High Salt Sensitivity Research Articles

Epidemiology and Clinical Features of Arterial Hypertension in Patients with Type 2 Diabetes Mellitus. Literature Review

Hypertension and type 2 diabetes mellitus are often combined and mutually enhance the adverse effect on vascular and renal prognosis. Hypertension is present in about 50 % of patients with type 2 diabetes, and diabetes, in turn, is detected in about 20 % of people with hypertension. The risk of developing hypertension in patients with type 2 diabetes is 2-2.5 times higher than in people without diabetes; the presence of hypertension increases the risk of type 2 diabetes by the same number of times. Hypertension and diabetes mutually burden each other: on the one hand, the presence of hypertension significantly increases the likelihood of developing diabetic macro- and microvascular complications (including diabetic nephropathy and retinopathy); on the other hand, type 2 diabetes, as a classic independent cardiovascular risk factor, increases the risk of complications inherent in hypertension by about 2 times Careful treatment of diabetes with maintenance of target values of glycemia for a long time may be associated with a decrease in the likelihood of developing hypertension by 24 % compared with less adequate control of glycemia. Hypertension in type 2 diabetes may have a number of features that distinguish such patients from the general population of people with hypertension. Such features include a higher proportion of isolated systolic hypertension and resistant hypertension, certain types of circadian rhythm disorders of blood pressure (categories “non-dipper” and “night-peaker”), frequent combination with albuminuria, frequent high salt sensitivity and volume-dependent nature of hypertension, and others.

Salt sensitivity risk derived from nocturnal dipping and 24-h heart rate predicts long-term blood pressure reduction following renal denervation.

Renal denervation (RDN) has been consistently shown in recent sham-controlled clinical trials to reduce blood pressure (BP). Salt sensitivity is a critical factor in hypertension pathogenesis, but cumbersome to assess by gold-standard methodology. Twenty-four-hour average heart rate (HR) and mean arterial pressure (MAP) dipping, taken by ambulatory blood pressure monitoring (ABPM), stratifies patients into high, moderate, and low salt sensitivity index (SSI) risk categories. We aimed to assess whether ABPM-derived SSI risk could predict the systolic blood pressure reduction at long-term follow-up in a real-world RDN patient cohort. Sixty participants had repeat ABPM as part of a renal denervation long-term follow-up. Average time since RDN was 8.9 ± 1.2 years. Based on baseline ABPM, participants were stratified into low (HR < 70 bpm and MAP dipping > 10%), moderate (HR ≥70 bpm or MAP dipping ≤ 10%), and high (HR ≥ 70 bpm and MAP dipping ≤ 10%) SSI risk groups, respectively. One-way ANOVA indicated a significant treatment effect ( P = 0.03) between low ( n = 15), moderate ( n = 35), and high ( n = 10) SSI risk with systolic BP reduction of 9.6 ± 3.7 mmHg, 8.4 ± 3.5 mmHg, and 28.2 ± 9.6 mmHg, respectively. Baseline BP was not significantly different between SSI Risk groups ( P = 0.18). High SSI risk independently correlated with systolic BP reduction ( P = 0.02). Our investigation indicates that SSI risk may be a simple and accessible measure for predicting the BP response to RDN. However, the influence of pharmacological therapy on these participants is an important extraneous variable requiring testing in prospective or drug naive RDN cohorts.

Management of nocturnal hypertension: An expert consensus document from Chinese Hypertension League.

Nocturnal hypertension is highly prevalent among Chinese and Asian populations, which is mainly attributed to high salt intake and high salt sensitivity. Nocturnal hypertension increases the risk of cardiovascular and all-cause mortality, independent of daytime blood pressure (BP). However, it can usually be detected by 24-h ambulatory BP monitoring, rather than routine office or home BP measurement, thus is often underdiagnosed in clinical practice. Currently, no specific guidance is available for the management of nocturnal hypertension in China or worldwide. Experts from the Chinese Hypertension League summarized the epidemiologic and pathophysiologic characteristics and clinical phenotype of nocturnal hypertension and provided consensus recommendations on optimal management of nocturnal hypertension, with the goal of maximally reducing the cardiovascular disease risks. In this consensus document, 24-h ABPM is recommended for screening and diagnosis of nocturnal hypertension, especially in the elderly, patients with diabetes, chronic kidney diseases, obstructive sleep apnea and other conditions prone to high nocturnal BP. Lifestyle modifications including salt intake restriction, exercise, weight loss, sleep improvement, and mental stress relief are recommended. Long-acting antihypertensive medications are preferred for nocturnal and 24-h BP control. Some newly developed agents, renal denervation, and other device-based therapy on nocturnal BP reduction are evaluated.

Exceptional high salt sensitivity of the small heat shock protein P26

Exceptional high salt sensitivity of the small heat shock protein P26

Resistant to refractory hypertension: Angiotensin receptor blocker/neprilysin inhibitor to the rescue

Hypertension in African starts early and runs a severe course; with appalling morbi-mortality statistics. When resistant to treatment, again a phenotype more common in the African, outcome is poorer. Search for effective management has continued, ranging from novel pharmacological agents to devise therapy. The latter is invasive and beyond the reach of many needing it. Angiotensin receptor blocker/Neprilysin inhibitors are relatively new in our environment and effective in hypertensives with high salt intake and sensitivity. Since this is the situation with majority of African hypertensives, it was given to a patient with diabetes and treatment resistant hypertension of the refractory phenotype. The outcome was satisfactory hence this case report.

PS-C28-9: AMBULATORY BP DERIVED SALT SENSITIVITY INDEX AS A PREDICTOR OF THE BP RESPONSE TO RENAL DENERVATION

Objective: Renal denervation (RDN) has been consistently shown in recent sham-controlled clinical trials to reduce clinic and ambulatory blood pressure (BP). Salt sensitivity is a critical factor in hypertension pathogenesis and severity, but cumbersome to assess by gold-standard methodology. 24-hour average heart rate and mean arterial pressure dipping, taken by ambulatory blood pressure monitoring (ABPM), can stratify patients into high, moderate and low salt sensitivity index (SSI) risk categories. Here we aimed to assess whether ABPM-derived SSI risk could predict the systolic blood pressure reduction at long-term follow-up in a real-world cohort of RDN patients. Design and Methods: 60 participants (70.0 ± 10.3 years, 76.3% male) had repeat ABPM assessment as part of a renal denervation long-term follow and compared to their pre-RDN baseline for calculating systolic BP changes. Average time since RDN was 8.7 years ± 1.09 years. Participants were stratified into low, moderate and high SSI Risk groups, respectively. MAP dipping less than 10% and heart rate (HR) greater than 70 indicated high-risk, MAP dipping greater than 10% and HR less than 70 indicated low risk. Remaining participants were classified as moderate risk. Systolic BP changes in risk groups were compared by One-way ANOVA. Multiple regression was computed for systolic BP response, baseline SBP and High SSI Risk status. Results: One-way ANOVA indicated a significant treatment effect (p = 0.03) between low, moderate and high salt-sensitivity index risk calculated by ABPM measures with systolic BP reduction of 9.64 ± 3.74 mmHg, 8.41 ± 3.48 mmHg, and 28.20 ± 9.55 mmHg, respectively. Baseline SBP was not significantly different between SSI Risk groups (p = 0.18), but trended upward with increasing SSI. High SSI risk independently correlated with systolic BP reduction (p = 0.02). Conclusions: Our preliminary investigation indicates that SSI risk may serve as a simple and easily accessible measure for prediction of the BP response to RDN. However, the influence of pharmacological therapy on these participants is an important extraneous variable requiring testing in prospective or drug-naive RDN cohorts.

Study on saltiness sensing during oral processing of dry-cured pork base on salivary proteomics

Recently, the concept of low-salt and healthy diet has been widely accepted, while the market recognition of low-salt meat products is generally inferior due to their inability to satisfy the oral pleasure of consumers. Therefore, to investigate the role of saliva in saltiness during oral processing of chewing high-salt dry-cured pork, a subset of 3 male subjects with high salt-sensitivity were selected to partake this study. Cooked dry-cured pork (5% salt added) as chewed and held in the oral cavity without swallowing for four different chewing stages during oral processing. Saliva from the 3 subjects was collected and analyzed for salivary proteomics by Data Independent Acquisition (DIA) combined with food oral processing methods. According to the analysis of human proteome (H.sapiens, UP000005640), the abundance of RAC1(RAS-related C3 botulinum toxin substrate 1) and calmodulin-like 3 (CALML 3) was first found to be related to the change of saltiness sensing during oral processing. Moreover, oral chewing leads to upregulation of RAC1 protein, which leads to positive regulation of protein kinase B signaling, ultimately leading to increased serine-type endopeptidase activity and salt perception.

Evaluation of groundwater quality for agricultural under different conditions using water quality indices, partial least squares regression models, and GIS approaches

Evaluating grouLindwater quality and associated hydrochemical properties is critical to manage groundwater resources in arid and semiarid environments. The current study examined groundwater quality and appropriateness for agriculture in the alluvial aquifer of Makkah Al-Mukarramah Province, Saudi Arabia, utilizing several irrigation water quality indices (IWQIs) such as irrigation water quality index (IWQI), total dissolved solids (TDS), sodium adsorption ratio (SAR), potential salinity (PS), magnesium hazard (MH), and residual sodium carbonate (RSC) assisted by multivariate modeling and GIS tools. One hundred fourteen groundwater wells were evaluated utilizing several physicochemical parameters, which indicating that the primary cation and anion concentrations were as follows: Na+ > Ca2+ > Mg2+ > K+, and Cl− > SO42˗ > HCO3˗ > NO3˗ > CO32˗, respectively, reflecting Ca–HCO3, Na–Cl, and mixed Ca–Mg–Cl–SO4 water facies under the stress of evaporation, saltwater intrusion, and reverse ion exchange processes. The IWQI, TDS, SAR, PS, MH, and RSC across two studied regions had mean values of 64.86, 2028.53, 4.98, 26.18, 38.70, and − 14.77, respectively. For example, the computed IWQI model indicated that approximately 31% of samples fell into the no restriction range, implying that salinity tolerance crops should be avoided, while approximately 33% of samples fell into the low to moderate restriction range, and approximately 36% of samples fell into the high to severe restriction range for irrigation, implying that moderate to high salt sensitivity crops should be irrigated in loose soil with no compacted layers. The partial least squares regression model (PLSR) produced a more accurate assessment of six IWQIs based on values of R2 and slope. In Val. datasets, the PLSR model generated strong estimates for six IWQIs with R2 varied from 0.72 to 1.00. There was a good slope value of the linear relationship between measured and predicted for each parameter and the highest slope value (1.00) was shown with RSC. In the PLSR models of six IWQIs, there were no overfitting or underfitting between the measuring, calibrating, and validating datasets. In conclusion, the combination of physicochemical characteristics, WQIs, PLSR, and GIS tools to assess groundwater suitability for irrigation and their regulating variables is beneficial and provides a clear picture of water quality.

High Dietary Salt Intake Is Associated With Histone Methylation in Salt-Sensitive Individuals

BackgroundHigh salt diet is one of the important risk factors of hypertension and cardiovascular diseases. Increasingly strong evidence supports epigenetic mechanisms' significant role in hypertension. We aimed to explore associations of epigenetics with high salt diet, salt sensitivity (SS), and SS hypertension.MethodsWe conducted a dietary intervention study of chronic salt loading in 339 subjects from northern China in 2004 and divided the subjects into different salt sensitivity phenotypes. A total of 152 participants were randomly selected from the same cohort for follow-up in 2018 to explore the effect of a high-salt diet on serum monomethylation of H3K4 (H3K4me1), histone methyltransferase Set7, and lysine-specific demethylase 1 (LSD-1).ResultsAmong SS individuals, the blood pressure (SBP: 140.8 vs. 132.9 mmHg; MAP: 104.2 vs. 98.7 mmHg) and prevalence of hypertension (58.8 vs. 32.8%) were significantly higher in high salt (HS) diet group than in normal salt (NS) diet group, but not in the salt-resistant (SR) individuals (P > 0.05). Serum H3K4me1 level (287.3 vs. 179.7 pg/ml, P < 0.05) significantly increased in HS group of SS individuals, but not in SR individuals. We found daily salt intake in SS individuals was positively correlated with serum H3K4me1 (r = 0.322, P = 0.005) and Set7 (r = 0.340, P = 0.005) levels after adjusting for age and gender, but not with LSD-1 (r = −0.137, P = 0.251). In addition, positive correlation between the serum H3K4me1 level and Set7 level (r = 0.326, P = 0.007) was also found in SS individuals. These correlations were not evident in SR individuals.ConclusionOur study indicates that high salt diet increases the serum H3K4me1 and Set7 levels in SS individuals.

Role of Black Salt to Reduce in Hypertension, Reality and Evidence Based Studies

Salt in diet is very important to make our life healthy and energetic. Quantity and quality of salt with appropriate ratio or balance in electrolytes which are responsible for volume of body, blood velocity, for functions of receptors and enzymes, to prevent inflammation, proliferation and to make balance in muscles contraction and nerve conduction through to avoid high stimulation of sympathetic nervous system. Hence, scanning and focus with monitoring and supply of healthy salt in limits may prevent volume overload, renal dysfunction &amp; left ventricular hypertrophy, to prevent cardiac functions, to avoid the weaken gut immunity and also to prevent cerebral oedema, cerebral aneurysm and hypertension cause stroke. Control of salt with intake of low quantity and high quality with more frequency of intervals during 24 hours in required amount of salt in balanced electrolytes may help to avoid high salt sensitivity. Balanced salt intake is also important to avoid volume expansion and obesity with reduction of insulin resistance leads to prevent hypertension and diabetes which are leading risk factors for cardio-renal syndrome, cardiovascular morbidity and mortality. Our data suggested a 2.5-fold higher risk for high blood pressure in sea or white salt users versus black salt or Himalayan rock salt which showed more potassium and magnesium with low sodium ions as compared to sea salt.

Metabolomics study of blood pressure salt-sensitivity and hypertension

Background and aimsIdentify novel metabolite associations with blood pressure (BP) salt-sensitivity and hypertension. Methods and resultsThe Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Replication study includes 698 Chinese participants who underwent a 3-day baseline examination followed by a 7-day low-sodium feeding and 7-day high-sodium feeding. Latent mixture models identified three trajectories of blood pressure (BP) responses to the sodium interventions. We selected 50 most highly salt-sensitive and 50 most salt-resistant participants for untargeted metabolomics profiling. Multivariable adjusted mixed logistic regression models tested the associations of baseline metabolites with BP salt-sensitivity. Multivariable adjusted mixed linear regression models tested the associations of BP salt-sensitivity with metabolite changes during the sodium interventions. Identified metabolites were tested for associations with hypertension among 1249 Bogalusa Heart Study (BHS) participants using multiple logistic regression. Fifteen salt-sensitivity metabolites were associated with hypertension in the BHS. Baseline values of serine, 2-methylbutyrylcarnitine and isoleucine directly associated with high salt-sensitivity. Among them, serine indirectly associated with hypertension while 2-methylbutyrylcarnitine and isoleucine directly associated with hypertension. Baseline salt-sensitivity status predicted changes in 14 metabolites when switching to low-sodium or high-sodium interventions. Among them, glutamate, 1-carboxyethylvaline, 2-methylbutyrylcarnitine, 3-methoxytyramine sulfate, glucose, alpha-ketoglutarate, hexanoylcarnitine, gamma-glutamylisoleucine, gamma-glutamylleucine, and gamma-glutamylphenylalanine directly associated with hypertension. Conversely, serine, histidine, threonate and 5-methyluridine indirectly associated with hypertension. Together, these metabolites explained an additional 7% of hypertension susceptibility when added to a model including traditional risk factors. ConclusionsOur findings contribute to the molecular characterization of BP response to sodium and provide novel biological insights into salt-sensitive hypertension.

Renal denervation alters ambulatory blood pressure-derived salt sensitivity index in patients with uncontrolled hypertension.

Renal denervation (RDN) has been proven in multiple sham-controlled trials to lower blood pressure (BP) in various forms of hypertension. RDN-mediated interruption of sympathetic signaling through its effects on renal blood flow, salt retention, and renin release are likely contributors to the BP-lowering effects. However, the impact of RDN on salt sensitivity in humans has not yet been explored. We, therefore, investigated the effect of RDN on ambulatory BP monitoring-derived salt sensitivity in a cohort of patients with uncontrolled hypertension on habitual salt intake. RDN was performed in 153 hypertensive patients, who were categorized into low intermediate and high-salt sensitivity groups, based on the ambulatory BP monitoring-derived salt sensitivity index estimated prior to (baseline) and at 3, 6 and 12 months after the procedure as previously described. Crude and adjusted mixed effects ordinal regression models were fitted to test for changes in the proportions of salt sensitivity risk during follow-up. The proportions of individuals in the intermediate and high-salt sensitivity risk group increased after RDN and the odds for being in a higher estimated salt sensitivity risk group at 3, 6 and 12 months follow-up compared with baseline were highly significant during the 12 months follow-up period. Increased salt sensitivity after RDN may represent a compensatory mechanism to maintain renal capacity for adequate salt handling. This novel finding may have implications for patient management after RDN, such as prescription of salt moderation to further optimize RDN-induced BP-lowering efficacy.

Advances in Genomics Research of Blood Pressure Responses to Dietary Sodium and Potassium Intakes.

More than half of US adults have hypertension by 40 years of age and a subsequent increase in atherosclerotic cardiovascular disease risk. Dietary sodium and potassium are intricately linked to the pathophysiology of hypertension. However, blood pressure responses to dietary sodium and potassium, phenomena known as salt and potassium sensitivity of blood pressure, respectively, are heterogenous and normally distributed in the general population. Like blood pressure, salt and potassium sensitivity are complex phenotypes, and previous research has shown that up to 75% of individuals experience a blood pressure change in response to such dietary minerals. Previous research has also implicated both high salt sensitivity and low salt sensitivity (or salt resistance) of blood pressure to an increased risk of hypertension and potentially atherosclerotic cardiovascular disease risk. Given the clinical challenges required to accurately measure the sodium and potassium response phenotypes, genomic characterization of these traits has become of interest for hypertension prevention initiatives on both the individual and population levels. Here, we review advances in human genomics research of blood pressure responses to dietary sodium and potassium by focusing on 3 main areas, including the phenotypic characterization of salt sensitivity and resistance, clinical challenges in diagnosing such phenotypes, and the genomic mechanisms that may help to explain salt and potassium sensitivity and resistance. Through this process, we hope to further underline the value of leveraging genomics and broader multiomics for characterizing the blood pressure response to sodium and potassium to improve precision in lifestyle approaches for primordial and primary atherosclerotic cardiovascular disease prevention.

Hypertension, cardiovascular disease, and nocturia: a systematic review of the pathophysiological mechanisms.

Nocturia significantly impairs quality of life, especially in the elderly population, and urinary retention is a main target of treatment for urologists. In addition to nocturia, cardiovascular diseases are common in the elderly population, and a systematic review showed that hypertension and heart failure are often associated with nocturia. One possible pathogenic mechanism underlying the development of hypertension is an increase in blood pressure due to excessive salt intake in people with high-salt sensitivity. From Guyton's natriuretic curve, we can infer that salt-sensitive hypertensive patients who consume too much salt do not excrete salt during the daytime and are forced to excrete salt at night, resulting in increased urine production and nocturia. In patients with heart failure, the nocturnal supine position leads to an increase in central fluid volume due to an increase in venous return from the periphery, and the secretion of natriuretic peptide is stimulated by the stretching of the atria and ventricles. Thus, natriuresis due to hypertension and hydrodiuresis due to heart failure may cause nocturia, which can effectively be treated by the administration of thiazide diuretics and loop diuretics in the morning, respectively. Because cardiovascular diseases, such as hypertension and heart failure, can cause nocturia and because the treatment methods differ depending on the cause, it is necessary to pay close attention to nocturia in the management of lifestyle-related diseases, such as cardiovascular disease.

Clinical significance of nocturnal home blood pressure monitoring and nocturnal hypertension in Asia.

Nocturnal home blood pressure (BP) monitoring has been used in clinical practice for ~20 years. The authors recently showed that nocturnal systolic BP (SBP) measured by a home BP monitoring (HBPM) device in a Japanese general practice population was a significant predictor of incident cardiovascular disease (CVD) events, independent of office and morning home SBP levels, and that masked nocturnal hypertension obtained by HBPM (defined as nocturnal home BP ≥ 120/70 mmHg and average morning and evening BP < 135/85 mmHg) was associated with an increased risk of CVD events compared with controlled BP (nocturnal home BP < 120/70 mmHg and average morning and evening BP < 135/85 mmHg). This evidence revealed that (a) it is feasible to use a nocturnal HBPM device for monitoring nocturnal BP levels, and (b) such a device may offer an alternative to ambulatory BP monitoring, which has been the gold standard for the measurement of nocturnal BP. However, many unresolved clinical problems remain, such as the measurement schedule and conditions for the use of nocturnal HBPM. Further investigation of the measurement of nocturnal BP using an HBPM device and assessments of the prognostic value are thus warranted. Asians are at high risk of developing nocturnal hypertension due to high salt sensitivity and salt intake, and the precise management of their nocturnal BP levels is important. Information and communication technology‐based monitoring devices are expected to facilitate the management of nocturnal hypertension in Asian populations.

Polyacrylonitrile-based carbon nanofibers as a matrix for laser desorption/ionization time-of-flight mass spectrometric analysis of small molecules under both positive and negative ionization modes.

Carbon fiber (CNF), prepared by carbonization of electrospun polyacrylonitrile (PAN) fibers, is systematically investigated as a mediator to replace conventional organic matrices for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-MS). CNF exhibits a high salt tolerance, sensitivity, and resolution for organic matrix-free laser desorption/ionization time-of-flight mass spectrometry (LDI-MS) analysis of various analytes under both positive and negative ionization modes. Especially, saccharides, a neutral molecule having low negative ionization efficiency, are successfully detected with CNF. Taken together, this study clearly demonstrates CNF is a promising material to develop an efficient and universal platform for LDI-MS analysis regardless of preferential ionization modes of analytes. Graphical abstract.

Firibastat: An Oral First-in-Class Brain Aminopeptidase A Inhibitor for Systemic Hypertension.

Systemic hypertension is the leading cause of death and disability worldwide. The management of hypertension is challenging in the high-risk patient population with high salt-sensitivity and low serum renin levels. The renin-angiotensin system (RAS) plays a central role in blood pressure (BP) regulation. While we have effective medications to act on peripheral RAS, our understanding of brain RAS and its effect on BP regulation is still in an evolving stage. Brain RAS hyperactivity is associated with the development and maintenance of hypertension. In comparison to peripheral RAS, where angiotensin II is the most crucial component responsible for BP regulation, angiotensin III is likely the main active peptide in the brain RAS. Angiotensin II is metabolized by aminopeptidase A into angiotensin III in the brain. EC33 is a potent inhibitor of brain aminopeptidase A tested in animal models. The use of EC33 in conscious spontaneously hypertensive rats, hypertensive deoxycorticosterone acetate-salt rats, and conscious normotensive rat models leads to a reduction in BP. In order to facilitate the passage of EC33 through the blood-brain barrier, the 2 molecules of EC33 were linked by a disulfide bridge to form a prodrug called RB150. RB150, later renamed as QGC001 or firibastat, was found to be effective in animal models and well-tolerated when used in healthy participants. Firibastat was found to be safe and effective in phase 2 trials, and is now planned to undergo a phase 3 trial. Firibastat has the potential to be groundbreaking in the management of resistant hypertension.

Deletion of S-Layer Associated Ig-Like Domain Protein Disrupts the Lactobacillus acidophilus Cell Surface.

Bacterial surface-layers (S-layers) are crystalline arrays of repeating proteinaceous subunits that coat the exterior of many cell envelopes. S-layers have demonstrated diverse functions in growth and survival, maintenance of cell integrity, and mediation of host interactions. Additionally, S-layers can act as scaffolds for the outward display of auxiliary proteins and glycoproteins. These non-covalently bound S-layer associated proteins (SLAPs) have characterized roles in cell division, adherence to intestinal cells, and modulation of the host immune response. Recently, IgdA (LBA0695), a Lactobacillus acidophilus SLAP that possesses a Group 3 immunoglobulin (Ig)-like domain and GW (Gly-Tryp) dipeptide surface anchor, was recognized for its high conservation among S-layer-forming lactobacilli, constitutive expression, and surface localization. These findings prompted its selection for examination within the present study. Although IgdA and corresponding orthologs were shown to be unique to host-adapted lactobacilli, the Ig domain itself was specific to vertebrate-adapted species suggesting a role in vertebrate adaptation. Using a counterselective gene replacement system, igdA was deleted from the L. acidophilus NCFM chromosome. The resultant mutant, NCK2532, exhibited a visibly disrupted cell surface which likely contributed to its higher salt sensitivity, severely reduced adhesive capacity, and altered immunogenicity profile. Transcriptomic analyses revealed the induction of several stress response genes and secondary surface proteins. Due to the broad impact of IgdA on the cellular physiology and probiotic attributes of L. acidophilus, identification of similar proteins in alternative bacterial species may help pinpoint next-generation host-adapted probiotic candidates.

Haptoglobin 1-1 phenotype: A risk factor for 24-hours polyuria.

Haptoglobin (Hp) displays three major phenotypes (Hp 1-1, Hp 2-2 and Hp 2-1). Hp 1-1 has been implicated in high blood pressure and salt sensitivity, and thus may mediate excess urine production. To explore the relationship between Hp polymorphisms and polyuria (>40mL/kg/24hours). Post hoc analysis of a prospective observational study of subjects who completed a renal function profile between October 2011 and February 2015 (n=170). Hp phenotypes were determined by starch gel electrophoresis using haemoglobin-supplemented serum. The distribution of Hp phenotypes in subjects with and without polyuria was compared to a reference group of the same geography and ethnic composition. Diuresis rate, sodium clearance and free water clearance were compared within and between phenotypes. The Hp1 allele frequency was significantly overexpressed in subjects with polyuria compared to the reference group (0.500 vs 0.400, P<.05). Consistently, the Hp 1-1 phenotype was more prevalent in subjects with polyuria compared to the reference group (28% vs 16%, P<.05). In contrast to Hp 2-1/2-2, Hp 1-1 demonstrated no circadian variation in diuresis rate, sodium clearance or free water clearance. A significant association between plasma Hp concentration and 24-hours sodium clearance was observed in Hp 1-1 subjects without polyuria (β=0.222; 95% CI 0.003-0.441; P=.047). The Hp1 allele was more frequent in subjects with polyuria, and participants with the Hp 1-1 phenotype were at greater risk for polyuria. Hp 1-1 subjects demonstrated an altered ability to concentrate urine with a slower continuous excretion of sodium throughout the day. Plasma Hp concentration of Hp 1-1 was positively correlated with 24-hours sodium clearance in subjects without polyuria.

Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins

Despite existing therapy, successful control of hypertension in the United States is estimated at less than 50%. In blacks, hypertension occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure (BP) control, especially in blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population. Two hundred fifty-six overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg BID orally for 2 weeks, then 500 mg BID if automated office blood pressure (AOBP) >140/90 mm Hg; hydrochlorothiazide 25 mg QD was added after 1 month if AOBP ≥160/110 mm Hg). The primary end point was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary end points include diastolic AOBP, 24-hour mean ambulatory BP and safety. Firibastat lowered systolic AOBP by 9.5 mm Hg ( P<0.0001) and diastolic AOBP by 4.2 mm Hg ( P<0.0001). 85% of the subjects did not receive hydrochlorothiazide and were treated with firibastat alone. Significant BP reduction was found across all subgroups regardless age, sex, body mass index, or race. Systolic AOBP decreased by 10.2 mm Hg ( P<0.0001) in obese patients, by 10.5 mm Hg ( P<0.0001) in blacks, and 8.9 mm Hg ( P<0.0001) in nonblacks. Most frequent adverse events were headaches (4%) and skin reactions (3%). No angioedema was reported. No change in potassium, sodium, and creatinine blood level were observed. Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant hypertension. URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03198793.