Cost-effectiveness of prophylaxis with recombinant vs plasma-derived VWF in severe von Willebrand disease in the United States.

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.

BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

Evidence Accumulates: Patients with Ascending Aneurysms Are Strongly Protected from Atherosclerotic Disease.

Ascending thoracic aortic aneurysms may be fatal upon rupture or dissection and remain a leading cause of death in the developed world. Understanding the pathophysiology of the development of ascending thoracic aortic aneurysms may help reduce the morbidity and mortality of this disease. In this review, we will discuss our current understanding of the protective relationship between ascending thoracic aortic aneurysms and the development of atherosclerosis, including decreased carotid intima-media thickness, low-density lipoprotein levels, coronary and aortic calcification, and incidence of myocardial infarction. We also propose several possible mechanisms driving this relationship, including matrix metalloproteinase proteins and transforming growth factor-ß.

Severe, Refractory Primary Warm Autoimmune Hemolytic Anemia Requiring 90 Erythrocyte Transfusions.

A previously healthy 60-year-old man presented to the hospital with a hemoglobin of 3.5 g/dL. He was diagnosed with severe warm autoimmune hemolytic anemia (wAIHA) with reticulocytopenia on hospital day 1 that was not responsive to steroids, immune globulin, and rituximab. Over a 42-day hospital stay, the patient remained continuously transfusion-dependent with a ninety red cell unit requirement for his refractory disease. He was trialed on therapeutic plasma exchange before ultimately undergoing inpatient splenectomy that led to a response within hours. He remains in complete remission at six months of follow-up.

Gender and Sex Differences in the Management, Intervention, and Outcomes of Patients With Severe Primary Mitral Regurgitation.

BACKGROUND: Gender- and sex-based disparities in mitral valve disease exist; however the factors associated with these differences are unknown. Identifying these differences is essential in devising mitigating strategies. We evaluated gender and sex differences among patients with severe primary mitral regurgitation (MR) across treatment phases. METHODS AND RESULTS: We conducted a retrospective cohort study of patients with new diagnoses of severe primary MR between 2016 and 2020. We compared multidisciplinary evaluation incidence and 2-year survival between men and women. We analyzed a subgroup meeting class 1 indications for intervention, which includes severe symptomatic MR or severe asymptomatic MR with ejection fraction <60% or left ventricular end-systolic diameter >40 mm. Logistic regression models identified predictors associated with the likelihood of multidisciplinary evaluation. Among 330 patients meeting class 1 indications, women were older (79 versus 76 years, P=0.01) and had higher Society of Thoracic Surgeons risk scores for mitral valve repair than men (2.5% versus 1.4%, P=0.003). Women were less likely to undergo multidisciplinary evaluation (57% versus 84%, P<0.001) and intervention (47% versus 69%, P<0.001) than men. Median days to intervention for women and men were 77 and 43, respectively. Women had a higher 2-year mortality rate than men (31% versus 21%, P=0.035). On a multivariable model, female sex and older age were associated with lower odds of undergoing multidisciplinary evaluation (odds ratio, 0.26; P<0.001; odds ratio, 0.95; P<0.001, respectively). CONCLUSIONS: Women with severe primary MR with class 1 indication for intervention were less likely to undergo multidisciplinary evaluation and intervention and had a longer interval to intervention than men. Survival was comparable after accounting for age and comorbidity differences.

The high-risk features among patients undergoing mitral valve operation for ischemic mitral regurgitation: The 3-strike score.

Objective: Ischemic mitral regurgitation is prevalent and associated with high surgical risk. With the less-invasive option of transcatheter edge-to-edge repair, the optimal patient selection for mitral valve operation for ischemic mitral regurgitation remains unclear. We sought to identify high-risk features in this group to guide patient selection. Methods: Using the Cardiothoracic Surgery Trial Network's severe ischemic mitral regurgitation trial data, we identified patient and echocardiographic characteristics associated with an increased risk of 2-year mortality using the support vector classifier and Cox proportional hazards model. We identified 6 high-risk features associated with 2-year survival. Patients were categorized into 3 groups, each having 1 or less, 2, or 3 or more of the 6 identified high-risk features. Results: Among the 251 patients, the median age was 69 (Q1 62, Q3 75) years, and 96 (38%) were female. Two-year mortality was 21% (n = 53). We identified 6 high-risk preoperative features: age 75 years or more (n = 69, 28%), prior sternotomy (n = 49, 20%), renal insufficiency (n = 69, 28%), gastrointestinal bleeding (n = 15, 6%), left ventricular ejection fraction less than 40% (n = 131, 52%), and ventricular end-systolic volume index less than 50 mL/m2 (n = 93, 37%). In patients who had 1 or less, 2, and 3 or more high-risk features, 90-day mortality was 4.2% (n = 5), 9.9% (n = 4), and 20.0% (n = 10), respectively (P = .006), and 2-year mortality was 10% (n = 12), 22% (n = 18), and 46% (n = 23) (P < .001), respectively. Conclusions: We developed the 3-strike score by identifying high-risk preoperative features for mitral valve surgery for ischemic mitral regurgitation. Patients having 3 or more of such high-risk features should undergo careful evaluation for surgical candidacy given the high early and late mortality after mitral valve operations.

Cost-effectiveness of bevacizumab therapy in the care of patients with hereditary hemorrhagic telangiectasia.

ABSTRACT: No US Food and Drug Administration- or European Medicines Agency-approved therapies exist for bleeding due to hereditary hemorrhagic telangiectasia (HHT), the second-most common inherited bleeding disorder worldwide. The current standard of care (SOC) includes iron and red cell supplementation, alongside the necessary hemostatic procedures, none of which target underlying disease pathogenesis. Recent evidence has demonstrated that bleeding pathophysiology is amenable to systemic antiangiogenic therapy with the anti-vascular endothelial growth factor bevacizumab. Despite its high cost, the addition of longitudinal bevacizumab to the current SOC may reduce overall health care resource use and improve patient quality of life. We conducted, to our knowledge, the first cost-effectiveness analysis of IV bevacizumab in patients with HHT with the moderate-to-severe phenotype, comparing bevacizumab added to SOC vs SOC alone. The primary outcome was the incremental net monetary benefit (iNMB) reported over a lifetime time horizon and across accepted willingness-to-pay thresholds, in US dollar per quality-adjusted life year (QALY). Bevacizumab therapy accrued 9.3 QALYs while generating $428 000 in costs, compared with 8.3 QALYs and $699 000 in costs accrued in the SOC strategy. The iNMB of bevacizumab therapy vs the SOC was $433 000. No parameter variation and no scenario analysis, including choice of iron supplementation product, changed the outcome of bevacizumab being a cost-saving strategy. Bevacizumab therapy also saved patients an average of 133 hours spent receiving HHT-specific care per year of life. In probabilistic sensitivity analysis, bevacizumab was favored in 100% of all 10 000 Monte Carlo iterations across base-case and all scenario analyses. Bevacizumab should be considered for more favorable formulary placement in the care of patients with moderate-to-severe HHT.

The HH-GLI2-CKS1B network regulates the proliferation-to-maturation transition of cardiomyocytes.

Cardiomyocyte (CM) proliferation and maturation are highly linked processes, however, the extent to which these processes are controlled by a single signaling axis is unclear. Here, we show the previously undescribed role of Hedgehog (HH)-GLI2-CKS1B cascade in regulation of the toggle between CM proliferation and maturation. Here we show downregulation of GLI-signaling in adult human CM, adult murine CM, and in late-stage hiPSC-CM leading to their maturation. In early-stage hiPSC-CM, inhibition of HH- or GLI-proteins enhanced CM maturation with increased maturation indices, increased calcium handling, and transcriptome. Mechanistically, we identified CKS1B, as a new effector of GLI2 in CMs. GLI2 binds the CKS1B promoter to regulate its expression. CKS1B overexpression in late-stage hiPSC-CMs led to increased proliferation with loss of maturation in CMs. Next, analysis of datasets of patients with heart disease showed a significant enrichment of GLI2-signaling in patients with ischemic heart failure (HF) or dilated-cardiomyopathy (DCM) disease, indicating operational GLI2-signaling in the stressed heart. Thus, the Hh-GLI2-CKS1B axis regulates the proliferation-maturation transition and provides targets to enhance cardiac tissue engineering and regenerative therapies.

Implementing Formal Mitral Heart Team Improves Multidisciplinary Evaluation Rate and Survival of Patients With Severe Primary Mitral Regurgitation.

BACKGROUND: Multidisciplinary heart team (HT) evaluation is recommended for patients with severe primary mitral regurgitation to optimize treatment decisions. However, its impact on patient outcomes remains unknown. We evaluated the impact of implementing mitral HT on patient survival. METHODS AND RESULTS: We conducted a retrospective cohort study of patients with new diagnoses of severe primary mitral regurgitation in a large healthcare network echocardiogram database between 2016 and 2020. We compared the incidence of multidisciplinary evaluation by structural cardiology and cardiac surgery services and 2-year survival before and after mitral HT implementation. The 1:1 propensity-score matching between pre- and post-mitral HT used Society of Thoracic Surgeons Predicted Risk of Mortality for mitral repair, age, sex, race, heart failure symptoms, inpatient setting, history of MI, and dementia as covariates. Logistic regression identified variables associated with the likelihood of undergoing multidisciplinary evaluation. Among 70 510 echocardiograms performed, 391 patients had severe primary mitral regurgitation (median age, 77 years; 46% women). Multidisciplinary evaluation increased from 29% to 89% (P<0.001), and intervention increased from 24% to 75% following mitral HT implementation (P<0.001). Among 180 propensity-score matched patients, mortality was lower post-mitral HT at 2 years (19% versus 32%, P=0.04). The multivariable model showed that mitral HT implementation and heart failure symptoms were associated with higher odds of undergoing multidisciplinary evaluation (OR [odds ratio], 18.7 and 2.72, respectively), whereas female sex and older age were associated with lower odds (OR, 0.39 and 0.93, respectively). CONCLUSIONS: Implementation of mitral HT was associated with drastic improvement in multidisciplinary evaluation for patients with severe primary mitral regurgitation. This coincided with higher proportions of patients undergoing mechanical correction of MR and improved overall patient survival.

Totally endoscopic, robotic-assisted tricuspid valve repair and biatrial CryoMAZE.

We describe in detail our technique for totally endoscopic, robotic-assisted tricuspid valve repair for iatrogenic tricuspid regurgitation and biatrial cryoMAZE.

Gender Representation Trends in Cardiothoracic Surgery Journal Editorial Boards.

OBJECTIVE: We aimed to characterize chronologic trends of gender composition of major cardiothoracic surgery journal editorial boards in the current era. METHODS: A cross-sectional analysis was performed of gender representation in editorial board members of two North American cardiothoracic surgery journals from 2008 to 2023. Member names and roles were collected from available monthly issues. Validated software programming was used to classify gender. The annual proportion of women representation was compared to the thoracic surgery workforce. RESULTS: During the study period, 558 individuals (3,641 names) were identified, 14.3% of whom were women. The total number of editorial board women increased for both journals. The proportion of women also increased from 2.5% (3/118) in 2008 to 17.8% (71/399) in 2023 (P < .001), exceeding the percentage of women in the thoracic surgery workforce which increased from 3.8% in 2007 to 8.3% in 2021 (P < .001). The average duration of participation was longer for men than for women (53.8 vs 44.5 months, P = .01). Women in editorial board senior roles also increased from 3.3% (1/30) in 2008 to 28.6% (42/147) in 2023 (P < .001), almost triple the increase in non-designated roles from 2.3% (2/88) in 2008 to 11.5% (29/252) in 2023 (P < .001). CONCLUSIONS: In recent years, the appointment of women to high-impact cardiothoracic surgery journal editorial boards and senior roles have proportionally exceeded the overall representation of women in cardiothoracic surgery. These findings indicate progress in inclusive efforts and offer insight towards reducing academic gender disparities.

Outcomes of patients with advanced liver disease undergoing cardiac surgery.

Objective: Liver disease (LD) is considered a risk factor for inferior outcomes in general and cardiac surgery, yet current cardiac surgery risk estimators exclude LD, and literature on the topic remains scant. We sought to evaluate whether the presence of advanced LD is associated with inferior outcomes following cardiac surgery. Methods: This single-center, retrospective, observational study included 285 patients diagnosed with LD who underwent cardiac surgery in 2010 to 2020. The cohort contained 3 groups, Child-Turcotte-Pugh (CTP) class A (n = 219), CTP early-class B (n = 34), and CTP advanced-class B (n = 32). A model for end-stage liver disease score of 12.7 points (determined using a receiver-operating characteristic curve analysis on 30-day mortality) dichotomized class B into early- and advanced-groups. Univariate and multivariate logistic regression analyses were performed to identify predictors of 30-day mortality. Results: Patients in CTP advanced-class B had the longest length of stay (14 days), highest incidence of prolonged ventilation (46.9%), renal failure (21.9%), 30-day mortality (18.8%), and in-hospital mortality (18.8%). Incidence of ≥1 postoperative complication was higher in CTP advanced-class B (59.4%), compared with CTP class A (37.9%) and CTP early-class B (38.2%). Multivariate logistic regression analysis demonstrated that female sex (odds ratio, 3.01; 95% CI, 1.07-8.77; P = .037) and peripheral vascular disease (odds ratio, 4.01; 95% CI, 1.33-12.2; P = .013) were independent predictors of 30-day mortality in patients with advanced LD. Conclusions: Severity of LD influences perioperative outcomes following cardiac surgery. Our data suggest that patients in CTP class A and selected patients in CTP class B (model for end-stage liver disease score <12.7) can undergo surgery with acceptable risk.

Porous PolyHIPE microspheres for protein delivery from an injectable bone graft.

Delivery of osteoinductive factors such as bone morphogenetic protein 2 (BMP-2) has emerged as a prominent strategy to improve regeneration in bone grafting procedures. However, it remains challenging to identify a carrier that provides the requisite loading efficiency and release kinetics without compromising the mechanical properties of the bone graft. Previously, we reported on porous, polymerized high internal phase emulsion (polyHIPE) microspheres fabricated using controlled fluidics. Uniquely, this solvent-free method provides advantages over current microsphere fabrication strategies including in-line loading of growth factors to improve loading efficiency. In the current study, we utilized this platform to fabricate protein-loaded microspheres and investigated the effect of particle size (∼400 vs ∼800 µm) and pore size (∼15 vs 30 µm) on release profiles. Although there was no significant effect of these variables on the substantial burst release profile of the microspheres, the incorporation of the protein-loaded microspheres within the injectable polyHIPE resulted in a sustained release of protein from the bulk scaffold over a two-week period with minimal burst release. Bioactivity retention of encapsulated BMP-2 was confirmed first using a genetically-modified osteoblast reporter cell line. A functional assay with human mesenchymal stem cells established that the BMP-2 release from microspheres induced osteogenic differentiation. Finally, microsphere incorporation had minimal effect on the cure and compressive properties of an injectable polyHIPE bone graft. Overall, this work demonstrates that these microsphere-polyHIPE composites have strong potential to enhance bone regeneration through controlled release of BMP-2 and other growth factors. STATEMENT OF SIGNIFICANCE: This manuscript describes a method for solvent-free fabrication of porous microspheres from high internal phase emulsions using a controlled fluids setup. The principles of emulsion templating and fluid dynamics provide exceptional control of particle size and pore architecture. In addition to the advantage of solvent-free fabrication, this method provides in-line loading of protein directly into the pores of the microspheres with high loading efficiencies. The incorporation of the protein-loaded microspheres within an injectable polyHIPE scaffold resulted in a sustained release of protein over a two-week period with minimal burst release. Retention of BMP-2 bioactivity and incorporation of microspheres with minimal effect on scaffold compressive properties highlights the potential of these new bone grafts.