Catecholamine-induced hypertensive crises: current insights and management.

Phaeochromocytomas and paragangliomas (PPGLs) release catecholamines leading to catecholamine-induced hypertensive (CIH) crises, with blood pressure greater than or equal to 180/120 mm Hg. CIH crises can be complicated by tachyarrhythmias, hypotension, or life-threatening target organ damage while treatment remains undefined, often requiring co-management between endocrinologists and cardiologists. Furthermore, biochemical diagnosis of a PPGL as a cause of a CIH crisis can be difficult to identify or confounded by comorbid conditions, potentially resulting in misdiagnosis. Here, we combine relevant evidence, 60 years of collective clinical experience, insights derived from assessing over 2600 patients with PPGL, and supplementary outcomes from 100 patients (treated at the National Institutes of Health) with a CIH crisis to inform diagnosis and treatment of CIH crises. Recognising that disparities exist between availability, cost, and familiarity of various agents, flexible approaches are delineated allowing for customisation, given institutional availability and provider preference. A CIH crisis and its complications are readily treatable with available drugs, with effective intervention defining an avenue for mitigating consequent morbidity and mortality in patients with PPGL.

Decoding Angiotensin Receptors: TOMAHAQ-Based Detection and Quantification of Angiotensin Type-1 and Type-2 Receptors.

Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the angiotensin type-1 and type-2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type-1 and type-2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non-antibody-based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type-1 and type-2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type-1 and type-2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin-angiotensin system activation, including oxidative stress, inflammation, amyloid-ß load, and paired helical filament-tau tangle burden. Conclusions These robust high-throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.

Association of cancer with the risk of developing hypertension.

BACKGROUND AND AIMS: Although the importance of hypertension in patients with cancer is widely recognized, little is known about the risk of developing hypertension in patients with a history of cancer. METHODS: This retrospective observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2022, including 78,162 patients with a history of cancer and 3,692,654 individuals without cancer. The primary endpoint was the incidence of hypertension. RESULTS: During a mean follow-up period of 1,208 ± 966 days, 311,197 participants developed hypertension. The incidence of hypertension was 364.6 (95% CI 357.0-372.2) per 10000 person-years among those with a history of cancer, and 247.2 (95% CI 246.3-248.1) per 10000 person-years in those without cancer. Individuals with a history of cancer had an elevated risk of developing hypertension according to multivariable Cox regression analyses (HR 1.17, 95% CI 1.15-1.20). Both cancer patients requiring active antineoplastic therapy (HR 2.01, 95% CI 1.85-2.20), and those who did not require active antineoplastic therapy (HR 1.14, 95% CI 1.12-1.17) had an increased risk of hypertension. A multitude of sensitivity analyses confirmed the robustness of the relationship between cancer and incident hypertension. Patients with certain types of cancer were found to have a higher risk of developing hypertension than those without cancer, with varying risks dependent on the type of cancer. CONCLUSIONS: Our analysis of a nationwide epidemiological database revealed that individuals with a history of cancer have a higher risk of developing hypertension, and that this finding applies to both cancer patients who require active antineoplastic therapy and those who do not.

Progressive Cardiac Metabolic Defects Accompany Diastolic and Severe Systolic Dysfunction in Spontaneously Hypertensive Rat Hearts.

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography in vivo in 9-, 12-, and 18-month-old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9-month-old SHR decreasing) 2-[18F] fluoro-2-deoxy-d-glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12-month-old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2-[18F] fluoro-2-deoxy-d-glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Evidence That Binding of Cyclic GMP to the Extracellular Domain of NKA (Sodium-Potassium ATPase) Mediates Natriuresis.

BACKGROUND: Extracellular renal interstitial guanosine cyclic 3',5'-monophosphate (cGMP) inhibits renal proximal tubule (RPT) sodium (Na+) reabsorption via Src (Src family kinase) activation. Through which target extracellular cGMP acts to induce natriuresis is unknown. We hypothesized that cGMP binds to the extracellular α1-subunit of NKA (sodium-potassium ATPase) on RPT basolateral membranes to inhibit Na+ transport similar to ouabain-a cardiotonic steroid. METHODS: Urine Na+ excretion was measured in uninephrectomized 12-week-old female Sprague-Dawley rats that received renal interstitial infusions of vehicle (5% dextrose in water), cGMP (18, 36, and 72 µg/kg per minute; 30 minutes each), or cGMP+rostafuroxin (12 ng/kg per minute) or were subjected to pressure-natriuresis±rostafuroxin infusion. Rostafuroxin is a digitoxigenin derivative that displaces ouabain from NKA. RESULTS: Renal interstitial cGMP and raised renal perfusion pressure induced natriuresis and increased phosphorylated SrcTyr416 and Erk 1/2 (extracellular signal-regulated protein kinase 1/2)Thr202/Tyr204; these responses were abolished with rostafuroxin coinfusion. To assess cGMP binding to NKA, we performed competitive binding studies with isolated rat RPTs using bodipy-ouabain (2 µM)+cGMP (10 µM) or rostafuroxin (10 µM) and 8-biotin-11-cGMP (2 µM)+ouabain (10 µM) or rostafuroxin (10 µM). cGMP or rostafuroxin reduced bodipy-ouabain fluorescence intensity, and ouabain or rostafuroxin reduced 8-biotin-11-cGMP staining. We cross-linked isolated rat RPTs with 4-N3-PET-8-biotin-11-cGMP (2 µM); 8-N3-6-biotin-10-cAMP served as negative control. Precipitation with streptavidin beads followed by immunoblot analysis showed that RPTs after cross-linking with 4-N3-PET-8-biotin-11-cGMP exhibited a significantly stronger signal for NKA than non-cross-linked samples and cross-linked or non-cross-linked 8-N3-6-biotin-10-cAMP RPTs. Ouabain (10 µM) reduced NKA in cross-linked 4-N3-PET-8-biotin-11-cGMP RPTs confirming fluorescence staining. 4-N3-PET-8-biotin-11-cGMP cross-linked samples were separated by SDS gel electrophoresis and slices corresponding to NKA molecular weight excised and processed for mass spectrometry. NKA was the second most abundant protein with 50 unique NKA peptides covering 47% of amino acids in NKA. Molecular modeling demonstrated a potential cGMP docking site in the ouabain-binding pocket of NKA. CONCLUSIONS: cGMP can bind to NKA and thereby mediate natriuresis.

Treatment of Hypertension: A Review.

Importance: Hypertension, defined as persistent systolic blood pressure (SBP) at least 130 mm Hg or diastolic BP (DBP) at least 80 mm Hg, affects approximately 116 million adults in the US and more than 1 billion adults worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death. Observations: First-line therapy for hypertension is lifestyle modification, including weight loss, healthy dietary pattern that includes low sodium and high potassium intake, physical activity, and moderation or elimination of alcohol consumption. The BP-lowering effects of individual lifestyle components are partially additive and enhance the efficacy of pharmacologic therapy. The decision to initiate antihypertensive medication should be based on the level of BP and the presence of high atherosclerotic CVD risk. First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic such as hydrochlorothiazide or chlorthalidone, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker such as enalapril or candesartan, and a calcium channel blocker such as amlodipine and should be titrated according to office and home SBP/DBP levels to achieve in most people an SBP/DBP target (<130/80 mm Hg for adults <65 years and SBP <130 mm Hg in adults ≥65 years). Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality. An SBP reduction of 10 mm Hg decreases risk of CVD events by approximately 20% to 30%. Despite the benefits of BP control, only 44% of US adults with hypertension have their SBP/DBP controlled to less than 140/90 mm Hg. Conclusions and Relevance: Hypertension affects approximately 116 million adults in the US and more than 1 billion adults worldwide and is a leading cause of CVD morbidity and mortality. First-line therapy for hypertension is lifestyle modification, consisting of weight loss, dietary sodium reduction and potassium supplementation, healthy dietary pattern, physical activity, and limited alcohol consumption. When drug therapy is required, first-line therapies are thiazide or thiazidelike diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and calcium channel blockers.

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity.

High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D2 receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS. Insight into this newly discovered paradoxical response to sodium is found by incubating cells in low sodium (LS) conditions that unveil cell physiologic differences that are then reversed by mir-485-5p miRNA blocker transfection and bypassing the genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an important counter-regulatory mechanism to prevent hyponatremia under LS conditions. Oversensitive RAS under LS conditions could partially explain the increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium transport in uRPTCs to a greater extent in individuals with ISS than SR. Downstream signaling of AngII is verified by identifying lowered expression of nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium sensitivity to AngII and renal sodium reabsorption which can contribute to inverse salt-sensitive hypertension.

The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target.

Discovered more than 30 years ago, the angiotensin AT2 receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research. SIGNIFICANCE STATEMENT: The angiotensin AT2 receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target.

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines.

The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

Reduction in blood pressure for elevated blood pressure/stage 1 hypertension according to the American College of Cardiology/American Heart Association guideline and cardiovascular outcomes.

AIMS: Few studies have examined the relationship of blood pressure (BP) change in adults with elevated BP or stage 1 hypertension according to the American College of Cardiology (ACC)/American Heart Association (AHA) guideline with cardiovascular outcomes. We sought to identify the effect of BP change among individuals with elevated BP or stage 1 hypertension on incident heart failure (HF) and other cardiovascular diseases (CVDs). METHODS AND RESULTS: We conducted a retrospective cohort study including 616 483 individuals (median age 46 years, 73.7% men) with elevated BP or stage 1 hypertension based on the ACC/AHA BP guideline. Participants were categorized using BP classification at one-year as normal BP (n = 173 558), elevated BP/stage 1 hypertension (n = 367 454), or stage 2 hypertension (n = 75 471). The primary outcome was HF, and the secondary outcomes included (separately) myocardial infarction (MI), angina pectoris (AP), and stroke. Over a mean follow-up of 1097 ± 908 days, 10 544 HFs, 1317 MIs, 11 070 APs, and 5198 strokes were recorded. Compared with elevated BP/stage 1 hypertension at one-year, normal BP at one-year was associated with a lower risk of developing HF [hazard ratio (HR): 0.89, 95% CI:0.85-0.94], whereas stage 2 hypertension at one-year was associated with an elevated risk of developing HF (HR:1.43, 95% CI:1.36-1.51). This association was also present in other cardiovascular outcomes including MI, AP, and stroke. The relationship was consistent in all subgroups stratified by age, sex, baseline BP category, and overweight/obesity. CONCLUSION: A one-year decline in BP was associated with the lower risk of HF, MI, AP, and stroke, suggesting the importance of lowering BP in individuals with elevated BP or stage 1 hypertension according to the ACC/AHA guideline to prevent the risk of developing CVD.

Repressed Ang 1-7 in COVID-19 Is Inversely Associated with Inflammation and Coagulation.

The coronavirus SARS-CoV-2 infects host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which belongs to an anti-inflammatory, anti-thrombotic counter-regulatory arm of the renin-angiotensin system (RAS). ACE2 dysfunction and RAS dysregulation has been explored as a driving force in acute respiratory distress syndrome (ARDS), but data from COVID-19 patients has been inconsistent and inconclusive. We sought to identify disruptions of the classical (ACE)/angiotensin (Ang) II/Ang II type-1 receptor (AT1R) and the counter-regulatory ACE2/Ang 1-7/Mas Receptor (MasR) pathways in patients with COVID-19 and correlate these with severity of infection and markers of inflammation and coagulation. Ang II and Ang 1-7 levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) for 230 patients, 166 of whom were SARS-CoV-2+. Ang 1-7 was repressed in COVID-19 patients compared to that in SARS-CoV-2 negative outpatient controls. Since the control cohort was less sick than the SARS-CoV-2+ group, this association between decreased Ang 1-7 and COVID-19 cannot be attributed to COVID-19 specifically as opposed to critical illness more generally. Multivariable logistic regression analyses demonstrated that every 10-pg/mL increase in plasma Ang 1-7 was associated with a 3% reduction in the odds of hospitalization (adjusted odds ratio [AOR] 0.97, confidence interval [CI] 0.95 to 0.99) and a 3% reduction in odds of requiring oxygen supplementation (AOR 0.97, CI 0.95 to 0.99) and/or ventilation (AOR 0.97, CI 0.94 to 0.99). Ang 1-7 was also inversely associated with pro-inflammatory cytokines and d-dimer in this patient cohort, suggesting that reduced activity in this protective counter-regulatory arm of the RAS contributes to the hyper-immune response and diffuse coagulation activation documented in COVID-19. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a unique disease, COVID-19, which ranges in severity from asymptomatic to causing severe respiratory failure and death. Viral transmission throughout the world continues at a high rate despite the development and widespread use of effective vaccines. For those patients who contract COVID-19 and become severely ill, few therapeutic options have been shown to provide benefits and mortality rates are high. Additionally, the pathophysiology underlying COVID-19 disease presentation, progression, and severity is incompletely understood. The significance of our research is in confirming the role of renin-angiotensin system dysfunction in COVID-19 pathogenesis in a large cohort of patients with diverse disease severity and outcomes. Additionally, to our knowledge, this is the first study to pair angiotensin peptide levels with inflammatory and thrombotic markers. These data support the role of ongoing clinical trials examining renin-angiotensin system-targeted therapeutics for the treatment of COVID-19.

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: Comparisons, Reflections, and Recommendations.

The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: Comparisons, Reflections, and Recommendations.

The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

Inverse Salt Sensitivity of Blood Pressure: Mechanisms and Potential Relevance for Prevention of Cardiovascular Disease.

PURPOSE OF REVIEW: To review the etiology of inverse salt sensitivity of blood pressure (BP). RECENT FINDINGS: Both high and low sodium (Na+) intake can be associated with increased BP and cardiovascular morbidity and mortality. However, little is known regarding the mechanisms involved in the increase in BP in response to low Na+ intake, a condition termed inverse salt sensitivity of BP, which affects approximately 15% of the adult population. The renal proximal tubule is important in regulating up to 70% of renal Na+ transport. The renin-angiotensin and renal dopaminergic systems play both synergistic and opposing roles in the regulation of Na+ transport in this nephron segment. Clinical studies have demonstrated that individuals express a "personal salt index" (PSI) that marks whether they are salt-resistant, salt-sensitive, or inverse salt-sensitive. Inverse salt sensitivity results in part from genetic polymorphisms in various Na+ regulatory genes leading to a decrease in natriuretic activity and an increase in renal tubular Na+ reabsorption leading to an increase in BP. This article reviews the potential mechanisms of a new pathophysiologic entity, inverse salt sensitivity of BP, which affects approximately 15% of the general adult population.

New wrinkles in hypertension management 2022.

PURPOSE OF REVIEW: High blood pressure (BP) is the world's leading risk factor for cardiovascular disease (CVD) and death. This review highlights findings during the past 18 months that apply to the management of high BP in adults in the context of the 2017 American College of Cardiology/American Heart Association (AHA) BP guideline. RECENT FINDINGS: A comprehensive meta-analysis of clinical trials that employed a novel statistical method identified a substantially linear relationship between dietary sodium intake and BP, strongly supporting the AHA daily dietary sodium intake recommendation of less than 1500 mg/day but suggesting that any reduction in sodium intake is likely to be beneficial. Among adults with hypertension, use of a salt substitute (containing reduced sodium and enhanced potassium) led to striking reductions in CVD outcomes. Young adults with stage 1 hypertension and a low 10-year atherosclerotic CVD risk score should be started on a 6-month course of vigorous lifestyle modification; if their BP treatment goal is not achieved, a first-line antihypertensive agent should be added to the lifestyle modification intervention. In patients with stage 4 renal disease, the thiazide-like diuretic chlorthalidone (as add-on therapy) lowered BP markedly compared with placebo. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) represent a new class of MRA that has been shown to lower BP and provide significant CVD protection. In Chinese adults aged 60-80 years at baseline, intensive BP control with a SBP target of 110-129 compared with 130-149 mmHg reduced CVD events with minimal side effects. SUMMARY: Recent findings have advanced our knowledge of hypertension management, clarifying, amplifying and supporting the 2017 ACC/AHA BP guideline recommendations.

Epithelial Sodium Channel Alpha Subunit (αENaC) Is Associated with Inverse Salt Sensitivity of Blood Pressure.

Salt sensitivity of blood pressure (BP) refers to an increase in BP following an increase in dietary salt, which is associated with increased incidence of cardiovascular disease and early death. However, decreased sodium intake also increases mortality and morbidity. Inverse salt sensitivity (ISS), defined as a paradoxical increase in BP on a low-salt diet, about 11% of the population, may be the cause of this phenomenon. The epithelial sodium channel (ENaC) is a major regulator of sodium reabsorption in the kidney. In this study, human renal tubular epithelial cells (hRTC) were cultured from the urine of phenotyped salt study participants. αENaC expression was significantly lower in ISS than salt resistant (SR) hRTC, while ENaC-like channel activity was dramatically increased by trypsin treatment in ISS cells analyzed by patch clamp. αENaC expression was also decreased under high-salt treatment and increased by aldosterone treatment in ISS cells. Moreover, the αENaC variant, rs4764586, was more prevalent in ISS. In summary, αENaC may be associated with ISS hypertension on low salt. These findings may contribute to understanding the mechanisms of ISS and low salt effect on morbidity and mortality.

Serum Concentrations of Losartan Metabolites Correlate With Improved Physical Function in a Pilot Study of Prefrail Older Adults.

Losartan is an oral antihypertensive agent that is rapidly metabolized to EXP3174 (angiotensin-subtype-1-receptor blocker) and EXP3179 (peroxisome proliferator-activated receptor gamma [PPARγ] agonist), which was shown in animal studies to reduce inflammation, enhance mitochondrial energetics, and improve muscle repair and physical performance. We conducted an exploratory pilot study evaluating losartan treatment in prefrail older adults (age 70-90 years, N = 25). Participants were randomized to control (placebo) or treatment (daily oral losartan beginning at 25 mg per day and increasing every 8 weeks) for a total of 6 months. Fatigue, hyperkalemia, and hypotension were the most observed side effects of losartan treatment. Participants in the losartan group had an estimated 89% lower odds of frailty (95% confidence interval [CI]: 18% to 99% lower odds, p = .03), with a 0.3-point lower frailty score than the placebo group (95% CI: 0.01-0.5 lower odds, p = .04). Frailty score was also negatively associated with serum losartan and EXP3179 concentrations. For every one standard deviation increase in EXP3179 (ie, 0.0011 ng/µL, based on sample values above detection limit) and EXP3174 (ie, 0.27 ng/µL, based on sample values above detection limit), there was a 0.0035 N (95% CI: 0.0019-0.0051, p < .001) and a 0.0027 N (95% CI: 0.00054-0.0043, p = .007) increase in average knee strength, respectively.

Intensive Blood Pressure Treatment Goals: Evidence for Cardiovascular Protection From Observational Studies and Clinical Trials.

Epidemiologic studies have consistently identified a strong, progressive relationship between blood pressure (BP) and cardiovascular disease (CVD) events, in a range of systolic BP (SBP) from as low as 90 mm Hg to as high as 180 mm Hg. Clinical trials have demonstrated greater prevention of CVD with more compared with less intensive antihypertensive drug treatment. Meta-analyses of randomized controlled trials provide strong evidence for more intensive antihypertensive drug therapy down to an SBP of 130 mm Hg, and to an SBP 120-124 mm Hg in the meta-analysis with the greatest statistical power. In the Systolic Blood Pressure Intervention Trial (SPRINT) randomization to an SBP treatment goal of <120 mm Hg compared with <140 mm Hg in persons with high CVD risk not only reduced the rate of CVD but also all-cause mortality. These benefits were noted in all of the prestated subgroups of interest, including those ≥65 years of age at baseline. In addition, cognitive impairment was less common in those randomized to the intensive compared with standard treatment. Most clinical practice guidelines recommend an SBP treatment target <130 mm Hg in adults with a high risk of CVD, which is the norm for many patients seen in clinical practice, especially those who are older, have diabetes mellitus, or chronic kidney disease.