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Int J Mol Sci. 2025 Sep 12;26(18):8902. doi: 10.3390/ijms26188902.

ABSTRACT

The purpose of this study was to explore the protective effect of 8 weeks of Moderate Intensity Continuous Training (MICT) on TMAO-induced myocardial injury in mice and its metabolic regulatory mechanism based on nuclear magnetic resonance (NMR) metabolomics methods. Male C57BL/6J mice were randomly allocated into the following groups: Control group (Con, n = 15), TMAO-induced myocardial injury group (TMAO, n = 15), and TMAO-induced with MICT intervention group (Exe, n = 15). TMAO and Exe groups underwent 8 weeks of high-dose TMAO gavage to establish a myocardial injury model, with the Exe group additionally receiving 8 weeks of MICT intervention (60 min/session, 5 sessions/week, 50% MRC). After the 8 weeks of interventions, the mouse heart function was tested using cardiac ultrasound equipment; myocardial histology was evaluated using HE staining; and myocardial tissue samples were collected for NMR metabolomics analysis. Compared with the Con group, the HR in the TMAO group was significantly increased, while EF and LVFS were significantly decreased. Compared with the TMAO group, the HR in the Exe group was significantly reduced, and EF and LVFS were significantly increased; NMR metabolomics analysis showed that, compared with the Con group, five metabolic pathways including phenylalanine metabolism, tyrosine metabolism, and TCA cycle were significantly altered in the TMAO group; compared with the TMAO group, ten metabolic pathways related to amino acid metabolism (such as alanine, glycine, etc.), energy metabolism (TCA cycle), and oxidative stress (purine metabolism) were significantly regulated in the Exe group. MICT could effectively alleviate TMAO-induced myocardial injury in mice by regulating multiple targets within the myocardial metabolic pathways. These findings provide a theoretical basis for the clinical application of exercise intervention in myocardial injury treatment.

PMID:41009469 | PMC:PMC12470193 | DOI:10.3390/ijms26188902

Antioxidants (Basel). 2025 Sep 22;14(9):1140. doi: 10.3390/antiox14091140.

ABSTRACT

Heat stress (HS), a pervasive environmental stressor, significantly disrupts systemic physiological homeostasis, posing substantial threats to human and animal health. Sheng Mai San (SMS), a classic Traditional Chinese Medicine (TCM) formula, exerts its therapeutic effects by replenishing qi (the vital energy governing physiological functions) and nourishing yin (the material basis responsible for moistening and cooling actions). This formula demonstrates significant efficacy in astringing sweating and preventing collapse. However, its precise molecular mechanisms against HS-induced myocardial injury remain incompletely elucidated. This study initially employed physicochemical analytical methods to determine the contents of total polysaccharides, saponins, and flavonoids in SMS and evaluated its antioxidant activity. Subsequently, both in vitro and in vivo rat models of HS were established to systematically assess the alterations in reactive oxygen species (ROS), antioxidant enzymes (GSH, SOD, CAT), and heat shock proteins (HSP70, HSP90) following SMS intervention, thereby investigating HS-induced myocardial injury and the protective effects of SMS. Furthermore, Western blot, immunofluorescence, and qRT-PCR techniques were utilized to quantitatively analyze key molecules in the Keap1-Nrf2-HO-1 and Stub1-HSF1 signaling pathways. The results demonstrated that total polysaccharides were the most concentrated in SMS, followed by total saponins. This formula exhibited potent free radical scavenging capacity against DPPH, ABTS, and OH-, along with significant reducing activity. HS-induced myocardial injury reached its peak severity at 6-12 h post-stress exposure. SMS intervention effectively suppressed excessive ROS generation, enhanced the activities of antioxidant enzymes (GSH, SOD, and CAT), and downregulated HSP70 and HSP90 mRNA expression levels, thereby significantly mitigating cardiomyocyte damage. Mechanistic investigations revealed that SMS conferred cardioprotection through dual modulation of the Keap1-Nrf2-HO-1 and Stub1-HSF1 signaling pathways. This study not only provides a novel TCM-based therapeutic strategy for preventing and treating HS-related cardiovascular disorders but also establishes a crucial theoretical foundation for further exploration of SMS's pharmacological mechanisms and clinical applications.

PMID:41009044 | PMC:PMC12466528 | DOI:10.3390/antiox14091140

Antioxidants (Basel). 2025 Sep 19;14(9):1137. doi: 10.3390/antiox14091137.

ABSTRACT

NADPH oxidase 4 (NOX4) plays a crucial role in regulating cardiac function and pathology through its involvement in oxidative stress, fibrosis, and maladaptive remodeling. Studies have demonstrated that NOX4 is upregulated in response to various cardiovascular stressors, including heart failure, myocardial infarction, arrhythmias, and diabetes. This upregulation contributes to detrimental processes like fibrosis, hypertrophy, and inflammation, which are hallmarks of cardiovascular diseases. Inhibition or knockout of NOX4 has shown promise in mitigating these pathological changes, suggesting that NOX4 represents a potential therapeutic target for treating heart disease. However, NOX4's role is not entirely negative. It also plays a protective role in the heart, supporting myocardial remodeling and angiogenesis and regulating cardiac energy metabolism. Its constitutive ROS production and ability to respond to environmental cues like hypoxia help maintain cellular homeostasis and facilitate adaptive responses to stress. The impact of NOX4 on cardiac health depends not only on its expression level but also on the nature of the stress, the duration of activation, and the balance between protective signaling and oxidative injury. Collectively, the findings suggest that NOX4 functions as a redox sensor, modulating cellular responses to fluctuations in oxidative stress by signaling the need to re-establish redox homeostasis. The ultimate impact of cardiac NOX4 activity, whether protective or deleterious, is highly context-dependent and should not be evaluated through a singular interpretative framework. In conclusion, NOX4 is a dual-function enzyme that can both exacerbate and protect against cardiac pathology, making it a promising, though complex, therapeutic target for various cardiovascular diseases.

PMID:41009041 | PMC:PMC12466861 | DOI:10.3390/antiox14091137

Commun Biol. 2025 Sep 26;8(1):1368. doi: 10.1038/s42003-025-08742-0.

ABSTRACT

Phospholipase Cε (PLCε) cleaves phosphatidylinositol lipids to increase intracellular Ca2+ and activate protein kinase C (PKC) in response to stimulation of cell surface receptors. PLCε is activated via direct binding of small GTPases at the cytoplasmic leaflets of cellular membranes. In the cardiovascular system, the RhoA GTPase regulates PLCε to initiate a pathway that protects against ischemia/reperfusion injuries, but the underlying molecular mechanism is not known. We present here the cryo-electron microscopy (cryo-EM) reconstruction of RhoA bound to PLCε, showing that the G protein binds a unique insertion within the PLCε EF hands. Deletion of or mutations to this PLCε insertion decrease RhoA-dependent activation without impacting its regulation by other G proteins. Together, our data support a model wherein RhoA binding to PLCε allosterically activates the lipase and increases its interactions with the membrane, resulting in maximum activity and cardiomyocyte survival.

PMID:41006770 | PMC:PMC12475037 | DOI:10.1038/s42003-025-08742-0

Cell Rep. 2025 Sep 25;44(10):116202. doi: 10.1016/j.celrep.2025.116202. Online ahead of print.

ABSTRACT

We developed an in vitro methodology to study trained immunity using murine bone-marrow-derived macrophages stimulated with β-glucan and lipopolysaccharide (LPS). Longitudinal analysis of interleukin (IL)-6 and tumor necrosis factor (TNF) production demonstrates that trained macrophages secrete higher cytokine levels following primary stimulation with β-glucan compared to unstimulated macrophages (step 1). After a resting period, trained macrophages return to basal levels of cytokine production (step 2) but rapidly produce enhanced levels of IL-6 and TNF after secondary stimulation with LPS, compared to macrophages individually stimulated with either β-glucan (step 3) or LPS (step 4) alone. The combined cytokine production of macrophages after single stimulation with β-glucan (stimulus 1) and LPS (stimulus 2) is significantly lower than the cytokine levels produced by trained macrophages sequentially stimulated with both β-glucan and LPS (stimulus 1 + 2) (step 5). These results experimentally reproduce the distinctive functional stages that macrophages undergo during the training process.

PMID:41014560 | DOI:10.1016/j.celrep.2025.116202

Immunol Res. 2025 Sep 27;73(1):137. doi: 10.1007/s12026-025-09689-4.

ABSTRACT

Autoimmune hepatitis (AIH) is an immune-mediated liver disease that currently lacks viable drug treatment methods. This study is to explore the role of piceatannol (PIC) in ConA-induced AIH and the related mechanisms. A mouse model of AIH was established by injecting ConA (i.v.), and PIC was administered as an intervention. The protective effect of PIC was evaluated by the liver function, liver pathology, and serum levels of inflammatory factors. Subsequently, network pharmacology was used to predict the pathways and targets of PIC in the treatment of AIH, and the predicted results were validated using flow cytometry, molecular docking, surface plasmon resonance (SPR) and so on. Finally, the immunosuppressive effect of PIC was further validated in a mouse heart transplantation model. PIC can improve liver function decline and reduce pathological liver damage, as well as inhibit the increase of serum inflammatory factor levels in mice with AIH induced by ConA. The protective effect is achieved by suppressing the immune activity of T cells and macrophages through binding to c-Jun. PIC can also extend the survival of cardiac allografts and inhibit acute rejection reactions. These results indicated that PIC can significantly improve ConA-induced AIH in mice by inhibiting the immune activity of T cells and macrophages through binding to c-Jun. PIC can also extend the survival of cardiac allografts in mice and inhibit acute rejection responses. The above results indicated that PIC may serve as a promising immunosuppressant and be effective for AIH.

PMID:41014384 | DOI:10.1007/s12026-025-09689-4

J Thorac Cardiovasc Surg. 2025 Sep 27:S0022-5223(25)00757-3. doi: 10.1016/j.jtcvs.2025.09.003. Online ahead of print.

NO ABSTRACT

PMID:41014310 | DOI:10.1016/j.jtcvs.2025.09.003

Int J Cancer. 2025 Sep 27. doi: 10.1002/ijc.70136. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome-wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co-development with hepatitis C virus-negative (HCV-negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV-negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV-negative HCC and blood-based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV-negative HCC and diseases associated with metabolic dysfunction-associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood-based biomarkers identified in this study for inferring HCC development among HCV-negative individuals.

PMID:41013983 | DOI:10.1002/ijc.70136

J Med Case Rep. 2025 Sep 26;19(1):453. doi: 10.1186/s13256-025-05488-5.

ABSTRACT

BACKGROUND: Fabry disease is an inherited lysosomal storage disease that can be reversed, or the progression slowed, by enzyme replacement therapy in the early stage. However, whether patients receiving renal replacement therapy benefit from enzyme replacement therapy remains controversial, especially in regard to patients on hemodialysis, who additionally suffer from uremia and abnormal hemodynamics.

CASE PRESENTATION: Two male Han Chinese patients diagnosed with uremia prior to Fabry disease underwent renal transplantation and hemodialysis, respectively. At the ages of 27 and 32 years, they began receiving agalsidase-α, an enzyme replacement therapy drug, in February 2022, lasting for 1.5 years. Cardiac structural and functional parameters were obtained using the 6-minute walk test, along with serum biomarkers and electrocardiogram and ultrasound examinations. Changes in the cardiac parameters and the plasma globotriaosylsphingosine concentration before and after enzyme replacement therapy were evaluated. Both patients received enzyme replacement therapy for 18 months, which was uneventful. One patient maintained normal renal function, while the other received adequate dialysis. The level of globotriaosylsphingosine was reduced by approximately two-thirds after the first 3-month enzyme replacement therapy and remained stable during follow-up. No significant changes were detected in cardiac structure or function parameters, with the exception of the PR interval and left atrial reservoir strain. The PR interval of the renal transplant patient was prolonged from 108 to 128 milliseconds. Left atrial reservoir strain improved significantly in both patients, from 29.4% to 53.1% and from 46.3% to 59.3%, respectively.

CONCLUSION: Patients with Fabry disease who are on renal replacement therapy may benefit from enzyme replacement therapy. Moreover, adequate hemodialysis does not compromise the cardioprotective effect of agalsidase-α.

PMID:41013812 | PMC:PMC12465962 | DOI:10.1186/s13256-025-05488-5

BMC Infect Dis. 2025 Sep 26;25(1):1153. doi: 10.1186/s12879-025-11579-x.

ABSTRACT

BACKGROUND: Bacterial infections, especially those caused by multidrug-resistant organisms, remain a major threat to the survival of organ transplant recipients. This review aimed to systematically assess the most common bacterial pathogens, risk factors, and prevention strategies in solid organ transplantation (SOT), focusing on liver, kidney, heart, and lung transplants.

METHODS: A systematic search was conducted across PubMed, Scopus, Web of Science, and Google Scholar databases for studies published between 2015 and 2024. Studies were selected based on inclusion criteria targeting bacterial infections in human transplant recipients. Data were extracted on infection types, bacterial species, risk factors, immunosuppressive regimens, and antimicrobial prophylaxis.

RESULTS: Among 75 eligible articles, 26 met the inclusion criteria. Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa were the predominant pathogens in most transplant types. Urinary tract infections were most frequent in kidney transplants, while lung, heart, and liver transplant recipients exhibited broader pathogen diversity, including MRSA, VRE, and Acinetobacter. Major risk factors included immunosuppressive therapy, pre-transplant colonization, prolonged ICU stay, and donor-derived MDR organisms. Antibiotic prophylaxis and immunosuppressive regimens varied across studies, with no universal consensus on optimal protocols.

CONCLUSIONS: Bacterial infections significantly impact graft survival and patient outcomes, particularly during the early post-transplant period. Efficient infection prevention, tailored antimicrobial prophylaxis, and optimized immunosuppressive management are essential for improving transplant success rates.

PMID:41013392 | PMC:PMC12465290 | DOI:10.1186/s12879-025-11579-x

Medicina (Kaunas). 2025 Sep 18;61(9):1696. doi: 10.3390/medicina61091696.

ABSTRACT

Background and Objectives: Normothermic ex situ heart preservation maintains donor heart viability by sustaining physiological conditions and reducing ischemic damage. However, the ideal perfusion pressure remains uncertain. This study aims to identify the optimal perfusion pressure to enhance graft preservation in rat heart transplantation. Materials and Methods: We utilized 20 male Sprague-Dawley rats (400-500 g). Donor hearts underwent normothermic preservation for 2 h using a Langendorff apparatus primed with 12 mL of solution at a consistent 3 mL/min flow. After preservation, hearts were transplanted heterotopically into the recipient's abdomen. We defined successful preservation by observing a QRS complex in electrocardiographic monitoring for 3 h post-transplantation. Histological assessments for myocardial integrity occurred after 4 h of reperfusion. We analyzed statistical differences between successful and unsuccessful preservation groups. Results: Electrocardiograms indicated preservation failure in 8 of the 20 donor hearts due to the absence of a QRS complex. We observed no significant differences in ischemic duration between groups. At 120 min, although serum lactate and potassium concentrations increased in the unsuccessful group, the differences were not statistically significant. Higher initial perfusion pressures (>65 mmHg) at a constant flow rate resulted in elevated lactate and potassium concentrations post-preservation, indicating suboptimal outcomes. Histologically, hematoxylin and eosin staining showed better myocardial preservation in successful hearts, while TUNEL assays demonstrated increased apoptosis in unsuccessful hearts. All hearts increased in weight after preservation, but significant increases occurred only in unsuccessful cases. Conclusions: Higher initial perfusion pressures (>65 mmHg) negatively affect heart preservation outcomes, resulting in elevated serum lactate and potassium levels, increased heart weight, and greater histological damage. Maintaining optimal perfusion pressures is essential to preserve myocardial integrity and functional viability during normothermic ex situ heart preservation.

PMID:41011087 | PMC:PMC12471859 | DOI:10.3390/medicina61091696

Medicina (Kaunas). 2025 Sep 11;61(9):1650. doi: 10.3390/medicina61091650.

ABSTRACT

Background and Objectives: This study aimed to assess the clinical and anatomical predictors of acute cardiac complications after transcatheter aortic valve implantation (TAVI). Materials and Methods: All patients who underwent a TAVI procedure for severe aortic stenosis between November 2016 and May 2025 at a tertiary center in Romania were screened for inclusion. Of those, patients who had available computer tomography valvular sizing reports were included in the present study. Results: A total of 485 patients were included in this study. Balloon-expandable valves were implanted in 381 patients (78.5%), while self-expanding valves were used in 104 patients (21.4%). A total of sixty-nine (14.2%) patients suffered at least one acute cardiac complication following TAVI, and in-hospital death occurred in nine (1.8%) patients. In the multivariable analysis, clinical parameters-such as diabetes mellitus, left bundle branch block, or left ventricular diameter-and anatomic parameters, such as left coronary artery height and sinotubular junction height, were predictors of acute complications. Similarly, periprocedural characteristics, such as maximum transprosthetic gradient and the use of the Portico/Navitor valve platform was also associated with the occurrence of acute complications. Conclusions: A high acute complications rate is typical for TAVI, although most complications can be successfully treated and the in-hospital death rate is low. Left coronary artery height and sinotubular junction height were predictors of acute complications, among other clinical and procedural characteristics.

PMID:41011039 | PMC:PMC12472114 | DOI:10.3390/medicina61091650

Medicina (Kaunas). 2025 Aug 27;61(9):1545. doi: 10.3390/medicina61091545.

ABSTRACT

Background and Objectives: Premature atrial contractions (PACs) and premature ventricular contractions (PVCs) commonly occur after coronary artery bypass grafting (CABG) surgery, with frequent ectopics linked to atrial fibrillation risk and reduced heart function. While CABG-induced inflammation causes arrhythmogenic changes, the connection between preoperative inflammatory markers and postoperative ectopic burden has not been studied. Therefore, the aim of the present study is to evaluate the association between preoperative inflammatory biomarkers and postoperative atrial and ventricular ectopic burden, and to determine their influence on clinical outcomes following elective CABG procedures. Materials and methods: This study assessed preoperative plasma levels of highly sensitive C-reactive protein (hs-CRP), von Willebrand factor (vWF), transforming growth factor-β (TGF-β), interleukin (IL)-2, IL-1β, IL-6, IL-8, and vascular endothelial growth factor (VEGF) using the Multiplex technique in patients undergoing elective CABG. A continuous 24-h ECG Holter monitoring was performed one day before CABG, as well as on days 2, 3, and 4 post-CABG. The PACs and PVCs burdens were quantified, and correlations with clinical parameters were analyzed. Results: Preoperative plasma concentrations of vWF, TGF-β, and IL-8 exhibited significant positive correlations with postoperative PACs (p < 0.001, p = 0.03, and p < 0.001, respectively). Preprocedural hs-CRP, TGF-β, IL-6, and IL-8 levels showed significant positive associations with PVCs (p < 0.0001, p < 0.0001, p = 0.02, and p < 0.0001, respectively). However, none of the tested biomarkers could predict other postoperative outcomes, such as acute kidney injury, acute liver failure, duration of inotropic support, and days of hospitalization. Conclusions: Preoperative inflammatory biomarkers may serve as predictive tools for postoperative ectopic activity following CABG. Early identification of high-risk patients could enable prophylactic strategies and improve post-CABG outcomes.

PMID:41010936 | PMC:PMC12471965 | DOI:10.3390/medicina61091545

J Clin Med. 2025 Sep 18;14(18):6590. doi: 10.3390/jcm14186590.

ABSTRACT

Background: Although there has been an improvement in the survival rates of patients following heart transplantation, many complications, such as hypertension, continue to develop. The aim of the study was to assess the 24-hour blood pressure profile and hypertension treatment among patients after heart transplantation and comparison to the control group. Methods: A retrospective data analysis included 26 male patients post-heart transplantation and 39 male patients in the control group. During a routine visit, the following data were collected: 24-hour blood pressure monitoring, laboratory tests, and medical history. Results: Hypertension was diagnosed in 76.9% of heart transplant recipients (HTXr) and in 56.4% of the control group (Cx). During the night-time rest period, diastolic blood pressure values ≥ 70 mmHg were observed in 76.9% of HTXr (vs. 33.33% Cx, p = 0.001). The average daytime systolic/diastolic blood pressure did not differ significantly between the groups. It was also observed that the groups differed in circadian blood pressure (Chi2ML = 15.87, p < 0.001), as there were significantly more reverse dippers in HTXr than in the control group (30.8% (8) vs. 10.3% (4)). The same proportions were also noted in HTXr and the control group in terms of isolated nocturnal hypertension. Conclusions: Heart transplant recipients require a tailored approach to hypertension management, including a variety of medications and appropriate chronotherapy.

PMID:41010793 | PMC:PMC12470993 | DOI:10.3390/jcm14186590

J Clin Med. 2025 Sep 17;14(18):6545. doi: 10.3390/jcm14186545.

ABSTRACT

Background/Objectives: Each year, the number of kidney transplants (KT) performed in older recipients continues to rise. The process of aging may impact early post-transplant outcomes. The aim of this study was to analyze one-year outcomes, clinical and surgical complications, as well as patient and graft survival in senior recipients. Methods: This retrospective, observational study included a total of 270 participants who underwent KT during the period between January 2021 and April 2024. Recipients were divided into two groups: the older group (≥60 years; n = 75) and the younger group (<60 years; n = 195) and then analyzed during a one-year follow-up period. Results: Older recipients were characterized by a higher body mass index (MD = 1.77, CI95 [0.63; 2.91], p = 0.002), suffered more often from diabetes mellitus (RR = 2.94, CI95 [1.79; 4.82], p < 0.001), cardiovascular diseases (RR = 5.20, CI95 [2.90; 9.32], p < 0.001) and were more likely to receive a kidney from older (MD = 12.37, CI95 [8.94; 15.80], p < 0.001) deceased (p < 0.001) donors. Senior patients had more infections (p = 0.019) and surgical complications (RR = 1.81, CI95 [1.14; 2.87], p = 0.020), more cardiac events (RR = 2.28, CI95 [1.17; 4.43], p = 0.025), and a higher incidence of delayed graft function (p < 0.001) compared to younger patients. The estimated glomerular filtration rate (eGFR) was significantly lower in the older group both at initial hospital discharge (MD = -6.50, CI95 [-13.00; -3.00], p = 0.004) and at one-year follow-up (MD = -11.79, CI95 [-17.32; -6.25], p < 0.001). No differences were observed in the incidence of biopsy-proven acute rejection, cytomegalovirus replication, and polyomavirus replication. One-year patient and graft survival was 97.3% and 94.7% in the older group, and 98.5% and 96.9% in the younger group, respectively. Conclusions: Kidney transplantation in older recipients is safe in the short term. Although eGFR was lower in the older group, it remained within an acceptable range.

PMID:41010748 | PMC:PMC12471075 | DOI:10.3390/jcm14186545

J Clin Med. 2025 Sep 11;14(18):6420. doi: 10.3390/jcm14186420.

ABSTRACT

Background: Lung transplantation (LTx) is a life-saving intervention for patients with advanced interstitial lung disease (ILD), markedly improving pulmonary function, exercise capacity, and right heart function, yet it is often accompanied by increased risks of metabolic, cardiovascular, and renal complications. Methods: We conducted a longitudinal analysis of 102 ILD patients post-LTx, integrating pulmonary, cardiovascular, metabolic, and functional parameters. Recovery was assessed using lung function parameters (FVC, DLCO, TLC, ITGV, and FEV1), 6MWD, Borg scores, sPAP, TAPSE, BMI, and weight, while the comorbidity burden was monitored via the Comorbidity-Polypharmacy Score (CPS). Results: Patients showed marked post-LTx improvements, with FVC and DLCO increasing by +37.99% and +42.90%, 6MWD by +166.5 m, and dyspnea decreasing by -3.25 points (Borg scale). Right heart function improved (sPAP -23.79 mmHg and TAPSE increased). Despite these gains, renal function (eGFR -14.14 mL/min/1.73 m2/year) and platelet counts (-17.79 × 109/L/year) declined, while the CPS nearly doubled (16 to 30), reflecting rising comorbidities, including hypertension, diabetes, osteoporosis, reflux, and malignancies. Conclusions: While LTx significantly enhances pulmonary function, exercise capacity, and hemodynamics in ILD patients, it also triggers complex systemic adaptations and a rising comorbidity burden, underscoring the need for dynamic risk stratification and integrated care to balance the benefits and burden over time.

PMID:41010625 | PMC:PMC12470646 | DOI:10.3390/jcm14186420

Life (Basel). 2025 Sep 17;15(9):1462. doi: 10.3390/life15091462.

ABSTRACT

Acute rejection and infections are the most frequent complications in the first year after lung transplantation, often representing relevant causes of death. There is still no consensus on the ideal strategy for preventing these events, with a still open debate on active bronchoscopic surveillance protocols vs. clinically mandated ones. The aim of our single-center exploratory study was to evaluate retrospectively the role of microbiology at bronchoalveolar lavage (BAL) at the first month from transplantation in asymptomatic patients in relation to the development of complications up to 12 months from surgery. We collected data from 28 patients who underwent surveillance bronchoscopies according to our center protocol (transbronchial biopsies and BAL at months 1, 4, 8, 12, 18, and 24 post-transplantation) who had a 12-month follow-up. The inclusion criterion was the absence of infiltrates at 1-month post-transplantation chest CT. We excluded patients transplanted due to suppurative diseases of the lung to minimize the pre-transplantation risk factors for infection. We also assessed differences in complications according to the underlying disease. We enrolled 15 patients with interstitial lung diseases (ILDs) and 13 with chronic obstructive pulmonary disease (COPD). Of the 28 patients, 11 had a positive BAL for bacteria. Patients with a positive BAL developed a higher number of pulmonary infectious complications (odds ratio of 18.33, p-value = 0.013 at regression model), with a near significance for moderate-severe pulmonary infections (odds ratio 4.8, p-value = 0.061). We did not find a significant correlation with rejection, cytomegalovirus reactivation, or pseudomembranes. We did not find differences in the rates of complications when grouping subjects according to pre-transplantation disease. Our results suggest a possible role for BAL positivity for bacteria in asymptomatic patients at surveillance bronchoscopy in predicting the development of future infections, warranting a tailored follow-up of patients that considers this data. Larger, multicentric studies are needed to explore and confirm the utility of our findings.

PMID:41010404 | PMC:PMC12471641 | DOI:10.3390/life15091462

Genes (Basel). 2025 Aug 26;16(9):1010. doi: 10.3390/genes16091010.

ABSTRACT

Background: Tacrolimus is a cornerstone of immunosuppressive therapy following heart transplantation. Despite routine therapeutic drug monitoring (TDM), substantial interindividual variability in tacrolimus pharmacokinetics presents a persistent challenge. Pharmacogenetic profiling-particularly of CYP3A5 and CYP3A4 polymorphisms-offers a promising approach to individualize tacrolimus dosing and improve clinical outcomes. Case Presentation: We describe a 54-year-old male heart transplant recipient with persistently subtherapeutic tacrolimus trough concentrations despite escalating standard doses. Tacrolimus dosing initially started at 3.5 mg twice daily, escalated to 7.0 mg twice daily, with final maintenance dosing at 6.5 mg twice daily. TDM values were persistently subtherapeutic at 3-5 ng/mL for over a month before achieving therapeutic targets >10 ng/mL. Pharmacogenetic testing revealed a CYP3A5 expresser genotype (*1/*3) and normal CYP3A4 activity (*1/*1), suggesting enhanced metabolic clearance. In accordance with CPIC guidelines, tacrolimus dosing was intensified and supported by co-administration of diltiazem (60 mg twice daily, later adjusted to 90 mg twice daily), a CYP3A4 inhibitor. Subsequent TDM confirmed achievement of therapeutic levels. At nine months post-transplant, the patient exhibited stable graft function and excellent clinical status. Discussion: This case underscores the value of genotype-informed tacrolimus dosing in clinical scenarios where standard TDM is insufficient. Pharmacogenetic variation-particularly involving CYP3A5 expression-has been consistently associated with altered tacrolimus exposure and dose requirements. The literature supports routine genotyping in solid organ transplant recipients, although implementation remains limited. Additional considerations include drug-drug interactions, notably with CYP3A-modulating agents such as diltiazem and antifungals, which may further influence tacrolimus pharmacokinetics. Current evidence suggests that the utility of CYP3A4 genotyping may be phase-dependent, being more impactful during early post-transplant periods. Conclusions: Incorporating pharmacogenetic data alongside TDM facilitates more precise and individualized tacrolimus therapy, optimizing immunosuppressive efficacy and minimizing risk. This case, supported by literature review, advocates for broader integration of genotype-guided strategies in transplant pharmacotherapy.

PMID:41009956 | PMC:PMC12469574 | DOI:10.3390/genes16091010

Antibiotics (Basel). 2025 Sep 16;14(9):934. doi: 10.3390/antibiotics14090934.

ABSTRACT

BACKGROUND: Infections following cardiac surgery are a significant cause of morbidity and mortality, particularly in intensive care units (ICUs). The role of antibiotic prophylaxis (AP) in preventing surgical site infections (SSIs) and other nosocomial infections is crucial; however, the optimal approach to agent selection, dosing, and duration remains controversial.

OBJECTIVE: This narrative review aims to summarise the current evidence and expert recommendations regarding the use of perioperative antibiotic prophylaxis (AP) in adults undergoing cardiac surgery, with a particular focus on intensive care settings, transplant recipients, and adult patients on extracorporeal membrane oxygenation (ECMO).

METHODS: A comprehensive review of recent literature was conducted, focusing on pharmacokinetic/pharmacodynamic (PK/PD) principles, microbial epidemiology, antimicrobial resistance (AMR), and practical strategies for tailored prophylaxis in high-risk populations.

RESULTS: Cefazolin remains the first-line agent for most procedures, with vancomycin or clindamycin reserved for patients who are allergic to β-lactams or who are colonised with MRSA. Redosing is recommended in cases of prolonged surgery or cardiopulmonary bypass. Evidence supports limiting prophylaxis to ≤24 h, with a potential extension to 48 h in select high-risk cases; however, continuation beyond this is discouraged due to the risk of resistance. In heart transplantation, multimodal prophylaxis against bacteria, fungi, and viruses is essential but must be tailored to the individual patient. In the ECMO setting, the current evidence does not support the routine administration of prophylaxis (AP), and therapy should be tailored based on pharmacokinetics (PK)/pharmacodynamics (PD) changes and the clinical context. A multidisciplinary, evidence-based approach to AP in cardiac surgery is essential. Prophylaxis should be patient-specific, microbiologically guided, and limited in duration to reduce the emergence of multidrug-resistant organisms. Integrating antimicrobial stewardship, non-pharmacological measures, and rigorous surveillance is crucial for optimising the prevention of infections in this vulnerable population.

PMID:41009912 | PMC:PMC12466373 | DOI:10.3390/antibiotics14090934

Int J Mol Sci. 2025 Sep 18;26(18):9136. doi: 10.3390/ijms26189136.

ABSTRACT

Cardiac allograft rejection remains a major cause of graft dysfunction post-transplant. While histology is the current diagnostic standard, it may miss early immune and inflammatory events. This study evaluated the immunohistochemical expression of matrix metalloproteinases 2 (MMP2), 9 (MMP9), and interleukin-1 beta (IL-1β) in cardiac transplant patients, correlating their expression with acute cellular rejection (ACR), antibody-mediated rejection (AMR), inflammation, vasculitis, the Quilty effect, and immune markers. Fifty-nine endomyocardial biopsy specimens were retrospectively analyzed. Immunohistochemical staining for MMP2, MMP9, and IL-1β was assessed based on nuclear, cytoplasmic, and membranous expression. Correlations were evaluated using Fisher's exact test and odds ratios (ORs) with 95% confidence intervals (CIs). IL-1β nuclear expression showed strong associations with ACR (p = 0.0001), inflammation, vasculitis, and immune/endothelial markers (all p < 0.003). Nuclear MMP9 expression correlated with ACR and immune cell markers and was borderline significant for AMR (p ≈ 0.05). Cytoplasmic MMP2 (>50%) was significantly associated with AMR (OR = 7.47, p = 0.0002). No marker correlated with the Quilty effect. The immunohistochemical profiles of IL-1β and MMP9 support their involvement in immune-mediated injury in cardiac allograft rejection, with IL-1β emerging as a sensitive marker of early inflammation. MMP2 appears to be more relevant to humoral rejection processes. These findings suggest that selected tissue biomarkers may enhance diagnostic precision and support early detection of graft injury when integrated with conventional histology.

PMID:41009699 | PMC:PMC12470548 | DOI:10.3390/ijms26189136