Search Results (167)

Hypertension is highly prevalent among patients with chronic kidney disease (CKD), contributing significantly to cardiovascular morbidity and progressive renal decline. This overview explores the intricate pathophysiologic mechanisms driving hypertension in renal insufficiency, including volume overload, renin–angiotensin–aldosterone system (RAAS) activation, sympathetic overactivity, and vascular dysfunction. Diagnostic challenges such as white-coat hypertension and the underuse of ambulatory monitoring are discussed, along with the importance of volume assessment and target organ evaluation. We also emphasize individualized management strategies combining lifestyle modification, pharmacotherapy—including RAAS inhibitors, diuretics, and novel agents—and the growing role of device-based interventions. In particular, renal denervation (RDN) has emerged as a potential adjunctive option for selected patients with resistant hypertension in CKD, with preliminary evidence suggesting blood pressure reduction in selected and carefully studied populations, including dialysis-dependent patients. Special considerations for transplant recipients, elderly individuals, and those on dialysis are highlighted, underscoring the need for nuanced, patient-centered care. Misconceptions surrounding RAAS blockade, dialysis hypotension, and therapeutic inertia are critically appraised. Finally, future directions point to biomarker-driven approaches, digital health integration, and large-scale trials on RDN to refine treatment paradigms. This comprehensive synthesis offers a pragmatic framework for clinicians managing hypertension in CKD, aligning mechanistic insights with emerging evidence and clinical realities. Full article

Hypertension has been traditionally known to be highlighted by mean blood pressure; however, emerging evidence exhibits that blood pressure variability (BPV), including short-term, day-to-day, and visit-to-visit fluctuations can have an implication across multiple body systems. Elevated BPV reflects repetitive hemodynamic stress, affecting the physiologic hemostasis contributing to vascular injury and end organ damage. This narrative review is a compilation of recent evidence on the prognostic value of BPV, explained by pathophysiology, various devices with its measurement approaches, and, essentially, the clinical implication of BPV and the use of such devices utilizing artificial intelligence. A comprehensive literature search across PubMed, Cochrane Library, Scopus, and Web of Science were conducted, focusing on observational studies, cohorts, randomized trials, and meta-analyses. Higher BPV has been associated with an increased risk of cardiovascular mortality, stroke, coronary events, and heart failure, the progression of chronic kidney disease, cognitive decline, and preeclampsia, among other end organ damage, despite mean blood pressure. The various pathophysiologic mechanisms include autonomic dysregulation, arterial stiffness, endothelial dysfunction, circadian rhythm alteration, and systemic inflammation, which result in vascular remodeling and multisystem damage. Antihypertensive medications such as calcium channel blockers and renin–angiotensin–aldosterone system inhibitors seem to reduce BPV; randomized trials have not specifically investigated their BPV-reducing effects. The aim of this review is to highlight that BPV is a dynamic marker of multisystem risk, and question how various AI-based devices can aid continuous BPV monitoring and patient specific risk stratification. Full article

Biventricular Takotsubo cardiomyopathy (TCM) is a rare variant characterized by involvement of both the left and right ventricles. This variant is associated with greater hemodynamic instability and longer hospital stays compared to the isolated left ventricular-only variant. We report the case of a 67-year-old female patient who underwent elective resection of a left adrenal adenoma. While her preoperative and intraoperative courses were uneventful, she developed cardiogenic shock postoperatively, necessitating prolonged intensive care unit (ICU) management and vasopressor support. Further evaluation revealed elevated high-sensitivity troponin levels and reduced ejection fraction on echocardiography (30–35%). Hypokinesis was noted in the apical and mid-ventricular segments of both ventricles. A coronary angiogram performed two months prior to admission showed no significant coronary artery disease. Based on these findings, a diagnosis of biventricular TCM was established. The patient was managed supportively and discharged in stable condition with ongoing therapy, including beta-blockers, renin–angiotensin–aldosterone system inhibitors (RAASis), and statins. Follow-up echocardiography showed resolution of regional wall motion abnormalities. Although rare, biventricular TCM is associated with increased severity and a higher risk of complications. Early recognition and timely management are essential to improve outcomes in affected patients. Full article

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease (CKD), providing cardiorenal and metabolic benefits that extend beyond glycemic control. While their clinical efficacy is well established, the underlying molecular mechanisms remain only partially understood. This review focuses on current knowledge of SGLT2 expression and regulation in health and metabolic diseases, as well as transcriptional and epigenetic consequences of pharmacological SGLT2 inhibition. Human and experimental studies demonstrate that SGLT2 expression is confined to proximal tubular cells and regulated by insulin, the renin–angiotensin–aldosterone system, the sympathetic nervous system, oxidative stress, and transcriptional and epigenetic pathways. SGLT2 expression follows a biphasic pattern in metabolic disorder-associated CKD: upregulation in early phases and reduction in advanced stages. Evidence from animal models and single-cell transcriptomic studies indicates that SGLT2is normalize metabolic and inflammatory gene networks. To our knowledge, a recent single-cell RNA sequencing study provides the only currently available human dataset linking SGLT2i therapy with tubular metabolic rewiring and suppression of the energy-sensitive mechanistic target of rapamycin complex 1. Collectively, these findings support a model in which SGLT2 inhibition mitigates metabolic stress by restoring energy homeostasis across multiple nephron segments. Full article

Background/Objectives: Human serum albumin (HSA) is a major endogenous inhibitor of angiotensin-converting enzyme (ACE) and helps fine-tune the activity of the renin–angiotensin–aldosterone system (RAAS), thereby potentially influencing the development of cardiovascular (CV) diseases. As the principal transport protein for free fatty acids (FFAs), HSA may have its ACE-inhibitory capacity modified by its FFA cargo and, through this mechanism, may also affect CV disease risk. We therefore tested the hypothesis that the composition of HSA-bound FFAs determines the magnitude of endogenous ACE inhibition. Methods: We quantified endogenous ACE inhibition and examined the effect of FFA concentration on this inhibition in clinical patients (n = 161 and n = 101, respectively). We measured the effects of HSA treated with saturated, monounsaturated, and polyunsaturated FFAs, as well as FFA-free HSA, on recombinant ACE and on tissue ACE. Results: Endogenous ACE inhibition was stronger in patients with higher serum HSA concentrations (Spearman’s rho = 0.422, 95% CI 0.281–0.544, p < 0.001), whereas total FFA concentration was not associated with endogenous ACE inhibition (Spearman’s rho = 0.088, p = 0.38, n = 101). However, removal of free fatty acids substantially worsened the ACE-inhibitory effect of HSA on recombinant ACE (charcoal-treated HSA: IC₅₀ = 23.24 [19.40–29.78] g/L vs. control HSA: 7.84 [6.58–9.75] g/L, p < 0.001) and on tissue ACE isolated from lung, heart, and lymph node. FFA chain length, degree and position of unsaturation, and cis/trans configuration all differentially modulated endogenous ACE inhibition. Among saturated fatty acids, stearic acid (IC₅₀ = 7.98 [7.04–9.23] g/L), and among omega-3 and omega-6 fatty acids, α-linolenic (IC₅₀ = 5.60 [4.28–6.15] g/L) and γ-linolenic acids (IC₅₀ = 5.09 [4.28–6.15] g/L) produced the greatest enhancement of the ACE-inhibitory capacity of HSA. Conclusions: The present results indicate that HSA concentration relates to endogenous ACE inhibition in serum, and in vitro experiments demonstrate that HSA-bound FFAs can modulate HSA-mediated ACE inhibition, a mechanism that may be relevant to cardiovascular physiology and disease. Full article

Overactivation of the renin–angiotensin–aldosterone system (RAAS) promotes haemodynamic overload, inflammation, and fibrosis in the heart and kidneys. Recently, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy in cardiorenal protection. Emerging data indicate that adding SGLT2 inhibitors to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or angiotensin receptor–neprilysin inhibitors confers additional cardiorenal protection, yet their mechanistic basis and optimal clinical use in cardiovascular (CV) disease remain unclear. This review will integrate pre-clinical and clinical evidence on dual RAAS/SGLT2 modulation in CV disease, providing mechanistic insight into dual therapy. The review will finally outline priorities for future translational and outcome studies. Clinically, adding SGLT2 inhibitors to RAAS-based therapy reduces heart failure hospitalizations and slows kidney disease progression without new safety liabilities in type 2 diabetes, heart failure, and chronic kidney disease. Mechanistically, SGLT2 inhibition restores tubuloglomerular feedback and constricts the afferent arteriole; RAAS blockade dilates the efferent arteriole, and together, they lower intraglomerular pressure. Both classes also reduce oxidative stress, inflammatory signalling, and pro-fibrotic pathways, with SGLT2 inhibitors in several settings shifting RAAS balance toward the protective ACE2/angiotensin-(1–7)/Mas receptor axis. Key gaps include the scarcity of adequately powered trials designed to test combination therapy versus either component alone, limited evidence on timing and sequencing, incomplete characterization in high-risk groups, and mechanistic insight limited by study design in animal and cell models. Collectively, current data support layering SGLT2 inhibitors onto RAAS-based therapy, while definitive evidence from dedicated clinical trials is awaited. Full article

Background/Objectives: The renin–angiotensin–aldosterone system (RAAS) is pivotal for neonatal circulation and renal adaptation; however, postnatal changes in serum renin and aldosterone immediately after birth remain unclear. This study aimed to establish postnatal changes in these hormones at birth and over the first week of life. Methods: We retrospectively analyzed 374 neonates admitted to Kobe University Hospital between October 2020 and September 2023, with serum renin and aldosterone measured on days 0 and 5 of life. Exclusion criteria were multiple congenital anomalies, severe asphyxia, major peripartum hemorrhage, and in utero exposure to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Hormone levels were compared between term and preterm infants, and correlations with gestational age were assessed. Results: Serum renin concentrations were higher on day 0 than on day 5 (median 99.9 pg/mL [2.6–773.3] vs. 19.9 pg/mL [0.6–2304], p < 0.0001), and aldosterone concentrations similarly decreased (714 pg/mL [6.9–6334] vs. 551 pg/mL [0–11,930], p < 0.0001). At birth, renin and aldosterone levels did not differ significantly between groups. By day 5, both renin (32.8 pg/mL [0.6–2304] vs. 14.5 pg/mL [0.6–208]) and aldosterone (689 pg/mL [4–11,930] vs. 471 pg/mL [13–4697]) concentrations were significantly higher in preterm than in term neonates (p < 0.0001). Conclusions: This study describes early postnatal changes in renin and aldosterone, with higher concentrations at birth than on day 5 and persistently elevated levels in preterm infants. These findings indicate increased RAAS activity in preterm neonates and suggest a greater vulnerability to fluid, electrolyte, and blood pressure instability during early life. Full article

The renin–angiotensin–aldosterone system (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from arterial hypertension (AH) to heart failure (HF). In this review, one of our objectives is to describe the new evidence over the last 4 years regarding the RAAS. Moreover, we pay attention to the structure and function of the angiotensin II type 1 receptor (AT1R) and its role in hypertension, as well as define its active site. Later, we discuss the most potent, selective inhibitors of AT1 receptors, based on in vitro and in vivo experiments, from 2020 to 2024. Large peptide molecules, small non-peptide-like molecules, and sartan derivatives are analyzed. The low IC₅₀ values of the entities that do not resemble sartans showcase the vast chemical space that can be explored for the creation of more potent antihypertensive medications. We have also employed computational chemistry tools in order to identify key molecular interactions between the compounds of the literature studied in order to elucidate the underlying reasons why these different molecules exhibit variations in their binding energies and overall potency. Full article

Potassium homeostasis is impaired in patients with chronic kidney disease (CKD) due to alterations in physiological mechanisms and use of agents that modulate the renin angiotensin aldosterone system (RAAS) to slow CKD progression and reduce cardiovascular risk. In recent years, a new paradox has emerged: while dietary potassium restriction has been dogmatically recommended to prevent hyperkalemia, emerging evidence suggests that a more liberated potassium intake may offer potential benefits, particularly in patients with early CKD. This has prompted a paradigm shift towards a more individualized approach to the management of hyperkalemia in CKD. This review aims to provide an overview of the latest management strategies for hyperkalemia in CKD and to summarize the current literature including publications and guidelines recommendations with respect to dietary potassium intake and use of potassium salt substitutes. Full article

The role of hepatic stellate cells (HSCs) in the development of liver fibrosis and portal hypertension has already been largely clarified. Activation of HSCs might lead to self-increased proliferation and enhanced contractile activity, causing their transdifferentiation into myofibroblasts (activated HSCs), which drive the release of proinflammatory mediators, collagen, proteoglycans, and other extracellular matrix components, responsible for liver fibrosis and portal hypertension development. A possible mechanism for the pathophysiological role of HSCs in liver fibrosis might be autophagy, which breaks down the lipid droplets in quiescent HSCs, releasing fatty acids and providing the energy required for their activation into myofibroblasts. An ever-growing body of scientific evidence indicates that renin–angiotensin system (RAS) blockade can inhibit the evolution of fibrosis in patients with chronic liver diseases, and especially metabolic dysfunction-associated steatotic liver disease (MASLD), although the use of both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has not yet been officially identified as a potential fibrosis treatment. More recently, researchers have shown that overexpression of ACE2, induced by ACE inhibitor (ACEI) activity and leading to the degradation of angiotensin (ANG) II into ANG 1-7, inhibition of autophagy and consequent HSC activation, might prevent liver fibrosis development. This review aims to summarize recent pre-clinical studies and to identify a common thread underlying the latest scientific evidence in this field. Full article

Renin, a key aspartic protease central to the renin–angiotensin–aldosterone system (RAAS), remains a therapeutic target for hypertension despite the withdrawal of the only approved direct renin inhibitor, Aliskiren, due to unfavorable drug–drug interactions and safety concerns. Here, we report a computational protein design-driven evaluation of (S)-3-((3-(1H-imidazol-1-yl)propyl)amino)-2-(((S)-1-carboxy-2-(cyclooctanecarboxamido)ethyl)amino)-3-oxopropanoic acid (N-CDAH), a novel lipophilic cyclooctanoyl- derivative, as a next-generation renin inhibitor scaffold. This scaffold was designed based on the rationale of leveraging the carnosine like backbone while optimizing lipophilicity and metabolic stability. Pharmacokinetic, ADME, and toxicity predictions (SwissADME, pkCSM) revealed greater predicted aqueous solubility, enhanced metabolic stability, and significantly reduced off-target liabilities compared with Aliskiren (specifically, non-inhibition of major CYP isoforms). Molecular docking (AutoDock Vina binding affinity: −8.08 kcal/mol; Maestro Induced Fit Docking score: −11.149 kcal/mol) and molecular dynamics simulations confirmed favorable binding interactions, conformational adaptability, and complex stability within the renin active site. To contextualize its performance within the broader chemical space, the diastereomeric analog of N-CDAH as well as structurally related compounds identified through SwissSimilarity were also examined using computational workflow. The MD analysis (200 ns) demonstrated that the inhibitor is anchored via a dual stabilization mechanism: hydrophobic enclosure coupled with persistent ionic interactions. These integrative in silico results highlight the potential of this derivative to overcome Aliskiren’s pharmacological shortcomings, providing a strong computational rationale for experimental validation and underscoring the role of structure-based drug design in antihypertensive drug discovery. Full article

Background/Objectives: Sodium glucose co-transporter 2 inhibitors (SGLT2is) have demonstrated a reduction in heart failure (HF) hospitalizations in HF patients and decreased recurrence of atrial fibrillation (AF), including in those who have undergone catheter ablation (CA). The effects of SGLT2i are likely due to suppression of the renin–angiotensin–aldosterone system, reduction in oxidative stress with subsequent improvement in myocardial efficiency, and attenuation of cardiac remodeling. We aim to present the effects of SGLT2i on AF recurrence in patients who have undergone CA for AF. Methods: This is a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective studies evaluating the effect of SGLT2i on AF recurrence following CA compared with non-SGLT2i. The primary outcome was the recurrence of AF by the final follow-up reported in each study. Secondary outcomes include AF recurrence by the first follow-up within 12 to 24 months and follow-up intervals (6, 12, 18, 24, and 36 to 42 months) post-ablation, multivariate risk of AF recurrence, and the effect on left atrial diameter (LAD) (less than 45 mm vs. greater than or equal to 45 mm). For risk of bias (ROB) analysis, the NIH ROB and Cochrane ROB2 tool were used. All statistical, heterogeneity, and sensitivity analyses were conducted using Cochrane Review Manager. A random-effect model was employed for all pooled statistical analyses. Results: A total of nine studies, two RCTs and seven retrospective studies, were included (N = 6874) for the primary outcome. Compared to non-SGLT2i (N = 3693), SGLT2i (N = 3181) significantly decreased AF recurrence by the final follow-up (OR = 0.62; 95% CI: 0.45–0.85; p = 0.008). For secondary outcomes, SGLT2i significantly reduced AF recurrence by the first follow-up within 12 to 24 months post-ablation (OR = 0.58; p = 0.0001) and by the different follow-up periods, 6-month (OR = 0.53; p = 0.02), 12-month (OR = 0.56; p = 0.0001), 18-month (OR = 0.55; p = 0.01), and 24-month (OR = 0.60; p = 0.12) follow-up periods. On the other hand, by 36 to 42 months, SGLT2i was associated with increased risk of AF recurrence (OR = 1.41; p = 0.004). Conclusions: We conclude that SGLT2i demonstrated a reduction in AF recurrence following CA, particularly by 12 to 18 months post-ablation. Full article

Vicadrostat, a selective aldosterone synthase inhibitor, reduced albuminuria with concurrent renin–angiotensin system inhibition and empagliflozin, suggesting additive efficacy for chronic kidney disease (CKD) treatment. Specific urinary extracellular vesicle microRNAs (uEV miRNAs) may reflect key mechanisms of kidney injury. We investigated how vicadrostat alone or with empagliflozin affected uEV miRNA expression in study participants. Small RNA sequencing was conducted on uEV miRNAs from 435 participants with CKD who completed 14 weeks treatment in the phase II trial of vicadrostat given with or without empagliflozin. Differentially expressed uEV miRNAs in participants with ≥30% UACR (urine albumin–creatinine ratio) reduction treated with 10 or 20 mg vicadrostat were pooled and evaluated with or without empagliflozin. Changes in miRNA-142-5p correlated significantly with changes in UACR in participants treated with vicadrostat alone, whereas changes in expression of eight additional uEV miRNAs (miR-192-5p, miR-194-5p, miR-6882-5p, miR-27a-5p, miR-381-3p, miR-192-3p, miR-513a-5p, and miR-199b-3p) correlated with ≥30% UACR improvements in patients treated with vicadrostat plus empagliflozin. Cellular deconvolution revealed that these miRNAs were expressed in various kidney cell types. Vicadrostat plus empagliflozin altered uEV miRNAs involved in immunomodulatory and fibrotic pathways irrespective of participant diabetes status. Regulation of miRNAs may provide insights into synergistic mechanisms of vicadrostat and empagliflozin in CKD treatment. Full article

Background & Objectives: Data on the efficacy and adverse effects of finerenone in patients with nondiabetic chronic kidney disease (CKD) are limited, particularly regarding ethnic diversity. This study aimed to evaluate the outcomes of finerenone in patients with nondiabetic CKD previously treated with standard therapies and investigate associated adverse effects, including hyperkalemia and hypotension. Methods: This is a retrospective exploratory study. It is a single-center study including patients with nondiabetic CKD who visited King Fahad Medical City in Riyadh, Saudi Arabia. The primary exposure was finerenone treatment, assessing its effects on albuminuria, kidney function, and blood pressure (BP), following prior use of renin–angiotensin–aldosterone system and sodium–glucose transport protein 2 inhibitors. The measured outcomes were the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The UACR (primary endpoint) was calculated as the mean of two morning spot urine samples collected consecutively 1 day apart. During each 4-week treatment period, secondary endpoints included changes in UACR, as determined by a 24 h urine sample, BP, and eGFR. The Wilcoxon signed-rank test was used to compare changes in continuous variables before and after therapy initiation. Statistical significance was set at p < 0.05. Results: This study included 16 patients with nondiabetic CKD (median age, 38.5 years [range, 35–50 years]; 56.3% male). The baseline eGFR was 66 mL/min/1.73 m² (47–82.5), with a UACR of 90.0 mg/g (58.8–132.5). No hyperkalemia was observed (potassium level, 4 mmol/L [3.8–4.4]). However, significant reductions in systolic and diastolic BPs were observed. Albuminuria improved significantly: the UACR decreased from 90.0 to 39.3 mg/g (p = 0.04). No adverse events, including hyperkalemia or hypotension, were reported. Conclusions: Finerenone showed promise in reducing albuminuria and blood pressure among patients with nondiabetic chronic kidney disease, with no significant adverse effects reported. These findings suggest potential benefits for this patient population, warranting further investigation. Full article

Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and heart failure. Central to this process are chronic low-grade inflammation (inflammaging), oxidative stress, cellular senescence, and maladaptive extracellular matrix remodeling. These hallmarks of aging interact to impair endothelial function, promote fibrosis, and compromise cardiac and vascular integrity. Key molecular pathways—including the renin–angiotensin–aldosterone system, NF-κB, NLRP3 inflammasome, IL-6, and TGF-β signaling—contribute to the transdifferentiation of vascular cells, immune dysregulation, and progressive tissue stiffening. We also highlight the role of the senescence-associated secretory phenotype and mitochondrial dysfunction in perpetuating inflammatory and fibrotic cascades. Emerging molecular therapies offer promising strategies to reverse or halt maladaptive remodeling. These include senescence-targeting agents (senolytics), Nrf2 activators, RNA-based drugs, and ECM-modulating compounds such as MMP inhibitors. Additionally, statins and anti-inflammatory biologics (e.g., IL-1β inhibitors) exhibit pleiotropic effects that extend beyond traditional risk factor control. Understanding the molecular basis of remodeling is essential for guiding future research and improving outcomes in older adults at risk of CVD. Full article