Treatment Of Resistant Hypertension Research Articles

Management of treatment-resistant ocular hypertension post EyeCee one IOL implantation: an observational study.

Management of treatment-resistant ocular hypertension post EyeCee one IOL implantation: an observational study.

Revisiting resistant hypertension in kidney disease.

As compared to controlled or uncontrolled hypertension, resistant hypertension in patients with chronic kidney disease (CKD) poses a significantly increased healthcare burden due to greater target end-organ damage including cardiovascular disease and CKD progression. Patients with CKD have two to three times higher risk of developing resistant hypertension. True resistant hypertension needs to be distinguished from apparent treatment resistant hypertension (aTRH); however, it is usually not possible in epidemiological studies. Moreover, impact of contemporary guidelines changes in the target blood pressure (BP) goal to less than 130/80 mmHg remains to be determined. Up to half of patients with CKD meet aTRH criteria using 2017 ACC/AHA target BP less than 130/80 mmHg. Excess sodium retention in extracellular and tissue compartment remains the cornerstone cause of resistance to the treatment in CKD. Maximizing and optimizing the diuretic regimen in addition to dietary sodium restriction plays a critical role in these patients. Management requires a trustworthy provider-patient relationship facilitating identification and intervention for the barriers restricting the uptake of lifestyle modifications and medications. Recently, renal denervation has been approved and many other novel agents are on the horizon for treatment of true resistant hypertension associated with CKD. This review discusses the latest in the pathophysiology, definition, identification and treatment strategies of resistant hypertension in individuals with CKD. Further investigations are required to identify the prevalence, future implication and treatment outcome data for true resistant hypertension associated with CKD.

Ocular biomarkers: useful incidental findings by deep learning algorithms in fundus photographs.

Artificial intelligence can assist with ocular image analysis for screening and diagnosis, but it is not yet capable of autonomous full-spectrum screening. Hypothetically, false-positive results may have unrealized screening potential arising from signals persisting despite training and/or ambiguous signals such as from biomarker overlap or high comorbidity. The study aimed to explore the potential to detect clinically useful incidental ocular biomarkers by screening fundus photographs of hypertensive adults using diabetic deep learning algorithms. Patients referred for treatment-resistant hypertension were imaged at a hospital unit in Perth, Australia, between 2016 and 2022. The same 45° colour fundus photograph selected for each of the 433 participants imaged was processed by three deep learning algorithms. Two expert retinal specialists graded all false-positive results for diabetic retinopathy in non-diabetic participants. Of the 29 non-diabetic participants misclassified as positive for diabetic retinopathy, 28 (97%) had clinically useful retinal biomarkers. The models designed to screen for fewer diseases captured more incidental disease. All three algorithms showed a positive correlation between severity of hypertensive retinopathy and misclassified diabetic retinopathy. The results suggest that diabetic deep learning models may be responsive to hypertensive and other clinically useful retinal biomarkers within an at-risk, hypertensive cohort. Observing that models trained for fewer diseases captured more incidental pathology increases confidence in signalling hypotheses aligned with using self-supervised learning to develop autonomous comprehensive screening. Meanwhile, non-referable and false-positive outputs of other deep learning screening models could be explored for immediate clinical use in other populations.

Renal denervation for uncontrolled hypertension: a systematic review and meta-analysis examining multiple subgroups.

This systematic review and meta-analysis was conducted to assess the randomized controlled trial (RCT) evidence available for renal denervation (RDN) in uncontrolled arterial hypertension. Twenty-five RCTs met the eligibility criteria for the systematic review, and 16 RCTs were included in the meta-analysis. The results of the random effects meta-analysis estimated a mean difference of -8.5 mmHg [95% confidence interval (CI) -13.5 to -3.6] for office SBP, -3.6 mmHg (95% CI -5.2 to -2.0) for 24 h SBP and -3.9 mmHg (95% CI -5.6 to -2.2) for ambulatory daytime SBP in favour of RDN compared with control (medication and/or sham-only) at primary follow-up. Similarly favourable results were observed across a range of prespecified subgroup analyses, including treatment-resistant hypertension. This meta-analysis suggests that the use of RDN in uncontrolled hypertension leads to consistent reductions in blood pressure. Reductions appear to be statistically consistent in the presence or absence of medications and in populations resistant to the use of three medications.

Renal Denervation for Uncontrolled Hypertension

What Is the Issue?
 
 It is estimated that 23% of adults in Canada have hypertension. About 1/3 of this population have uncontrolled hypertension, a condition in which (BP) blood pressure levels continue to remain high despite treatment. People with high BP despite being prescribed 3 or more blood pressure-lowering (antihypertensive) medicines are considered to have uncontrolled resistant hypertension.
 Renal denervation is a therapy that involves disrupting activity in the sympathetic nerves in the renal artery using a minimally invasive catheter-based procedure to treat high BP.
 We wanted to know if renal denervation would effectively and safely reduce BP in people with uncontrolled hypertension.
 
 What Did We Do?
 
 We identified and summarized the literature comparing the clinical effectiveness and safety of renal denervation in individuals with uncontrolled hypertension to help guide decisions on the use of this intervention.
 An information specialist searched for peer-reviewed and grey literature sources published between January 1, 2019, and February 5, 2024. The search was limited to English-language documents. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.
 
 What Did We Find?
 
 The evidence for this report was based on 2 systematic reviews and 3 randomized controlled trials (RCTs).
 Renal denervation could lead to a reduction in BP compared to sham in adults with uncontrolled nonresistant hypertension.
 It is uncertain if renal denervation is an effective treatment for resistant hypertension and suspected hypertensive heart disease due to the methodological limitations of the included studies.
 Serious side effects of renal denervation were rare.
 
 What Does This Mean?
 
 Our findings agree with evidence-based guidelines and real-world evidence that suggest renal denervation can be considered a treatment option for patients with uncontrolled nonresistant hypertension. Other factors, including costs and resources, equity, acceptability, and patient selection, should be considered when implementing renal denervation in Canada, where it remains an emerging medical technology.
 Future research should assess important patient outcomes, such as quality of life.

Best-Practice Alert to promote screening for primary aldosteronism among people with apparent treatment resistant hypertension

Guidelines recommend that all people with resistant hypertension (RH) should be screened for primary aldosteronism (PA). However, less than 2% of people with RH are screened for PA. We aimed to develop a non-interruptive Best Practice Alert (BPA) and assess if implementation of the BPA in the Electronic Health Record (EHR) improved the screening rate for PA among people with apparent treatment resistant hypertension (aTRH). We implemented a non-interruptive BPA on 9/17/2022 at our ambulatory Primary care, Endocrinology, Nephrology, and Cardiology clinics. We assessed clinical parameters of people with aTRH before (9/17/2021-9/16/2022) and after (9/17/2022-9/16/2023) the BPA was implemented. The non-interruptive BPA embedded with an order set identified people with aTRH and recommended screening for PA if it was not previously performed. There were 10,944 and 11,463 people with aTRH who attended office visits during the 12 months before and after the BPA implementation, respectively. There were no statistically significant differences in median age (p=0.096), sex (p=0.577), race (p=0.753), and ethnicity (p=0.472) between the pre- and post- BPA implementation groups. There was a significant increase in PA screening orders placed (227 (2.1%) vs 476 (4.2%), p<0.001), and PA screening labs performed (169 (1.5%) vs 382 (3.3%), p<0.001) after BPA implementation. PA screening tests were positive in 26% (44/169) and 23% (88/382) of people in the pre- and post- BPA groups, respectively (p=0.447). In summary, implementation of a real-time EHR BPA doubled the screening rate for PA among people with aTRH however the overall screening rate was low.

CT-guided ozone-mediated lumbar-renal sympathetic denervation for resistant hypertension treatment: A pilot single-arm clinical trial

BackgroundRenal sympathetic denervation (RDN) reduces blood pressure (BP). MethodsThis single-arm open-label study enrolled patients with resistant hypertension (RH) and treat them by CT-guided ozone mediated lumbar-renal sympathetic denervation (L-RDN). The primary endpoint was to assess the changes of BP over 24-h ambulatory BP monitoring (ABPM) and to evaluate the anti-hypertensive medication burden (AHMB) at 3-month follow-up. This study was registered in Chictr.org.cn (ChiCTR2300071375). Results17 patients (mean age 65.12 ± 10.77 years) with AHMB of 4.12 ± 1.11 were enrolled. After the procedure, 7 patients (46.7 %) matched the criteria for antihypertensive medication reduction. The AHMB decreased to 3.87 ± 0.96 for the whole objectives and from 3.87 ± 0.96 to 3.55 ± 0.78 for patients with normal baseline renal function. On top of the lessened AHMB, L-RDN further reduced morning systolic BP (SBP) by −8.6 ± 4.0 mmHg (p = 0.034) and diastolic BP (DBP) by −4.6 ± 2.1 mmHg (p = 0.032) for all participants and morning SBP by −13.2 ± 3.6 mmHg (p < 0.001), morning DBP by −6.2 ± 2.4 mmHg (p = 0.011) and daytime SBP by −4.1 ± 1.6 mmHg (p = 0.009) for those with normal baseline renal function at 3-month of follow-up. No adverse events were reported intra- and post operation. ConclusionsCT-guided ozone-mediated L-RDN might be an innovative approach of RDN for treating RH. Confirmatory studies are warranted.

Prediction of cardiovascular and renal risk among patients with apparent treatment-resistant hypertension in the United States using machine learning methods.

Apparent treatment-resistant hypertension (aTRH), defined as blood pressure (BP) that remains uncontrolled despite unconfirmed concurrent treatment with threeantihypertensives, is associated with an increased risk of developing cardiovascular and renal complications compared with controlled hypertension. We aimed to identify the characteristics of aTRH patients with an elevated risk of major adverse cardiovascular events plus (MACE+; defined as stroke, myocardial infarction, or heart failure hospitalization) and end stage renal disease (ESRD). This retrospective cohort study included aTRH patients (BP ≥140/90mmHg and taking ≥3antihypertensives) from the United States-based Optum® de-identified Electronic Health Record dataset and used machine learning models to identify risk factors of MACE+ or ESRD. Patients had claims for ≥3antihypertensive classes within 30 days between January 1, 2015andJune 30, 2021, and two office BP measures recorded 1-90 days apart within 30 days to 11 months after the index regimen date. Of a total 18797 070 patients identified with any hypertension, 71100 patients had aTRH. During the study period (mean 25.5 months), 4944 (7.0%) patients had a MACE+ and 2403 (3.4%) developed ESRD. In total, 22risk factors were included in the MACE+ model and 16 in the ESRD model, and most were significantly associated with study outcomes. The risk factors with the largest impact on MACE+ risk were congestive heart failure, stages 4 and 5 chronic kidney disease (CKD), age ≥80years, and living in the Southern region of the United States. The risk factors with the largest impact on ESRD risk, other than pre-existing CKD, were anemia, congestive heart failure, and type 2 diabetes. The overall study cohort had a 5-year predicted MACE+ risk of 13.4%; this risk was increased in those in the top 50% and 25% high-risk groups (21.2% and 29.5%, respectively). The overall study cohort had a predicted 5-year risk of ESRD of 6.8%, which was increased in the top 50% and 25% high-risk groups (10.9% and 17.1%, respectively). We conclude that risk models developed in our study can reliably identify patients with aTRH at risk of MACE+ and ESRD based on information available in electronic health records; such models may be used to identify aTRH patients at high risk of adverse outcomes who may benefit from novel treatment interventions.

Echocardiographic findings following renal sympathetic denervation for treatment resistant hypertension, the ReShape CV-risk study

Objective The aim of this study was to describe and compare echocardiographic findings before renal sympathetic denervation (RDN) and 6 and 24 months after the procedure. Materials and methods Patients with treatment resistant hypertension (TRH) were included in this non-randomised intervention study. RDN was performed by a single experienced operator using the Symplicity Catheter System. Echocardiographic measurements were performed at baseline, and after 6 and 24 months. Results The cohort consisted of 21 patients with TRH, with a mean systolic office blood pressure (BP) of 163 mmHg and mean diastolic BP 109 mmHg. Mixed model analysis showed no significant change in left ventricular (LV) mass index (LVMI) or left atrium volume index (LAVI) after the RDN procedure. Higher LVMI at baseline was significantly associated with greater reduction in LVMI (p < 0.001). Relative wall thickness (RWT) increased over time (0.48 mm after two years) regardless of change in BP. There was a small but significant reduction in LV end-diastolic (LVIDd) and end-systolic (LVIDs) diameters after RDN, with a mean reduction of 2.6 and 2.4 mm, respectively, after two years. Progression to concentric hypertrophy was observed only in in patients who did not achieve normal BP values, despite BP reduction after RDN. Conclusion There was no reduction of LV mass after RDN. We found a small statistically significant reduction in LVIDd and LVIDs, which together with increase in RWT can indicate progression towards concentric hypertrophy. BP reduction after RDN on its own does not reverse concentric remodelling if target BP is not achieved.

Resistant hypertension.

Resistant hypertension (RH) is characterized by persistently elevated blood pressure despite the concurrent use of three antihypertensive medications, including a diuretic, at optimal doses. This clinical phenomenon poses a significant burden on healthcare systems worldwide due to its association with increased cardiovascular disease morbidity and mortality. Ongoing studies on device-based treatment of RH, with aim to reduce sympathetic nervous system outflow, have shown promising evidence in management of RH which may in turn decrease the incidence of composite cardiovascular outcome faced by the affected population. This paper aims to provide a comprehensive overview of RH, and review some of the diagnostic and therapeutic approaches in management of RH.

Real-World Impact of Blood Pressure Control in Patients With Apparent Treatment-Resistant or Difficult-to-Control Hypertension and Stages 3 and 4 Chronic Kidney Disease.

Chronic kidney disease (CKD) is a common comorbidity in patients with apparent treatment-resistant hypertension (aTRH). We assessed clinical outcomes, healthcare resource utilization events, and costs in patients with aTRH or difficult-to-control hypertension and stage 3-4 CKD with uncontrolled vs. controlled BP. This retrospective cohort study used linked IQVIA Ambulatory EMR-US and IQVIA PharMetrics Plus claims databases. Adult patients had claims for ≥3 antihypertensive medication classes within 30 days between 01/01/2015 and 06/30/2021, 2 office BP measures recorded 1-90 days apart, ≥1 claim with ICD-9/10-CM diagnosis codes for CKD 3/4, and ≥1 year of continuous enrollment. Baseline BP was defined as uncontrolled (≥130/80 mm Hg) or controlled (<130/80 mm Hg) BP. Outcomes included risk of major adverse cardiovascular events plus (MACE+; stroke, myocardial infarction, heart failure hospitalization), end-stage renal disease (ESRD), healthcare resource utilization events, and costs during follow-up. Of 3,966 patients with stage 3-4 CKD using ≥3 antihypertensive medications, 2,479 had uncontrolled BP and 1,487 had controlled BP. After adjusting for baseline differences, patients with uncontrolled vs. controlled BP had a higher risk of MACE+ (HR [95% CI]: 1.18 [1.03-1.36]), ESRD (1.85 [1.44-2.39]), inpatient hospitalization (rate ratio [95% CI]: 1.35 [1.28-1.43]), and outpatient visits (1.12 [1.11-1.12]) and incurred higher total medical and pharmacy costs (mean difference [95% CI]: $10,055 [$6,741-$13,646] per patient per year). Patients with aTRH and stage 3-4 CKD and uncontrolled BP despite treatment with ≥3 antihypertensive classes had an increased risk of MACE+ and ESRD and incurred greater healthcare resource utilization and medical expenditures compared with patients taking ≥3 antihypertensive classes with controlled BP.

Use of Genomics to Develop Novel Therapeutics and Personalize Hypertension Therapy.

Hypertension is a prevalent public health problem, contributing to >10 million deaths annually. Though multiple therapeutics exist, many patients suffer from treatment-resistant hypertension or try several medications before achieving blood pressure control. Genomic advances offer mechanistic understanding of blood pressure variability, therapeutic targets, therapeutic response, and promise a stratified approach to treatment of primary hypertension. Cyclic guanosine monophosphate augmentation, aldosterone synthase inhibitors, and angiotensinogen blockade with silencing RNA and antisense therapies are among the promising novel approaches. Pharmacogenomic studies have also been done to explore the genetic bases underpinning interindividual variability in response to existing therapeutics. A polygenic approach using risk scores is likely to be the next frontier in stratifying responses to existing therapeutics.

Emerging Therapies for Treatment-Resistant Hypertension: A Review of Lorundrostat and Related Selective Aldosterone Synthase Inhibitors.

The target-hypertension (Target-HTN) trial investigated the efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, as an antihypertensive. Cohort 1 of the trial includes patients with suppressed plasma renin activity and elevated aldosterone levels. Lorundrostat doses of 100 mg and 50 mg daily significantly decreased systolic blood pressure compared to the placebo group. Cohort 2 also demonstrated a reduction in systolic blood pressure with the 100 mg daily dose of lorundrostat. Lorundrostat is more selective for the inhibition of CYP11B2 versus CYP11B1, which makes it preferable to other aldosterone synthase inhibitors that inhibit cortisol synthesis, such as osilodrostat. Phase 3 trials are needed to validate the safety and efficacy of lorundrostat, and further research should be performed on other selective aldosterone synthase inhibitors such as baxdrostat, dexfadrostat, and BI 690517.

Apparent Treatment-Resistant Hypertension in the First Year Associated with CV Mortality in PD Patients.

Few reports have focused on the association between apparent treatment-resistant hypertension (aTRH) and cardiovascular (CV) mortality in peritoneal dialysis (PD) population, thus we conducted this retrospective cohort to explore it.Patients and Methods: This was a retrospective cohort study conducted from January 2011 to January 2020 with PD patients in 4 Chinese dialysis centers. ATRH was defined according to the American College of Cardiology and American Heart Association guidelines. ATRH duration was calculated as the total number of months when patients met the diagnostic criteria in the first PD year. The primary outcome was CV mortality, and the secondary outcomes were CV events, all-cause mortality, combined endpoint (all-cause mortality and transferred to HD), and PD withdrawal (all-cause mortality, transferred to HD and kidney transplantation). Cox proportional hazards models were used to assess the association. A total of 1,422 patients were finally included in the analysis. During a median follow-up period of 26 months, 83 (5.8%) PD patients incurred CV mortality. The prevalence of aTRH was 24.1%, 19.9%, 24.6% at 0, 3, 12 months after PD initiation respectively. Overall, aTRH duration in the first PD year positively associated with CV mortality (per 3 months increment, adjusted HR, 1.29; 95% CI 1.10, 1.53; P=0.002). After categorized, those with aTRH duration more than 6 months presented the highest adjusted HR of 2.92. Similar results were found for secondary outcomes, except for the CV event. Longer aTRH duration in the first PD year is associated with higher CV mortality and worse long-term clinical outcomes. Larger studies are warranted to confirm these findings.

Evaluation of a Best-Practice Advisory for Primary Aldosteronism Screening

Primary aldosteronism (PA) is a common cause of secondary hypertension and an independent risk factor for cardiovascular morbidity and mortality. Fewer than 2% to 4% of patients at risk are evaluated for PA. To develop and evaluate an electronic health record best-practice advisory (BPA) that assists with PA screening. This prospective quality improvement study was conducted at academic center outpatient clinics. Data analysis was performed between February and June 2023 and included adults with hypertension and at least 1 of the following: 4 or more current antihypertensive medications; hypokalemia; age younger than 35 years; or adrenal nodule(s). Patients previously tested for PA were excluded. A noninterruptive BPA was developed to trigger for PA screening candidates seen in outpatient setting by clinicians who treat hypertension. The BPA included an order set for PA screening and a link to results interpretation guidance. (1) The number of PA screening candidates identified by the BPA between October 1, 2021, and December 31, 2022; (2) the rates of PA screening; and (3) the BPA use patterns, stratified by physician specialty were assessed. Over 15 months, the BPA identified 14 603 unique candidates (mean [SD] age, 65.5 [16.9] years; 7300 women [49.9%]; 371 [2.5%] Asian, 2383 [16.3%] Black, and 11 225 [76.9%] White individuals) for PA screening, including 7028 (48.1%) with treatment-resistant hypertension, 6351 (43.5%) with hypokalemia, 1537 (10.5%) younger than 35 years, and 445 (3.1%) with adrenal nodule(s). In total, 2040 patients (14.0%) received orders for PA screening. Of these, 1439 patients (70.5%) completed the recommended screening within the system, and 250 (17.4%) had positive screening results. Most screening orders were placed by internists (40.0%) and family medicine physicians (28.1%). Family practitioners (80.3%) and internists (68.9%) placed most orders via the embedded order set, while specialists placed most orders (83.0%-95.4%) outside the BPA. Patients who received screening were younger and included more women and Black patients than those not screened. The likelihood of screening was higher among patients with obesity and dyslipidemia and lower in those with chronic kidney disease and established cardiovascular complications. The study results suggest that noninterruptive BPAs are potentially promising PA screening-assistance tools, particularly among primary care physicians. Combined with artificial intelligence algorithms that optimize the detection yield, refined BPAs may contribute to personalized hypertension care.

Sacubitril-Valsartan (LCZ696) in the Treatment of Systemic Hypertension: An Updated Review of Neprilysin Inhibition Combined with Angiotensin II Receptor Blockade.

Sacubitril-valsartan (LCZ696) has been demonstrated to be a highly effective treatment for heart failure with preserved ejection fraction since its Food and Drug Administration approval in 2015, and a growing body of evidence suggests its emergence as a hypertensive medication. It acts as an inhibitor of both neprilysin and the renin-angiotensin-aldosterone system, approaching the control of a multi-faceted pathology in multiple unique ways. Because 48% of US adults are affected by hypertension, with less than half of patients achieving controlled blood pressure, and the high correlation between uncontrolled hypertension and cardiovascular mortality, it is crucial to investigate new pharmacotherapies for managing this disease. This review discusses the current evidence of sacubitril-valsartan trials in hypertension management, with a focus on distinct populations and hypertension subsets. Asian populations are predisposed to salt-sensitive hypertension and have been shown to benefit from sacubitril-valsartan more than olmesartan, an angiotensin receptor blocker (ARB). Systolic hypertension from stiff, aging arteries commonly affects individuals over the age of 65 years, and responds demonstrably better to sacubitril-valsartan than ARB monotherapy. Patients with treatment-resistant hypertension, especially those with heart failure, also show significantly improved blood pressure when treated with sacubitril-valsartan over ARBs. We conclude with a discussion of sacubitril-valsartan's potential role in managing noncardiac disease.

Aldosterone Synthase Inhibitors for Treatment of Hypertension and Chronic Kidney Disease

Aldosterone excess is known to worsen hypertension and kidney function. Three selective aldosterone synthase inhibitors (ASIs) were evaluated in 3 phase 2 trials. In the first study, the ASI baxdrostat 2 mg orally once daily decreased systolic blood pressure (SBP) by 11.0 mmHg compared with placebo after 12 weeks in patients with treatment-resistant hypertension. In the second study including patients with uncontrolled hypertension, placebo-corrected reduction in SBP with lorundrostat 50 mg once daily was 9.6 mmHg after 8 weeks. Patients receiving thiazides and those with body mass index (BMI) &gt; 30 kg/m2 had the optimum blood pressure (BP) response to lorundrostat, whereas plasma renin activity (PRA) did not affect its antihypertensive potency. In the third trial including patients with chronic kidney disease (CKD), the ASI BI 690517 (10 mg once daily) decreased urinary albumin creatinine ratio (UACR) by 39% after 14 weeks compared with 3% reduction with placebo. Reduction in UACR was generally similar in presence or absence of concomitant treatment with empagliflozin. The 3 ASIs mildly decreased (by &lt;15%) estimated glomerular filtration rate (eGFR) compared with placebo. The most common adverse effects of ASIs were hyperkalemia occurring in 2.9% and 7.9% among patients randomized to baxdrostat and lorundrostat, respectively versus none in the placebo groups. In patients with CKD, frequency of hyperkalemia was higher: 14.2% and 6.0% with BI 690517 and placebo, respectively. Adrenal insufficiency was reported in 1.3% of patients randomized to BI 690517 versus 1.0% with placebo. Preliminary data suggest that selective ASIs are effective in lowering BP in patients with resistant and uncontrolled hypertension and decreasing albuminuria in CKD. Phase 3 clinical trials should be conducted to assess long-term efficacy and safety of ASIs in a wide spectrum of patients with uncontrolled BP and CKD.

Dose Selection for Clinical Development in the Treatment of Hypertension: The Aprocitentan Case and Lessons from the Past

Dose selection plays a critical role in the clinical development of a drug. This current review highlights the lessons learned from previous dose finding studies (DFSs) of antihypertensive drugs and from the recent example of aprocitentan, a novel endothelin receptor antagonist for the treatment of resistant hypertension. Based on these, the authors provide 10 key recommendations for an efficient DFS for a new antihypertensive medication. These recommendations respect critical comments repeatedly made by the U.S. Food and Drug Administration (FDA) Division of Cardiology and Nephrology over the last 5 decades and go beyond the more limited recommendations made in the 2016 Committee for Medicinal Products for Human Use (CHMP) guideline on the development of new antihypertensive medications. The added value of a dose-response modelling approach enriches prior regulatory advice on DFSs.

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Spironolactone improves left atrial function and atrioventricular coupling in patients with resistant hypertension.

To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Patients with RHTN (n = 36, mean age 55 ± 7) were prospectively recruited. Spironolactone was initiated at 25mg/day and increased to 50mg/day after 4 weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after 6 months of spironolactone treatment and changes in LA functional metrics were assessed. LA size and function parameters were improved (p < 0.05) from baseline to month-6: LA volumes indexed to body surface area (LAVI) were reduced (LAVImaximum 41.4±12 vs. 33.2±9.7 mL/m2; LAVIpre-A 32.6±9.8 vs. 25.6±8.1 mL/m2; median LAVIminimum 18.5 [13.9-24.8] vs. 14.1 [10.9-19.2] mL/m2); left atrioventricular coupling index was reduced (28.2±11.5 vs. 22.7±9.2%); LA emptying fractions (LAEF) were increased (median total LAEF 52.4 [48.7-60.3] vs. 55.9 [50.3-61.1] %; active LAEF 40.2±8.6 vs. 43.1±7.8%). LA global longitudinal strain in the active phase was increased (16.3±4.1 vs. 17.8±4.2%). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-h urine aldosterone). Treatment of RHTN with spironolactone is associated with improvements in LA size and function, and atrioventricular coupling, regardless of whether aldosterone levels were normal or high at baseline. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.