are still validation issues that need to be addressed by manufacturers and regulatory agencies before these devices become widely used.

Office Blood Pressure Measurement

Office BP measurement is the time-honored method for the diagnosis and management of hypertension. It is strongly associated with hypertension-related outcomes based on more than 50 years of observational and clinical trial data. Accordingly, guidance provided to clinicians for the diagnosis and treatment of hypertension by most major guidelines is based on office BP values.

Attention to BP measurement technique is essential. Fig. 46.6 displays the key elements necessary for optimal BP measurement including attention to equipment and environment, patient preparation, and positioning. Averaging of several measurements is important to minimize variability, avoid over/undertreatment, and best predict clinical outcomes.

Steps for optimal blood pressure measurement.

From Cheung AK, Whelton PK, Muntner P, et al. International Consensus on Standardized Clinic Blood Pressure Measurement—A Call to Action. Am J Med. 2023;136:438–445 e1.

Many oscillometric automated BP devices allow automatic performance of three to five unwitnessed BP measurements. Such features (unwitnessed measurements) had been considered a better proxy for overall BP burden than conventional office BP, but current evidence does not support a difference between witnessed and unwitnessed measurements as long as both are performed in a similarly rigorous manner.

Most patients should have their BP measured in the arm in the seated position. In selected situations, such as malformations, injuries, or extensive vascular disease of the upper extremities, or when comparing BP levels in the upper and lower extremities, it may be necessary to use thigh measurements with an appropriately sized thigh cuff, which should be obtained in the prone position to allow the cuff to be at the level of the heart. Mercury sphygmomanometers are now seldom available in clinical practice because of environmental concerns. Aneroid and electronic oscillometric manometers are accurate but should have periodic maintenance (every 12 months) to ensure that they are properly calibrated, as well as any time poor function is suspected. It is important that accurate BP devices be used for BP measurement. STRIDE BP (

Home

) is an international nonprofit organization founded by hypertension experts with the mission of improving the accuracy of BP measurement. STRIDE BP provides guidance and tools for accurate BP measurement, including an up-to-date list of validated BP monitors for use in the office and ambulatory settings.

All current hypertension guidelines recognize the value of out-of-office BP in the diagnosis of hypertension, particularly in patients with office BP <160/100 mm Hg. The ACC/AHA guidelines also recommend the use of out-of-office BP to evaluate patients who are receiving treatment for hypertension but remain above goal in the office, with the explicit caveat that the recommendation is based on expert opinion. A finding to support this recommendation is the high prevalence (∼40%–51%) of a white coat effect in patients with resistant hypertension, and the use of ABPM is formally recommended by both the U.S. and European guidelines to diagnose true-resistant hypertension. ^, Another caveat is that patients with office BP above 160/100 mm Hg do not need confirmation and should all be treated.

A practical approach to the use of home and ABPM in clinical practice is provided in Fig. 46.7 .

Practical approach to the integration of home and 24-hour ambulatory blood pressure monitoring for the evaluation and management of hypertension.

Similar to the history and physical examination, laboratory tests, imaging, and other complementary tests also focus on the evaluation of comorbid conditions, established target-organ damage, and possible secondary causes. In the absence of worrisome signs or symptoms during the initial evaluation, the clinician should obtain a basic set of tests, including renal function; levels of electrolytes, calcium, glucose, and hemoglobin; lipid profile; urinalysis; and electrocardiogram ( Table 46.6 ).

Further testing may be required in case any of these initial test results are abnormal or in case there are specific symptoms or physical findings suggesting a diagnosis (see “Secondary Hypertension” section). Likewise, patients who are resistant to treatment during follow-up have higher rates of secondary causes of hypertension, in particular sleep apnea, primary aldosteronism, and renovascular disease, thus deserving a more dedicated search for secondary causes in their evaluation.

Secondary hypertension is elevated BP due to a specific cause. In general clinical practice, there is a higher probability of secondary hypertension in patients 1. with higher levels of untreated BP, especially if control was recently lost; 2. with characteristic physical signs (for details, see later; 3. with treatment-resistant hypertension; 4. seen in tertiary referral centers (largely due to “referral bias”); and 5. “younger” patients (e.g., younger than 30 years old), though this has been a subject of controversy since the American Academy of Pediatrics limited its recommendations for work of children with hypertension only to those younger than the age of 6 years unless there is clinical evidence of a secondary cause. A systematic review of the prevalence of secondary causes of hypertension in children and adolescents showed point estimates of 9% in studies in primary care and 44% in studies from specialty clinics. Among factors associated with higher prevalence of secondary causes, the most prominent were a family history of secondary hypertension, low birth weight, history of premature birth, younger age (younger than 6 years), albuminuria, normal serum urate, high ambulatory BP load, and nocturnal hypertension.

The prevalence of secondary hypertension in hypertensive adults varies widely. In a large prospective study reported from a primary care setting that evaluated 1020 consecutive patients with hypertension in Japan, 9.1% of patients had a secondary cause, which was primary aldosteronism in 6%, Cushing syndrome (full-blown in 1% and preclinical in 1%), pheochromocytoma (0.6%), and renovascular hypertension (0.5%).

The largest series of consecutive patients evaluated by a whole-day protocol from 1976 to 1994 in a tertiary referral center came from Syracuse, New York. In this study, 10.1% of 4429 patients with hypertension had secondary hypertension: 3.1% with renovascular hypertension, 1.4% with primary aldosteronism, 0.5% with Cushing syndrome, 0.3% with pheochromocytoma, 3% with primary hypothyroidism, and 1.8% with hypertension attributed to CKD. Later series from all over the globe have suggested that primary aldosteronism (especially due to sleep-disordered breathing and obstructive sleep apnea) is far more common than previously thought, with an average prevalence of approximately 10% in population-based studies; the prevalence is roughly twice that in patients with resistant hypertension.

Pheochromocytoma

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine chromaffin tumors (estimated incidence: 2–8 cases per million per year) that are derived from the adrenal medulla and extraadrenal sympathetic or parasympathetic ganglia, respectively. Diagnosis and management of these tumors is critical because: 1. they can cause fatal hypertensive crises and associated complications, 2. 15% to 25% of PCC/PGL can become metastatic, 3. specific therapy can be curative if diagnosed early, and 4. approximately 40% of these tumors are due to inherited germline mutations.

Catecholamine-secreting tumors are found in 0.2% to 0.6% of patients with hypertension, may be more common in hypertensive children (1.7%), and are often found incidentally, or only at autopsy. The clinical presentation of patients with these tumors is quite variable, as symptoms may occur constantly, in paroxysms or, less often, patients can be totally asymptomatic.

Patients classically present with a triad of symptoms including headache, palpitations, and sweating with hypertension, which may be persistently elevated, labile, or normal. The presentation is highly variable, so a high index of suspicion is required, even when faced with common presenting conditions (e.g., heart failure or aortic dissection, which can be precipitated, if not exacerbated, by a functioning tumor). Some of the inherited germline mutations associated with PPGLs have characteristic physical signs (e.g., café au lait spots and neurofibromas in von Hippel Landau [vHL]); hyperparathyroidism, multiple mucosal neuromas, intestinal ganglioneuromas, and often a marfanoid habitus with multiple endocrine neoplasia (MEN)-associated tumors.

Tumors in the adrenal gland are termed “pheochromocytomas,” all other extraadrenal tumors are termed paragangliomas (PGL), and tumors occurring in the head and neck region are termed head and neck paragangliomas (HNPGLs). Adrenal and extraadrenal tumors are usually derived from sympathetic ganglia, which hypersecrete catecholamines, whereas HNPGLs are usually derived from parasympathetic ganglia and are often nonsecretory. Ninety percent of tumors are found in or in close proximity to an adrenal gland. Paragangliomas can occur anywhere along the sympathetic ganglia but most commonly in or near the organ of Zuckerkandl (at the aortic bifurcation) or near the bladder (which gives rise to the triad of symptoms that occur related to micturition).

PPGLs are the most commonly associated tumors with a germline mutation in a known susceptibility gene more than any other solid tumor type and due to the high prevalence of associated germline mutations, all patients with proven PPGL should undergo genetic testing. There are more than 12 pathogenic germline mutations now associated with PPGL that can be clinically tested. MEN syndromes are autosomal dominant and are caused by activating mutations in the RET protooncogene. Approximately 50% of MEN2 patients will develop pheochromocytoma, which can be bilateral in about half of cases and can present synchronously or metachronously. MEN2A accounts for 95% of cases and has a high penetrance for medullary thyroid carcinoma (MTC) or C-cell hyperplasia (nearly 100%), pheochromocytoma (50%), and multiglandular parathyroid hyperplasia or adenoma (20%–30%), leading to primary hyperparathyroidism, whereas MEN2B and the rare familial medullary thyroid cancer subtype account for the rest. MEN2B typically does not develop primary hyperparathyroidism. The mean age at diagnosis of pheochromocytoma is between 30 and 40 years old, and the malignancy rate is <5%. Most MEN-associated pheochromocytomas are metanephrine predominant.

vHL is an autosomal dominant hereditary cancer syndrome, with a 95% penetrance by age 60, characterized by the development of a variety of tumors such as hemangioblastomas of the CNS including the retina, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors, pheochromocytomas (60% will have bilateral tumors), endolymphatic sac tumors, and visceral cysts (including renal and pancreatic). Patients with VHL type 1 (typically those with truncating mutations) have a lower risk of developing pheochromocytomas and lower risk of developing RCC. Patients with VHL type 2 disease (typically those with missense mutations) have a higher risk of developing pheochromocytomas. The overall frequency of PPGL is 20% overall but increases to 60% in patients with VHL type 2. The risk of metastatic disease is about 5%, and most tumors are pheochromocytomas with PGLs occurring rarely. Most VHL-associated PPGL are normetanephrine predominant, due to a lack of expression of phenylethanolamine-N-methyltransferase, the enzyme that converts norepinephrine to epinephrine.

NF1 is an autosomal dominant tumor-predisposition syndrome characterized by café au lait spots, neurofibromas, axillary or inguinal freckling, and optic gliomas; Lisch nodules (benign iris hamartomas); and bone lesions. About 10% to 15% of patients with NF1 will develop pheochromocytomas, which can be bilateral, and the risk of metastatic disease is around 12%. NF1-associated PCCs tend to have metanephrine predominance.

Hereditary paraganglioma-pheochromocytoma syndromes are caused by autosomal dominant mutations in succinate dehydrogenase (SDH), complex II of the mitochondrial respiratory chain. Mutations can occur in any of the subunit genes (SDHA, SDHB, SDHC, SDHD) or cofactor (SDHAF2). SDHB is the most commonly mutated subunit leading to PPGL. Mutation carriers develop extraadrenal PGL but can also develop pheochromocytomas and HNPGL. SDHB mutation carriers have the highest risk of developing metastatic disease and can also develop renal cell carcinomata. SDHD is also commonly mutated and is associated with multiple primary tumors often in the head and neck area but can also develop pheochromocytomas and rarely metastatic disease. SDH mutations in the other subunits occur less often, and the risk of malignancy is lower. Given the higher risk for metastatic disease in patients with SDHB mutations and reported cases of early-onset of disease during childhood, it is proposed to start screening patients with known mutations at age 6–10 for asymptomatic SDHB mutation carriers and at age 10–15 for carriers of mutations in SDHA, SDHC, and SDHD genes. Biochemical testing should be performed at least every 2 years during childhood (i.e., age <18) and every year during adulthood, and full-body magnetic resonance imaging (MRI) from the skull base to pelvis should be performed every 2 to 3 years from the time the variant is known. Some suggest that a 68Ga-DOTATE positron emission tomography/computed tomography (CT) scan can be used instead of MRI, if available.

If PPGL is suspected, biochemical testing for plasma-free metanephrines and/or urinary-fractionated metanephrines and catecholamines should be performed. Plasma-free metanephrines have at least equal sensitivity and specificity (98% and 92%, respectively) as 24-hour urine collections and are more convenient for patients. Abnormal results are at least two to four times above the upper limit of normal. Indeterminate results may be due to interfering factors and include medications (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and α-adrenergic blockers), drugs (e.g., cocaine, marijuana, stimulants, and caffeine), or position (i.e., sitting up rather than lying down for the plasma tests).

To improve cost-effectiveness and reduce radiation exposure, imaging studies for pheochromocytoma and related tumors are generally not ordered until after biochemical evidence of catecholamine overproduction is obtained. Cross-sectional imaging to localize the tumor using CT scan or MRI starting with the abdomen/pelvis is recommended as 80% to 85% of PPGL will be in this region. If metastatic disease is suspected, functional imaging with DOTATATE positron emission tomography/CT or MIBG scans can be useful.

When planning for surgical resection, patients should absolutely undergo α-1 blockade before resection. Surgical resection is the treatment of choice for PCC/PGL, but the hypersecretion of catecholamines can be life threatening perioperatively; the use of α-blockade and modern anesthesia have reduced surgical morbidity and mortality. α-1 adrenergic blockers are the mainstay of perioperative management in patients with PCC/PGL. Competitive and noncompetitive α-blockers are used in perioperative management. Phenoxybenzamine is a noncompetitive inhibitor that covalently binds to α-1 and α-2 receptors irreversibly. Therefore the extra release of catecholamines intraoperatively with manipulation of the tumor mass cannot overcome the inhibition of phenoxybenzamine as de novo synthesis of α receptors is required. This helps to prevent intraoperative hypertensive crisis; however, this irreversible binding can lead to hypotension after the tumor is resected, thereby removing the source of catecholamine production. Vasopressor support and intravenous fluids may be required for 24 to 48 hours postoperatively to maintain BP. Side effects of phenoxybenzamine include orthostasis and nasal congestion. Other α-blockers used include the selective α-1 receptor blockers doxazosin, terazosin, and prazosin. These are competitive inhibitors with relatively shorter durations of action and therefore can be overcome by the extra catecholamine release intraoperatively which can lead to hypertensive crisis. However, the shorter half-life makes these inhibitors less likely to result in hypotension after tumor removal.

Other antihypertensive medications are used occasionally in the perioperative blockade. CCBs, such as nicardipine or amlodipine, work by inhibiting norepinephrine-mediated transmembrane calcium influx into smooth muscle. Β-blockers should never be used alone in patients with PPGL as the unopposed α-adrenergic effect can cause severe vasoconstriction leading to hypertensive crisis. Β-blockers, such as selective β-1 antagonists like metoprolol, do have a role in perioperative blockade after full α-blocking has been achieved as a known side effect of a full α-blockade is reflex tachycardia. At this point, β-blockers can be added to reduce the tachycardia.

Most surgeons favor laparoscopic procedures for small adrenal pheochromocytomas or paragangliomas in accessible locations. Biochemistries should be checked 6 weeks after surgery to ensure levels have returned to normal and should be checked annually in all patients due to the risk of recurrence. All patients should be referred for genetic testing. If biochemistries remain elevated and metastatic disease is suspected, patients should be referred to centers of excellence with experience for further evaluation.

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