Classes Of Antihypertensive Agents Research Articles

Orthostatic Hypotension in Adults With Hypertension: A Scientific Statement From the American Heart Association.

Although orthostatic hypotension (OH) has long been recognized as a manifestation of autonomic dysfunction, a growing body of literature has identified OH as a common comorbidity of hypertension. This connection is complex, related to pathophysiology in blood pressure regulation and the manner by which OH is derived as the difference between 2 blood pressure measurements. While traditional therapeutic approaches to OH among patients with neurodegenerative disorders focus on increasing upright blood pressure to prevent cerebral hypoperfusion, the management of OH among patients with hypertension is more nuanced; resting hypertension is itself associated with adverse outcomes among these patients. Although there is substantial evidence that intensive blood pressure treatment does not cause OH in the majority of patients with essential hypertension, some classes of antihypertensive agents may unmask OH in patients with an underlying autonomic impairment. Practical steps to manage OH among adults with hypertension start with (1) a thorough characterization of its patterns, triggers, and cause; (2) review and removal of aggravating factors (often pharmacological agents not related to hypertension treatment); (3) optimization of an antihypertensive regimen; and (4) adoption of a tailored treatment strategy that avoids exacerbating hypertension. These strategies include countermaneuvers and short-acting vasoactive agents (midodrine, droxidopa). Ultimately, further research is needed on the epidemiology of OH, the impact of hypertension treatment on OH, approaches to the screening and diagnosis of OH, and OH treatment among adults with hypertension to improve the care of these patients and their complex blood pressure pathophysiology.

Antihypertensive prescribing patterns in non-dialysis dependent chronic kidney disease: Findings from the Salford Kidney Study.

Hypertension is commonly observed in patients living with chronic kidney disease (CKD). Finding an optimal treatment regime remains challenging due to the complex bidirectional cause-and-effect relationship between hypertension and CKD. There remains variability in antihypertensive treatment practices. To analyze data from the Salford Kidney Study database in relation to antihypertensive prescribing patterns amongst CKD patients. The Salford Kidney Study is an ongoing prospective study that has been recruiting CKD patients since 2002. All patients are followed up annually, and their medical records including the list of medications are updated until they reach study endpoints [starting on renal replacement therapy or reaching estimated glomerular filtration rate (eGFR) expressed as mL/min/1.73 m2 ≤ 10 mL/min/1.73 m2, or the last follow-up date, or data lock on December 31, 2021, or death]. Data on antihypertensive prescription practices in correspondence to baseline eGFR, urine albumin-creatinine ratio, primary CKD aetiology, and cardiovascular disease were evaluated. Associations between patients who were prescribed three or more antihypertensive agents and their clinical outcomes were studied by Cox regression analysis. Kaplan-Meier analysis demonstrated differences in survival probabilities. Three thousand two hundred and thirty non-dialysis-dependent CKD patients with data collected between October 2002 and December 2019 were included. The median age was 65 years. A greater proportion of patients were taking three or more antihypertensive agents with advancing CKD stages (53% of eGFR ≤ 15 mL/min/1.73 m2 vs 26% of eGFR ≥ 60 mL/min/1.73 m2, P < 0.001). An increased number of patients receiving more classes of antihypertensive agents was observed as the urine albumin-creatinine ratio category increased (category A3: 62% vs category A1: 40%, P < 0.001), with the upward trends particularly noticeable in the number of individuals prescribed renin angiotensin system blockers. The prescription of three or more antihypertensive agents was associated with all-cause mortality, independent of blood pressure control (hazard ratio: 1.15; 95% confidence interval: 1.04-1.27, P = 0.006). Kaplan-Meier analysis illustrated significant differences in survival outcomes between patients with three or more and those with less than three antihypertensive agents prescribed (log-rank, P < 0.001). Antihypertensive prescribing patterns in the Salford Kidney Study based on CKD stage were consistent with expectations from the current United Kingdom National Institute of Health and Care Excellence guideline algorithm. Outcomes were poorer in patients with poor blood pressure control despite being on multiple antihypertensive agents. Continued research is required to bridge remaining variations in hypertension treatment practices worldwide.

1512-P: The Novel Roles of Intracellular Calcium and Phosphoinositides in Insulin Signaling and Metabolic Disease

Insulin resistance is closely associated with elevated intracellular Ca2+ concentration under ectopic lipid accumulation and hyperglycemia-induced intracellular stress conditions. We recently identified that obesity impairs intracellular Ca2+ homeostasis, which prevents membrane localization of PH domain-containing proteins such as AKT, PLCδ, and IRS through the formation of Ca2+-phosphoinositides (PIPs), resulting in dysregulation of glucose homeostasis and insulin resistance. It is unclear, however, whether insulin sensitivity can be improved by targeting intracellular Ca2+ overload. Therefore, we screened nine angiotensin-II-receptor blockers (ARBs), a class of antihypertensive agents, for beneficial effects on palmitic acid (PA)-induced insulin resistance in human HepG2 cells. Two of the ARBs attenuated PA-induced intracellular Ca2+ overload by inhibiting dysregulated store-operated channel (SOC)-mediated Ca2+ entry into cells, which ameliorated insulin resistance by promoting insulin-stimulated membrane localization of AKT and by increasing the phosphorylation of AKT and its downstream substrates in PA-treated HepG2 cells. Furthermore, certain ARBs ameliorated obesity-induced insulin resistance, hepatic steatosis, and tissue inflammation in mice fed a high-fat diet. Meanwhile, certain ARBs normalized intracellular Ca2+ homeostasis by regulating obesity-associated SOC-mediated Ca2+ entry, which rescued impaired insulin signaling in liver and muscle tissues by promoting postprandial membrane localization of AKT and IRS2. These findings underscore the contribution of dysregulated intracellular Ca2+ homeostasis to the pathophysiology of insulin resistance and suggest a therapeutic strategy to use specific ARBs to ameliorate insulin resistance. Disclosure J.Lee: None. Y.Jung: None. S.Im: None. D.Lee: None. H.Lee: None. I.Hong: None. O.Kim: None. B.Oh: None. Funding Korean Ministry of Health &amp; Welfare (HI14C1135 to B-C.O.); Basic Science Research Program (2021R1I1A1A01051429 to O-H.K.); Mid-Career Researcher Program (2019R1A2C2008130, 2022R1A2C2092700 to B-C.O.); National Research Foundation of Korea (2021R1A5A203033)

SEQUENTIAL NEPHRON BLOCKADE VERSUS DUAL RENIN-ANGIOTENSIN SYSTEM BLOCKADE IN TRUE RESISTANT HYPERTENSIVE PATIENTS: A SYSTEMATIC REVIEW

Objective: True resistant hypertension (RHTN) is a challenging medical condition in which the blood pressure remains uncontrolled despite the use of three different classes of antihypertensive agents at maximum tolerated dose. In order to reduce the sodium and volume overload in these patients and bring the blood pressure to acceptable levels, several pharmacologic agents that promote sequential nephron blockade (SNB) or dual renin- angiotensin system blockade (DRASB) can be used. Therefore, this review aims to evaluate the data presented in some clinical trials comparing the SNB to the DRASB. Design and method: A systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was conducted in MEDLINE, Cochrane Library, EMBASE and LILACS, resulting in a total of 123 articles. One abstract and 4 randomized controlled trials were selected to be assessed in this review. Results: Both treatments decreased systolic blood pressure and diastolic blood pressure in ambulatory blood pressure monitoring. In one of the protocols, the decreases in the SNB group were significantly greater than in the DRASB group. A sub-analysis showed that the improvements in blood pressure were significant only in those with acceptable adherence to treatment. The two interventions reduced office blood pressure, with one study indicating that the reduction was superior in SNB. In markers of arterial stiffening and aging, there were no significant improvements. Pulse wave velocity and common carotid artery stiffness were similar in both groups and tended to decrease. One of the studies showed improvement in echocardiographic parameters for diastolic dysfunction. Conclusions: Despite the improvements in blood pressure in both groups, SNB therapy has a higher potential as a treatment for RHTN, especially when there is good adherence to the medication. Also, SNB tended to improve arterial stiffness and diastolic dysfunction. Nonetheless, there is a need for more studies for a better evaluation of these outcomes.

PS-P15-9: EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON HOME BLOOD PRESSURE AND CARDIAC HYPERTROPHY IN HYPERTENSIVE PATIENTS WITH LVH (ESES-LVH STUDY)

Objective: Cardiac hypertrophy is a prognostic factor in hypertensive patients, and attenuation of the hypertrophy with sustained antihypertensive treatment is important to delay the progression to heart failure. Although most classes of antihypertensive agents have evidence of cardiac hypertrophy regression, there is insufficient evidence for mineralocorticoid receptor blockers (MRB); only one report states that MRB has a more pronounced regressive effect when used in combination with a renin-angiotensin system (RAS) inhibitor. Esaxerenone is a novel selective nonsteroidal MRB which has been recently approved for the treatment of hypertension, to date however, there is little evidence of the effectiveness and safety of esaxerenone in hypertensive patients with cardiac hypertrophy. The study was aimed to evaluate the effectiveness and safety of esaxerenone in Japanese hypertensive patients with left ventricular hypertrophy (LVH) whose blood pressure (BP) was inadequately controlled with a RAS inhibitor or calcium channel blocker (CCB). Design and method: ESES-LVH study (jRCTs071190043) was a multicenter, open-label, interventional study. Main inclusion criteria were hypertensive patients (20 years) with morning and bedtime home BP: 135–159 mmHg systolic BP (SBP) and/or 85–99 mmHg diastolic BP (DBP) taking a RAS inhibitor or CCB, and patients with LVH (diagnosed with echocardiography, ECG, or left ventricular mass index [LVMI]). Over the 24-week study period, the initial dose of esaxerenone was started at 1.25 or 2.5 mg/day, and increased to 5 mg/day at weeks 4 and 8, based on the individual patient's condition. The primary endpoints were change from baseline in morning home BP, and change and %change in LVMI, at the end of treatment (EOT). Secondary endpoints included changes in bedtime home and office BP, proportion of patients achieving target BP, changes in echocardiographic parameters, and safety variables including adverse events, eGFR, and serum potassium levels. Results: Baseline characteristics of the 58 enrolled patients were mean age, 64.8 years; male, 70.7%; RAS inhibitor/CCB, 32.8/67.2%; mean morning home SBP/DBP, 142.8/85.0 mmHg; mean LVMI 118.1 g/m2; left ventricular ejection fraction 62.8%; serum potassium level 4.1 mEq/L; and mean eGFRcreat 71.3 mL/min/1.73m2. Mean change from baseline at EOT was -11.5/-4.7 mmHg in the morning home BP, and mean change and % change in LVMI were -9.9 g/m2 and-8.5%, respectively (p &lt; 0.001 each). Detailed effectiveness and safety results will be presented. Conclusions: ESES-LVH study will provide the first clinical evidence of not only the antihypertensive and LVH-regressive effects of esaxerenone, but also its safety in Japanese hypertensive patients with cardiac hypertrophy.

Abstract 10138: Evening Blood Pressure and Heart Rate: An Age-Specific Association of Nocturia in the Japanese at High-Risk of Cardiovascular Disease

Background: Earlier epidemiologic studies have reported a significant relationship between hypertension and nocturia. However, the underlying pathophysiology has not been established in relation to heart rate (HR). Hypothesis: We hypothesized that blood pressure (BP), HR, and the class of antihypertensive agent might be associated with severity of nocturia in the Japanese at high-risk of cardiovascular disease. In addition, these associations were hypothesized to be moderated by age. Methods: In the Japan Morning Surge-Home Blood Pressure Study, measurements of home BP as well as HR at evening (mean 11.2 days) were performed in the 4310 patients with one or more cardiovascular risks (64.9 years old, male 47%). A self-administered questionnaire included items on nocturia was used. Results: The mean levels of evening systolic BP (SBP) and HR were 130±15mmHg and 70±9.6bpm, respectively. According to the number of nocturia, we divided into the three groups (no void: n= 2382; one void: n=847; &gt; 2 voids per night: n=1082). In the multinomial logistic regression analysis adjustment for confounders including age, gender, smoking, total cholesterol, fasting blood glucose, HbA1c, log B-type natriuretic peptide, beta-adrenergic blockade use, clinic SBP and clinic HR, the use of diuretics (OR, 1.23, 95%CI, 1.01-1.50, p&lt;0.05) was significantly associated with one nocturnal void, while evening SBP (OR per 1SD, 1.14, 95%CI, 1.05-1.24, p&lt;0.01) and evening HR (OR per 1SD, 1.12, 95%CI: 1.02-1.24, p&lt;0.05) were significantly associated with multiple nocturnal voids. In the lower aged group (&lt;66yrs), only evening HR remained significant (p=0.003), while only evening SBP remained significant for multiple nocturnal voids in the higher aged group (66yrs &lt; ) (p=0.007). A significant interaction was found between age and evening HR for multiple nocturnal voids (p&lt;0.05). Conclusions: In this study, evening SBP and evening HR were significant indicators of multiple nocturnal voids in the high-risk Japanese population. Increased evening HR was specifically associated with severe nocturia in the lower aged group. Age-stratified approach to reduce BP and HR burdens might be important to improve sleep disturbance caused by nocturia.

Sex-specific associations of evening blood pressure burden and cardiac load with nocturia severity in the Japanese at high-risk of cardiovascular disease

Abstract Background Earlier epidemiologic studies have reported a significant relationship between hypertension and nocturia. However, the underlying pathophysiology has not been established. We hypothesized that blood pressure (BP) burden, the classes of antihypertensive agents and cardiac load were associated with severity of nocturia, and that these associations might be moderated by gender. Purpose To investigate the relationships of home BP (HBP) level, the class of antihypertensive agent, brain natriuretic peptide (BNP) with nocturia severity, and to investigate these associations stratified by gender in the Japanese at high-risk of cardiovascular disease. Methods In the Japan Morning Surge-Home Blood Pressure Study, measurements of HBP at evening (mean 11.2 days) as well as BNP were performed in the 4310 patients with one or more cardiovascular risks (64.9 years old, male 47%). A self-administered questionnaire included items on nocturia was used. Results According to the number of nocturia (no void: n=2382; one void: n=847; &amp;gt;2 voids per night: n=1082), significant associations of systolic BP (SBP) at evening (130 vs 130 vs 132 mmHg, p&amp;lt;0.0001) and logBNP (1.20 vs 1.30 vs 1.42, p&amp;lt;0.0001) were observed with nocturia severity. In the multinomial logistic regression analysis adjustment for confounders including age, smoking, total cholesterol, fasting blood glucose, HbA1c and clinic SBP, the use of diuretics (OR: 1.26, 95% CI: 1.06–1.52, p&amp;lt;0.05) was significantly associated with one nocturnal void, while evening SBP (OR: 1.009, 95% CI: 1.003–1.014, p&amp;lt;0.01) and logBNP (1.43, 95% CI: 1.19–1.73, p&amp;lt;0.001) were significantly associated with multiple nocturnal voids. While no significant interaction was found between evening SBP and logBNP for multiple nocturnal voids in the total population, a significant interaction was found between evening SBP and logBNP for multiple nocturnal voids in females (p&amp;lt;0.05). Conclusions In this study, the use of diuretics was a significant indicator of single nocturnal void, while evening SBP and BNP were those of multiple nocturnal voids in the high-risk Japanese population. Specifically, in the females, treatment to reduce BP burden as well as cardiac overload might be important to improve sleep disturbance caused by nocturia. Funding Acknowledgement Type of funding sources: None.

Robust estimation of heterogeneous treatment effects: an algorithm-based approach

Heterogeneous treatment effect estimation is an essential element in the practice of tailoring treatment to suit the characteristics of individual patients. Most existing methods are not sufficiently robust against data irregularities. To enhance the robustness of the existing methods, we recently put forward a general estimating equation that unifies many existing learners. But the performance of model-based learners depends heavily on the correctness of the underlying treatment effect model. This paper addresses this vulnerability by converting the treatment effect estimation to a weighted supervised learning problem. We combine the general estimating equation with supervised learning algorithms, such as the gradient boosting machine, random forest, and artificial neural network, with appropriate modifications. This extension retains the estimators’ robustness while enhancing their flexibility and scalability. Simulation shows that the algorithm-based estimation methods outperform their model-based counterparts in the presence of nonlinearity and non-additivity. We developed an R package, RCATE, for public access to the proposed methods. To illustrate the methods, we present a real data example to compare the blood pressure-lowering effects of two classes of antihypertensive agents.

A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre‐eclampsia

A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre‐eclampsia

Calcium Channel Blockers Are Associated with Nocturia in Men Aged 40 Years or Older.

Background: The associations of nocturia with hypertension and anti-hypertensive agents (AHTs) remain to be validated. Methods: This cross-sectional study examined whether blood pressure and/or frequently used classes of AHTs had consistent associations with nocturia. Methods: A total of 418 male patients aged ≥ 40 years were retrospectively assessed in terms of the International Prostate Symptom Score (IPSS), prescription medications, and blood pressure. Nocturia was evaluated using item 7 of the IPSS, and two or more episodes of nocturia per night was considered to indicate clinically important nocturia. Results: Patients taking calcium channel blockers (CCBs), but not other AHTs, experienced more episodes of nocturia than patients not taking AHTs (1.77 ± 1.07, 1.90 ± 1.19, and 1.48 ± 0.98 in CCBs alone, CCBs + other AHTs, and other AHTs alone, vs. 1.35 ± 1.08 in not taking AHTs; p = 0.014, p < 0.0001, and p = 0.91, respectively), whereas there was no significant difference in the number of nocturia episodes between patients with elevated and normal blood pressure. In multivariate analysis, CCB (odds ratio (OR) = 2.68, p < 0.0001) and age (OR = 1.06, p < 0.0001) were independently associated with clinically important nocturia. Conclusion: CCB was associated with nocturia, while AHTs other than CCBs and elevated blood pressure were not.

Cardiovascular disease history and β-blocker prescription patterns among Japanese and American patients with CKD: a cross-sectional study of the CRIC and CKD-JAC studies.

Cardiovascular disease (CVD) is a major complication in individuals with chronic kidney disease (CKD). In Japan, the incidence of CVD among persons with CKD is lower than that in the United States. Although various classes of antihypertensive agents are prescribed to prevent CVD, the proportion varies between the United States and Japan. Until now, few studies have compared clinical practices and CVD prevalence among patients with CKD in the United States vs. Japan. In this study, we performed a cross-sectional comparison of the prevalence of CVD and the prescription of β-blockers at study entry to the Chronic Kidney Disease Japan Cohort (CKD-JAC) Study and the Chronic Renal Insufficiency Cohort (CRIC) Study. The mean patient age was 58.2 and 60.3 years, the mean estimated glomerular filtration rate (eGFR) was 42.8 and 28.9 (mL/min/1.73 m2), and the median urinary albumin:creatinine ratio was 51.9 and 485.9 (mg/g) among 3939 participants in the CRIC Study and 2966 participants in the CKD-JAC Study, respectively. The prevalence of any CVD according to a self-report (CRIC Study) was 33%, while that according to a medical chart review (CKD-JAC Study) was 24%. These findings were consistent across eGFR levels. Prescriptions for β-blockers differed between the CRIC and CKD-JAC Studies (49% and 20%, respectively). The odds ratios for the association of any history of CVD and β-blocker prescription were 3.0 [2.6-3.5] in the CRIC Study and 2.0 [1.6-2.5] in the CKD-JAC Study (P < 0.001 for the interaction). In conclusion, the prevalence of CVD and treatment with β-blockers were higher in the CRIC Study across eGFR levels.

Sound Science before Quick Judgement Regarding RAS Blockade in COVID-19.

There has been much speculation in journals as well as social and traditional media about a link between popularly used classes of drugs that inhibit the renin-angiotensin system (RAS) and novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) infection or coronavirus

Trends of antihypertensive agents in patients with hypertension and coronary artery disease in a tertiary hospital of China.

Background Except for hypertension control, antihypertensive agents play an essential role in the secondary prevention of coronary artery disease. Objective This study aimed to describe the use of antihypertensive agents in patients with hypertension and coronary artery disease by assessing the compliance to the updated European and Chinese hypertension guidelines through analyzing the frequencies, monthly trends and the influencing factors of antihypertensive agents. Setting Beijing Friendship Hospital, Capital Medical University, a 2000-bed tertiary Chinese university teaching hospital. Method Prescriptions of patients diagnosed with hypertension and coronary artery disease were extracted from medical records of this tertiary hospital from 2013 to 2016. Frequencies, trends, co-existing prescription patterns of five classes of antihypertensive agents were analyzed. Influencing factors of prescription patterns were evaluated by logistic regression. Main outcome measure The frequencies and monthly trends of different antihypertensive agents within four years. Result In total, 286,155 prescriptions met the inclusion criteria. β-blockers (64,0%) were the most widely used antihypertensive agents, followed by calcium channel blockers (53.57%), angiotensin receptor blockers (42.6%), angiotensin-converting-enzyme inhibitors (23.7%) and diuretics (16.4%). During the 4years, frequencies of β-blockers, angiotensin receptor blockers, calcium channel blockers and diuretics increased over time, while that of angiotensin-converting-enzyme inhibitors declined. Multivariate logistic regression indicated that gender, age and comorbidities including stroke, diabetes, heart failure and arrhythmia could affect antihypertensive selections to varying degrees. Conclusion The compliance to guidelines is overall well for patients with hypertension and coronary artery disease, but improvements is needed for patients with type 2 diabetes. Multi-center studies with large-scale data are required to further assess the usage of antihypertensive agents in patients.

DETERMINATION OF IN VITRO OUTLET OF LIZINOPRIL CONTAINING MEDICAL PREPARATION ”LIZINOCOR” AND ITS ANALOGUE USING METHOD OF HIGHPERFORMANCE LIQUID CHROMATOGRAPHY

ACE Inhibitors represent the first class of anti hypertensive agents that was designed and developed on the basis of a well-defined physiopathol ogical axis of arterial hypertension, a vascular disorder that is now becoming one of the major causes of morbidity/mortality, not only in developed societies but also in the highly populated developing countries. An angiotensin-converting enzyme (ACE) inhibitor, the carboxylalkyl compounds derivated lizinopril is apharmaceutical drug, used primarily for the treatment of hypertension (elevated blood pressure) and congestive heart failure. Purpose of investigation was – comparison of in vitro outlet of 5 mg tablets of ”Lizinocor” containing Lizinopril , produced by the Georgian pharmaceutical company “GMP” and its analogue ”Zestril” using method of high-performance liquid chromatography. According to the received results average percent quantity outlet of ”lizinocor” is 97,65 %, ”Zestril” – 95, 88%;. Inclination in comparison with Zestril is 1,85 %, (norm ± 5 %). ”Lizinocor” 5 mg tablets containing Lizinopril produced by the Georgian pharmaceutical company ”GMP” are characterized by good outlet quality.

What is New in New Generation Calcium Channel Blocker

Hypertension is a multifactorial and multisystem disease in which elevated blood pressure is only one sign of multiple underlying physiological abnormalities. It affects approximately 26% of the population worldwide. Hypertension is one of the leading cause of death as a "silent killer". Several classes of antihypertensive agents have been in clinical use, but CCBs exert most potent antihypertensive action and are widely used as a first line antihypertensive drug in elderly with very few contraindication.Four generations of dihydropyridines CCBs are now available.The fourth-generation highly lipophilic dihydropyridines, lercanidipine, cilnidipine and lacidipine are now available which provide a real degree of therapeutic comfort in terms of stable activity, a reduction in adverse effects and a broad therapeutic spectrum. Cilnidipine is a recently developed CCB, and possesses both L- and N-type calcium channel blocking activity.Cilnidipine causing less reflex tachycardia, less pedal edema, better control of proteinuria, suppressing podocyte damage, increasing insulin sensitivity.This article reviews the current understanding of the pharmacological profile and clinical utility of cilnidipine as a unique antihypertensive drug.&#x0D; Anwer Khan Modern Medical College Journal Vol. 10, No. 1: Jan 2019, P 77-83

P4554Central-acting aminopeptidase a inhibitors for new treatment of hypertension: from discovery to clinical trial

Abstract The hyperactivity of the brain renin–angiotensin system (RAS) has been implicated in the development and maintenance of arterial hypertension (HTA). Our aim was to demonstrate that normalizing brain RAS hyperactivity could constitute a new therapeutic approach for HTA treatment We first demonstrated in the brain that aminopeptidase A (APA) is the enzyme generating angiotensin III (AngIII) from AngII. Then, using the specific and selective APA inhibitor, EC33 ((3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid), we showed that AngIII is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in hypertensive rats. This suggests that brain APA may be a potential therapeutic target for HTA treatment. We then designed RB150 {4,4-dithio[bis(3-aminobutyl sulfonic acid)]}, an orally active prodrug of EC33. RB150, given orally in conscious deoxycorticosterone acetate-salt (DOCA-salt) rats or spontaneously hypertensive rats, crosses the intestinal, hepatic and blood-brain barriers, enters the brain, where it is cleaved by brain reductases, generating two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and induce a marked and sustained decrease in BP. The RB150-induced BP decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances and the improvement of the baroreflex function (Figure below). RB150 was renamed firibastat by OMS. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well-tolerated in healthy volunteers. Firibastat could constitute the first drug candidate of a new class of antihypertensive agents targeting the brain RAS, the clinical efficacy of which (Phase IIa and Phase IIb) in hypertensive patients was achieved. Acknowledgement/Funding INSERM, College de France, ANR LabCom, Quantum Genomics

Visit-to-visit Blood Pressure Variability and Arterial Stiffness: Which Came First: The Chicken or the Egg?

Earlier studies have shown that visit-to-visit blood pressure (BP) variability (VVV) served as a significant independent risk factor of stroke, specifically, in the high-risk elderly of cardiovascular disease (CVD). Although the mechanism is not clearly understood, arterial remodeling such as carotid artery, coronary artery and large aortic artery would be a strong moderator in the relationship between VVV and CVD incidence. Recent studies have provided evidence that VVV predicted the progression of arterial stiffness. While the class of antihypertensive agents is suggested to be an important determinant of VVV, long-acting calcium channel blockers use (CCBs) is associated with the reduction of VVV, and thus, is suggested to decrease the arterial stiffness. Specifically, the relationship between VVV and coronary arterial remodeling has never been reviewed until now. This article summarizes the recent literature on these topics. In the elderly hypertensives, strict BP control using CCBs could play a pivotal role in suppressing arterial stiffening via VVV reduction.

Potential Deep Brain Stimulation Targets for the Management of Refractory Hypertension.

Hypertension is the single greatest contributor to human disease and mortality affecting over 75 million people in the United States alone. Hypertension is defined according to the American College of Cardiology as systolic blood pressure (SBP) greater than 120 mm Hg and diastolic blood pressure (DBP) above 80 mm Hg measured on two separate occasions. While there are multiple medication classes available for blood pressure control, fewer than 50% of hypertensive patients maintain appropriate control. In fact, 0.5% of patients are refractory to medical treatment which is defined as uncontrolled blood pressure despite treatment with five classes of antihypertensive agents. With new guidelines to define hypertension that will increase the incidence of hypertension world-wide, the prevalence of refractory hypertension is expected to increase. Thus, investigation into alternative methods of blood pressure control will be crucial to reduce comorbidities such as higher risk of myocardial infarction, cardiovascular accident, aneurysm formation, heart failure, coronary artery disease, end stage renal disease, arrhythmia, left ventricular hypertrophy, intracerebral hemorrhage, hypertensive enchaphelopathy, hypertensive retinopathy, glomerulosclerosis, limb loss due to arterial occlusion, and sudden death. Recently, studies demonstrated efficacious treatment of neurological diseases with deep brain stimulation (DBS) for Tourette’s, depression, intermittent explosive disorder, epilepsy, chronic pain, and headache as these diseases have defined neurophysiology with anatomical targets. Currently, clinical applications of DBS is limited to neurological conditions as such conditions have well-defined neurophysiology and anatomy. However, rapidly expanding knowledge about neuroanatomical controls of systemic conditions such as hypertension are expanding the possibilities for DBS neuromodulation. Within the central autonomic network (CAN), multiple regions play a role in homeostasis and blood pressure control that could be DBS targets. While the best defined autonomic target is the ventrolateral periaqueductal gray matter, other targets including the subcallosal neocortex, subthalamic nucleus (STN), posterior hypothalamus, rostrocaudal cingulate gyrus, orbitofrontal gyrus, and insular cortex are being further characterized as potential targets. This review aims to summarize the current knowledge regarding neurologic contribution to the pathophysiology of hypertension, delineate the complex interactions between neuroanatomic structures involved in blood pressure homeostasis, and then discuss the potential for using DBS as a treatment for refractory hypertension.

A3401 A case report of a 33-year-old man with resistant hypertension and slightly elevated cortisol and aldosterone

Objectives: Describe a unusual case of familial glucocorticoid resistance (FGR). FGR, an autosomal dominant from of monogenic hypertension, is characterized by hypertension, hypokalemia, metabolic alkalosis but no Cushing syndrome. Here, we describe the case of a 33-year-old man patient with resistant hypertension (mean blood pressure above 180/120mmHg after administration six different classes of antihypertensive agents) and slightly elevated cortisol and aldosterone but no hypokalemia, metabolic alkalosis and Cushing syndrome. Our aim was to find the cause and to control the high blood pressure of the patients. Methods: We did a series of checks and excluded primary aldosteronism and hypercortisolism and other diseases. After the DNA sequencing, we found that the patient had a mutation Pro9Arg (c.26C > G) in the NR3C1 gene and the familial glucocorticoid resistance was diagnosed. Results: After taking 0.75 mg dexamethasone at 8 o’clock and 2 kinds of antihypertensive drugs (a calcium-channel blocker plus an angiotensin-II receptor blocker), the average blood pressure of the patient was below 140/90mmHg. Conclusion: The role of genetic testing and genetic counseling in establishing the early diagnosis of FGR is important. FGR can result in resistant hypertension. C.26C > G in the NR3C1 gene that caused p.Pro9Arg is a new mutation of FGR.

Use of Antihypertensive Agents and Association With Risk of Adverse Outcomes in Chronic Kidney Disease: Focus on Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers.

BackgroundOur objective was to determine patterns of antihypertensive agent use by stage of chronic kidney disease (CKD) and to evaluate the association between different classes of antihypertensive agents with nonrenal outcomes, especially in advanced CKD.Methods and ResultsWe studied 3939 participants of the CRIC (Chronic Renal Insufficiency Cohort) study. Predictors were time‐dependent angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker , β‐blocker, and calcium channel blocker use (versus nonuse of agents in each class). Outcomes were adjudicated heart failure events or death. Adjusted Cox models were used to determine the association between predictors and outcomes. We also examined whether the associations differed based on the severity of CKD (early [stage 2–3 CKD] versus advanced disease [stage 4–5 CKD]). During median follow‐up of 7.5 years, renin‐angiotensin‐aldosterone system inhibitor use plateaued during CKD stage 3 (75%) and declined to 37% by stage 5, while β‐blocker, calcium channel blocker, and diuretic use increased steadily with advancing CKD. Renin‐angiotensin‐aldosterone system inhibitor use was associated with lower risk of heart failure (hazard ratio, 0.79; 95% confidence interval, 0.67–0.97) and death (hazard ratio, 0.78; 95% confidence interval, 0.67–0.90), regardless of severity of CKD. Calcium channel blocker use was not associated with risk of heart failure or death, regardless of the severity of CKD. β‐Blocker use was associated with higher risk of heart failure (hazard ratio, 1.62; 95% confidence interval, 1.29–2.04) and death (hazard ratio, 1.22; 95% confidence interval, 1.03–1.43), especially during early CKD (P<0.05 for interaction).ConclusionsAngiotensin‐converting enzyme inhibitor and angiotensin receptor blocker use decreased, while use of other agents increased with advancing CKD. Use of agents besides angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers may be associated with suboptimal outcomes in patients with CKD.