Citations

Percutaneous ventricular assist devices (pVAD) decrease mortality in cardiogenic shock (CS) patients, but at a high adverse event rate. Novel pVADs need to improve cardiac power output (CPO) to improve efficacy and reduce profile to reduce adverse events. Venstramedical has developed an impeller with nitinol and polymer which can collapse for low-profile insertion and expand in the body to provide optimal CPO. We have also developed a unique 9 French (9Fr) delivery system. In vitro and in vivo testing have been performed to develop this device. Head-flow (HQ) tests generate 5.0 L/min with a pressure differential of 80 mm Hg and 7.0 L/min against 60 mm Hg. Durability testing demonstrated continuous operation of up to 20 days. In the acute healthy ovine model, we demonstrated full flow (7–9 L against 60–80 mm Hg), transcatheter 9Fr delivery, retrieval of the device, and resting of the native heart during pumping. In a CS animal, we demonstrated survival and resting of the native heart during the acute study with decreased stroke work (SW), decreased stroke volume (SV), while total cardiac output was up to 7 L/min and maintaining adequate pressure with low hemolysis. We also demonstrated multiday functioning of the device in a healthy ovine model with good CO and low hemolysis.

This study examines the relevance of minimum case volume recommendations in contemporary practice.

Multiple myeloma (MM) treatment outcomes in developing countries may be impacted by resource constraints. This systematic review and meta-analysis evaluated efficacy outcomes of MM treatments across developing regions. Comprehensive searches in five major databases identified 37 eligible studies from Asia, Africa, Latin America, and Eastern Europe. The Newcastle-Ottawa Scale was used to assess risk of bias. Newer novel agents including daratumumab, carfilzomib, and pomalidomide showed limited use across studies. For patients receiving autologous stem cell transplantation (ASCT), the pooled overall survival rate at longest follow-up (2.5-12.5 years) was 62% (95% CI: 48-75%), with high heterogeneity (I²=92%), while the progression-free survival rate at longest follow-up (3-8 years) was 44% (95% CI: 23-67%). Comparative analyses demonstrated ASCT was associated with significantly superior 5-year survival compared to conventional chemotherapy (RR: 1.59; 95% CI: 1.38-1.82). Bortezomib-based regimens showed better outcomes than thalidomide-based therapies (HR for overall survival (OS) at 4 years: 0.73; 95% CI: 0.53-1.0) and alkylating agent-based regimens (HR: 0.48; 95% CI: 0.28-0.83). Despite resource limitations, ASCT and certain novel agents are associated with improved survival outcomes for MM patients in developing countries. However, substantial heterogeneity in outcomes suggests variability in healthcare infrastructure, treatment accessibility, and clinical expertise across these regions.

Background: Doxorubicin (DOX) is an effective chemotherapy but limited by severe cardiotoxicity. Chemokine receptors CXCR4 and CXCR7 are involved in regulating cardiac survival, inflammation, and fibrosis, yet their specific roles in DOX-induced cardiotoxicity (DICT) remain unclear. Objective: We investigated the cardioprotective effects of TC14012, a dual-target CXCR4 antagonist and CXCR7 agonist, against DICT. Methods: Male C57BL/6J mice received chronic or acute DOX administration with twice-weekly TC14012 treatment. Cardiac function was evaluated by echocardiography. Markers of cardiac fibrosis and inflammation were assessed. RNA-seq analysis was performed to explore associated molecular pathways. Key pathways were validated in cardiac cells and bone marrow-derived mast cells. Results: TC14012 significantly improved cardiac function, indicated by preservation of ejection fraction and fractional shortening, and increased survival rates optimally at 5 mg/kg, which were accompanied with reductions in cardiac collagen deposition and infiltration of macrophages and neutrophils. RNA-seq revealed that TC14012 protecting against DICT was associated with a remarkable stimulation of signals involving in cardiac contraction and energy reserve metabolism processes, particularly glycogen and glucan metabolism that are crucial for meeting the cardiac energy demand in response to DOX induction. These signals could be further enriched into AMPK signalling pathway and validated by enhancement of cardiac AMPK phosphorylation both in vivo and in vitro . Meanwhile, TC14012’s cardioprotective effects were accompanied by a reduction in signals involving in cardiac mast cell activation and degranulation, which could be enriched into Rap1 signalling pathway and validated by TC14012 inhibiting mast cell activation and Rap1-GTP activity in vitro . Importantly, TC14012 did not compromise DOX’s antitumor efficacy in EL-4 lymphoma-bearing mice. Conclusions: TC14012 may prevent DICT by activating CXCR7-AMPK signalling to reprogram cardiomyocyte metabolism and antagonizing CXCR4-Rap1 signalling to blunt mast cell-mediated sentinel effects without compromising the anticancer efficacy DOX.

Introduction/Background: Despite numerous medical advances, 30% of patients with Fontan circulation require heart transplantation by 21. Current risk stratification relies on clinical metrics that lack strong correlations to patient outcomes, leading to a high waitlist mortality. Hypothesis: Integration of physics-based hemodynamic modeling with interpretable machine learning will improve prediction of patient outcomes (listing for heart transplant and/or cardiac death) by quantifying physiologic mechanisms inaccessible through clinical measures alone. Goals/Aims: 1. Develop a lumped-parameter mechanistic model (LPMM) of Fontan circulation 2. Identify patient clusters and predictors of patient outcomes 3. Validate model-informed classifiers against clinical-only approaches Methods/Approach: A LPMM incorporating ventricular sarcomere mechanics, atrial hemodynamics, and vascular viscoelastic effects was optimized to cardiac catheterization and echocardiography data from 51 patients (age 25±8 years). Thirty-eight parameters (ventricular inotropy, atrial stiffness, pulmonary elastance, etc.) were calibrated via surrogate optimization, minimizing least-squares error versus 11 clinical targets. Partial least-squares regression with leave-one-out cross-validation compared clinical-only versus model-informed classifiers of outcomes. Results/Data: The LPMM achieved 2% mean error across hemodynamic targets, with CVP and pulmonary pressures matching clinical measurements within 1%. Model-derived minimum atrial pressure (4.46±1.78 vs 2.68±0.87 mmHg, p<0.05) outperformed all clinical variables in discriminating patient outcomes. Integration of LPMM parameters increased AUROC from 0.67 to 0.78 for patient outcome prediction. Conclusions: Physics-based modeling identifies ventricular passive stiffness, atrial end-diastolic volume, and minimum atrial pressure, along with patient age (a clinical value) as critical determinants of Fontan failure. Combined mechanistic-machine learning approaches enable phenotype-specific risk stratification, supporting earlier referral for advanced therapies. This methodology establishes a framework for precision management of complex congenital circulations.

Background: Cardiac fibrosis is a central pathological process that leads to worse outcomes in various cardiomyopathies. Recent evidence shows that CDCP1 (CUB domain-containing protein 1) modulates myocardial recovery by attenuating human cardiac fibroblast (HCF) proliferation. This study investigates the hypothesis that selective targeting of the CDCP1 cleavage domain can mitigate fibroblast proliferation, thereby offering a novel therapeutic approach to reducing cardiac fibrosis. Methods: A high-throughput in silico screening was performed using the Enamine compound library, focusing on structural regions that include the cleavage and adjacent sites of CDCP1 . A total of 147 candidate compounds were prioritized based on docking scores and binding stability profiles. Selected compounds were subsequently evaluated in vitro using HCF cultures seeded at 3,000 cells/well in 96-well plates. Each compound was administered at 10 μM concentration, and cell proliferation and viability were assessed by time-lapse imaging in the Incucyte® system at 24 and 96 hours. All experiments were done in triplicate with appropriate DMSO vehicle controls. Results: Compound C3 significantly reduced HCF proliferation (Fig B) to 27.3±2.4% relative to DMSO controls (99.9±0.5%, P <0.001) at 96 hours. Detailed structural modeling indicated that C3 binds to the CDCP1 cleavage site (Fig C) with a favorable Glide XP docking score of -7.66 kcal/mol. The interaction is stabilized by hydrogen bonds with Lys365 and Cys374 (Fig D), and supplementary hydrophobic interactions between aromatic rings and aliphatic groups, which contribute to a strong inhibitory effect. Conclusion: Targeting the CDCP1 cleavage domain with compound C3 effectively diminishes HCF proliferation in vitro. Therefore, these results substantiate the therapeutic potential of CDCP1 inhibition in cardiac fibrosis. Ongoing in vivo studies will explore the translational relevance of these findings.

Background: Heart transplantation is the gold standard treatment for end-stage heart failure patients. However, only about half of patients will receive a transplant, and hearts from donors >55 years of age are often not transplanted due to concerns about primary graft dysfunction (PGD). The molecular mechanisms behind the increased risk of PGD in old donor age are not well-known. Methods: We examine the chromatin architecture changes in old and young human donor hearts via HiC. We determine the effects of Brd4 inhibition on the on old mouse donor heart cold preservation quality via ex vivo perfusion. Results: we found that older human donor hearts are associated with upregulated BRD4 expression and increased chromatin accessibility. We also identified that human cardiac aging is associated with altered 3D chromatin architecture at BRD4 sites at baseline. Unexpectedly, the cold preservation process in older donor hearts further intensifies chromatin looping at BRD4 sites. Functionally, we showed that old murine donor hearts are more susceptible to cold preservation-reperfusion injury. Importantly, Brd4 inhibition with JQ1 improved the function of ex vivo cold-preserved old donor hearts, restoring them to levels comparable to young donor hearts. Moreover, AAV9-mediated Brd4 knockdown in cardiomyocytes similarly improved ex vivo old donor heart function after cold preservation. Conclusions: Brd4-associated 3D chromatin reorganization plays a critical role in the vulnerability of old donor hearts to cold preservation injury. Therefore, Brd4 could be a potential target for aging-associated PGD.

BACKGROUND The use of Mohs micrographic surgery as a treatment for melanoma is rising, but the reliability of Mohs surgeons in assessing MART-1 melanoma en-face margins has not been evaluated. OBJECTIVE To evaluate interrater and intrarater reliability of Mohs surgeons in interpreting margins of early-stage melanoma. METHODS Twenty Mohs surgeons were asked to independently review images of frozen section MART-1 en-face peripheral margins of in situ or early-stage melanoma. Surgeons determined margins as positive or negative at initial evaluation and 6 weeks later. Primary outcomes were interrater and intrarater reliability. RESULTS Interrater agreement was 84.1% (95% confidence interval [CI]: 75.5%–92.8%) for assessment 1 and 87.5% (95% CI: 78.4%–96.4%) for assessment 2, with kappa values 0.68 (95% CI: 0.50–0.82) and 0.75 (95% CI: 0.57–0.88). Average intrarater percent agreement was 95.0% (95% CI: 70.6%–100.0%) with average kappa 0.90 (95% CI: 0.50–1.00). CONCLUSION Substantial interrater and nearly perfect intrarater agreement was identified among surgeons assessing melanoma margins utilizing MART-1 immunostaining, demonstrating consistent and reproducible assessment of melanoma margins during Mohs cases.