Mineralocorticoid receptor (MR) antagonists play a vital role in the management of conditions such as heart failure and hypertension. The recent approval of finerenone for diabetic kidney disease, along with expanding opportunities to treat chronic kidney disease and heart failure with preserved ejection fraction has led to a continued interest in MR antagonism. This article describes the identification and initial optimization of MR antagonists based on a phenylglycine scaffold containing an acylurea motif. Optimization efforts aimed at enhancing MR potency and DMPK properties revealed that replacing the phenylglycine scaffold with l-alanine avoided a risk of racemization at the stereocenter. The most potent compound exhibited an MR binding affinity of pKi = 9.3 and a potency in human MR reporter gene assay of pIC50 = 8.4. X-ray crystallography of a protein-ligand complex structure with an l-alanine based compound revealed an internal hydrogen bond imposing a cyclic conformation on the acylurea, which in turn formed a bidentate hydrogen bond interaction with the side chain of Asn770, a key polar interaction site in MR for endogenous as well as synthetic ligands. Further lead generation efforts identified two compounds with suitable in vivo PK properties allowing assessment of their effect on acute urinary electrolyte excretion.

Warfarin is a widely used oral anticoagulant with a narrow therapeutic index and multiple drug-drug interactions that may significantly alter its anticoagulant effect. Torsemide, a loop diuretic commonly prescribed for heart failure and fluid overload, shares metabolic pathways with warfarin, raising the possibility of clinically significant interactions. However, the evidence regarding this interaction remains limited and inconsistent. A 66-year-old male with a history of type 2 diabetes mellitus, hypertension, chronic kidney disease, and prior aortic valve replacement on chronic warfarin therapy presented with extensive soft tissue necrosis of the left leg following minor trauma. During hospitalization, warfarin (3 mg once daily) and Torsemide (20 mg once daily) were initiated concurrently. Subsequently, the patient developed a progressive elevation in international normalized ratio (INR), necessitating repeated fresh frozen plasma transfusions due to increased bleeding risk. Despite supportive management, INR remained elevated. Torsemide was discontinued and replaced with furosemide, after which a gradual stabilization of INR levels was observed. The patient later required left above-knee amputation due to worsening necrosis but recovered following multidisciplinary management. Assessment using the Naranjo Adverse Drug Reaction Probability Scale suggested a possible interaction between warfarin and Torsemide. This case highlights a potential interaction between warfarin and Torsemide resulting in elevated INR and increased bleeding risk. Clinicians should exercise caution and ensure close INR monitoring when initiating Torsemide in patients receiving warfarin therapy.

The 2025 pediatric advanced life support guidelines, developed by the American Heart Association and the American Academy of Pediatrics, are a resource for healthcare professionals caring for infants and children under 18 years of age in peri-arrest and other emergency care situations. The new guidelines address evolving pediatric cardiac arrest patterns, characterized predominantly by respiratory failure or shock, with persistent disparities in out-of-hospital survival and neurological outcomes. Major revisions include setting a blood pressure target above the 10th centile post-cardiac arrest, administering epinephrine after two attempts of defibrillation in a shockable rhythm, and administering early epinephrine in non-shockable cardiac arrest, as well as preventing hyperthermia. It also emphasizes evidence-based strategies such as early high-quality cardiopulmonary resuscitation (CPR), targeted post-arrest care, continuous electroencephalogram for neurological monitoring, and IV sotalol as an option for refractory supraventricular tachycardia. Long-term survivor support and family presence during resuscitation are integrated as vital aspects of care. While core recommendations-such as CPR technique, ventilation strategies, and shock management-are reaffirmed, the update provides a robust framework for multicentric harmonization. The adoption of these updated protocols in promises enhanced resuscitation outcomes, consistent neurological recovery, and the development of context-specific best practices in pediatric emergency care.

Menopause is associated with a marked increase in cardiac hypertrophy and progression to heart failure with preserved ejection fraction (HFpEF), a condition that disproportionately affects women and lacks effective targeted therapies. Although estrogen deficiency has long been implicated in postmenopausal cardiac remodeling, emerging evidence highlights a critical role for cytochrome P450 (CYP)-derived arachidonic acid metabolites as central regulators of myocardial structure and function. In a healthy premenopausal heart, a balance between cardioprotective epoxyeicosatrienoic acids (EETs), produced by the CYP2J2 and CYP2C enzymes, and the pro-hypertrophic metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), produced by the CYP4A and CYP4F isoforms, supports adaptive remodeling and diastolic function. Menopause disrupts this equilibrium by estrogen-mediated reprogramming of CYP expression and activity, leading to diminished EET bioavailability, heightened 20-HETE signaling, and accelerated EETs breakdown by soluble epoxide hydrolase (sEH). This metabolic shift induces oxidative stress, calcium imbalance, fibroblast activation, extracellular matrix buildup, and cardiomyocyte enlargement, which together lead to ventricular stiffness and diastolic failure. This review aims to consolidate contemporary experimental and translational evidence linking CYP-derived eicosanoids to menopause-related cardiac hypertrophy and to assess novel non-hormonal therapeutic approaches, including sEH inhibitors, stable EET analogs, and CYP4A/20-HETE inhibitors, that target these molecular pathways. Targeting CYP-derived metabolites represents a promising mechanism-based approach to prevent or reverse postmenopausal cardiac hypertrophy and to modify the natural history of HFpEF. Importantly, these non-hormonal strategies may offer a safer therapeutic alternative to hormone replacement therapy by avoiding the systemic risks associated with exogenous estrogen exposure while directly targeting disease-specific molecular pathways.

Infiltrative cardiomyopathies, a subset of restrictive cardiomyopathies, are rare but clinically essential disorders often lead to heart failure, which is a major global health issue. Although interest in these conditions is growing, they remain poorly understood due to their low occurrence, vague clinical signs, and frequent underreporting. Advances in diagnosis have been made through multimodal imaging techniques-including cardiac magnetic resonance, nuclear imaging, and computed tomography-as well as genetic testing and new biomarkers for amyloidosis. However, a universal biomarker that applies across the entire range of infiltrative cardiomyopathies has yet to be identified. This review discusses albumin, a vital regulator of physiological balance, as a promising biomarker candidate. In this narrative review, we explore disease mechanisms, identify knowledge gaps in research, and suggest new connections to direct future studies and enhance diagnostic accuracy.

The failing heart displays marked alterations of energy substrate metabolism, with a reduced oxidation of long chain fatty acids (FA) associated with increased glucose oxidation. Recent pre-clinical and human studies have shown that the delivery of ketone bodies as an alternative substrate reduces pathologic cardiac remodeling and dysfunction in heart failure. However, chronic administration of ketone bodies is challenging. Therefore, using a clinically relevant canine model of tachypacing-induced dilated cardiomyopathy, we tested the hypothesis that other shorter chain FA may also be beneficial. Seven dogs received cardiac tachypacing and continuous infusion of sodium octanoate, a medium-chain FA, starting after 2 weeks of pacing when cardiac dysfunction was still moderate. Six dogs received cardiac pacing with no octanoate infusion. Octanoate did not significantly alter circulating levels of ketone bodies, while it still exerted protection resulting in a delayed progression of systolic and diastolic cardiac dysfunction and normalized myocardial metabolism. These results identify the delivery of medium-chain FA as a potential actionable therapeutic for heart failure with reduced ejection fraction. Octanoate has translational promise due to proven methods of dietary supplementation with no need for parenteral administration.

Pulmonary homeostasis and regeneration require coordination between epithelial cells, immune populations, vascular networks, extracellular matrix, and stromal cells. This mini review examines recent advances in lung niche biology that were a focus of the 2025 Stem Cells, Cell Therapy and Bioengineering in Lung Biology and Diseases Conference. Here we emphasize the impact of non-epithelial compartments essential for tissue function and repair. Reflecting the conference's emphasis on comprehensive niche biology, we highlight how non-epithelial compartments, including stromal, vascular, and immune cells, serve as essential regulators of tissue function and repair, a perspective that unified many of the presentations and discussions. In diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease, disruption of these niche interactions, rather than isolated cellular defects, drives regenerative failure. Spatial transcriptomic approaches reveal how pathological cell states colocalize within aberrant micro-niches. These insights suggest that effective therapeutics must target entire multicellular ecosystems, with advanced organoid platforms offering promising tools for developing niche-modulating interventions.

Sepsis, a life-threatening systemic inflammatory response induced by infection, remains a major therapeutic challenge with high mortality rates, especially when progressing to multiple organ dysfunction syndrome. Ulinastatin (UTI), a serine protease inhibitor with anti-inflammatory and antioxidative properties, has emerged as a promising therapeutic candidate for sepsis-induced organ injury. This article systematically reviews recent advances in the multiorgan protective effects of UTI against sepsis, focusing on its mechanisms through modulating key signaling pathways, reducing inflammatory cytokine release, inhibiting oxidative stress, and regulating cellular apoptosis/autophagy. Clinical and preclinical evidence demonstrates UTI's efficacy in alleviating injury in critical organs, including lungs, heart, liver, spleen, intestines, and kidneys. The current review clarifies the mechanism by which UTI mitigates sepsis-related multiple organ dysfunction syndrome and provides a theoretical basis for identifying potential therapeutic targets of UTI to mitigate sepsis injury.

Shortness of breath (SoB), sleep disturbance, and fatigue are the most common physical symptoms (PS) among patients with Heart Failure (HF). Depressive symptoms (DS) are the most common psychological symptoms that might affect the severity of PS. Perceived control (PC) has positive effects among patients with HF. This study determined whether PC mediated the relationship between DS and PS severity among patients with HF. Three hundred participants were recruited conveniently from four hospitals in Amman, Jodan. Arabic versions of the Hospital Anxiety and Depression Scale, the Control Attitude Scale-Revised, and the Symptom Status Questionnaire-Heart Failure were used to collect the data. Baron and Kenny's approach through multiple regression demonstrated that DS and PC were independent predictors for sleep disturbance, SoB, and fatigue. This indicated that PC partially mediated the relationship between DS and PS severity. Addressing DS and PC may reduce symptoms; future research should evaluate longitudinal and interventional effects.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder in which right heart failure remains the leading cause of morbidity and mortality. Although PAH occurs more frequently in women, female patients consistently demonstrate superior right ventricular (RV) function, more favorable RV-pulmonary arterial coupling, and improved survival compared with men-a phenomenon commonly referred to as the sex paradox in PAH. These observations highlight the central role of biological sex in shaping RV adaptation to chronic pressure overload and underscore RV dysfunction as an independent determinant of clinical outcomes in PAH. In this brief review, we synthesize emerging clinical, translational, and experimental evidence delineating sex-specific differences in RV adaptation and maladaptation in PAH. We focus on key biological processes that exhibit pronounced sexual dimorphism, including immune and inflammatory signaling, angiogenesis and microvascular remodeling, metabolic reprogramming and mitochondrial function, and fibrotic remodeling of the pressure-overloaded RV. Accumulating data indicate that estrogen signaling confers RV protection through coordinated effects on myocardial contractility, metabolic efficiency, angiogenic capacity, and immune regulation, whereas androgens and male-predominant pathways are associated with maladaptive hypertrophy, fibrosis, and earlier RV-pulmonary artery uncoupling. Importantly, these sex-linked mechanisms help explain why reductions in pulmonary vascular resistance alone are often insufficient to prevent right heart failure and why current PAH therapies exert limited direct effects on the RV. We further discuss the clinical implications of sex differences in PAH, including their relevance for risk stratification, therapeutic response, and trial design, and highlight emerging RV-directed therapeutic strategies targeting sex hormone signaling, immune pathways, metabolism, angiogenesis, and fibrosis. We discuss how hormonal states across the lifespan (eg, pregnancy, menopause, exogenous hormone exposure, and gender-affirming care) shape clinical outcomes in PAH. Finally, we identify key knowledge gaps and future directions needed to advance sex-informed, RV-centric precision medicine approaches for PAH.