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    Role of Dietary K in Natriuresis, Blood Pressure Reduction, Cardiovascular Protection, and Renoprotection. Gritter Martin,Rotmans Joris I,Hoorn Ewout J Hypertension (Dallas, Tex. : 1979) 10.1161/HYPERTENSIONAHA.118.11209
    Role of potassium in regulating blood flow and blood pressure. Haddy Francis J,Vanhoutte Paul M,Feletou Michel American journal of physiology. Regulatory, integrative and comparative physiology Unlike sodium, potassium is vasoactive; for example, when infused into the arterial supply of a vascular bed, blood flow increases. The vasodilation results from hyperpolarization of the vascular smooth muscle cell subsequent to potassium stimulation by the ion of the electrogenic Na+-K+ pump and/or activating the inwardly rectifying Kir channels. In the case of skeletal muscle and brain, the increased flow sustains the augmented metabolic needs of the tissues. Potassium ions are also released by the endothelial cells in response to neurohumoral mediators and physical forces (such as shear stress) and contribute to the endothelium-dependent relaxations, being a component of endothelium-derived hyperpolarization factor-mediated responses. Dietary supplementation of potassium can lower blood pressure in normal and some hypertensive patients. Again, in contrast to NaCl restriction, the response to potassium supplementation is slow to appear, taking approximately 4 wk. Such supplementation reduces the need for antihypertensive medication. "Salt-sensitive" hypertension responds particularly well, perhaps, in part, because supplementation with potassium increases the urinary excretion of sodium chloride. Potassium supplementation may even reduce organ system complications (e.g., stroke). 10.1152/ajpregu.00491.2005
    Hyperkalemia and blood pressure regulation. Mutig Kerim,Bachmann Sebastian Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Hypertension is common in the general population. Management of hypertensive patients at risk of hyperkalemia is challenging due to potential life-threatening complications such as cardiac arrest. Chronic hyperkalemia is often associated with impaired renal ability to excrete excessive potassium ions (K+). This may refer to chronic kidney disease or certain pharmacological interventions, including broadly used renin-angiotensin-aldosterone system and calcineurin inhibitors. Understanding the intrinsic mechanisms permitting kidney adaptations to hyperkalemia is critical for choosing therapeutic strategies. Valuable insights were obtained from the analysis of familial hyperkalemic hypertension (FHHt) syndrome, which became a classic model for coincidence of high blood pressure and hyperkalemia. FHHt can be caused by mutations in several genes, all of them resulting in excessive activity of with-no-lysine kinases (WNKs) in the distal nephron of the kidney. WNKs have been increasingly recognized as key signalling enzymes in the regulation of renal sodium ions (Na+) and K+ handling, enabling adaptive responses to systemic shifts of potassium homoeostasis consequent to variations in dietary potassium intake or disease. The WNK signalling pathway recruits a complex protein network mediating catalytic and non-catalytic effects of distinct WNK isoforms on relevant Na+- or K+-transporting proteins. In this review article, we summarize recent progress in understanding WNK signalling. An update of available models for renal adaptation to hyperkalemic conditions is presented. Consequences for blood pressure regulation are discussed. Pharmacological targeting of WNKs or their substrates offers promising options to manage hypertension while preventing hyperkalemia. 10.1093/ndt/gfz218
    Potassium and Its Discontents: New Insight, New Treatments. Ellison David H,Terker Andrew S,Gamba Gerardo Journal of the American Society of Nephrology : JASN Hyperkalemia is common in patients with impaired kidney function or who take drugs that inhibit the renin-angiotensin-aldosterone axis. During the past decade, substantial advances in understanding how the body controls potassium excretion have been made, which may lead to improved standard of care for these patients. Renal potassium disposition is primarily handled by a short segment of the nephron, comprising part of the distal convoluted tubule and the connecting tubule, and regulation results from the interplay between aldosterone and plasma potassium. When dietary potassium intake and plasma potassium are low, the electroneutral sodium chloride cotransporter is activated, leading to salt retention. This effect limits sodium delivery to potassium secretory segments, limiting potassium losses. In contrast, when dietary potassium intake is high, aldosterone is stimulated. Simultaneously, potassium inhibits the sodium chloride cotransporter. Because more sodium is then delivered to potassium secretory segments, primed by aldosterone, kaliuresis results. When these processes are disrupted, hyperkalemia results. Recently, new agents capable of removing potassium from the body and treating hyperkalemia have been tested in clinical trials. This development suggests that more effective and safer approaches to the prevention and treatment of hyperkalemia may be on the horizon. 10.1681/ASN.2015070751
    Sodium and potassium in the pathogenesis of hypertension. Adrogué Horacio J,Madias Nicolaos E The New England journal of medicine 10.1056/NEJMra064486
    Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses. Aburto Nancy J,Hanson Sara,Gutierrez Hialy,Hooper Lee,Elliott Paul,Cappuccio Francesco P BMJ (Clinical research ed.) OBJECTIVE:To conduct a systematic review of the literature and meta-analyses to fill the gaps in knowledge on potassium intake and health. DATA SOURCES:Cochrane Central Register of Controlled Trials, Medline, Embase, WHO International Clinical Trials Registry Platform, Latin American and Caribbean Health Science Literature Database, and the reference lists of previous reviews. STUDY SELECTION:Randomised controlled trials and cohort studies reporting the effects of potassium intake on blood pressure, renal function, blood lipids, catecholamine concentrations, all cause mortality, cardiovascular disease, stroke, and coronary heart disease were included. DATA EXTRACTION AND SYNTHESIS:Potential studies were independently screened in duplicate, and their characteristics and outcomes were extracted. When possible, meta-analysis was done to estimate the effects (mean difference or risk ratio with 95% confidence interval) of higher potassium intake by using the inverse variance method and a random effect model. RESULTS:22 randomised controlled trials (including 1606 participants) reporting blood pressure, blood lipids, catecholamine concentrations, and renal function and 11 cohort studies (127,038 participants) reporting all cause mortality, cardiovascular disease, stroke, or coronary heart disease in adults were included in the meta-analyses. Increased potassium intake reduced systolic blood pressure by 3.49 (95% confidence interval 1.82 to 5.15) mm Hg and diastolic blood pressure by 1.96 (0.86 to 3.06) mm Hg in adults, an effect seen in people with hypertension but not in those without hypertension. Systolic blood pressure was reduced by 7.16 (1.91 to 12.41) mm Hg when the higher potassium intake was 90-120 mmol/day, without any dose response. Increased potassium intake had no significant adverse effect on renal function, blood lipids, or catecholamine concentrations in adults. An inverse statistically significant association was seen between potassium intake and risk of incident stroke (risk ratio 0.76, 0.66 to 0.89). Associations between potassium intake and incident cardiovascular disease (risk ratio 0.88, 0.70 to 1.11) or coronary heart disease (0.96, 0.78 to 1.19) were not statistically significant. In children, three controlled trials and one cohort study suggested that increased potassium intake reduced systolic blood pressure by a non-significant 0.28 (-0.49 to 1.05) mm Hg. CONCLUSIONS:High quality evidence shows that increased potassium intake reduces blood pressure in people with hypertension and has no adverse effect on blood lipid concentrations, catecholamine concentrations, or renal function in adults. Higher potassium intake was associated with a 24% lower risk of stroke (moderate quality evidence). These results suggest that increased potassium intake is potentially beneficial to most people without impaired renal handling of potassium for the prevention and control of elevated blood pressure and stroke. 10.1136/bmj.f1378
    The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation. Moes Arthur D,van der Lubbe Nils,Zietse Robert,Loffing Johannes,Hoorn Ewout J Pflugers Archiv : European journal of physiology SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10% of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions. 10.1007/s00424-013-1407-9
    Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis. Hoorn Ewout J,Gritter Martin,Cuevas Catherina A,Fenton Robert A Physiological reviews Daily dietary potassium (K) intake may be as large as the extracellular K pool. To avoid acute hyperkalemia, rapid removal of K from the extracellular space is essential. This is achieved by translocating K into cells and increasing urinary K excretion. Emerging data now indicate that the renal thiazide-sensitive NaCl cotransporter (NCC) is critically involved in this homeostatic kaliuretic response. This suggests that the early distal convoluted tubule (DCT) is a K sensor that can modify sodium (Na) delivery to downstream segments to promote or limit K secretion. K sensing is mediated by the basolateral K channels Kir4.1/5.1, a capacity that the DCT likely shares with other nephron segments. Thus, next to K-induced aldosterone secretion, K sensing by renal epithelial cells represents a second feedback mechanism to control K balance. NCC's role in K homeostasis has both physiological and pathophysiological implications. During hypovolemia, NCC activation by the renin-angiotensin system stimulates Na reabsorption while preventing K secretion. Conversely, NCC inactivation by high dietary K intake maximizes kaliuresis and limits Na retention, despite high aldosterone levels. NCC activation by a low-K diet contributes to salt-sensitive hypertension. K-induced natriuresis through NCC offers a novel explanation for the antihypertensive effects of a high-K diet. A possible role for K in chronic kidney disease is also emerging, as epidemiological data reveal associations between higher urinary K excretion and improved renal outcomes. This comprehensive review will embed these novel insights on NCC regulation into existing concepts of K homeostasis in health and disease. 10.1152/physrev.00044.2018
    Regulation of Potassium Homeostasis in CKD. DuBose Thomas D Advances in chronic kidney disease Disturbances of potassium homeostasis can cause either hyperkalemia or hypokalemia and result in serious consequences. Although the consequences of acute and chronic hyperkalemia and treatment of these conditions in CKD have been widely appreciated by nephrologists, more recent information has focused attention on the consequences of chronic hypokalemia. Several recent studies have documented a "U-shaped" relationship between the serum [K] and higher mortality in several clinical studies. The causes of dyskalemias are placed into the unique perspective of patients with CKD and its evolution with progression of CKD to later stages and focuses on the pathophysiology of these disorders. Emphasis is placed on the high mortality associated with both low and high levels of potassium that are unique to patients with CKD. Recent information regarding sensors of changes in the serum [K] that evoke changes in NaCl transport in the DCT1 and subsequent efferent responses by aldosterone-responsive cells in the DCT2 and cortical collecting duct to adjust K secretion by the renal outer medullary potassium channel is reviewed in detail. These sensing mechanisms can be interrupted by drugs, such as the calcineurin inhibitors to cause both hypertension and hyperkalemia in kidney transplant patients, or can be inherited as familial hypertensive hyperkalemia. The role and pathogenesis of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in causing hyperkalemia is a common stop point for cessation of these important drugs, but, and newer agents to lower the serum [K] that might allow continuation of angiotensin-converting enzyme or angiotensin receptor blocker therapy are examined. Finally, the importance of emphasis on potassium-containing foods, such as fresh produce and fruit in the diets of patients with early-stage CKD, is examined as an under-appreciated area requiring more emphasis by nephrologists caring for these patients and may be unique to food-challenged patients with CKD. 10.1053/j.ackd.2017.06.002
    Distal tubule basolateral potassium channels: cellular and molecular mechanisms of regulation. Palygin Oleg,Pochynyuk Oleh,Staruschenko Alexander Current opinion in nephrology and hypertension PURPOSE OF REVIEW:Multiple clinical and translational evidence support benefits of high potassium diet; however, there many uncertainties underlying the molecular and cellular mechanisms determining effects of dietary potassium. Kir4.1 and Kir5.1 proteins form a functional heteromer (Kir4.1/Kir5.1), which is the primary inwardly rectifying potassium channel on the basolateral membrane of both distal convoluted tubule (DCT) and the collecting duct principal cells. The purpose of this mini-review is to summarize latest advances in our understanding of the evolution, physiological relevance and mechanisms controlling these channels. RECENT FINDINGS:Kir4.1 and Kir5.1 channels play a critical role in determining electrolyte homeostasis in the kidney and blood pressure, respectively. It was reported that Kir4.1/Kir5.1 serves as potassium sensors in the distal nephron responding to variations in dietary intake and hormonal stimuli. Global and kidney specific knockouts of either channel resulted in hypokalemia and severe cardiorenal phenotypes. Furthermore, knock out of Kir5.1 in Dahl salt-sensitive rat background revealed the crucial role of the Kir4.1/Kir5.1 channel in salt-induced hypertension. SUMMARY:Here, we focus on reviewing novel experimental evidence of the physiological function, expression and hormonal regulation of renal basolateral inwardly rectifying potassium channels. Further investigation of molecular and cellular mechanisms controlling Kir4.1 and Kir4.1/Kir5.1-mediating pathways and development of specific compounds targeting these channels function is essential for proper control of electrolyte homeostasis and blood pressure. 10.1097/MNH.0000000000000437
    Beneficial Effects of High Potassium: Contribution of Renal Basolateral K Channels. Staruschenko Alexander Hypertension (Dallas, Tex. : 1979) 10.1161/HYPERTENSIONAHA.118.10267
    Kidney Is Essential for Blood Pressure Modulation by Dietary Potassium. Su Xiao-Tong,Yang Chao-Ling,Ellison David H Current cardiology reports Eating more potassium may reduce blood pressure and the occurrence of other cardiovascular diseases by actions on various systems, including the vasculature, the sympathetic nervous system, systemic metabolism, and body fluid volume. Among these, the kidney plays a major role in the potassium-rich diet-mediated blood pressure reduction. PURPOSE OF REVIEW: To provide an overview of recent discoveries about the mechanisms by which a potassium-rich diet leads to natriuresis. RECENT FINDINGS: Although the distal convoluted tubule (DCT) is a short part of the nephron that reabsorbs salt, via the sodium-chloride cotransporter (NCC), it is highly sensitive to changes in plasma potassium concentration. Activation or inhibition of NCC raises or lowers blood pressure. Recent work suggests that extracellular potassium concentration is sensed by the DCT via intracellular chloride concentration which regulates WNK kinases in the DCT. High-potassium diet targets NCC in the DCT, resulting in natriuresis and fluid volume reduction, which are protective from hypertension and other cardiovascular problems. 10.1007/s11886-020-01359-1
    Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases. Hadchouel Juliette,Ellison David H,Gamba Gerardo Annual review of physiology The discovery of four genes responsible for pseudohypoaldosteronism type II, or familial hyperkalemic hypertension, which features arterial hypertension with hyperkalemia and metabolic acidosis, unmasked a complex multiprotein system that regulates electrolyte transport in the distal nephron. Two of these genes encode the serine-threonine kinases WNK1 and WNK4. The other two genes [kelch-like 3 (KLHL3) and cullin 3 (CUL3)] form a RING-type E3-ubiquitin ligase complex that modulates WNK1 and WNK4 abundance. WNKs regulate the activity of the Na(+):Cl(-) cotransporter (NCC), the epithelial sodium channel (ENaC), the renal outer medullary potassium channel (ROMK), and other transport pathways. Interestingly, the modulation of NCC occurs via the phosphorylation by WNKs of other serine-threonine kinases known as SPAK-OSR1. In contrast, the process of regulating the channels is independent of SPAK-OSR1. We present a review of the remarkable advances in this area in the past 10 years. 10.1146/annurev-physiol-021115-105431
    Pulmonary Hypertension in Heart Failure: Pathophysiology, Pathobiology, and Emerging Clinical Perspectives. Guazzi Marco,Naeije Robert Journal of the American College of Cardiology Pulmonary hypertension is a common hemodynamic complication of heart failure. Interest in left-sided pulmonary hypertension has increased remarkably in recent years because its development and consequences for the right heart are now seen as mainstay abnormalities that begin in the early stages of the disease and bear unfavorable prognostic insights. However, some knowledge gaps limit our ability to influence this complex condition. Accordingly, attention is now focused on: 1) establishing a definitive consensus for a hemodynamic definition, perhaps incorporating exercise and fluid challenge; 2) implementing the limited data available on the pathobiology of lung capillaries and small arteries; 3) developing standard methods for assessing right ventricular function and, hopefully, its coupling to pulmonary circulation; and 4) searching for effective therapies that may benefit lung vessels and the remodeled right ventricle. The authors review the pathophysiology, pathobiology, and emerging clinical perspectives on pulmonary hypertension across the broad spectrum of heart failure stages. 10.1016/j.jacc.2017.01.051
    Acute Severe Hypertension. Peixoto Aldo J The New England journal of medicine 10.1056/NEJMcp1901117
    Treatment of Hypertension in Patients with Asthma. Christiansen Sandra C,Zuraw Bruce L The New England journal of medicine 10.1056/NEJMra1800345
    Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies. Mente Andrew,O'Donnell Martin,Rangarajan Sumathy,Dagenais Gilles,Lear Scott,McQueen Matthew,Diaz Rafael,Avezum Alvaro,Lopez-Jaramillo Patricio,Lanas Fernando,Li Wei,Lu Yin,Yi Sun,Rensheng Lei,Iqbal Romaina,Mony Prem,Yusuf Rita,Yusoff Khalid,Szuba Andrzej,Oguz Aytekin,Rosengren Annika,Bahonar Ahmad,Yusufali Afzalhussein,Schutte Aletta Elisabeth,Chifamba Jephat,Mann Johannes F E,Anand Sonia S,Teo Koon,Yusuf S, Lancet (London, England) BACKGROUND:Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status. METHODS:In this pooled analysis, we studied 133,118 individuals (63,559 with hypertension and 69,559 without hypertension), median age of 55 years (IQR 45-63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4.2 years (IQR 3.0-5.0) and blood pressure. FINDINGS:Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2.08 mm Hg change per g sodium increase) compared with individuals without hypertension (1.22 mm Hg change per g; pinteraction<0.0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 1.23 [95% CI 1.11-1.37]; p<0.0001) and less than 3 g/day (7006 [11%] of population with hypertension: 1.34 [1.23-1.47]; p<0.0001) were both associated with increased risk compared with sodium excretion of 4-5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4-5 g/day (18,508 [27%] of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (≥ 7 g/day in 6271 [9%] of the population without hypertension; HR 0.90 [95% CI 0.76-1.08]; p=0.2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 [11%] of the population without hypertension; HR 1.26 [95% CI 1.10-1.45]; p=0.0009). INTERPRETATION:Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets. FUNDING:Full funding sources listed at end of paper (see Acknowledgments). 10.1016/S0140-6736(16)30467-6
    Catheter-based renal denervation for treatment of hypertension. Azizi Michel Lancet (London, England) 10.1016/S0140-6736(17)32293-6
    Initial Treatment of Hypertension. Taler Sandra J The New England journal of medicine 10.1056/NEJMcp1613481
    Hypertension in 2016: Blood pressure goals, variability and SGLT2 blockade in CKD. Cohen Debbie L,Townsend Raymond R Nature reviews. Nephrology 10.1038/nrneph.2016.189
    Beyond gut feelings: how the gut microbiota regulates blood pressure. Marques Francine Z,Mackay Charles R,Kaye David M Nature reviews. Cardiology Hypertension is the leading risk factor for heart disease and stroke, and is estimated to cause 9.4 million deaths globally every year. The pathogenesis of hypertension is complex, but lifestyle factors such as diet are important contributors to the disease. High dietary intake of fruit and vegetables is associated with reduced blood pressure and lower cardiovascular mortality. A critical relationship between dietary intake and the composition of the gut microbiota has been described in the literature, and a growing body of evidence supports the role of the gut microbiota in the regulation of blood pressure. In this Review, we describe the mechanisms by which the gut microbiota and its metabolites, including short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides, act on downstream cellular targets to prevent or contribute to the pathogenesis of hypertension. These effects have a direct influence on tissues such as the kidney, the endothelium, and the heart. Finally, we consider the role of the gut microbiota in resistant hypertension, the possible intergenerational effect of the gut microbiota on blood pressure regulation, and the promising therapeutic potential of gut microbiota modification to improve health and prevent disease. 10.1038/nrcardio.2017.120
    Masked hypertension: understanding its complexity. Franklin Stanley S,O'Brien Eoin,Staessen Jan A European heart journal Masked hypertension, which is present when in-office normotension translates to out-of-office hypertension, is present in a surprisingly high percentage of untreated persons and an even higher percentage of patients after beginning antihypertensive medication. Not only are persons with prehypertension more likely to have masked hypertension than those with optimal blood pressure (BP), but also they frequently develop target organ damage prior to transitioning to sustained hypertension. Furthermore, the frequency of masked hypertension is high in individuals of African inheritance and in the presence of increased cardiovascular risk factors and disease states, such as diabetes and chronic renal failure. Nocturnal hypertension and non-dipping may be early markers of masked hypertension. Twenty-four hour ambulatory BP monitoring (ABPM), which can detect nighttime and 24 h elevated BP, remains the gold standard for diagnosing masked hypertension. Almost one-third of treated patients with masked hypertension remain as 'masked uncontrolled hypertension', and it becomes important, therefore, to use ABPM (and supplemental home BP monitoring) for the effective diagnosis and control of hypertension. 10.1093/eurheartj/ehw502
    Treatment of Resistant and Refractory Hypertension. Acelajado Maria Czarina,Hughes Zachary H,Oparil Suzanne,Calhoun David A Circulation research Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity. 10.1161/CIRCRESAHA.118.312156
    Neurovascular and Cognitive Dysfunction in Hypertension. Iadecola Costantino,Gottesman Rebecca F Circulation research Hypertension has emerged as a leading cause of age-related cognitive impairment. Long known to be associated with dementia caused by vascular factors, hypertension has more recently been linked also to Alzheimer disease-the major cause of dementia in older people. Thus, although midlife hypertension is a risk factor for late-life dementia, hypertension may also promote the neurodegenerative pathology underlying Alzheimer disease. The mechanistic bases of these harmful effects remain to be established. Hypertension is well known to alter in the structure and function of cerebral blood vessels, but how these cerebrovascular effects lead to cognitive impairment and promote Alzheimer disease pathology is not well understood. Furthermore, critical questions also concern whether treatment of hypertension prevents cognitive impairment, the blood pressure threshold for treatment, and the antihypertensive agents to be used. Recent advances in neurovascular biology, epidemiology, brain imaging, and biomarker development have started to provide new insights into these critical issues. In this review, we will examine the progress made to date, and, after a critical evaluation of the evidence, we will highlight questions still outstanding and seek to provide a path forward for future studies. 10.1161/CIRCRESAHA.118.313260
    Metabolic Surgery for Hypertension in Patients With Obesity. Pareek Manan,Bhatt Deepak L,Schiavon Carlos Aurelio,Schauer Philip R Circulation research The global prevalence of overweight and obesity has risen substantially over the past 4 decades and is accompanied by an increasing burden of cardiovascular risk factors such as hypertension. Metabolic surgery is the most effective method to treat obesity and may further improve associated conditions. Although most research has been directed toward the glycemic effects of weight loss surgery, there has been a growing interest in exploring its potential blood pressure-reducing properties. Systematic reviews and meta-analyses based primarily on observational data have suggested that metabolic surgery may aid in controlling hypertension. Only one randomized controlled trial specifically addressing this concept has been conducted, though supportive of the findings from observational studies. We review contemporary procedures for weight loss and their effects on cardiometabolic risk, particularly hypertension. In addition, we describe potential pathophysiological mechanisms and the effects of metabolic surgery on cardiovascular events and mortality. 10.1161/CIRCRESAHA.118.313320
    Obesity, kidney dysfunction and hypertension: mechanistic links. Hall John E,do Carmo Jussara M,da Silva Alexandre A,Wang Zhen,Hall Michael E Nature reviews. Nephrology Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension, which is often mild before the development of target organ injury. Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal and renal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin. The renal and neurohormonal pathways of obesity and hypertension are intertwined. For example, leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway, and kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation. Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity. Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension. Patient management therefore often requires multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes and inflammation. If more effective strategies for the prevention and control of obesity are not developed, cardiorenal, metabolic and other obesity-associated diseases could overwhelm health-care systems in the future. 10.1038/s41581-019-0145-4
    Interventional procedures and future drug therapy for hypertension. Lobo Melvin D,Sobotka Paul A,Pathak Atul European heart journal Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care. 10.1093/eurheartj/ehw303
    Immune mechanisms of hypertension. Drummond Grant R,Vinh Antony,Guzik Tomasz J,Sobey Christopher G Nature reviews. Immunology Hypertension affects 30% of adults and is the leading risk factor for heart attack and stroke. Traditionally, hypertension has been regarded as a disorder of two systems that are involved in the regulation of salt-water balance and cardiovascular function: the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). However, current treatments that aim to limit the influence of the RAAS or SNS on blood pressure fail in ~40% of cases, which suggests that other mechanisms must be involved. This Review summarizes the clinical and experimental evidence supporting a contribution of immune mechanisms to the development of hypertension. In this context, we highlight the immune cell subsets that are postulated to either promote or protect against hypertension through modulation of cardiac output and/or peripheral vascular resistance. We conclude with an appraisal of knowledge gaps still to be addressed before immunomodulatory therapies might be applied to at least a subset of patients with hypertension. 10.1038/s41577-019-0160-5
    Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? Lonardo Amedeo,Nascimbeni Fabio,Mantovani Alessandro,Targher Giovanni Journal of hepatology Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. NAFLD has traditionally been considered a consequence of metabolic syndrome (MetS). However, the link between NAFLD and MetS components, especially type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) is more complex than previously thought. Indeed, the adverse effects of NAFLD extend far beyond the liver, with a large body of clinical evidence now suggesting that NAFLD may precede and/or promote the development of T2DM, HTN and atherosclerosis/CVD. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD is associated with an increased risk of incident T2DM and HTN. Moreover, long-term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. In this review, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NAFLD and CVD morbidity and mortality. Finally, we discuss the most updated putative biological mechanisms through which NAFLD may contribute to the development of HTN, T2DM and CVD. 10.1016/j.jhep.2017.09.021
    Genetics of Human Primary Hypertension: Focus on Hormonal Mechanisms. Manosroi Worapaka,Williams Gordon H Endocrine reviews Increasingly, primary hypertension is being considered a syndrome and not a disease, with the individual causes (diseases) having a common sign-an elevated blood pressure. To determine these causes, genetic tools are increasingly employed. This review identified 62 proposed genes. However, only 21 of them met our inclusion criteria: (i) primary hypertension, (ii) two or more supporting cohorts from different publications or within a single publication or one supporting cohort with a confirmatory genetically modified animal study, and (iii) 600 or more subjects in the primary cohort; when including our exclusion criteria: (i) meta-analyses or reviews, (ii) secondary and monogenic hypertension, (iii) only hypertensive complications, (iv) genes related to blood pressure but not hypertension per se, (v) nonsupporting studies more common than supporting ones, and (vi) studies that did not perform a Bonferroni or similar multiassessment correction. These 21 genes were organized in a four-tiered structure: distant phenotype (hypertension); intermediate phenotype [salt-sensitive (18) or salt-resistant (0)]; subintermediate phenotypes under salt-sensitive hypertension [normal renin (4), low renin (8), and unclassified renin (6)]; and proximate phenotypes (specific genetically driven hypertensive subgroup). Many proximate hypertensive phenotypes had a substantial endocrine component. In conclusion, primary hypertension is a syndrome; many proposed genes are likely to be false positives; and deep phenotyping will be required to determine the utility of genetics in the treatment of hypertension. However, to date, the positive genes are associated with nearly 50% of primary hypertensives, suggesting that in the near term precise, mechanistically driven treatment and prevention strategies for the specific primary hypertension subgroups are feasible. 10.1210/er.2018-00071
    The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease. Yang Tao,Richards Elaine M,Pepine Carl J,Raizada Mohan K Nature reviews. Nephrology Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension. 10.1038/s41581-018-0018-2
    Hypertension. Oparil Suzanne,Acelajado Maria Czarina,Bakris George L,Berlowitz Dan R,Cífková Renata,Dominiczak Anna F,Grassi Guido,Jordan Jens,Poulter Neil R,Rodgers Anthony,Whelton Paul K Nature reviews. Disease primers Systemic arterial hypertension is the most important modifiable risk factor for all-cause morbidity and mortality worldwide and is associated with an increased risk of cardiovascular disease (CVD). Fewer than half of those with hypertension are aware of their condition, and many others are aware but not treated or inadequately treated, although successful treatment of hypertension reduces the global burden of disease and mortality. The aetiology of hypertension involves the complex interplay of environmental and pathophysiological factors that affect multiple systems, as well as genetic predisposition. The evaluation of patients with hypertension includes accurate standardized blood pressure (BP) measurement, assessment of the patients' predicted risk of atherosclerotic CVD and evidence of target-organ damage, and detection of secondary causes of hypertension and presence of comorbidities (such as CVD and kidney disease). Lifestyle changes, including dietary modifications and increased physical activity, are effective in lowering BP and preventing hypertension and its CVD sequelae. Pharmacological therapy is very effective in lowering BP and in preventing CVD outcomes in most patients; first-line antihypertensive medications include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, dihydropyridine calcium-channel blockers and thiazide diuretics. 10.1038/nrdp.2018.14
    Arterial stiffness as a risk factor for clinical hypertension. Safar Michel E Nature reviews. Cardiology In patients with uncomplicated essential hypertension, cardiac output remains within normal ranges and intravascular volume is normal or low, assuming the presence of a sufficient Windkessel effect and usual resistance and compliance calculations. However, mean circulatory pressure is elevated in these patients. In addition, vascular resistance is augmented, and most importantly, the viscoelasticity of the cardiovascular system is substantially impaired. Such considerations are essential to understanding the mechanisms behind carotid-femoral arterial stiffness, a major risk factor in individuals with hypertension. Arterial stiffness, measured from pulse wave velocity, is substantially increased in hypertension even independently of blood pressure levels. Structural vascular changes and endothelial dysfunction are consistently associated with vessel impairments in animal models of hypertension. Increased arterial stiffness has a major effect on pulse pressure (the difference between systolic and diastolic blood pressure), wave reflections, kidney function, and above all, cardiovascular risk. This increased cardiovascular risk is particularly deleterious in patients with hypertension and/or type 2 diabetes mellitus, who are at risk of both renal and cardiovascular events. In this Review, we discuss the importance of arterial stiffness in the diagnosis and management of hypertension and the need for new approaches for the treatment of hypertension in patients with or without diabetes and/or renal impairment. 10.1038/nrcardio.2017.155
    Role of the Immune System in Hypertension. Rodriguez-Iturbe Bernardo,Pons Hector,Johnson Richard J Physiological reviews High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system. Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation. Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance. Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease. 10.1152/physrev.00031.2016