Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium ...channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the “white-coat effect” (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.
Race is a social construct, but self-identified Black people are known to have higher prevalence and worse outcomes of hypertension than White people. This may be partly due to the disproportionate ...incidence of salt sensitivity of blood pressure in Black people, a cardiovascular risk factor that is independent of blood pressure and has no proven therapy. We review the multiple physiological systems involved in regulation of blood pressure, discuss what, if anything is known about the differences between Black and White people in these systems and how they affect salt sensitivity of blood pressure. The contributions of genetics, epigenetics, environment, and social determinants of health are briefly touched on, with the hope of stimulating further work in the field.
Salt sensitivity of blood pressure is an independent risk factor for cardiovascular mortality not only in hypertensive but also in normotensive adults. The diagnosis of salt sensitivity of blood ...pressure is not feasible in the clinic due to lack of a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to understand the mechanisms of salt sensitivity of blood pressure have focused on renal regulation of sodium. However, salt retention or plasma volume expansion is not different between salt-sensitive and salt-resistant individuals. In addition, over 70% of extracellular fluid is interstitial and, therefore, not directly controlled by renal salt and water excretion. We discuss in this review how the seminal work by Harry Goldblatt paved the way for our attempts at understanding the mechanisms that underlie immune activation by salt in hypertension. We describe our findings that sodium, entering antigen-presenting cells via an epithelial sodium channel, triggers a PKC (protein kinase C)- and SGK1 (serum/glucocorticoid kinase 1)-stimulated activation of nicotinamide adenine dinucleotide phosphate oxidase, which, in turn, enhances lipid oxidation with generation of highly reactive isolevuglandins. Isolevuglandins adduct to proteins, with the potential to generate degraded peptide neoantigens. Activated antigen-presenting cells increase production of the TH17 polarizing cytokines, IL (interleukin)-6, IL-1β, and IL-23, which leads to differentiation and proliferation of IL-17A producing T cells. Our laboratory and others have shown that this cytokine contributes to hypertension. We also discuss where this sodium activation of antigen-presenting cells may occur in vivo and describe the multiple experiments, with pharmacological antagonists and knockout mice that we used to unravel this sequence of events in rodents. Finally, we describe experiments in mononuclear cells obtained from normotensive or hypertensive volunteers, which confirm that analogous processes of salt-induced immunity take place in humans.
Abstract
Aims
Monocytes play an important role in hypertension. Circulating monocytes in humans exist as classical, intermediate, and non-classical forms. Monocyte differentiation can be influenced ...by the endothelium, which in turn is activated in hypertension by mechanical stretch. We sought to examine the role of increased endothelial stretch and hypertension on monocyte phenotype and function.
Methods and results
Human monocytes were cultured with confluent human aortic endothelial cells undergoing either 5% or 10% cyclical stretch. We also characterized circulating monocytes in normotensive and hypertensive humans. In addition, we quantified accumulation of activated monocytes and monocyte-derived cells in aortas and kidneys of mice with Angiotensin II-induced hypertension. Increased endothelial stretch enhanced monocyte conversion to CD14++CD16+ intermediate monocytes and monocytes bearing the CD209 marker and markedly stimulated monocyte mRNA expression of interleukin (IL)-6, IL-1β, IL-23, chemokine (C-C motif) ligand 4, and tumour necrosis factor α. STAT3 in monocytes was activated by increased endothelial stretch. Inhibition of STAT3, neutralization of IL-6 and scavenging of hydrogen peroxide prevented formation of intermediate monocytes in response to increased endothelial stretch. We also found evidence that nitric oxide (NO) inhibits formation of intermediate monocytes and STAT3 activation. In vivo studies demonstrated that humans with hypertension have increased intermediate and non-classical monocytes and that intermediate monocytes demonstrate evidence of STAT3 activation. Mice with experimental hypertension exhibit increased aortic and renal infiltration of monocytes, dendritic cells, and macrophages with activated STAT3.
Conclusions
These findings provide insight into how monocytes are activated by the vascular endothelium during hypertension. This is likely in part due to a loss of NO signalling and increased release of IL-6 and hydrogen peroxide by the dysfunctional endothelium and a parallel increase in STAT activation in adjacent monocytes. Interventions to enhance bioavailable NO, reduce IL-6 or hydrogen peroxide production or to inhibit STAT3 may have anti-inflammatory roles in hypertension and related conditions.
Elevated cardiovascular risk including stroke, heart failure, and heart attack is present even after normalization of blood pressure in patients with hypertension. Underlying immune cell activation ...is a likely culprit. Although immune cells are important for protection against invading pathogens, their chronic overactivation may lead to tissue damage and high blood pressure. Triggers that may initiate immune activation include viral infections, autoimmunity, and lifestyle factors such as excess dietary salt. These conditions activate the immune system either directly or through their impact on the gut microbiome, which ultimately produces chronic inflammation and hypertension. T cells are central to the immune responses contributing to hypertension. They are activated in part by binding specific antigens that are presented in major histocompatibility complex molecules on professional antigen-presenting cells, and they generate repertoires of rearranged T-cell receptors. Activated T cells infiltrate tissues and produce cytokines including interleukin 17A, which promote renal and vascular dysfunction and end-organ damage leading to hypertension. In this comprehensive review, we highlight environmental, genetic, and microbial associated mechanisms contributing to both innate and adaptive immune cell activation leading to hypertension. Targeting the underlying chronic immune cell activation in hypertension has the potential to mitigate the excess cardiovascular risk associated with this common and deadly disease.
We investigated 24-hour hemodynamic changes produced by salt loading and depletion in 8 salt-sensitive (SS) and 13 salt-resistant (SR) normotensive volunteers. After salt loading, mean arterial ...pressure was higher in SS (96.5±2.8) than in SR (84.2±2.7 mm Hg), P<0.01, owing to higher total peripheral resistance in SS (1791±148) than in SR (1549±66 dyn*cm*s), P=0.05, whereas cardiac output was not different between groups (SS 4.5±0.3 versus SR 4.4±0.2 L/min, not significant). Following salt depletion, cardiac output was equally reduced in both groups. Total peripheral resistance increased 24±6% (P<0.001) in SR, whose mean arterial pressure remained unchanged. In contrast, total peripheral resistance did not change in SS (1±6%, not significant). Thus, their mean arterial pressure was reduced, abolishing the mean arterial pressure difference between groups. SS had higher E/e′ ratios than SR in both phases of the protocol. In these 21 subjects and in 32 hypertensive patients, Na balance was similar in SR and SS during salt loading or depletion. However, SR did not gain weight during salt retention (−158±250 g), whereas SS did (819±204), commensurate to iso-osmolar water retention. During salt depletion, SR lost the expected amount of weight for iso-osmolar Na excretion, whereas SS lost a greater amount that failed to fully correct the fluid retention from the previous day. We conclude that SS are unable to modulate total peripheral resistance in response to salt depletion, mirroring their inability to vasodilate in response to salt loading. We suggest that differences in water balance between SS and SR indicate differences in salt-and-water storage in the interstitial compartment that may relate to vascular dysfunction in SS.
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