Acute respiratory distress syndrome (ARDS), characterized by inflammation-induced pulmonary reactive oxygen species (ROS) elevation, causes severe alveolar epithelial cells damage and promotes M1 polarization of alveolar macrophages (AMs). M1-polarized AMs generate substantial ROS and potent pro-inflammatory cytokines, triggering a widespread secondary inflammatory cascade. Therefore, ARDS is trapped in a vicious "ROS-M1 macrophages polarization-inflammation-ROS" cycle, which markedly exacerbates disease progression. Constrained by this, previous monotargeted therapeutic approaches exhibited suboptimal efficacy and failed to meet clinical needs. Herein, a vicious cycle-normalizing strategy was introduced to target the dual pathogenic mediators in the ARDS microenvironment. Specifically, phosphatidylserine-modified and metformin-loaded biomimetic honeycomb manganese dioxide nanoparticles (PS-HM/M NPs) were developed, with superoxide dismutase (SOD) and catalase (CAT)-mimetic properties to eliminate excessive intracellular ROS while metformin efficiently promotes phenotypic transition of AMs toward the pro-resolution M2 state. In an acute lung injury (ALI) model, PS-HM/M NPs successfully interrupted the malignant cycle and significantly resolved inflammation. In conclusion, this work highlighted the critical role of regulating the ROS-macrophage crosstalk and provided a promising avenue for ARDS therapy.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as cornerstone therapies for heart failure with reduced ejection fraction (HFrEF), owing to their cardioprotective and hematologic effects. While their impact on hemoglobin and hematocrit levels is increasingly recognized, the influence of SGLT2 inhibitors on mean platelet volume (MPV), a surrogate marker of platelet activation and cardiovascular risk, remains underexplored in HFrEF patients. While SGLT2 inhibitors' effects on MPV have been studied in DM, this is the first study examining MPV changes specifically in HFrEF patients with adjustment for diuretic therapy. This retrospective study included 80 HFrEF patients receiving guideline-directed medical therapy to which SGLT2 inhibitors were subsequently added. Baseline and 6-month follow-up data on hematological and biochemical parameters were collected. Exclusion criteria included active infection, malignancy, advanced renal failure, hematologic disorders, and recent transfusions. MPV and platelet counts were analyzed using standardized protocols and equipment. Following 6 months of SGLT2 inhibitor therapy, MPV values decreased significantly (p < 0.05), while platelet counts increased significantly (p < 0.05). Although hemoglobin and hematocrit levels showed upward trends, these changes were not statistically significant. No significant correlation was observed between ΔMPV and ΔPLT. Other biochemical markers remained stable throughout the study period. SGLT2 inhibitor therapy was associated with a significant reduction in MPV and an increase in platelet count among patients with HFrEF. These hematological changes may represent an additional mechanism by which SGLT2 inhibitors exert cardiovascular benefit. However, prospective, randomized trials are needed to validate these findings and explore the clinical significance of MPV modulation in heart failure management.
Adults with congenital heart disease frequently experience gaps in lifelong adult congenital heart disease (ACHD) specialty care, leading to preventable complications, hospitalizations, and premature mortality. However, effective, scalable, accessible, and sustainable strategies to reduce these gaps are lacking. Digital health offers potential solutions but requires a rigorous scientific approach in its design to address the needs of the target population. This study aims to describe the development of a theory-based, community co-designed digital health intervention to improve lifelong ACHD care. We integrated theory-based behavioral frameworks, semistructured qualitative interviews with patients and clinicians, and a community-engaged approach to develop a digital health intervention for ACHD. The primary behavioral target was completing an ACHD specialist appointment. We conducted Capability, Opportunity, Motivation, and Behavior (COM-B)-guided semistructured interviews with patients with ACHD and clinicians to identify barriers to specialized care amenable to a digital intervention, and patient-centered goals for the digital tool. The community partners helped develop key intervention objectives, create a theory-driven framework, and specify how each intervention component targets specific COM-B barriers. We interviewed 54 participants (n=37 patients with ACHD, and n=17 clinicians) and engaged 21 community partners representing 4 advocacy organizations. Design objectives emphasized addressing patient loneliness, ensuring accessibility and credibility, and enabling scalability while centering patient perspectives. Participants identified 4 priorities: providing credible resources, uplifting patient voices, customizing to patient needs, and centering positivity and joy. The digital tool, named by community partners as Empower My Congenital Heart (EMCH), was designed within the web- and mobile-based, Apple- and Android-compatible, Eureka Digital Research platform (University of California, San Francisco). Key intervention components included educational modules, peer support, appointment planning nudges, and a digital medical passport. The EMCH's theory-driven framework specifies how each intervention component targets specific COM-B barriers to specialized ACHD care. The theory-driven, community co-designed EMCH digital tool provides a scalable approach to promote lifelong ACHD specialist care. Ongoing process evaluation and a planned randomized controlled trial will assess acceptability, engagement, and effectiveness in reducing care gaps. If proven effective, EMCH has the potential to prevent complications, emergency hospitalizations, and mortality affecting the majority of adults with congenital heart disease.
BackgroundVericiguat improves outcomes in heart failure with reduced ejection fraction (HFrEF), but its vascular and hemodynamic effects remain unclear. We explored changes in flow-mediated dilation (FMD) and invasive hemodynamics after vericiguat in symptomatic patients with HFrEF receiving guideline-directed medical therapy (GDMT).MethodsIn this single-center, open-label, single-arm exploratory pilot study, 10 patients with symptomatic HFrEF underwent assessment of FMD, right heart catheterization at rest and during 20-W supine exercise, echocardiography, laboratory testing, and 6-min walk distance (6MWD) before and after vericiguat. Vericiguat was uptitrated to 10 mg/day where tolerated.ResultsAfter treatment, FMD increased from 4.7 (3.0-6.1) to 6.9 (5.5-7.6)% (P = .015), GLS improved from -6.8 (-8.6 to -5.5) to -9.0 (-10.5 to -6.7)% (P = .009), resting cardiac output increased from 3.8 (3.6-5.4) to 4.6 (3.5-5.4) L/min (P = .047), resting systemic vascular resistance decreased from 1664.1 (1327.2-1781.2) to 1293.1 (1143.6-1623.5) dyn·s·cm-5 (P = .002), and 6MWD increased from 334.0 (251.3-395.0) to 355.0 (262.5-453.8) m (P = .036). During 20-W exercise, cardiac output increased from 5.4 (4.6-5.9) to 6.5 (4.8-6.9) L/min (P = .030), whereas exercise systemic vascular resistance showed only a decreasing trend (P = .070).ConclusionsIn symptomatic patients with HFrEF receiving GDMT, vericiguat was associated with changes in peripheral vascular function and resting hemodynamic indices. However, exercise systemic vascular resistance did not improve significantly. These findings are exploratory and hypothesis-generating.
Little is known about the differences in left atrial (LA) volume and strain assessed with two-dimensional (2DE) and three-dimensional echocardiography(3DE). Therefore, this study aimed to compare 2DE and 3DE parameters in healthy subjects. We obtained LA volumes and strains by 3DE and 2DE in 328 healthy subjects (52 ± 13 years; 51.83% men). Means of 3DE LA volume indexes (LAVIs) were higher than those derived from 2DE (maximal LAVI: 26.75 vs. 22.66 mL/m2; minimal LAVI: 11.76 vs. 9.30 mL/m2; preA LAVI: 19.52 vs. 16.23 mL/m2, respectively, all p < 0.001). Conversely, means of 3DE LA phasic strains were lower than those derived from 2DE (LA reservoir strain: 25.16 vs. 32.01%; LA conduit strain: 13.09 vs. 16.52%; LA contractile strain: 12.12 vs. 15.52%, respectively, all p < 0.001). Similarly, total, passive, and active LA emptying fractions (EF) were lower with 3DE than those with 2DE (all p < 0.05). Correlation between 3DE and 2DE was moderate for LAVIs (all r > 0.65, all p < 0.001), with 2DE showing a systematic underestimation (bias: -4.09 mL/m2 for maximal LAVI; -2.46 mL/m2 for minimal LAVI, -3.30 mL/m2 for preA LAVI). For LA strain parameters, only conduit strain showed moderate correlation (r = 0.65, p < 0.001) with an overestimation bias of +3.42%, while reservoir and contractile strains correlated poorly between modalities with wide limits of agreement. LAEFs also demonstrated poor inter-modality agreement. 2DE yielded lower LAVIs but higher LA strain and EF values compared to 3DE. Although there was a significant correlation between the 2D and 3D parameters, agreement analysis indicated that their normal reference values were not interchangeable.
Hydrogels are promising for flexible electronics due to their unique properties, but their practical use is hindered by freezing and dehydration in extreme environments. Inspired by natural cryoprotection, we designed a hydrophilic deep eutectic solvent (DES) composed of acryloyloxyethyltrimethylammonium chloride (AETC) and urea. This DES/H2O binary solvent was then polymerized into a multifunctional hydrogel via a facile one-step photopolymerization. The dense hydrogen-bonding network within the DES effectively confines the motion of water molecules, thereby endowing the hydrogel with exceptional anti-freezing properties (down to -80°C) and long-term moisture retention. The unique structural design, which features highly entangled polyelectrolyte chains and a dense network of dynamic sacrificial bonds that undergo breaking and reconstruction, enables the fabrication of an elastic hydrogel. Moreover, the as-prepared PAETC-urea hydrogels exhibit high transparency (95%), remarkable stretchability (>3000% elongation), strong adhesion to various engineering substrates, and efficient self-healing capability. These collective features ensure the reliable performance as a wearable strain sensor for accurately detecting human motions and high-fidelity electrophysiological signals, demonstrating great potential for next-generation flexible electronics.
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Pulmonary hypertension (PH) is a multifaceted disease driven by increased pulmonary vascular resistance and right ventricular afterload, eventually progressing to right-sided heart failure and a high mortality rate. Kidney dysfunction, a common comorbidity in patients with PH, complicates treatment and impacts prognosis. In this literature review, we seek to broadly explore this coincidence of diseases, primarily focusing on chronic kidney disease (CKD) developing after a primary diagnosis of pulmonary arterial hypertension (PAH). We discuss prevalence, pathophysiologic mechanisms of disease, management of disease including the use of primary PAH therapies in the setting of renal disease, as well as background therapy for kidney disease and PAH comorbidities. This paper further seeks to evaluate associated comorbid conditions such as anemia and iron deficiency. We performed a literature search of several online medical databases, with a primary focus on Pubmed, to explore the findings of multiple systematic reviews and meta-analyses, clinical trials, and preclinical studies using animal models, among others. We found that while there is generally a good amount of consensus data for PH, CKD, and PH in the setting of preexisting CKD, little has been published regarding the specific focus of patients developing kidney dysfunction in the setting of PH.
Inflammation-based indices, derived from routine complete blood count parameters such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII), have garnered considerable attention as potential prognostic markers for treatment response in breast cancer. Nevertheless, their predictive utility in patients undergoing neoadjuvant chemotherapy (NACT) remains equivocal. This study aimed to investigate the association between pre-treatment inflammatory indices and pathological complete response (pCR) and residual cancer burden (RCB) in breast cancer patients receiving NACT. A retrospective analysis was conducted on 110 consecutive patients with invasive breast carcinoma who received NACT followed by curative surgery at a single institution. Pre-treatment values for NLR, PLR, LMR, and SII were calculated from routine laboratory data. Given the non-normal distribution of inflammatory indices, as determined by Shapiro-Wilk testing, non-parametric analyses were employed. Group comparisons utilized the Mann-Whitney U and Kruskal-Wallis tests. Predictive performance was assessed using receiver operating characteristic (ROC) analysis with 500-iteration bootstrap resampling. Multivariable logistic regression was applied to identify independent predictors of pCR. The findings revealed no significant associations between any of the inflammatory indices and pCR or RCB class distribution. ROC analyses indicated poor discriminatory performance for all indices, with area under the curve (AUC) values consistently approximating 0.50. In the multivariable analysis, only Ki-67 ≥14% independently predicted pCR (OR 7.077, 95% CI 2.210-22.662; p=0.001). In conclusion, pre-treatment NLR, PLR, LMR, and SII did not exhibit clinically meaningful predictive value for pathological response to NACT within this cohort. Tumor proliferative activity, as reflected by Ki-67, remained the most robust independent predictor of treatment response.
Iatrogenic pulmonary vein (PV) stenosis results from radiofrequency ablation or surgical trauma, causing venous narrowing that may lead to irreversible pulmonary hypertension if untreated. A 77-year-old woman with recent mitral valve replacement aided by right upper PV (RUPV) venting, left ventricular pseudoaneurysm repair, and atrial flutter radiofrequency ablation presents with progressive dyspnea. Work-up revealed elevated right-sided intracardiac pressures with regional pulmonary capillary wedge pressure variation and angiographic confirmation of RUPV chronic total occlusion. Treatment included 2 drug-coated balloon (DCB) angioplasties followed by stent placement, with eventually normalized RUPV flow. Iatrogenic PV stenosis is suspected in patients with refractory dyspnea after PV intervention. DCB angioplasty reduces restenosis rates in PV chronic total occlusions. When restenosis occurs despite DCB, residual microchannels may facilitate subsequent stenting. Persistent dyspnea with regional pulmonary capillary wedge pressure variation warrants PV stenosis evaluation with dedicated angiography and staged DCB and stent-based intervention.
Hypoparathyroidism is a rare disease characterized by hypocalcemia and deficient parathyroid hormone secretion. Cohort studies suggest a higher risk of cardiovascular disease. However, imaging-based assessment of coronary artery disease is limited. We aimed to characterize cardiovascular risk factors and coronary artery disease in 50 patients with chronic post-surgical hypoparathyroidism and 50 age- and sex-matched individuals from the general population, using coronary computed tomography angiography. The mean age of patients was 60 (range 31-84) years, 86% were female, and the median duration of hypoparathyroidism was 12 (range 5-49) years. Compared with controls, patients had a lower estimated glomerular filtration rate (78 vs. 83 mL/min, p = 0.04) and were more frequently treated with antihypertensive medication (56% vs. 36%, p = 0.05). Use of lipid-lowering therapy was more frequent (34% vs. 18%, p = 0.07). Prevalence of diabetes, smoking status, and arterial stiffness assessed by carotid-femoral wave velocity did not differ between groups. Angiography revealed coronary atherosclerotic plaques in 68% of patients, compared with 42% in controls (p < 0.01). This association remained significant after adjustment for sex, age, and presence of any cardiovascular risk factor, corresponding to a 24-percentage point higher prevalence of coronary atherosclerosis. Severe coronary artery disease (coronary artery calcium score ≥400) was present in 18% of patients versus 2% of controls (p = 0.02). Hypoparathyroidism was associated with increased odds of coronary calcification (coronary artery calcium score >0; OR 3.19, 95% CI 1.40-7.24, p < 0.01), independent of renal function. Compared with controls, patients had aortic valve calcification more often (29% vs. 8%, p<0.01) and calcifications of the ascending and descending aorta (34% vs. 8%, p<0.01). In conclusion, chronic post-surgical hypoparathyroidism is associated with an increased burden of atherosclerosis, which may explain the increased cardiovascular risk. Enhanced cardiovascular risk stratification and preventive strategies are warranted. Hypoparathyroidism is a rare disease associated with an increased risk of heart disease. We examined the presence of atherosclerosis (calcium buildup in heart vessels) and compared the risk profiles of patients with age- and gender-matched healthy individuals. Even with similar risk factors, imaging revealed that 68% of patients had atherosclerosis, compared with 42% in the control group. This suggests that, in addition to traditional risk factors, hypoparathyroidism itself may contribute to atherosclerosis, prompting consideration of preventive treatments such as statins for these patients.
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Pulsed field ablation (PFA) is a non-thermal ablation modality, but repeated high-voltage applications can still cause Joule heating at the electrode-tissue interface. We evaluated the effects of application repetition and inter-application intervals on temperature rise and lesion depth using a circular-shaped PFA catheter. In an in vitro potato model, a circular-shaped PFA catheter was tested under five settings: 1×, 2×, 2× with a 10-s interval, 4×, and 4× with a 10-s interval. Maximum electrode surface temperature was measured using a thermal camera, and lesion depth was assessed by TTC staining (n = 5 per setting). Temperature increased significantly with application repetition and was attenuated by a 10-s interval (overall P < 0.0001). Lesion depth also increased with repetition (overall P < 0.0001), but did not differ significantly between interval and no-interval conditions at equal application numbers. In this simplified in vitro model, a short inter-application interval was associated with attenuation of temperature rise during repeated PFA delivery, while lesion depth was not significantly reduced.
Quantify inter-operator variation in referred coronary artery bypass grafting (CABG) following angiography and evaluate associations with practice patterns and long-term outcomes. Observational study using administrative health data in British Columbia, Canada (2010-2024). Interventional cardiologist level CABG Rate was defined as the proportion of referred CABGs to total angiograms performed. Variation across Interventionalists was correlated with other practice characteristics. Among patients undergoing angiography followed by revascularization, associations between operator CABG Rate and all-cause mortality, major adverse cardiovascular events (MACE), and repeat revascularization were evaluated using hierarchical Cox regression. Among 252,408 angiograms by 40 Interventionalists, CABG Rate varied 13-fold (2.03%-26.4%) and was not explained by hospital-level factors alone (ICC: 0.358; 95% CI: 0.054-0.621). Higher CABG Rates were associated with lower percutaneous coronary intervention (PCI) utilization (R=-0.60;P<.001), lower PCI extensiveness (R=-0.52;P<.001), and lower procedural volume (R=-0.36;P=.022). In 73,603 first-time revascularized patients, CABG Rate was associated with reduced repeat revascularization (HR = 0.075;P<.001), without differences in mortality or MACE. Referred CABG varies markedly between Interventionalists and reflects operator practice style. Higher CABG utilization is associated with more durable revascularization without impact on survival or MACE. Broader implementation of multidisciplinary Heart Teams may improve consistency of care.
The long-term association of central obesity with brain structural integrity remains poorly understood. This study aimed to investigate the longitudinal association between cumulative Weight-adjusted-waist Index (WWI) exposure and multi-modal neuroimaging markers of brain health. This prospective community-based cohort study included 935 participants from the META-KLS Study. Cumulative WWI was calculated as the time-weighted average over 12 years prior to MRI acquisition. Neuroimaging outcomes included regional gray matter volume, white matter hyperintensity (WMH), and diffusion tensor imaging (DTI) metrics. Generalized linear models, restricted cubic splines, and mediation analyzes were performed. Elevated cumulative WWI was associated with adverse brain structural outcomes, particularly in females. In women, higher WWI was linked to extensive WMH burden (pFDR = 0.002), widespread microstructural disintegration (pFDR = 0.023), and specific atrophy in the orbital frontal cortex. A J-shaped dose-response relationship was identified for white matter injury, suggesting a tipping point for metabolic resilience. In exploratory mediation analyzes, FBG, SBP, and hs-CRP statistically accounted for 14.7%, 11.3%, and 11.3% of the association between cumulative WWI and WMH burden, respectively, while SBP accounted for 17.8% of the association with global MD. Cumulative WWI serves as a potential predictor of adverse brain structural outcomes, particularly manifesting as white matter injury and atrophy in women. Early monitoring of WWI offers a vital window for targeted metabolic interventions to preserve brain structural integrity.
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The use of cardiac implantable electronic devices (CIEDs) in patients with cancer is rising, given the increasing prevalence and incidence of cardiovascular disease in this population, such as arrhythmias and heart failure. Device therapy in oncology patients presents unique clinical, procedural, and ethical challenges, not completely addressed by current guidelines. This review summarizes current evidence regarding the indications, implantation challenges, long-term management, prognostic considerations and emerging technologies related to CIED therapy in oncology patients. Cancer-specific factors, such as thrombocytopenia, immunosuppression, prior surgery, and radiation-induced anatomical changes, complicate device implantation and follow-up. Increased infection risk, venous thromboembolism, and altered pacing thresholds, particularly in conditions like cardiac amyloidosis, require individualized approaches. The integration of leadless pacemakers, subcutaneous implantable cardioverter defibrillators (ICDs), wearable defibrillators, and remote monitoring offers promising alternatives for high-risk patients. Prognostic considerations and ethical dilemmas, including ICD implantation in patients with limited life expectancy and device deactivation at end-of-life, necessitate multidisciplinary decision-making. Future research and collaborative efforts are essential to address cancer-specific complexities and bridge existing gaps to optimize care for this growing patient population.
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IntroductionLymphoma survivors are at increased cardiovascular risk due to cardiotoxic therapies and commonly experience reduced cardiorespiratory fitness and quality of life. Telehealth-supported home-based exercise (HBE) may extend access to cardio-oncology rehabilitation (CORE); however, evidence from randomized trials in lymphoma survivors remains limited. This trial compared the short-term effects of telehealth-supported HBE versus center-based exercise (CBE) in lymphoma survivors entering CORE.Materials and MethodsIn this single-center, single-blind, parallel-group randomized controlled trial, lymphoma survivors in remission were randomized 1:1 to a 12-week telehealth-supported HBE program or supervised CBE. The primary endpoint was cardiorespiratory fitness, operationalized as peak oxygen uptake (pVO2, mL·kg-1·min-1) assessed by cardiopulmonary exercise testing (CPET) at 12 weeks. Key secondary outcomes were maximal workload (W) and SF-36 Physical Functioning. Between-group effects were estimated using ANCOVA with baseline adjustment (intention-to-treat; missing outcomes handled by multiple imputation).ResultsEighty participants were randomized (HBE n=40; CBE n=40); post-intervention CPET outcomes were available for 69 participants (HBE n=34; CBE n=35). pVO2 improved in both groups, with no significant baseline-adjusted between-group difference at 12 weeks (adjusted mean difference HBE-CBE -0.60 mL·kg-1·min-1, 95% CI -2.38 to 1.17; p=0.504). No between-group differences were observed for maximal workload (2.05 W, 95% CI -9.20 to 13.30; p=0.721) or SF-36 Physical Functioning (1.69 points, 95% CI -3.37 to 6.74; p=0.512). Adherence was high in both groups (HBE 80.1% vs CBE 77.9%). No adverse events were reported. Costs per participant were CZK 13,032 for HBE versus CZK 24,900 for CBE (48% lower for HBE).ConclusionTelehealth-supported HBE achieved comparable short-term improvements in exercise capacity and physical functioning to supervised CBE among lymphoma survivors entering CORE, with high adherence, no reported adverse events, and substantially lower provider costs. Telehealth-guided HBE represents a pragmatic, lower-cost delivery option to expand access to CORE.
Inflammasome activation has emerged as a promising therapeutic target to reduce residual cardiovascular risk in patients on guideline lipid-lowering therapy. IL-1β and IL-6 have been intensively studied, whereas the role of the inflammasome-related cytokine IL-18 has gained less attention. Here we aimed to assess the associations of IL-18 with risk of coronary events and severity of atherosclerosis. The study included 4,742 participants participating in a prospective Swedish Malmö Diet and Cancer (MDC) cohort study, 54,219 general population participants in the UK Biobank, and 1,500 participants with type 2 diabetes and/or known cardiovascular disease in the European multicenter SUMMIT VIP imaging study. Plasma levels of IL-18 were analyzed using proximity extension assay and atherosclerosis by carotid ultrasound. The incidence of MI and CV death was registered during a 23-year follow-up for MDC cohort and for a 15-year follow-up for the UK Biobank cohort.There were 617 cases of MI and 644 CV deaths in the MDC cohort and 2,454 cases of MI and 1,537 CV deaths in the UK Biobank cohort. Elevated IL-18 was associated with an increased risk of MI and CV death independent of hsCRP and IL-6 in both cohorts. In Cox proportional hazards regression models this association was independent of major CV risk factors in the UK Biobank but not in the MDC cohort. IL-18 did not provide clinically meaningful risk reclassification in the UK biobank cohort. The association of IL-18 with carotid atherosclerosis in the SUMMIT VIP cohort was weaker than that of IL-6. IL-18 is independently associated with risk of MI and CV death in the general population but does not improve clinical risk stratification. Targeting IL-18 directly or through inflammasome inhibition represents a promising approach for treatment of residual inflammatory risk in high-risk atherosclerosis patients that merits to be evaluated in future randomized clinical trials.