BACKGROUND: Hypertensive disorders of pregnancy (HDPs) are associated with an increased risk of long-term maternal cardiovascular disease. Lactation is associated with favorable cardiometabolic profiles, but its impact on blood pressure (BP) recovery following an HDP is less clear. OBJECTIVE: We sought to assess the relationship of lactation initiation and duration with BP among individuals with prior HDP. MATERIALS AND METHODS: We used prospectively collected data from individuals with prepregnancy overweight or obesity with HDP and no prepregnancy hypertension who participated in a postpartum pilot lifestyle intervention trial. The parent trial assessed BP in triplicate and self-reported lactation status at enrollment and follow-up (8-12 months postpartum) study visits. Daily BPs were obtained by home BP monitoring for the first 6 weeks postpartum, then 1 week per month for the remainder of the first year postpartum. Hypertension was defined as BP ≥ 130/80 mmHg or the use of antihypertensive medications. We compared demographic and cardiometabolic outcomes by lactation initiation and created multivariable logistic regression models adjusted for age, race, education, and prepregnancy body mass index (BMI) to assess the relationship of lactation with hypertension. RESULTS: Data from 129 individuals included 14,177 home BPs. Overall, 81% of participants initiated lactation, and median lactation duration was 6 months [Interquartile range (IQR) 2,9]. At follow-up (10.9 ± 2.1 months postpartum), both systolic (SBP; = 0.004) and diastolic (DBP; = 0.008) BP were lower in individuals who initiated lactation compared with those who did not. Each month of lactation was associated with a 12% [adjusted odds ratio 0.88; 95% confidence interval (CI) 0.78-0.98] decreased odds of hypertension at 1 year postpartum with adjustment for age, race, education, and BMI. CONCLUSIONS: In overweight and obese individuals with an HDP, lactation is associated with a significant reduction in SBP and DBP at 1 year postpartum and throughout the first year postpartum. CLINICAL TRIALS REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03749746.

OBJECTIVE: To describe liberation in a population of dogs undergoing ≥24 h of mechanical ventilation (MV) and to assess for differences between successful and unsuccessful liberation attempts as well as adherence to criteria for veterinary and human readiness to discontinue MV. DESIGN: Retrospective study. SETTING: University teaching hospital. ANIMALS: Forty-seven client-owned dogs undergoing ≥24 h of MV. MEASUREMENTS AND MAIN RESULTS: Medical records were retrospectively reviewed; signalment, underlying disease, indications for MV, and survival to discharge were recorded. Data were collected up to 2 h before discontinuation of MV, noting ventilator settings and physiologic and blood gas variables. Twenty-four of 47 (51.1%) cases undergoing MV were successfully liberated; of these, 22 (91.7%) dogs survived to discharge. Dogs were successfully liberated using various modes of ventilation, including assist control (15/24 [62.5%]), synchronized intermittent mandatory ventilation (8/24 [33.3%]), and pressure support ventilation (1/24 [4.2%]). Forty-eight attempts at liberation occurred in 30 dogs. Of these, 24 of 48 (50%) were successful. Only end-tidal carbon dioxide (ETCO) was different between successful and unsuccessful liberation attempts, being higher in unsuccessful attempts (35 ± 6.8 vs. 43.7 ± 5.5 mm Hg; p < 0.0001). Sufficient information was available to assess adherence to veterinary liberation criteria in 31-36 liberation attempts, depending on the criterion. Liberation success did not differ between dogs that met the criteria and those that did not. Of dogs with complete data that were successfully liberated, 55% (10/18) did not meet current veterinary criteria to undergo a spontaneous breathing trial (SBT). The prevailing reason for failing to meet the veterinary criteria was cardiovascular instability (8/10), often due to vasopressor use (n = 7). CONCLUSIONS: Most successfully liberated cases did not fulfill the veterinary criteria for readiness to undergo an SBT. Dogs should not necessarily be precluded from undergoing an SBT or liberation attempt if they are receiving vasopressors but meet the remaining criteria.

BACKGROUND: While PCI is widely used for chronic coronary disease (CCD), older adults (≥ 75 years) face distinct procedural risks, and their outcomes compared with younger patients remain incompletely understood. METHODS: We investigated age-related differences in health outcomes following PCI for CCD using Vizient Clinical Data Base that includes both inpatient and outpatient PCI. Vizient aggregates clinical and outcome data from over 97% of U.S. academic medical centers and 1000+ community hospitals. We included all patients that underwent PCI for CCD between January 2016 and June 2022. The primary outcome was the occurrence of major adverse cardiovascular events (MACE). After propensity-score matching older (≥ 75 years) and younger (< 75 years) adults, we analyzed major adverse cardiovascular events (MACE) in the year following index PCI using Kaplan-Meier curves. Relative risks (RR) were calculated using Zou's modified Poisson approach. Secondary outcomes included all-cause mortality, repeat PCI, major bleeding, and cardiovascular-related hospitalizations. RESULTS: A total of 176,492 patients were included. 70.5% of patients were < 75 years old, while 29.5% were ≥ 75 years old. Most PCIs for CCD occurred in the outpatient setting (51.0%), followed by inpatient (28.6%), observation (17.1%), and other (3.3%) settings. Older adults experienced lower adjusted risk of MACE (relative risk [RR] 0.93, 95% confidence interval [CI] 0.89-0.96), as well as MI or repeat PCI, compared with younger adults. They experienced higher risk of hospitalization for a cardiovascular cause (RR 1.40, 95% CI 1.36-1.44). No significant difference was observed in the risk of all-cause mortality or major bleeding. CONCLUSION: After adjusting for baseline differences, older adults who undergo PCI for CCD have a risk of MACE and major bleeding that is comparable to younger patients. However, older adults do experience higher rates of subsequent cardiovascular hospitalizations following PCI for CCD.

Atherosclerotic lesions within carotid and cerebral vessels are likely to influence hemodynamics and manifest into vascular pathologies, including Alzheimer's Disease and ischemic stroke. Hemodynamics are influenced by changes in luminal diameter of vessels and wall shear stress derived from vortex formation which directly relates to the surface topography of the lumen. In this study, we performed a quantitative assessment of surface metrology of carotid and cerebral arteries in relation to calcification, vessel size and location among individuals. We speculate intracranial vessels will follow suit of extracranial vessels, with increased surface roughness in larger-diameter vessels. Samples of the internal carotid, common carotid, and multiple branches of the Circle of Willis were collected at 18 different sites from 10 human whole body donors. For each vessel, arterial calcification was quantified from image analyses of Alizarin red stained histological sections. The arterial surface metrology of the adjacent parts of the same segments was opened and gently cleaned, and then analyzed using a Sensofar S Neox 3D optical profiler, from which scale-sensitive fractal analyses (SSFA) were analyzed using SensoMap software. ANOVAs testing for the influence of calcification percentage, vessel identity, vessel size, individual differences, age, sex, and the role of cardiovascular disease in the donor's cause of death found no significant differences in SSFA variables for vessel identity, individuals, age, sex, and cause of death. The most significant differences are correlated with vessel calcification percentage, though surface roughness appears also greater in the larger vessels. These findings support ideas that calcification plays a role in alterations of vortex formation and wall shear stresses in intracranial vessels as they do in coronaries. With further research in this field, the pathophysiology of intracranial atherosclerosis and the role of atherosclerosis in neurodegenerative disorders might be understood at another, more granular level.

AIMS: It remains largely unknown whether and how plant-based diets are associated with mortality and life expectancy among people with cardiometabolic disorders, who have a significantly increased risk of mortality. We examined associations of plant-based diets with mortality and life expectancy among people with cardiometabolic disorders. METHODS: We followed 78,151 participants with cardiometabolic disorders, including obesity, diabetes, or cardiovascular diseases (CVD) from UK Biobank (UKB) (2006-2022), US National Health and Nutrition Examination Survey (NHANES) (1999-2019) and Chinese Longitudinal Healthy Longevity Survey (CLHLS) (2008-2019). We created an overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). We used Cox models to compute HRs for mortality, and applied life table to estimate life expectancy. RESULTS: During a mean follow-up of 11.4 years, 12,150 deaths occurred in three cohorts. A higher PDI was associated with lower all-cause, CVD, and other mortality among participants with cardiometabolic disorders. The pooled HR and 95%CI for extreme quartiles of PDI was 0.85 (0.81, 0.90) for all-cause mortality, 0.82 (0.72, 0.93) for CVD mortality, and 0.82 (0.69, 0.97) for other mortality. Compared with people in the lowest quartile of hPDI or uPDI, those in the highest quartile of hPDI had 19-29% lower all-cause, CVD, cancer, and other mortality; while people in the highest quartile of uPDI had 28-43% higher all-cause, CVD, cancer, and other mortality. Comparing extreme quartiles, PDI, hPDI, and uPDI were associated with 1.22-year and 2.10-year longer life expectancy, and 2.22-year shorter life expectancy at age 65 years, respectively. These associations remained similar across the three cohorts and among people with obesity, T2D, and CVD, separately. CONCLUSIONS: Among participants with cardiometabolic disorders, overall and healthful plant-based diets were associated with lower all-cause and cause-specific mortality and longer life expectancy, while unhealthful plant-based diet was associated with higher mortality and shorter life expectancy.

INTRODUCTION: Water fasting involves completely abstaining from all caloric intake. Multiple studies have demonstrated that water fasting for up to 21 days is well-tolerated, but none focused on patients with severe obesity (body mass index ≥ 40) or utilized treatment with glucagon-like peptide-1 receptor agonists (GLP-1). METHODS: The patient was a 44-year-old male with severe morbid obesity, heart failure, oxygen-dependent obesity hypoventilation syndrome, uncontrolled hypertension, anemia, and depression. He underwent a 27 day inpatient fast with weekly tirzepatide, including 21 day water fast with structured refeeding. RESULTS: The patient lost 125 pounds during the fast. He regained independent ambulation and chronic oxygen supplementation was discontinued. Chronic anemia resolved and depression improved as measured by Patient Health Questionnaire. Systolic blood pressure improved despite discontinuation of his antihypertensives. His chronic leg wound resolved without antibiotics. Left ventricular mass decreased and fasting insulin normalized. Appetite remained tolerable, and the only complication was mild transaminitis. CONCLUSION: This case suggests prolonged medically-supervised water fasting with GLP-1 use is an effective short-term weight reduction strategy that allows for bridging to bariatric surgery with improvement in multiple chronic diseases. As the fast ended for surgery rather than intolerance, research into longer water fasts could be considered.

Shoshin beriberi is an acute, fulminant form of cardiovascular beriberi characterized by hemodynamic deterioration due to thiamine deficiency. Its rarity and non-specific symptoms often make diagnosis challenging. Clinical improvement is rapid after intravenous infusion of thiamine, but some patients with persistent severe myocardial necrosis may be left chronic cardiac insufficiency. We report the case of a 14-year-old boy with a history of malnutrition who developed high-output heart failure, refractory lactic acidosis, and severe myocardial necrosis. Hemodynamics deteriorated rapidly with vasoactive drug support and blood purification therapy. And blood pressure is barely maintained with ECMO support. Hemodynamics reversed rapidly after thiamine administration on day 5 of admission. Because of severe myocardial necrosis, cardiac dysfunction appeared gradually and the patient died of acute respiratory distress syndrome (ARDS) on the 21st day after admission. This case highlights the need for early diagnosis and immediate empirical treatment with intravenous thiamine in patients presenting with unexplained severe metabolic acidosis and circulatory shock. Severe and persistent myocardial necrosis may suggest a poor prognosis.

Conventional, rigid simulators and therapeutic devices for cardiovascular disease have several fundamental limitations, such as poor biomimetic fidelity, substantial surgical invasiveness and mismatch at the tissue-device interface. Soft robotic devices, with tissue-like materials, structures and functions, are emerging as promising alternatives. In this Review, by matching clinical demands to technological breakthroughs, we identify three emerging complementary frontiers in which soft robotic devices are redefining cardiovascular medicine - soft robotic simulators, such as in vitro ventricular simulators and in vivo assistive simulators; soft robotic interventional instruments, such as percutaneous instruments, endovascular continuum instruments and untethered mini-scale robots; and soft robotic implants for vascular disease, arrhythmia and heart failure. We describe the unique advantages of soft robotic devices as well as their applicable scope and technical implementation. Finally, we highlight promising technological opportunities for next-generation soft cardiac devices, evaluate the clinical maturity of existing devices and propose a translational roadmap for the coming decade. With this Review, we aim to foster further integration of soft robotics into cardiovascular medicine by identifying device solutions with translational potential to address unmet clinical needs.

BACKGROUND AND AIMS: Embolic stroke of undetermined source (ESUS) is biologically heterogeneous and often presumed cardioembolic (CE). We investigated whether thrombus composition can capture etiologic heterogeneity within ESUS, clarifying its overall similarity to CE stroke and exploring whether selected radiological features are associated with atherothrombotic-like thrombus patterns. METHODS: Retrospective single-center study of anterior-circulation ischemic stroke patients treated with mechanical thrombectomy (MT) (2022-2025) with available thrombus, classified as large-artery atherosclerosis (LAA), CE, or ESUS. Thrombus composition (RBCs, fibrin, leukocytes; % thrombus area) was analyzed using prespecified non-parametric hierarchical comparisons with Bonferroni correction (k = 3). Reference analyses compared LAA vs. CE; primary analyses ESUS vs. LAA and CE; secondary and tertiary analyses stratified ESUS by ipsilateral high-risk non-stenotic carotid plaque (hrNSCP - vs. hrNSCP+, defined by CTA-based Plaque-RADS score 3-4). Robustness was assessed using isometric log-ratio transformation and exploratory multivariable models. RESULTS: Among 344 MT-treated patients, 159 (46.2%) were included (91 CE, 18 LAA, 50 ESUS). LAA and CE showed distinct thrombus profiles, with higher RBC and lower fibrin content in LAA compared with CE (p < 0.01). ESUS thrombi were descriptively CE-like, without significant differences versus CE or LAA after correction. After stratification, two distinct and biologically coherent thrombus phenotypes emerged: ESUS hrNSCP- (n = 42) thrombi overlapped with CE, whereas ESUS hrNSCP+ (n = 8) thrombi were indistinguishable from LAA; these patterns were confirmed by compositional and multivariable analyses. CONCLUSIONS: When etiologic heterogeneity is taken into account, thrombus composition reveals distinct cardioembolic-like and atherothrombotic-like patterns within ESUS, supporting its role as a complementary tool for etiologic attribution alongside clinical and imaging data.

The present study aimed to investigate the protective effects of platelet-rich plasma combined with post-conditioning on testicular ischemia-reperfusion injury in a rat model. Thirty-two adult male rats were randomly assigned to four groups (n = 8 each): Sham (SH), Ischemia-reperfusion (I/R), post-conditioning (PC), and platelet-rich plasma-post conditioning PRP/PC. Testicular torsion was induced for 3 h, followed by 24 h of reperfusion. After 24 h, blood and testicular tissues were collected for histopathological and immunohistochemical analyses. Ischemia-reperfusion notably increased oxidative stress, apoptosis, and inflammatory markers, as shown by higher levels of malondialdehyde, caspase-3, TNF-α, and IL-6 (p < 0.05). These changes were reduced by PC and more effectively by PRP/PC. Antioxidant markers, including catalase, reduced glutathione (p < 0.0001), eNOS, HSP70, and VEGF (p < 0.0001), were significantly higher in the treated groups than in the I/R group. Histological analysis demonstrated improved testicular structure, with Johnsen's scores of 8-10 (SH), 2-3 (I/R), 6-9 (PC), and 4-9 (PRP/PC). Notably, PRP/PC showed increased expression of Bax and NF-κB. Hematological results revealed significant changes in Hb, RBCs, and HCT, while MCHC and MCH remained unchanged, and MCV showed minor differences. The data of the present study indicated that combined with PC provided partial protection against testicular I/R injury, reducing oxidative stress, apoptosis, and inflammation while preserving testicular architecture. These findings suggest early restorative effects rather than complete functional recovery.

Bicuspid aortic valve, a prevalent congenital malformation, predisposes individuals to severe complications. Although the condition exhibits substantial heritability, known protein-coding and common regulatory mutations explain a minority of cases. To assess the contribution of rare regulatory variants, here we integrate high-resolution three-dimensional genome organization profiling with matched whole-genome sequencing from eight individuals with bicuspid aortic valves and eight with standard tricuspid aortic valves. In bicuspid aortic valve patients, mutation-driven chromatin rewiring affected 1.8-fold more valve development genes than in healthy individuals. Genome-wide in silico analyses show that rare regulatory mutations disrupt the transcriptomes of mesenchymal cell populations necessary for endocardial cushion formation. We identify 198 candidate genes associated with bicuspid aortic valve, revealing pronounced heterogeneity and complex interplay between coding and regulatory mutations. Collectively, our findings establish rare regulatory mutations as contributors to the heritability of bicuspid aortic valve and underscore the need to elucidate their mechanistic roles in disease pathogenesis.

Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.

Myotonic dystrophy type 1 is the most prevalent adult-onset muscular dystrophy and is characterized by progressive muscle weakness, myotonia, cardiac conduction defects, endocrine dysfunction, and central nervous system involvement. Myotonic dystrophy type 1 is caused by an unstable CTG repeat expansion in the 3' untranslated region of the DMPK gene, which produces toxic CUG-expanded transcripts that sequester RNA-binding proteins such as Muscleblind-like, induce widespread alternative splicing defects, and drive an RNA gain-of-function mechanism rather than simple DMPK haploinsufficiency. Despite major advances in understanding the molecular pathogenesis of myotonic dystrophy type 1, there is still no approved cure or disease-modifying therapy. This review summarizes the molecular basis of myotonic dystrophy type 1 and provides an in-depth overview of emerging therapeutic strategies that directly target the underlying pathogenic cascade at the DNA and RNA levels. Gene therapy-based approaches, including CRISPR-mediated genome editing, aim to reduce or eliminate the expanded CTG repeats or expanded DMPK allele and its toxic transcripts. In parallel, a broad spectrum of RNA-directed interventions is being developed, encompassing antisense oligonucleotides, antibody-penetrating and cell-penetrating peptide-conjugated antisense oligonucleotides to enhance skeletal and cardiac muscle delivery, small interfering RNAs, and microRNA-based tools such as antagomiRs. Additional strategies exploit engineered RNA-binding proteins and peptide decoys to disrupt toxic ribonuclear aggregates, polyadenylation signal-driven premature transcriptional termination to selectively silence mutant DMPK, and small molecules that modulate RNA metabolism, dissolve CUG RNA foci, or correct downstream mis-splicing. By integrating data from preclinical models and ongoing clinical trials, including recent advances with muscle‑targeted antisense oligonucleotide conjugates and gene therapy, this review outlines the current status, strengths, and limitations of these mechanism-based therapies for myotonic dystrophy type 1. The discussion highlights key translational challenges such as efficient delivery to skeletal muscle, the heart, and brain, long-term safety, and robust pharmacodynamic biomarkers as well as opportunities for combination and next-generation approaches aimed at converting molecular correction into durable clinical benefit for patients with myotonic dystrophy type 1.

The prevalence of cardiovascular morbidity and mortality is higher in females than in males, probably for different pathogenetic mechanisms operating in the onset and progression of atherosclerotic vascular disease. Endothelial dysfunction is also recognized as an important and independent predictor of cardiovascular events. Thus, we designed this study to detect possible differences in endothelial function between sexes and their effect on cardiovascular prognosis. We enrolled 844 Caucasian hypertensives (451 males and 393 females, aged 49.5 + 10.9 years). Endothelial function was investigated by strain-gauge plethysmography. Compared with males, females showed a significantly lower endothelium-dependent vasodilation (acetylcholine-stimulated peak percent increase 268  ± 1113 vs 309 ± 108% increase from basal). During the follow-up period of 9.3 ± 3.2 years, 252 new fatal and non-fatal cardiovascular outcomes (3.20%) occurred: 151 coronary (1.92%), 61 cerebrovascular (0.77%), and 40 deaths (0.51%), with a higher incidence in females than in males [MACE (3.79 vs 2.68%; P = 0.001) and coronary events (2.24 vs 1.69%; P = 0.035), cerebrovascular events (0.93 vs 0.64%; P = 0.135) and all-cause mortality (0.63 vs 0.40%; P = 0.155)]. In multivariate Cox regression analysis, endothelial function resulted an independent predictor of MACE (HR = 0.82; 95% CI 0.73-0.952) and coronary events (HR = 0.81; 95% CI 0.69-0.95), together with hs-CRP, age, LDL-cholesterol and triglyceride in the whole population, and in females and males, separately. These results were also confirmed in ROC analysis, that demonstrated a different cut-off value of endothelial function between groups (275% for males, 214% for females). Our results confirm, in hypertensive patients, the existence of significant differences between sexes in the occurrence of cardiovascular events, probably attributable to a lower vasodilating property of vascular endothelium in females.

INTRODUCTION: To compare the efficacy and safety of a low-viscosity 0.3% hyaluronic acid (HA) ophthalmic solution with those of a comparator 0.3% HA formulation in patients with dry eye disease (DED). METHODS: In this double-blind, randomized, multicenter, noninferiority clinical trial, patients with mild-to-moderate DED were allocated at a 1:1 ratio to receive either low-viscosity or comparator 0.3% HA eye drops. Participants instilled the assigned study medications 5-6 times daily for 12 weeks, and a follow-up evaluation was conducted 1 week after the final instillation. The primary end point was the mean change in the corneal fluorescein staining (CFS) score from baseline to week 12. Secondary outcomes included the conjunctival staining score, tear break-up time (TBUT), nonanesthetized Schirmer test results, ocular surface disease index (OSDI) score, and ocular soreness. RESULTS: A total of 292 participants were included in the full analysis set. The change in CFS score at week 12 (-0.03; 95% CI -0.1873 to 0.1346) met the predefined noninferiority margin. Compared with the baseline parameters, both formulations significantly improved all ocular surface parameters except ocular soreness score (all P < 0.01). No significant between-group differences were observed across all secondary outcomes. Notably, blurred vision immediately after instillation was significantly less frequent in the low-viscosity HA group at all time points (P < 0.01). CONCLUSIONS: Compared with the comparator 0.3% HA formulation, the low-viscosity 0.3% HA formulation demonstrated comparable therapeutic benefits while reducing the incidence of viscosity-related adverse events. These findings indicated that the low-viscosity 0.3% HA ophthalmic solution may serve as a clinically meaningful alternative for patients with mild-to-moderate DED. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06388070.

Anthracycline-induced cardiotoxicity remains a major clinical challenge, often progressing to heart failure years after therapy. Conventional cardioprotective agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, are widely used to preserve cardiac function; however, their effectiveness is limited by their inability to comprehensively address the complex, multifactorial pathophysiology of anthracycline-induced cardiotoxicity. This underscores the critical need for more effective and mechanism-based cardioprotective strategies that directly target the underlying molecular mechanisms, particularly oxidative stress and mitochondrial dysfunction. In recent years, the apelin-APJ signalling axis has attracted increasing attention as a potential therapeutic target in cardiovascular diseases owing to its multifaceted biological actions, including positive inotropy, vasodilation, anti-inflammatory, anti-fibrotic, anti-apoptotic, antioxidant, and pro-angiogenic effects. These pleiotropic actions are primarily mediated through the activation of key signalling pathways such as phosphoinositide 3-kinase/protein kinase B, extracellular signal-regulated kinases 1/2, and AMP-activated protein kinase. Given that these signalling cascades are disrupted during anthracycline-induced cardiotoxicity, pharmacological activation of the apelin-APJ axis may represent a promising avenue to mitigate anthracycline-associated cardiac injury with greater efficacy than conventional therapies. While native apelin isoforms (apelin-12, -13, -17, and [Pyr¹]apelin-13) are limited by their short half-lives, chemically modified analogues such as LIT01-196 and apelin-17(A2) exhibit enhanced stability and efficacy, with demonstrated cardioprotective effects in preclinical cardiovascular models and patients with chronic heart failure. However, their therapeutic potential in anthracycline-induced cardiotoxicity remains largely unexplored. This review highlights its promise as a novel cardioprotective strategy for mitigating anthracycline-induced cardiotoxicity.

AIMS/HYPOTHESIS: Lactation is associated with reduced maternal risk of future diabetes mellitus and cardiovascular disease. Human milk oligosaccharides (HMOs), bioactive glycans produced in the mammary gland and already detectable in the maternal circulation during pregnancy, are hypothesised to exert endocrine and metabolic effects. We investigated circulating HMOs in the postpartum period, and assessed their short-term modulation by glucose and insulin, and the relationship between plasma and milk HMO profiles. METHODS: At 5-7 weeks postpartum, 28 women (16 with prior gestational diabetes [GDM]; 18 who were breastfeeding) underwent both a 75 g oral glucose tolerance test (OGTT) and a hyperinsulinaemic-euglycaemic clamp. HMOs were quantified in plasma and milk using HPLC. RESULTS: Seventeen HMOs were detected in milk, of which six were also detected in plasma at concentrations that were approximately 10,000-fold lower but were highly correlated across the two compartments. The lactosamine-based glycans 3'-sialyllactosamine (3'SLN) and 6'-sialyllactosamine (6'SLN) were only found in plasma. Lactation status had no significant impact on plasma HMO levels, except for a lower 6'SLN level in breastfeeding women. Women with prior GDM showed lower HMO concentrations in milk when fasting. Plasma HMOs exhibited short-term changes during both tests: during the OGTT, the levels of the fucosylated HMOs 2'-fucosyllactose (2'FL), lacto-N-fucopentaose 1 (LNFP1) and lacto-N-difucohexaose (LNDFH) significantly decreased, while that of 3'-sialyllactose (3'SL) increased; during the clamp, the levels of all fucosylated HMOs and 3'SL declined, whereas that of 3'SLN increased with rising insulin levels. In milk, only the levels of 2'FL and lactodifucotetraose (LDFT) decreased significantly during the clamp. During the clamp, the area under the curve (AUC) of plasma oligosaccharides partly correlated with BMI and metabolic clearance rate. CONCLUSIONS/INTERPRETATION: Circulating HMOs persist during lactation and are acutely regulated by glucose and insulin. The differential response of fucosylated and sialylated species suggests metabolic regulation of HMO biosynthesis, secretion or clearance. These findings support the concept of HMOs as candidate signal molecules in maternal metabolism, linking lactation with postpartum metabolic adaptation.

BACKGROUND: Pulmonary vein stenosis (PVS) is a rare but serious condition in children, often requiring surgical or catheter-based interventions. The initial optimal treatment strategy remains unclear due to disease complexity, progression, and high rates of recurrence. METHODS: In this retrospective, single-center study, we identified children with primary or secondary PVS from a cardiac catheterization and surgical database between 2015 and 2023. Patients with single ventricle physiology were excluded. Demographics and outcomes were compared between patients who underwent catheter-based intervention only and those who underwent at least one surgical pulmonary vein repair, with or without subsequent catheter-based reintervention. Reintervention following surgical repair was assessed using Kaplan-Meier analysis. RESULTS: Among 56 children with biventricular physiology and PVS (33 males, 59%), 16 (29%) underwent at least one surgical repair at a median age of 9 months (IQR 4-20), while 40 (71%) were managed with catheter-based interventions alone. Surgical repair was more frequently performed in patients with bilateral or complex disease, particularly those without prematurity or with coexisting congenital heart defects requiring open-heart surgery. Over time, catheter-based approaches became increasingly preferred. Overall, 92% of surgical patients required reintervention, most within the first year. Mortality did not significantly differ between groups (p = 0.294). In the surgical group, elevated right ventricular/systemic systolic pressure ratio (HR: 1.25, p = 0.048) and the presence of scimitar syndrome (HR: 8.25, p = 0.011) were associated with increased mortality. CONCLUSIONS: Surgical pulmonary vein repair remains an important option, particularly in cases where catheter-based intervention is not feasible due to anatomical challenges or when multiple pulmonary veins are severely affected. However, recurrent pulmonary vein re-intervention is common, regardless of whether the initial approach was surgical or catheter-based.

Diabetes heightens cardiovascular risk. The selective sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) shows cardiovascular benefits in heart failure, type 2 diabetes and chronic kidney disease. While EMPA protects against myocardial ischemia/reperfusion injury (MIRI) in diabetic and non-diabetic hearts, its mechanisms and impact on specific endpoints, including autophagy, angiocrine signaling, and metabolic flexibility, remain incompletely defined. We explored the systemic and myocardial effects of chronic EMPA pretreatment on these endpoints in diabetic and non-diabetic animals subjected to MIRI. In streptozotocin (STZ, 65 mg/kg) diabetic rats, EMPA (15 mg/kg/d, 4 weeks) reduced water intake without affecting hyperphagia or weight loss. EMPA ameliorated glucose and lipid profiles, tended to restore myocardial GLUT4 and counteract alterations in myocardial hydroxymethylglutaryl-CoA synthase (HMGCS2) and 3-oxoacid CoA-transferase 1 (OXCT1) levels. EMPA improved biomarkers of myocardial damage (BNP, NT-proBNP, CK-MB, galectin 3), inflammation (cardiac NLRP3, plasma IL-1β), oxidative stress (plasma SOD and malondialdehyde), angiocrine imbalance (VEGF and apelin), fibrosis, and collagen deposition, while showing a tendency to improve autophagy and apoptosis signaling. Ex vivo, EMPA improved baseline contractility and post-ischemic recovery of left ventricular pressure (dLVP from baseline: ~+4% in STZ+EMPA vs. -25% in STZ; ~+3% in EMPA vs. -28% in MIRI), enhanced coronary flow recovery, and reduced cardiac contracture, infarct size, and coronary LDH leakage in both diabetic and non-diabetic hearts. These effects may be associated with post-ischemic histological improvements, reduced vascular congestion, increased eNOS phosphorylation, activation of cardioprotective pathways, and inhibition of mPTP opening. Consistently, EMPA enhances wound healing and preserves eNOS phosphorylation in high-glucose (HG) human cardiac microvascular endothelial cells. In human cardiomyocytes, EMPA reduced hypoxia/reoxygenation (H/R) cell death, preserved nitrate and nitrite levels-effects abolished in the presence of L-NAME-and improved mitochondrial membrane potential in HG and/or H/R conditions. EMPA improved metabolic health and protected myocardial and coronary function likely via a permissive microvascular and myocardial phenotype that limits reperfusion injury, supporting its use against MIRI in normal and diabetic settings.