Search Results (188)

Myxomatous mitral valve disease (MMVD) is the most common acquired heart valve disease in dogs and it may contribute to cardiovascular–renal axis disorders (CvRD) in dogs. Sensitive and early biomarkers of renal involvement are needed. In this prospective and observational study, 84 dogs were enrolled (20 healthy dogs and 64 dogs with MMVD), categorised using the American College of Veterinary Internal Medicine guidelines. Serum and urinary parameters were analysed, including tubular biomarkers expressed as creatinine-ratios: urinary alkaline phosphatase (uALPc), gamma-glutamyl transferase (uGGTc), N-acetyl-β-D-glucosaminidase (uNAGc), and cystatin C (uCystc). uALPc, uGGTc, and uNAGc were higher in MMVD than in controls; uALPc and uGGTc were increased from stage B1, uNAGc was higher in stages with cardiomegaly (B2 and C+D), and uCystc increased mainly in clinical stages (C+D). Serum renal markers increased only in clinical stages. ROC analysis showed good discrimination for MMVD with uALPc (AUC 0.87) and uGGTc (0.86); for cardiomegaly with uALPc (0.77) and uNAGc (0.75); and for congestive heart failure with SDMA (0.85) and uCystc (0.75). No urinary biomarker was associated with daily furosemide dose. Urinary tubular biomarkers, particularly uALPc and uGGTc, detect early CvRD in dogs with MMVD and complement traditional serum markers. Full article

Introduction: We evaluated the furosemide stress test as an early predictor of acute kidney injury following pediatric cardiac surgery, in comparison with the Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. Materials and Methods: This single-centre retrospective study evaluated pediatric patients who underwent open cardiac surgery between March 2019 and September 2024 at Koç University Hospital. The evaluation included pre-operative, intra-operative, and postoperative variables; a two-hour assessment of urinary response to the first dose of furosemide upon admission to the intensive care unit; and rates of acute kidney injury. Results: A total of 254 patients were included, and 53 patients (20.8%) developed acute kidney injury according to KDIGO criteria. The mean furosemide stress test response was 9.86 ± 5.84 (median: 9.10) mL/kg/h in the non-AKI group and was significantly lower in the AKI group at 5.07 ± 4.73 (median: 3.33) mL/kg/h (p < 0.001). Receiver operating characteristic analysis demonstrated that the furosemide stress test has discriminative ability to predict acute kidney injury. The cut-off value was 6.104 mL/kg/h, and patients with a lower response had a higher risk of developing acute kidney injury. Sensitivity and specificity were 69.8% and 69.7%, respectively. Acute kidney injury was diagnosed at a median of 18 h using KDIGO criteria, whereas the furosemide stress test enabled earlier prediction of acute kidney injury risk at a median of 5 h. Conclusions: The findings support the potential clinical utility of the furosemide stress test in the early stages after pediatric cardiac surgery to predict acute kidney injury. Full article

Background/Objectives: Cardiac resynchronization therapy (CRT) is a cornerstone treatment for heart failure with reduced ejection fraction (HFrEF), yet many patients remain symptomatic despite long-term electrical optimization. Although sacubitril/valsartan (ARNI) is central to guideline-directed medical therapy (GDMT), data on its late initiation in patients with chronic CRT are scarce. This study evaluated the impact of delayed ARNI initiation on clinical status, functional capacity, and cardiac remodelling in a real-world CRT population. Methods: We performed a single-centre, retrospective observational study including 76 HFrEF patients with chronic CRT who started ARNI between 2022 and late 2024. Patients underwent standardized assessment at baseline (T0) and after 12 ± 3 months (T1), including clinical evaluation, 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), symptom-limited bicycle exercise testing, and comprehensive echocardiography. The primary endpoint was change in quality of life (QoL). Secondary endpoints included exercise capacity, echocardiographic reverse remodelling, NYHA class, loop diuretic dose, and device-detected arrhythmias. Dose–response and multidimensional response patterns were explored. Results: KCCQ-12 increased from 52.96 ± 16.33 to 75.55 ± 18.12 (Δ +22.59 ± 13.22, p < 0.001), with 89.5% achieving a clinically meaningful improvement. Exercise duration and peak workload improved significantly. LVEF increased from 35.08 ± 6.96% to 43.18 ± 8.42% (Δ +8.11%, p < 0.001), with reductions in left ventricular and atrial volumes. Loop diuretic dose decreased (median −10 mg/day furosemide equivalent, p < 0.001), and 26.3% discontinued diuretics. A lower prevalence of device-detected arrhythmias was observed at follow-up, from 34.2% to 6.6% (p < 0.001). Higher ARNI doses were associated with greater likelihood of clinical, functional, and structural response. Longer CRT duration reduced the probability of structural remodelling but not symptomatic or functional benefit. Conclusions: In patients with long-standing CRT, delayed ARNI initiation was associated with improvements in QoL, exercise capacity, cardiac remodelling, congestion status, and electrical stability. These findings suggest that CRT is not a therapeutic ceiling and that late ARNI initiation remains a valuable component of comprehensive GDMT. Full article

Background: Cardiovascular polypharmacy inherently amplifies the risk of drug–drug interactions (DDIs), yet most studies remain limited to isolated drug pairs or predefined high-risk classes, without mapping the systemic architecture through which interactions accumulate. Objectives: To characterize the burden, severity, and network structure of potential DDIs in a real-world cohort of hospitalized cardiovascular patients using interaction profiling combined with graph-theoretic network analysis. Methods: This retrospective observational study included 250 hospitalized cardiovascular patients. All home medications at admission were analyzed using the Drugs.com interaction database, and a drug interaction network was constructed to compute topological metrics (i.e., degree, betweenness, and eigenvector centrality). Results: Polypharmacy was highly prevalent, with a mean of 7.7 drugs per patient, and 98.4% of patients exhibited at least one potential DDI. A total of 4353 interactions were identified, of which 12.1% were classified as major, and 35.2% of patients presented high-risk profiles with ≥3 major interactions. Interaction burden showed a strong correlation with medication count (r = 0.929). Network analysis revealed a limited cluster of hub medications, particularly pantoprazole, furosemide, spironolactone, amiodarone, and perindopril, that disproportionately governed both interaction density and high-severity risk. Conclusions: These findings move beyond conventional pairwise screening by demonstrating how interaction risk propagates through interconnected therapeutic networks. The study supports the integration of hub-focused deprescribing, targeted monitoring strategies, and network-informed clinical decision support to mitigate DDI risk in cardiovascular polypharmacy. Future studies should link potential DDIs to clinical outcomes and validate network-based prediction models in prospective settings. Full article

Background/Objectives: Hemodynamic and neurohormonal factors, including renal perfusion and venous pressure, may affect diuretic response, which may be modulated by body position. This study aimed to assess whether supine versus upright positioning influences diuretic efficacy and neurohormonal activation during early decongestion in patients with AHF and reduced ejection fraction (HFrEF). Methods: This single-center, prospective, pilot randomized study enrolled 12 hospitalized patients with decompensated HFrEF receiving guideline-directed medical therapy. Participants were randomized (1:1) to remain in either the supine or upright/seated position during intravenous furosemide administration (1 mg/kg: half of the dose administered as a bolus, half as a 2-h infusion). Serial measurements of urine volume, electrolyte excretion, and neurohormonal biomarkers (renin, aldosterone, catecholamines) were performed at baseline, 2, and 6 h after diuretic administration. Results: No significant differences were found between supine and upright groups in total urine output, urine dilution, sodium excretion, or weight change after 6 h. There were no statistically significant differences in renin and aldosterone levels across subsequent timepoints; however, renin concentration tended to be higher in upright than in supine individuals. Interestingly, supine participants demonstrated greater urinary adrenaline concentration after furosemide administration, alone and after adjustment for urinary creatinine. Conclusions: No clinically meaningful differences were found between supine versus upright position patients with AHF, receiving neurohormonal blockade. Full article

Background/Objectives: Fluid overload in critically ill patients is linked to adverse outcomes. While resuscitation strategies are well established, guidance for the de-resuscitation phase remains limited. This study aimed to identify clinical factors associated with diuretic response and achieving negative fluid balance (FB) in critically ill patients. Methods: We conducted a single-center, retrospective cohort study of ICU patients who received intravenous furosemide between 2017 and 2023. A CHAID (Chi-square Automatic Interaction Detector) decision tree identified clinical variables associated with fluid removal after the first dose, and a mixed-effects model analyzed repeated measurements. Results: The cohort comprised 1764 patients over 6632 ICU days. Mean arterial pressure (MAP) was the strongest predictor of negative FB. MAP ≤ 75 mmHg yielded minimal negative FB (−33 ± 1054 mL/24 h); MAP 75–90 mmHg yielded intermediate negative FB (−467 ± 1140 mL/24 h); and MAP > 90 mmHg produced the greatest negative FB (−899 ± 1415 mL/24 h; p < 0.001). Secondary associations varied by MAP: creatinine at low MAP, blood urea nitrogen at mid-range MAP, and SOFA score at high MAP, all inversely related to negative FB. In mixed-effects analyses, each 1 mmHg MAP increase was associated with 23.3 mL greater fluid removal (p < 0.001). Independent factors linked to reduced negative FB included vasopressor use (noradrenaline), elevated creatinine, and higher SOFA scores. Conclusions: In this cohort, MAP was significantly associated with the likelihood of achieving a negative fluid balance during de-resuscitation. Conversely, vasopressor use, renal dysfunction, and higher illness severity were linked to reduced diuretic responsiveness. These findings support individualized de-resuscitation strategies. Full article

Background/Objectives: Plant-derived diuretics are attracting increasing interest due to their promising efficacy and improved safety profile compared with synthetic drugs. This study aimed to characterize the phytochemical composition of Astragalus boeticus (A. boeticus) extracts, evaluate their diuretic activity, and assess the oral safety of their main phenolic compound. Methods: Aqueous (AQE) and hydroethanolic (EtOHE) extracts were analyzed using LC–MS/MS, while in silico toxicity prediction of trans-resveratrol was performed using ProTox-II and ADMETlab 2.0. Diuretic activity was evaluated in male Wistar rats (n = 24) divided into four groups: control (distilled water, 10 mL/kg), furosemide (10 mg/kg), AQE (300 mg/kg), and EtOHE (300 mg/kg). Urine and plasma samples were collected after 15 days to determine electrolyte concentrations, creatinine level, creatinine clearance, and hepatic enzyme profile. Results: LC–MS/MS profiling identified fourteen phenolic compounds, with trans-resveratrol (270 µg/g in AQE) being the most abundant, followed by cyanidin-3-O-glucoside and gentisic acid. In silico assessments revealed no hepatotoxic, mutagenic, or neurotoxic effects of trans-resveratrol. Both extracts significantly enhanced urinary output, chloride excretion, and creatinine clearance, while maintaining stable renal and hepatic biochemical parameters, indicating potent diuretic activity without toxicity. Conclusions: A. boeticus extracts demonstrate strong diuretic potential associated with a favorable safety profile, likely linked to their phenolic composition dominated by trans-resveratrol. These findings support the use of A. boeticus as a natural and safe diuretic source. Further investigation is recommended to elucidate its pharmacological mechanisms and therapeutic relevance. Full article

The increasing use of multiple medications among older adults raises concerns about potentially inappropriate medications (PIMs), which are associated with adverse health outcomes and increased healthcare costs. This study aimed to assess the prevalence and types of PIMs dispensed to older adults living in Northwest Italy using real-world pharmacy claims data. An observational, retrospective analysis was conducted on anonymized drug dispensing datasets from two local health authorities, covering individuals aged 65 years or older between 2018 and 2021. PIMs were identified according to the 2019 American Geriatrics Society Beers Criteria, focusing on drugs that are inappropriate or should be used with caution in older adults or have anticholinergic properties. Over half of older adults who received medications during the study period were dispensed at least one PIM, with stable or slight increased prevalence over time with no differences by sex or region. Proton-pump inhibitors used for more than 8 weeks and paroxetine were the most common PIMs, while furosemide and sulfonylureas were also frequently reported PIMs. These findings indicate a persistently high burden of inappropriate prescribing in older adults and highlight the need for coordinated deprescribing interventions and prescriber education to promote safer, evidence-based pharmacotherapy in aging populations. Full article

Left-sided congestive heart failure (CHF) is a common cause of acute respiratory distress in cats, and echocardiographic assessment of left atrial (LA) size is an important test to differentiate it from respiratory diseases that cause similar clinical signs. Furosemide, a potent loop diuretic, is the first-line therapy for cardiogenic pulmonary edema, but its effect on LA size has not been systematically investigated in cats. Some dyspneic cats are referred after having received high doses of furosemide by the referring veterinarian without prior point-of-care ultrasound (POCUS). This can make the diagnosis of CHF challenging. If furosemide significantly reduces left atrial size, it could potentially lead to misdiagnosis, by erroneously categorizing these cats as not having CHF. This prospective, observational multicenter study enrolled 25 cats with acute left-sided CHF. Point-of-care ultrasound was used to assess LA to aortic ratio (LA:Ao) and maximal LA diameter (LAD) at admission and three hours after furosemide administration. Significant reductions were observed in LA:Ao (2.48 ± 0.35 to 2.17 ± 0.40; p < 0.001), LAD (21.0 ± 2.8 mm to 18.4 ± 3.2 mm; p < 0.001), and respiratory rate (64 ± 30 to 40 ± 14 breaths/min; p < 0.001). Normalization of respiratory rate occurred in 50% of cats, while normalization of maximum LAD occurred in 32%. One cat achieved normalization of LA:Ao. We found that furosemide induced rapid reduction in LA size and respiratory rate in cats with left-sided CHF. Clinicians should be aware that severe LA dilation can be absent in referred dyspneic cats that had already received furosemide. Full article

Background/Objectives: Advanced heart failure (AdvHF) characterizes patients with impaired functional capacity, severe systolic or diastolic cardiac function, unplanned visits or hospitalizations, raised natriuretic peptides, and increased mortality. Methods: Ninety-five consecutive AdvHF patients followed in a tertiary academic center in Northwestern Greece (2nd Department of Cardiology, University Hospital of Ioannina) were enrolled over a 30-month period. Three distinctive patterns of management were recognized and assessed: intermittent levosimendan administration to 33 patients, intermittent intravenous furosemide administration to 17 patients, and 45 patients were followed up exclusively on an outpatient basis with frequent visits. MAGGIC, SHFM, and BCN-Bio scores were assessed in all patients and mortality was also assessed. Results: Mean age was 73 (±10) years, and 38% were females, 41% had diabetes mellitus, 41% had chronic obstructive pulmonary disease, 59% had coronary artery disease (CAD), 73% had a history of atrial fibrillation, and 82.1% had a cardiac device implanted. The median duration of follow-up was 24 months (IQ range 14, 30). The 12-month and 30-month mortality rates were 19% and 49%, respectively. Higher rates of 1-year mortality were observed in the levosimendan group (30%). The median 12-month mortality of the three scores was comparable to the actual mortality, but their prognostic value was not satisfactory (AUC < 0.540 and p > 0.05 for all), while they performed better for 30-month mortality (AUC < 0.756 and p > 0.05 for all). In the current study, mortality at 12 months was associated with decreasing diastolic blood pressure (DBP) and sodium levels; the presence of CAD (p < 0.05 for all) and mortality at 30 months was associated with decreasing systolic blood pressure, as well as DBP and left ventricle ejection fraction, but also with the presence of CAD and the use of renin–angiotensin–aldosterone system blockers. Logistic regression-based models incorporating these factors have a greater diagnostic accuracy (AUC = 0.824 and 0.817 for 12 and 30 months, respectively; p < 0.001 for both). Conclusions: AdvHF patients represent a complex population requiring close follow-up and novel strategies to improve survival. Larger studies are needed to refine and update predictive scores in this population. Full article

Background/Objectives: Hyponatremia is defined as a serum sodium concentration below 135 mEq/L. It is associated with increased morbidity and mortality. This study aimed to determine the factors associated with mortality in patients hospitalized with moderate to severe hyponatremia in the nephrology clinic and nephrology intensive care unit during an eight-year follow-up period. Methods: This retrospective study included patients admitted between January 2018 and October 2025 who were hospitalized due to moderate or severe hyponatremia. Results: Of 4270 patients, 337 (7.8%) were hospitalized with moderate to severe hyponatremia. The majority of patients were female (60.2%; n = 203). 242 patients (71.8%) had severe hyponatremia. The most common presenting complaint was nausea and vomiting, the most common month and season of presentation was July-Summer, and the most common cause of hyponatremia was drug-induced hyponatremia. The mortality rate was 40.7% (n = 137). The most common cause of death was decompensated heart failure. Factors independently affecting mortality; age (HR = 1.018, 95% CI 1.001–1.037, p = 0.047), malignancy (HR = 2.397, 95% CI 1.459–3.939, p < 0.001), number of hospitalizations (HR = 0.377, 95% CI 0.228–0.623, p < 0.001), EF (HR = 0.972, 95% CI 0.956–0.988, p < 0.001), high phosphorus (HR = 2.397, 95% CI 1.527–3.764, p < 0.001), furosemide use (HR = 1.638, 95% CI 1.018–2.636, p = 0.042) and fluid restriction. Conclusions: Advanced age, malignancy, high phosphorus levels, furosemide use, and fluid restriction were associated with increased mortality, whereas higher ejection fraction and greater number of hospitalizations were protective. These findings emphasize the importance of individualized management strategies and close follow-up in patients with moderate to severe hyponatremia. Full article

Background: Sudden cardiac death (SCD) remains a major cause of cardiovascular mortality. Implantable cardioverter-defibrillators (ICDs) reduce arrhythmic mortality, but current selection based largely on left ventricular ejection fraction (LVEF) lacks precision. Many patients undergo device implantation without ever receiving therapy, while others at risk remain unprotected. Interpretable machine learning (ML) can integrate diverse clinical variables and refine patient selection while maintaining transparency in clinical reasoning. Methods: We retrospectively analyzed 607 patients who underwent ICD or CRT-D implantation at a Croatian tertiary care center. Baseline demographic, clinical, echocardiographic, laboratory, and device-related variables were collected. Patients were followed through routine device interrogations, with appropriate ICD activation serving as a surrogate for SCD prevention. A logistic regression (LR) model was trained to predict appropriate device activation. Results: LR model demonstrated strong predictive ability (AUC-ROC 0.74, sensitivity 86.50%). Significant predictors included ventricular tachycardia (VT) burden, sustained VT, longer follow-up, and secondary prevention. The combination of furosemide and spironolactone therapy was linked to lower predicted SCD risk. Conclusions: ML applied to routinely collected data can support risk stratification in SCD and complement existing guideline criteria by reinforcing known predictors and uncovering novel associations. Full article

Furosemide appears to contribute to the accumulation of protein-bound uremic toxins (PBUTs) and to induce adverse drug reactions. We investigated the extent to which the association between the furosemide dose and serum PBUT concentrations mediates the relationship between the furosemide dose and the symptom burden in patients with chronic kidney disease (CKD). This cross-sectional analysis included patients with CKD stages 2 to 5 from the CKD-REIN cohort and with data on the baseline serum concentrations of the free fractions of indoxyl sulphate (IS), kynurenine (KYN), p-cresyl sulphate (PCS), and indole-3-acetic acid (IAA), as measured by liquid chromatography–tandem mass spectrometry. The symptom burden was also assessed with a modified (8-item) symptom subscale from the Kidney Disease Quality of Life-36 (e.g., muscle soreness, cramps, itchy skin, dry skin, dizziness, appetite, numbness, and nausea). We used beta regressions to model the association between the furosemide dose and the symptom burden and used structural equation models to quantify the mediating effect of PBUT on this association. Among the 2053 included patients (males: 66%, median age: 68; mean estimated glomerular filtration rate: 35 mL/min/1.73 m²), those prescribed high-dose furosemide (>120 mg/day) had higher symptom burden than those not prescribed furosemide (i.e., a 5.67-point lower symptom score, 95%CI 1.41–9.93). The sum of PBUTs explained 3.78% (95%CI 0.10–18.01%) of this association. Similar results were observed for IS, KYN, and IAA, considered separately, but not for PCS, whose estimated mediation effect was nearly null. Although high-dose furosemide was associated with a greater symptom burden in patients with CKD, mediation by PBUT accumulation appeared to be minimal. Full article

Background: Acute heart failure (AHF) is a common cause of hospital admission with high morbidity and mortality. Up to one-third of AHF patients require rehospitalization during the first three months after discharge due to the nature of disease and the patient’s characteristics. In this regard, the first 3 months after an episode of decompensation of heart failure are called the “vulnerable” period. However, there is a gap in knowledge about the significance of this rehospitalization on heart failure course. The aim of the study is to evaluate impact on mortality of AHF rehospitalization during 3 months after hospital discharge on a retrospective registry with 3 year follow-up. Methods: Patients after AHF hospitalization episode between 1 December 2020 and 30 November 2023 were monitored via electronical medical records for 3 year follow-up. All patients who survived after index hospitalization were included. The primary endpoint was all-cause mortality. COX-multiple regression was used to evaluate the impact of rehospitalization during 90 days after index discharge on outcomes. p values less than 0.05 were considered to be significant. Results: A cohort of 204 patients, 56.6% males, with an average age of 72 ± 13 years, were included in the study with medium follow-up of 22 ± 12 months. Within 3 months after discharge, 55 (27%) patients were rehospitalized for AHF, and 11 (5%) patients died. Patients who experienced a recurrent episode of AHF were characterized by a history of previous hospitalizations for AHF before inclusion (39 (71%) vs. 72 (48%); p = 0.005), the use of intravenous inotropic drugs (5 (9%) vs. 2 (1%); p = 0.007), higher initial doses of furosemide during index hospitalization (98 ± 46 vs. 82 ± 37; p = 0.01), and higher doses of furosemide at discharge (54 ± 41; 41 ± 33; p = 0.02). Left ventricular ejection fraction (LVEF), prevalence of atrial fibrillation (AF), diabetes mellitus (DM), and chronic kidney disease (CKD) did not differ between the groups. Over 3 years follow-up, 68 (33.2%) patients died, and cardiovascular mortality was 15.6% (32 patients). In multivariate COX-regression age (HR 1.04 [1.008–1.07]), heart rate (HR) on admission (HR 1.02 [1.004–1.03]), and hospitalization within the first 3 months after discharge were independent predictors of death (HR 2.21 [1.32–3.83]). Conclusions: Readmission for AHF within the first 3 months after discharge is an independent risk factor for all-cause cardiovascular mortality during 3 years follow-up. Full article

Background: Heart failure (HF), as the end stage of various cardiac diseases, alters blood flow to key organs responsible for drug clearance. This can lead to unpredictable and often suboptimal drug exposure, creating a critical need for quantitative tools to guide precise dosing in this vulnerable population. Methods: This study aimed to establish a whole-body physiologically based pharmacokinetic (PBPK) model for characterizing drug pharmacokinetics in both healthy subjects and patients across the HF severity spectrum. Eight commonly used drugs (digoxin, furosemide, bumetanide, torasemide, captopril, valsartan, felodipine and midazolam) for treating HF and its comorbidities were selected. Following successful validation against clinical data from healthy subjects, the PBPK model was extrapolated to HF patients. Pharmacokinetics of the eight drugs in 1000 virtual HF patients were simulated by replacing tissue blood flows and compared using clinical observations. Results: Most of the observed concentrations were encompassed within the 5th–95th percentiles of simulated values from 1000 virtual HF patients. Predicted area under the concentration–time curve and maximum plasma concentration fell within the 0.5~2.0-fold range relative to clinical observations. Sensitivity analysis demonstrated that intrinsic renal clearance, unbound fraction in blood, muscular blood flow, and effective permeability coefficient significantly impact plasma exposure of digoxin at a steady state. Oral digoxin dosing regimens for HF patients were optimized via the validated PBPK model to ensure that steady-state plasma concentrations in all HF patients remain below the toxicity threshold (2.0 ng/mL). Conclusions: A PBPK model was successfully developed to predict the plasma concentration–time profiles of the eight tested drugs in both healthy subjects and HF patients. Furthermore, this model may also be applied to guide digoxin dose optimization for HF patients. Full article