Association between systemic microvascular dysfunction and resistant hypertension: Insights from a clinical observational study.

The aim of this paper is to evaluate the effectiveness of percutaneous angiographic stenting in carefully selected, symptomatic patients diagnosed with hemodynamically significant atherosclerotic renal artery stenosis (ARAS) followed in our clinic. This retrospective study included 69 patients who underwent renal artery stenting due to renal artery stenosis between 2011 and 2023 in our clinic. Demographic, clinical, and laboratory data were retrospectively retrieved from the hospital's electronic health records. Duplex ultrasonography (DU) was used as the primary screening tool; however, the decision to stent was made only after confirmatory catheter angiography demonstrated ≥60% stenosis with an anatomically treatable lesion in a clinically high-risk context (resistant hypertension, acute kidney injury/acute-on-chronic kidney disease, or flash pulmonary edema). Laboratory parameters, blood pressure levels, and antihypertensive medication requirements were compared at baseline and 1 month following the procedure. Over the 12-year study period, 69 patients underwent renal artery stenting involving a total of 86 renal arteries. Of these patients, 31 (44.9%) were female, and the mean age was 65.75 years (SD=10.75; range = 41-87 years). Conventional angiography was performed in 51 patients (73.9%), while carbon dioxide angiography was utilized in 18 patients (26.1%). All 69 patients underwent simultaneous stent placement during angiography. One month post procedure, urea and creatinine levels decreased in these patients; notably, among 20 patients who presented with acute kidney injury, creatinine levels returned to normal in 11 patients (55%) at 1-month follow-up. Additionally, in 6 out of 12 patients (50%) with acute exacerbations of chronic kidney disease, creatinine levels reverted to baseline. Pulmonary edema, observed in 16 patients (23.2%) at presentation, resolved completely in all affected patients 1 month after the intervention. The reduction rates in systolic blood pressure (SBP) and diastolic blood pressure (DBP) 1 month post procedure were 23.28±11.67% and 20.48±12.49%, respectively, both statistically significant (for SBP: p = 7 × 10-13, effect size r = 0.868, matched-pairs rank-biserial correlation rrb = -1; for DBP: p = 5.4 × 10-12, effect size r = 0.869, matched-pairs rank-biserial correlation rrb = -1). The mean number of antihypertensive medications significantly decreased from baseline to 1month after renal artery stenting (mean±SD: 3.36±1.37 vs. 2.10±1.12; Wilcoxon signed-rank test, V=1.693, p<0.001, effect size r = 0.85> 0.50). Intervention with stent placement in symptomatic/high-risk ARAS patients presenting with resistant hypertension, acute kidney injury, or flash pulmonary edema associated with significant renal artery stenosis can result in clinical improvement and a reduction in antihypertensive medication requirements, even within a short follow-up period of 4 weeks. Given the retrospective design, lack of a control group, and short follow-up, these findings should be interpreted as association rather than causation and cannot address long-term outcomes (e.g., restenosis, durable renal preservation, or cardiovascular events).

The World Health Organization estimates that the number of people living with hypertension [blood pressure (BP) of ≥140 mmHg systolic or ≥90 mmHg diastolic or on medication] doubled between 1990 and 2019, from 650 million to 1.28 billion. Elevated BP is associated with increased risks of stroke, coronary artery disease, heart failure, and chronic kidney disease. Resistant hypertension is defined as office BP ≥140/90 mmHg despite treatment with 3 classes of antihypertensive agents (including a diuretic) at maximally tolerated doses, or the need for 4 or more agents regardless of BP level. Device-based antihypertensive therapies primarily target autonomic nervous system through techniques, such as renal denervation, carotid baroreceptor activation, and carotid body ablation. This review outlines the pathophysiological basis of selected interventions, critically evaluates existing clinical evidence, and highlights future directions for their development and integration into clinical practice.

Patients with difficult to control hypertension (HTN) are often referred by general practitioners to specialized centers to estimate global cardiovascular (CV) risk profile, evaluate hypertension-mediated organ damage (HMOD), and optimize antihypertensive therapy. This referral provides a unique opportunity to analyse patients with high CV risk and HTN in a real-world setting, characterized by the rigorous adoption of uniform and state-of-the-art procedures by expert personnel. To examine (1) global CV risk profile, office and out-of-office blood pressure (BP) levels, and markers of HMOD in adult patients referred to a high-volume European Hypertension center; (2) to evaluate how these clinical parameters impact on the choice of different antihypertensive therapies. An observational, cross-sectional study was conducted in adult patients of both sexes, aged ≥ 18 years, with essential treated hypertension, who were consecutively evaluated at the Excellence Hypertension Center at Sant'Andrea Hospital in Rome, Italy. Office and out-of-office BP levels were measured, and different hypertension phenotypes were set according to European guidelines. CV risk profile was estimated according using SCORE2. Only patients with treated HTN were selected for the analysis and stratified according to antihypertensive therapies: (1) angiotensin receptor blockers (ARBs); (2) angiotensin converting enzyme (ACE) inhibitors; (3) other drugs (including diuretics, beta-blockers, calcium channel blockers, alpha-blockers, mineralocorticoid receptor antagonists). From an overall database of 11,168 outpatients, a total of 5,677 patients with treated HTN were analysed (46.3% females, age 63.6 ± 13.1 years, BMI 27.4 ± 4.8kg/m2, office BP 140.6 ± 17.5/85.5 ± 11.5 mmHg, 24-hour BP 128.7 ± 13.7/77.2 ± 9.7 mmHg, SCORE2 5.4 ± 4.3%). Among these, 52.9% were treated with ARBs, 30.2% with ACE inhibitors and 17.0% with other drugs. Patients treated with ARBs were more frequently males, and significantly older, had more frequently obesity (P < 0.001), dyslipidaemia (p < 0.001), and diabetes (p < 0.001) than those treated with other drug classes. They also had more frequently CV comorbidities (P < 0.001) and resistant HTN (P < 0.001). They received more BP lowering agents (P < 0.001), being more frequently treated with triple (P < 0.001), quadruple (P < 0.001), or more complex (P < 0.001) combination therapies. Comparable office and out-of-office BP control were recorded between patients treated with ARBs and those patients managed with either ACE inhibitors or other drugs. Among adult outpatients referred to an excellence hypertension center, the majority were treated with ARBs, alone or in combination therapies. ARB-treated patients presented more frequently CV risk factors, comorbidities, and difficult-to-treat HTN.

Despite widespread use of renin-angiotensin-aldosterone system blockade, resistant and uncontrolled hypertension remain common, highlighting the need for novel therapeutic strategies. Growing recognition of aldosterone excess as a central driver of vascular, cardiac, and kidney injury has renewed interest in targeting this pathway. Recent advances in highly-selective aldosterone synthase inhibition (ASI) suggest this is a clinically viable approach. ASIs, including baxdrostat and lorundrostat, demonstrate consistent blood pressure reductions of approximately 8-12 mmHg when administered in addition to standard antihypertensive therapy across phase 2 and phase 3 trials. These drugs may overcome limitations of mineralocorticoid receptor antagonists by suppressing aldosterone production upstream, mitigating aldosterone escape, and reducing adverse effects. There may also be benefits among patients with chronic kidney disease, primary aldosteronism, and heart failure with preserved ejection fraction, supporting a broader cardiorenal role. Aldosterone synthase inhibition represents an advance in hypertension therapeutics. If ongoing and future outcome-driven trials confirm cardiovascular and renal benefit, ASIs may reshape treatment algorithms, complement existing renin-angiotensin-aldosterone-based strategies, and enable more precise targeting of aldosterone-mediated disease.

Baroreflex activation therapy for resistant hypertension: promise present or passed?

Radiofrequency renal denervation (RF RDN) has achieved meaningful clinical benefit as an adjunct treatment for uncontrolled and resistant hypertension. This analysis evaluated the cost-effectiveness and budget impact of RF RDN in Italy. A previously published and validated Markov model was adapted to project strategy-specific costs, quality-adjusted life years (QALY), and clinical events over a lifetime horizon for RF RDN and standard of care (SOC) cohorts. The model consisted of seven primary health states, with state transitions informed by multivariate risk equations. Italian costs, utilities, and survival data informed key model inputs. Clinical data from the SPYRAL HTN-ON MED trial informed the base case treatment effect (- 4.9 mmHg reduction in office systolic blood pressure vs. sham), with alternative effect sizes explored in sensitivity analyses. Cost-effectiveness was evaluated against a threshold of €25,000 per QALY gained. The ten-year budget impact was evaluated. Over ten years, RF RDN was associated with meaningful reductions in relative risk for: myocardial infarction (0.88), stroke (0.80), and heart failure (0.72). Over lifetime, RF RDN added €3,418 in costs and 0.41 QALYs, resulting in an incremental cost-effectiveness ratio of €8282 per QALY gained. RF RDN was cost-effective across all scenarios explored. At ten years, RF RDN uptake among resistant hypertension patients was associated with per-patient cost savings of - €4302 (€8526 RF RDN vs. €12,829 SOC) from avoided clinical events. RF RDN was cost-effective over a lifetime horizon, with the associated increase in ten-year budget impact justified by corresponding reductions in clinical events.

Aldosterone synthase inhibitors in uncontrolled and resistant hypertension: promise, pitfalls, and unanswered questions.

Resistant hypertension (rHTN) is defined as uncontrolled blood pressure despite ≥3 antihypertensives, including a diuretic. While fourth-line intensification is recommended, comparative evidence remains scattered. This meta-analysis evaluates the efficacy and safety of fourth-line antihypertensives in reducing clinic systolic blood pressure (SBP) in rHTN. A literature search across PubMed, Embase, Scopus, and Web of Science (2015-2026) identified eligible randomized controlled trials (RCTs) of ≥4 weeks duration. Risk of bias was assessed using Cochrane RoB 2. An initially planned network meta-analysis was deemed unreliable due to statistical inconsistencies and transitivity violations across the evidence base. Consequently, data were analyzed via pairwise meta-analysis using R software (version 4.5.1) to calculate mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI). Eleven RCTs involving 3,931 adults with rHTN were included. Pairwise comparisons against placebo showed that aldosterone targeted therapies produced the largest reductions in SBP, with lorundrostat (MD -11.70 mmHg [95% CI -16.07, -7.33]) and baxdrostat 2 mg (MD -10.10 [-12.63, -7.58]) showing comparable effects, while baxdrostat 1 mg (MD -8.56 [-11.08 to -6.04]) demonstrated reductions similar in magnitude to spironolactone (MD -7.95 [-10.10, -5.80]). β-blockers, including bisoprolol (MD = -6.71 mm Hg), also demonstrated modest SBP reductions, while aprocitentan 12.5 mg reduced SBP by -3.80 mmHg [-6.65, -0.95]. No intervention significantly increased serious adverse events versus placebo. Significant increases in any adverse events were observed with aprocitentan 25 mg (RR 1.89 [1.39, 2.57]) and doxazosin (RR 1.55 [1.09, 2.20]). Fourth-line agents targeting the aldosterone pathway, including aldosterone synthase inhibitors and spironolactone, provide clinically significant SBP reductions in rHTN without increasing serious adverse event risk. Due to transitivity violations across trials, indirect comparative rankings remain invalid. Future trials are required to establish efficacy and assess outcomes.

This national expert consensus statement, endorsed by the Portuguese Association of Interventional Cardiology of the Portuguese Society of Cardiology (APIC-SPC) and the Portuguese Society of Hypertension (SPH), provides practical guidance on the appropriate use of renal denervation for blood pressure management in adults with uncontrolled hypertension in spite of optimally tolerated guideline-directed therapy and lifestyle measures. It synthesizes evidence from contemporary sham-controlled trials and large real-world registries, which show sustained blood pressure reductions with both radiofrequency and ultrasound systems, and a favorable and consistent safety profile, while acknowledging remaining uncertainties in long-term clinical outcomes and individual response prediction. The document emphasizes rigorous patient selection within a structured pathway coordinated by multidisciplinary hypertension teams. It outlines organizational requirements for centers performing renal denervation, key elements of pre-procedural imaging and peri-procedural management, and a standardized follow-up strategy using office, home, and ambulatory monitoring to enable timely therapy adjustment. Beyond resistant hypertension, this statement discusses carefully selected scenarios in which RDN may be considered as an adjunctive option, while reinforcing that renal denervation is not first-line therapy and should be integrated into a comprehensive hypertension care. This consensus aims to clarify for which patients renal denervation may be a viable therapeutic option, identify the main clinical and procedural considerations for its implementation, and promote its optimal and safe use through appropriate patient selection and multidisciplinary evaluation.

Eplerenone is a mineralocorticoid receptor antagonist with minimal affinity for androgen receptors. Mineralocorticoid receptor antagonists are efficacious in the management of resistant hypertension, obstructive sleep apnea, cardiac dysfunction, renal tubular disorders, hepatic cirrhosis, portal hypertension, diabetic nephropathy, proteinuric kidney disease, and chronic central serous chorioretinopathy in the general population. Five cases describing the use of eplerenone in pregnancy are discussed, the previous literature reviewed, and potential indications for the use of eplerenone in pregnancy discussed.

Comprehensive evaluation of secondary causes of hypertension: Integrated screening for obstructive sleep apnea and primary aldosteronism.

Resistant hypertension remains a major clinical challenge. This systematic review/meta-analysis evaluated whether the addition of a single pharmacological or device-based intervention (renal denervation [RDN]) can achieve effective blood pressure (BP) control in patients with true resistant hypertension. A systematic search of MEDLINE/PubMed was performed to identify studies assessing the antihypertensive effects of adding a single pharmacological or device-based intervention in patients with true resistant hypertension. Primary analyses were conducted using a single-arm framework. Sixty-eight studies were included (n=6297; weighted mean age, 60 years; males 60%; diabetes 35%; smoking 16%; cardiovascular disease 27%). Participants received an average of 4.8 antihypertensive medications, with baseline office BP of 164/92 mm Hg and 24-hour ambulatory BP of 148/85 mm Hg. The median follow-up was 6 months. Meta-analysis of 58 studies (n=4579; 52% RDN) demonstrated a pooled mean 24-hour systolic ambulatory BP reduction from baseline of -11.3 mm Hg (95% CI, -12.3 to -10.2). Meta-analysis of 15 studies (n=2700; 15% RDN) showed a pooled hypertension control rate during follow-up of 35% (95% CI, 28-42). No significant differences were observed between RDN and pharmacotherapy or between randomized and nonrandomized studies. A single intervention-either pharmacological or RDN-on top of guideline-directed background therapy resulted in clinically meaningful BP reduction in patients with true resistant hypertension; however, only one-third of patients achieved BP control. Future clinical trials are needed to evaluate whether combination treatment strategies integrating optimized pharmacological regimens with RDN can provide more effective and durable BP control in this particularly challenging patient population.

Treating Resistant Hypertension; The Overlooked Role of Combined Alpha- + Beta-blockade.

Cardiovascular Disease (CVD) continuum often begins with uncontrolled hypertension, progressing through structural/functional impairment of the cardiovascular system and atherosclerosis toward myocardial infarction, stroke, and cardiovascular death. Hypertension affects over one billion people globally, yet less than half have been diagnosed and received treatment. Suboptimal management of elevated Blood Pressure (BP) remains a challenge across low- and middle-income countries, including India. This review outlined the CVD continuum associated with hypertension, along with guideline-recommended new paradigm and emerging/ novel approaches for managing hypertension and CVD risk. Data from PubMed and Google Scholar have been extracted using the following search terms: cardiovascular disease continuum, hypertension management, cardiovascular risk reduction, anti-hypertensive drugs, non-pharmacological approach, guideline recommendations, evolving strategies, and herbal medicine. A total of 101 articles, published between 2004 and 2025, were included, comprising 20 systematic reviews and meta-analyses, 27 trials, 24 research articles, 10 guidelines, 18 review articles, and 2 editorials. The evidence and guideline recommendations on clinical and therapeutic considerations for effective management of hypertension have been discussed. Several guidelines preferred initial treatment (BP threshold: 130-140/80-90 mmHg) with monotherapy (angiotensin-converting enzyme inhibitor/ angiotensin-receptor blocker/ calcium channel blocker/ diuretic/ beta-blocker) or combination therapy of two or more medications with complementary mechanisms (in a single-pill) for managing cardiovascular complications and improving treatment adherence. Beta-blockers are thought to be recommended for people with cardiovascular complications, but their effect in reducing stroke, infarction, and mortality is inferior to other drug classes. The addition of an anti-aldosterone drug to the first-line therapy is recommended for managing resistant hypertension. Recent pharmacological advancements, including anti- aldosterone agents, non-steroidal mineralocorticoid receptor antagonists, endothelin receptor antagonists, etc., have demonstrated remarkable efficacy in BP reduction with tolerable safety profiles. A holistic management strategy integrating standard medical care along with lifestyle modifications, herbal medicines, and digital health platforms could enhance treatment adherence and interrupt the CVD continuum.

Resistant Hypertension (RHTN) is defined as blood pressure remaining above target levels despite adherence to three or more antihypertensive agents of different classes, including a diuretic. RHTN was found to be a significant prognostic factor for cardiovascular and renal complications among individuals with Type 2 Diabetes Mellitus (T2DM). This systematic review and meta-analysis aimed to estimate the global prevalence of RHTN among patients with T2DM and to explore key demographic and clinical correlates. A systematic literature search was conducted across multiple electronic databases, including PubMed, Scopus, Web of Science, Embase, and the Cochrane Library, to identify studies examining the prevalence of resistant hypertension among patients diagnosed with T2DM. Data synthesis was accomplished using a random-effects model. Between-study heterogeneity was assessed utilising the I² statistic. Assessment of potential publication bias was performed through the Doi plot analysis and the Luis Furuya-Kanamori index (LFK index) methodology. Statistical significance was established at p < 0.05. The study was prospectively registered in PROSPERO (CRD42024549125). Nine studies encompassing 159,082 participants from various regions worldwide were incorporated. The synthesis of data revealed a pooled prevalence rate of RHTN in individuals with T2DM of 14% (95% CI, 11-17%), accompanied by a substantial degree of heterogeneity (I2=98%). Meta-regression revealed that resistant hypertension among diabetic cases increased with increasing mean age [Beta = 0.02]. The Doi plot asymmetry and LFK index [-2.93] revealed publication bias. This review highlighted the significant prevalence of RHTN among the T2DM population. However, given the high heterogeneity, publication bias, and limited geographical representation, these findings should be interpreted with caution. Subgroup analysis also revealed no significant reduction in heterogeneity, underscoring the need for further qualitative studies to assess contextual factors. Meta-analysis revealed 14% of individuals with T2DM have RHTN, highlighting the need for routine screening along with personalised blood pressure management in this population. To strengthen clinical practice and improve comparability, future research should prioritise robust study designs and standardised diagnostic criteria.

Systemic arterial hypertension remains the leading modifiable risk factor for cardiovascular mortality, yet the optimal blood pressure target remains a subject of intense global debate. While recent American guidelines advocate for a lower diagnostic threshold (≥130/80 mmHg), European and Asian guidelines largely maintain a conservative threshold (≥140/90 mmHg). This narrative review addresses the central clinical question: "Is lower always better?" We synthesize evidence from landmark trials, including SPRINT and STEP, which demonstrate that intensive systolic blood pressure control (<120-130 mmHg) significantly reduces cardiovascular events and mortality, particularly in high-risk phenotypes such as resistant hypertension. However, this benefit is not without cost. We discuss the physiological "J-curve," the increased risk of adverse events such as hypotension and acute kidney injury, and emerging concerns regarding the long-term durability of stroke prevention observed in the ESPRIT trial. Furthermore, the dominant narrative of "intensification" is challenged by the recent STOP-Trial, which validated a framework for safe de-prescribing in low-risk hypertensive patients using home-based monitoring. Crucially, the divergent findings of the CREOLE and TOPSPIN trials reveal that therapeutic efficacy varies profoundly by ethnicity and geography, rendering a "one-size-fits-all" approach obsolete. We conclude that while intensive control is a life-saving opportunity for high-risk cohorts, it is not a universal mandate. The future of hypertension management lies in the transition from a single numerical target toward precision medicine - utilizing pharmacogenomics and population-specific strategies to maximize protection while minimizing harm, mandating development of "population-based guidelines" aiming for personalized blood pressure targets.

Ectopic adrenocorticotropic hormone (ACTH)‐dependent Cushing’s syndrome (CS), ectopic ACTH secretion (EAS) is a rare condition caused by ACTH‐secreting neuroendocrine tumors (NETs), such as bronchial carcinoids. We report a 65‐year‐old woman with severe EAS complicated by bowel perforation. She presented with hypokalemia (K+ 2.3 mmol/L), metabolic alkalosis, resistant hypertension (180/110 mmHg), worsening diabetes (HbA1c 6.7%–9.1%), proximal muscle weakness, and 14 kg weight gain over 3 months. A silent sigmoid colon perforation required emergency resection and colostomy. Biochemical tests confirmed hypercortisolism (urine free cortisol [UFC], 1256 µg/24 h, plasma ACTH 175 pg/mL, and cortisol >40 µg/dL post‐dexamethasone). Imaging identified a 2.3 cm pulmonary nodule with mild uptake on Ga‐68 DOTATATE PET/CT. Bronchoscopic biopsy confirmed an ACTH‐positive low‐grade bronchial carcinoid tumor. Initial treatment with osilodrostat was interrupted due to acute illness and oral medication intolerance. Intravenous etomidate was employed in the ICU for rapid cortisol suppression, followed by resumption of osilodrostat after stabilization. Thoracoscopic lobectomy confirmed a low‐grade carcinoid tumor (Ki‐67 < 2%). Postoperatively, cortisol normalized, electrolytes stabilized, and HbA1c improved to 6.5%. This case highlights bowel perforation as a severe complication of EAS and underscores the importance of dynamic, alternating therapy with osilodrostat and etomidate, along with individualized surgical and medical management strategies.

Clinical outcomes in patients with hypertension and renal artery stenosis across age categories.

BackgroundAldosterone synthase inhibitors (ASIs) have emerged as a mechanistically targeted strategy for resistant and uncontrolled hypertension; however, no head-to-head trials exist, and comparative efficacy and safety remain uncertain. We compared their efficacy and safety using network and pairwise meta-analysis of randomized trials.MethodsThis systematic review and meta-analysis adhered to the PRISMA guidelines. PubMed/MEDLINE, Scopus, Embase, ClinicalTrials.gov, and Cochrane Library were searched from inception to January 14, 2026, for randomized trials evaluating ASIs versus placebo or standard care. A frequentist random-effects network meta-analysis assessed systolic (SBP) and diastolic blood pressure (DBP). Dichotomous safety outcomes were pooled using Hartung–Knapp random-effects models. Network consistency was evaluated using design-by-treatment interaction modeling. Prespecified subgroup analyses stratified outcomes by hypertension phenotype (resistant vs uncontrolled).ResultsAcross 7 RCTs (n = 2,828), all ASIs significantly reduced SBP versus placebo: baxdrostat −8.63 mmHg (95% CI −10.84 to −6.42), lorundrostat −7.47 mmHg (95% CI −9.54 to −5.40), and LCI699/osilodrostat −5.63 mmHg (95% CI −9.15 to −2.12), with no significant indirect differences between agents. In resistant hypertension, lorundrostat (−9.00 mmHg; 95% CI −13.19 to −4.81) and baxdrostat (−8.77 mmHg; 95% CI −10.50 to −7.05) demonstrated pronounced reductions. In uncontrolled hypertension, LCI699/osilodrostat showed the largest point estimate (−10.55 mmHg; 95% CI −16.49 to −4.61), though this derives from a single early-phase trial and requires cautious interpretation. DBP reductions were significant for baxdrostat (−3.23 mmHg; 95% CI −4.73 to −1.73) and lorundrostat (−3.60 mmHg; 95% CI −5.43 to −1.77). Hypotension (RR 2.67), hyperkalemia (RR 7.94), and hyponatremia (RR 2.07) were significantly increased; serious adverse events, discontinuation, and network inconsistency were not detected.ConclusionsASIs provide clinically meaningful BP reduction across both hypertension phenotypes; however, short-term use is associated with hypotension and electrolyte disturbances, necessitating careful monitoring. Phenotype-specific efficacy and long-term safety require validation in outcome-driven trials. Systematic Review Registration: PROSPERO CRD420251266257