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Background: Smooth muscle cell (SMC) phenotypic reprogramming toward a mixed synthetic-proteolytic state is a central feature of aortic root aneurysm in Marfan syndrome (MFS). Previous work identified Klf4 as a potential mediator of SMC plasticity in MFS. Methods: MFS ( Fbn1 C1041G/+ ) mouse strains with an inducible vascular SMC fluorescent reporter ( MFS SMC ) with or without SMC-specific deletion of Klf4 exons 2 to 3 ( MFS SMC-Klf4Δ ) were generated. Simultaneous SMC tracing and Klf4 loss-of-function ( Klf4Δ mice) was induced at 6 weeks of age. Aneurysm growth was assessed via serial echocardiography (4–24 weeks). Twenty-four-week-old mice were assessed via histology, RNA in situ hybridization, and aortic single-cell RNA sequencing. Results: MFS mice demonstrated progressive aortic root dilatation compared with control (WT SMC ) mice regardless of Klf4 genotype ( P MFS SMC-Klf4Δ versus MFS SMC ( P =0.884). Efficient SMC Klf4 deletion was confirmed via lineage-stratified genotyping, RNA in situ hybridization, and immunohistochemistry. Single-cell RNA sequencing of traced SMCs revealed a highly similar pattern of phenotype modulation marked by loss of contractile markers (eg, Myh11, Cnn1 ) and heightened expression of matrix genes (eg, Col1a1, Fn1 ) between Klf4 genotypes. Pseudotemporal quantitation of SMC dedifferentiation confirmed that Klf4 deletion did not alter the global extent of phenotype modulation, but reduced expression of 23 genes during this phenotype transition in MFS SMC-Klf4Δ mice, including multiple chondrogenic genes expressed by only the most severely dedifferentiated SMCs (eg, Cytl1, Tnfrsf11b ). Conclusions: Klf4 is not required to initiate SMC phenotype modulation in MFS aneurysm but may exert regulatory control over chondrogenic genes expressed in highly dedifferentiated SMCs.

Background: Aortic root smooth muscle cells (SMC) develop from both the second heart field (SHF) and neural crest. Disparate responses to disease-causing Fbn1 variants by these lineages are proposed to promote focal aortic root aneurysm formation in Marfan syndrome (MFS), but lineage-stratified SMC analysis in vivo is lacking. Methods: We generated SHF lineage-traced MFS mice and performed integrated multiomic (single-cell RNA and assay for transposase-accessible chromatin sequencing) analysis stratified by embryological origin. SMC subtypes were spatially identified via RNA in situ hybridization. Response to TWIST1 overexpression was determined via lentiviral transduction in human aortic SMCs. Results: Lineage stratification enabled nuanced characterization of aortic root cells. We identified heightened SHF-derived SMC heterogeneity including a subset of Tnnt2 (cardiac troponin T)-expressing cells distinguished by altered proteoglycan expression. MFS aneurysm-associated SMC phenotypic modulation was identified in both SHF-traced and nontraced (neural crest–derived) SMCs; however, transcriptomic responses were distinct between lineages. SHF-derived modulated SMCs overexpressed collagen synthetic genes and small leucine-rich proteoglycans while nontraced SMCs activated chondrogenic genes. These modulated SMCs clustered focally in the aneurysmal aortic root at the region of SHF/neural crest lineage overlap. Integrated RNA-assay for transposase-accessible chromatin analysis identified enriched Twist1 and Smad2/3/4 complex binding motifs in SHF-derived modulated SMCs. TWIST1 overexpression promoted collagen and SLRP gene expression in vitro, suggesting TWIST1 may drive SHF-enriched collagen synthesis in MFS aneurysm. Conclusions: SMCs derived from both SHF and neural crest lineages undergo phenotypic modulation in MFS aneurysm but are defined by subtly distinct transcriptional responses. Enhanced TWIST1 transcription factor activity may contribute to enriched collagen synthetic pathways SHF-derived SMCs in MFS.

Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate incorrect and sometimes even toxic statements. In this study, we develop Almanac, a large language model framework augmented with retrieval capabilities for medical guideline and treatment recommendations. Performance on a novel dataset of clinical scenarios (n = 130) evaluated by a panel of 5 board-certified and resident physicians demonstrates significant increases in factuality (mean of 18% at p-value < 0.05) across all specialties, with improvements in completeness and safety. Our results demonstrate the potential for large language models to be effective tools in the clinical decision-making process, while also emphasizing the impor- tance of careful testing and deployment to mitigate their shortcomings.

We describe surgical repair of a Stanford Type A aortic dissection with concurrent aortic valve Streptococcus equi endocarditis in the setting of subarachnoid hemorrhage and disseminated i...

Bicuspid aortic valve is the most common congenital heart defect, affecting 1-2% of the global population. Patients with bicuspid valves frequently develop dilation and aneurysms of the ascending aorta. Both hemodynamic and genetic factors are believed to contribute to dilation, yet the precise mechanism underlying this progression remains under debate. Controlled comparisons of hemodynamics in patients with different forms of bicuspid valve disease are challenging because of confounding factors, and simulations offer the opportunity for direct and systematic comparisons. Using fluid-structure interaction simulations, we simulate flows through multiple aortic valve models in a patient-specific geometry. The aortic geometry is based on a healthy patient with no known aortic or valvular disease, which allows us to isolate the hemodynamic consequences of changes to the valve alone. Four fully-passive, elastic model valves are studied: a tricuspid valve and bicuspid valves with fusion of the left- and right-, right- and non-, and non- and left-coronary cusps. The resulting tricuspid flow is relatively uniform, with little secondary or reverse flow, and little to no pressure gradient across the valve. The bicuspid cases show localized jets of forward flow, excess streamwise momentum, elevated secondary and reverse flow, and clinically significant levels of stenosis. Localized high flow rates correspond to locations of dilation observed in patients, with the location related to which valve cusps are fused. Thus, the simulations support the hypothesis that chronic exposure to high local flow contributes to localized dilation and aneurysm formation.

BACKGROUND: To delineate the effects of integrin αv signaling in Marfan syndrome (MFS) and examine the potential efficacy of integrin αv blockade as a therapeutic strategy for MFS aneurysms. METHODS: Induced pluripotent stem cells were differentiated into aortic smooth muscle cells (SMCs) of the second heart field (SHF) and neural crest lineages, enabling in vitro modeling of thoracic aortic aneurysm in MFS. Fbn1 C1039G/+ MFS mice treated with integrin αv antagonist (GLPG0187) confirmed the pathological role of integrin αv on aneurysm formation. RESULTS: Induced pluripotent stem cell–derived MFS SHF SMCs overexpress integrin αv relative to MFS neural crest and healthy control SHF cells. Furthermore, downstream targets of integrin αv (FAK [focal adhesion kinase]/Akt Thr308 /mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment GLPG0187 reduced p-FAK/p-Akt Thr308 /mTORC1 activity in MFS SHF back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS neural crest and control SMCs, which was then inhibited by GLPG0187 treatment. In the Fbn1 C1039G/+ MFS mouse model, integrin αv, p-Akt Thr308 , and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6–14 weeks) resulted in reduced aneurysm growth, elastin fragmentation, and normalization of the FAK/Akt Thr308 /mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing. CONCLUSIONS: The integrin αv-FAK-Akt Thr308 signaling pathway is activated in induced pluripotent stem cell SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-Akt Thr308 signaling in Fbn1 C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.

Objective Aortic incompetence (AI) is observed to be accelerated in the continuous-flow left ventricular assist device (LVAD) population and is related to increased mortality. Using computational fluid dynamics (CFD), we investigated the hemodynamic conditions related to the orientation of the LVAD outflow in these patients. Method We identified 10 patients with new aortic regurgitation, and 20 who did not, after LVAD implantation between 2009 and 2018. Three-dimensional models of patients' aortas were created from their computed tomography scans. The geometry of the LVAD outflow graft in relation to the aorta was quantified using azimuth angles (AA), polar angles (PAs), and distance from aortic root. The models were used to run CFD simulations, which calculated the pressures and wall shear stress (rWSS) exerted on the aortic root. Results The AA and PA were found to be similar. However, for combinations of high values of AA and low values of PA, there were no patients with AI. The distance from aortic root to the outflow graft was also smaller in patients who developed AI (3.39 ± 0.7 vs 4.07 ± 0.77 cm, P = .04). There was no significant difference in aortic root pressures in the 2 groups. The rWSS was greater in AI patients (4.60 ± 5.70 vs 2.37 ± 1.20 dyne/cm2, P Conclusions Using CFD simulations, we demonstrated that patients who developed de novo AI have greater rWSS at the aortic root, and their outflow grafts were placed closer to the aortic roots than those patients without de novo AI.

Introduction Traditionally, implantation of Left Ventricular Assist Devices (LVADs) is performed via median sternotomy . Recently, less invasive thoracotomy approaches are growing in popularity as they involve less surgical trauma, potentially less bleeding, and may preserve right ventricular function . We hypothesized implantation of LVADs via thoracotomy has less perioperative right ventricular failure (RVF) and shorter postoperative length of stay (LOS). Methods Continuous flow LVAD implants from Intermacs between February 6, 2014 - December 31, 2018 were identified. Patients implanted via thoracotomy were propensity matched in a 1:1 ratio with patients implanted via sternotomy. Outcomes were compared between sternotomy and thoracotomy approach and by device type (axial, centrifugal-flow with hybrid levitation (CF-HL), centrifugal-flow with full magnetic levitation devices (CF-FML)). The primary outcome was time to first moderate or severe RVF. Secondary outcomes included survival and LOS. Results Overall 978 thoracotomy patients were matched with 978 sternotomy patients. Over the study period, 242 thoracotomy patients and 219 sternotomy patients developed RVF with no significant difference in time to first moderate to severe RVF by surgical approach overall ( p = 0.27) or within CF-HL (p = 0.36) or CF-FML devices (p = 0.25). Survival did not differ by implant technique (150 deaths in thoracotomy group, 154 deaths in sternotomy group; p = 0.58). However, sternotomy approach was associated with a significantly shorter LOS (17 Vs 18 days, p = 0.009). Conclusion As compared to sternotomy, implantation of continuous flow LVADs via thoracotomy approach does not reduce moderate to severe RVF or improve survival but does reduce post-operative LOS. Device type did not influence outcomes and most centers did a small volume of thoracotomy implants.

Objective To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis. Design Retrospective cohort study. Setting Academic hospital. Participants Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018). Intervention FEIBA administered to control perioperative hemorrhage. Measurements and Main Results The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68 × 103/mL, p = 0.004), prior cardiac surgery (36.6% v 21.9%, p = 0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p = 0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p = 0.343) or mortality rate (3.7% v 1.3%, p = 0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk. Conclusions In this retrospective cohort study, the use of FEIBA (∼1,000 units, ∼13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.

BACKGROUND Multicenter data on long term survival following LVAD implantation that make use of contemporary definitions of RV failure are limited. Furthermore, traditional survival analyses censor patients who receive a bridge to heart transplant. Here we compare the outcomes of LVAD patients who develop post-operative RV failure accounting for the transitional probability of receiving an interim heart transplantation. METHODS We use a retrospective cohort of LVAD patients sourced from multiple high-volume centers based in the United States. Five- and ten-year survival accounting for transition probabilities of receiving a heart transplant were calculated using a multi-state Aalen Johansen survival model. RESULTS Of the 897 patients included in the study, 238 (26.5%) developed post-operative RV failure at index hospitalization. At 10 years the probability of death with post-op RV failure was 79.28% vs 61.70% in patients without (HR 2.10; 95% CI 1.72 - 2.57; p = < .001). Though not significant, patients with RV failure were less likely to be bridged to a heart transplant (HR 0.87, p = .4). Once transplanted the risk of death between both patient groups remained equivalent; the probability of death after a heart transplant was 3.97% in those with post-operative RV failure shortly after index LVAD implant, as compared to 14.71% in those without. CONCLUSIONS AND RELEVANCE Long-term durable mechanical circulatory support is associated with significantly higher mortality in patients who develop post-operative RV failure. Improving outcomes may necessitate expeditious bridge to heart transplant wherever appropriate, along with critical reassessment of organ allocation policies.

Assessing the efficacy of cancer therapeutics in mouse models is a critical step in treatment development. However, low-resolution measurement tools and small sample sizes make determining drug efficacy in vivo a difficult and time-intensive task. Here, we present a commercially scalable wearable electronic strain sensor that automates the in vivo testing of cancer therapeutics by continuously monitoring the micrometer-scale progression or regression of subcutaneously implanted tumors at the minute time scale. In two in vivo cancer mouse models, our sensor discerned differences in tumor volume dynamics between drug- and vehicle-treated tumors within 5 hours following therapy initiation. These short-term regression measurements were validated through histology, and caliper and bioluminescence measurements taken over weeklong treatment periods demonstrated the correlation with longer-term treatment response. We anticipate that real-time tumor regression datasets could help expedite and automate the process of screening cancer therapies in vivo.

Severe symptomatic degenerative mitral regurgitation (DMR) has a poor prognosis in the absence of treatment, and new transcatheter options are emerging.The CLASP IID randomized trial (NCT03706833) is the first to evaluate the safety and effectiveness of the PASCAL system compared to the MitraClip system in patients with significant symptomatic DMR. In this report, we present the primary safety and effectiveness endpoints for the trial.Patients with 3+ or 4+ DMR at prohibitive surgical risk were assessed by a central screening committee and randomized 2:1 (PASCAL:MitraClip). Study oversight also included an echocardiographic core laboratory and a clinical events committee. The primary safety endpoint was a composite major adverse event (MAE) rate at 30 days. The primary effectiveness endpoint was the proportion of patients with MR ≤2+ at 6 months.A pre-specified interim analysis in 180 patients demonstrated non-inferiority of the PASCAL system vs. MitraClip system for the primary safety and effectiveness endpoints, MAE: 3.4% vs. 4.8%, MR ≤2+: 96.5% vs. 96.8%, respectively. Functional and quality-of-life outcomes significantly improved in both groups (p0.05). The proportion of patients with MR ≤1+ was durable in the PASCAL group from discharge to 6 months [PASCAL: 87.2% and 83.7% (p=0.317 vs. discharge); MitraClip: 88.5% and 71.2% (p=0.003 vs. discharge), respectively].The CLASP IID trial demonstrated safety and effectiveness of the PASCAL system and met non-inferiority endpoints, expanding transcatheter treatment options for prohibitive surgical risk patients with significant symptomatic DMR.

Introduction: Heart transplantation provides lifesaving therapy for patients with end-stage heart failure. The longevity of the therapy is limited by Cardiac Graft Dysfunction (CGD), which is an acquired cardiomyopathy affecting transplanted hearts associated with diastolic and/or systolic dysfunction. Some clinical risk factors for CGD have been identified, but none of them are easily modifiable. An unexplored potential contributor to CGD is the choice of immunosuppression agent used despite multiple clinical reports suggesting reduced adverse cardiac remodeling with mammalian target of rapamycin (mTOR) inhibitors compared to calcineurin inhibitors (CNI). This study examines mechanisms of differential cardiac remodeling effects of CNI versus mTOR inhibitors in a human cellular cardiac model. Methods/Results: We utilized 3D cardiac spheres composed of induced pluripotent stem cell-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells (cardiac organoids). Cardiac organoids were treated with 5 days of vehicle, tacrolimus (CNI), or sirolimus (mTOR inhibitor). We did not observe a significant difference in surrogates of systolic or diastolic function in treated cardiac organoids. We pursued single cell-RNA sequencing of drug-treated cardiac organoids and identified gene expression changes consistent with increased extracellular matrix deposition and fibroblast activity in response to CNI treatment. In addition, CNI-treated cardiac organoids cellular composition was notable for increased proportion of fibroblasts and less cardiomyocytes compared to mTOR inhibitor-treated cardiac organoids. To validate gene expression changes observed, we treated cardiac fibroblasts with drugs and observed an increase in collagen production in response to CNI treatment and a reduction in fibroblast number and collagen production in response to mTOR inhibitor treatment. Furthermore, we observed increased ATP production in CNI-treated cardiac fibroblasts, but a reduction in mTOR-treated counterparts. Conclusion: We identify reduced extracellular matrix deposition and cardiac fibroblast proliferation in response to mTOR inhibitor as a potential mechanism for the more favorable remodeling profile observed clinically.

Background: Vascular smooth muscle cell (SMC) phenotype modulation produces a mixed proteolytic/collagen synthetic state in Marfan syndrome (MFS) aortic root aneurysm. While the transcriptomic changes associated with this process are established, upstream regulators governing this plasticity are poorly characterized. Methods/Results: We performed concurrent single-cell RNA sequencing (scRNAseq) and assay for transposase-accessible chromatin using sequencing (scATACseq) on aortic root aneurysm tissue from adult Fbn1 C1041G/+ (MFS) mice and littermate controls. MFS/control scRNAseq data analysis identified four SMC subtypes including MFS-specific ‘modulated’ cells (modSMCs) which enriched for extracellular matrix organization and collagen synthesis pathway activation. These SMC clusters were projected onto the MFS/control scATAC dataset via integrative label transfer to study dynamic chromatin accessibility during SMC phenotype modulation. We compared DNA accessibility in modSMCs versus mature SMCs, finding 336 enriched and 29 suppressed peaks, suggesting increased open chromatin during modulation. Using chromVAR, we identified 242 enriched transcription factor motifs overrepresented in modSMCs. Motifs representing central but nonspecific transcription factor families including numerous AP-1 (FOS/JUN/ATF) heterodimers and TEAD family members showed highest enrichment, while enriched TWIST1, HAND2, and SMAD2:SMAD3:SMAD4 complex motifs suggested more specific functions. To functionally validate these findings, we examined TWIST1 as a potential regulator of SMC modulation in vitro via lentiviral overexpression in MFS patient-derived aortic SMCs.In SMCs with forced TWIST1 overexpression, we found heightened promoter region DNA accessibility (via bulk ATACseq) and increased mRNA expression (via RT-PCR) for specific modSMC markers (e.g., COL1A1 and LUM confirming TWIST1 promotes collagen synthesis. Conclusions: Integrated single-cell transcriptomic/epigenomic analysis permits identification of critical upstream regulatory signals promoting disease-specific cell phenotype changes. TWIST1 is a potential driver of SMC modulation and a target for therapeutic agent design in MFS aortic aneurysm.

Objective: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1 C1041G/ + (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1 C1041G/ + mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE −/− mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 ( Serpine1 ) and Kruppel-like factor 4 ( Klf4 ). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1 C1041G/ + SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1 C1041G/ + mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1 C1041G/ + descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-β (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets. Conclusions: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-β plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-β signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

Severe primary graft dysfunction (PGD) is the leading cause of early postoperative mortality following orthotopic heart transplantation (OHT). Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used as salvage therapy. This study aimed to evaluate the outcomes in adult OHT recipients who underwent VA-ECMO for severe PGD. We retrospectively reviewed 899 adult (≥18 years) patients who underwent primary OHT at our institution between 1997 and 2017. Recipients treated with VA-ECMO (19, 2.1%) exhibited a higher incidence of previous cardiac surgery (p = .0220), chronic obstructive pulmonary disease (p = .0352), and treatment with a calcium channel blocker (p = .0018) and amiodarone (p = .0148). Cardiopulmonary bypass (p = .0410) and aortic cross-clamp times (p = .0477) were longer in the VA-ECMO cohort and they were more likely to have received postoperative transfusion (p = .0013); intra-aortic balloon pump (IABP, p < .0001), and reoperation for bleeding or tamponade (p < .0001). The 30-day, 1-year, and overall survival after transplantation of non-ECMO patients were 95.9, 88.8, and 67.4%, respectively, compared to 73.7, 57.9, and 47.4%, respectively in the ECMO cohort. Fourteen (73.7%) of the ECMO patients were weaned after a median of 7 days following OHT (range: 1–12 days). Following OHT, VA-ECMO may be a useful salvage therapy for severe PGD and can potentially support the usage of marginal donor hearts.

Patients undergoing heart transplant (HT) and ventricular assist device (VAD) implant may experience intra- and postoperative complications requiring high-dose vasopressor agents and/or mechanical circulatory support. These complications increase the risk of nonocclusive bowel ischemia (NOBI) and inadequate enteral nutrition (EN) delivery, and guidance for this high-risk patient population is limited. To optimize nutrition support practices in this patient population at our institution, we created the High-Risk Nutrition Support Protocol (HRNSP) to improve nutrient delivery and promote safer EN practices in the setting of NOBI risk factors after HT and VAD implant.We developed and implemented a nutrition support protocol as a quality improvement (QI) initiative. Data were obtained before (n = 62) and after (n = 52) protocol initiation. We compared nutrition and clinical outcomes between the pre- and post-intervention groups.Fewer calorie deficits (P 0.001), fewer protein deficits (P 0.001), a greater proportion of calorie/protein needs met (P 0.001), zero NOBI cases (0%), and decreased intensive care unit (ICU) length of stay (LOS) (P = 0.005) were observed with 100% (n = 52 of 54) HRNSP implementation success. Increased use of parenteral nutrition did not increase central line-associated bloodstream infections (P = 0.46). There was no difference in hospital LOS (P = 0.44) or 90-day and 1-year mortality (P = 0.56, P = 0.35).This single-center, QI pre- and post-protocol intervention outcome study suggests that implementing and adhering to a nutrition support protocol for VAD implant/HT patients with hemodynamic complications increases nutrient delivery and is associated with reduced ICU LOS and NOBI.

Introduction: Aortic dilation and aneurysm formation is common in patients with a bicuspid aortic valve. Hemodynamics and genetics are both believed to cause dilation, but the relative contributions remain controversial. Further, retrospective studies assess hemodynamics when dilation has already set in. We simulate flows through a tricuspid and three bicuspid aortic valves and study their hemodynamics from a baseline non-dilated aorta. Hypothesis: We hypothesize that the bicuspid phenotype determines flow in the ascending aortic, and high velocity jets will correlate with known regions of dilation in patients with bicuspid valves. Methods: Using methods we recently developed, we constructed a tricuspid valve and bicuspid valves with left/right (LR), right/non (RN) and non/left (NL) coronary cusp fusion. To isolate the effect of leaflet fusion phenotype, we use one healthy, patient-specific aortic geometry throughout. Fluid-structure interaction simulations were performed. Results: Dramatic differences in flow occur between all cases. The tricuspid case shows a relatively uniform flow profile, velocities of ~200cm/s, normalized streamwise momentum 300cm/s, normalized streamwise momentum >2.0, normalized tangential flow strength >1.0, >50% transient reverse flow and sustained pressure gradients >18 mmHg. With LR fusion, the jet hugs the outer curvature of the aorta from the sinotubular junction through the ascending aorta. With RN fusion, the jet moves from the inner to outer curvature of the aorta. Conclusions: With LR and RN cusp fusion, high flow rate jets occur at regions that generally correlate with dilation in prior studies, suggesting that hemodynamic factors alone may be sufficient to cause aortic dilation. This hypothesis should be tested in an animal model.

The left ventricular assist device (LVAD) is an established treatment for select patients with end-stage heart failure. Some patients recovered and are considered for explantation. Assessing recovery involves exercise testing and echo ramping on full and minimal LVAD support. Combined cardiopulmonary exercise testing with simultaneous echo ramping (CPET-R) has not been well studied. Patients were included if they had CPET within the previous 6 months, were clinically stable, and had an INR2.0 on the day of examination. Patients had CPET-R on two occasions within 14 days: (a) with LVAD at therapeutic speed and (b) with LVAD at the lowest speed possible. Six patients were between 29 and 75 years (two female). One patient did not complete a turn-down test due to evidence of ischemia on initial CPET-R subsequently confirmed as a significant coronary artery stenosis on angiography. There were no significant differences in CPET or echo metrics between LVAD speeds. Two patients were explanted due to presumed LV recovery and remained event free for 30 and 47 months, respectively. Serial CPET-R seems safe and feasible for the evaluation of LV and global function and may result in improved clinical decision making for LVAD explantation.

Perioperative bleeding and transfusion cause morbidity and mortality in patients receiving left ventricular assist devices (LVADs). We assessed factors associated with transfusions within 30 days of durable LVAD implantation and the clinical outcomes associated with transfusions. A retrospective cohort study of patients undergoing initial durable LVAD implantation between 2014 and 2016 was performed. Rates of packed red blood cell (PRBC) or other blood product transfusions (platelets or fresh frozen plasma) were assessed. Ordinal multivariable regression analysis was performed to determine factors independently associated with transfusion. Analysis included 156 patients, mean age 54.6 years and 74.4% male, who received a mean of 11.7 units of PRBC and 10.0 units of other products within 30 days. Preimplant mechanical ventilation, dialysis, higher INR, previous sternotomy, higher model for end-stage liver disease score, and lower hemoglobin were associated with increased PRBC transfusion rates. Higher preoperative central venous pressure, mechanical ventilation, concomitant surgical procedures, previous sternotomy, and lower hemoglobin were associated with increased PRBC transfusion rates within 48 hours of implant (adjusted odds ratio [OR] 1.46, P = 0.013 per 5 mm Hg). There were no significant associations with ferritin (adjusted OR 1.00, P = 0.236) or transferrin saturation (adjusted OR 1.17, P = 0.068). Transfusions were associated with an increase in ventilation duration, intensive care unit length of stay, reoperation for bleeding, and all-cause mortality. In patients undergoing LVAD implantation, perioperative blood product exposure is common and associated with increased morbidity and mortality. Elevated central venous pressure and anemia are potentially modifiable factors associated with increased early PRBC transfusion rates.

Background Double lung transplantation (DLT) remains the gold standard for end-stage lung disease. Although DLT was historically performed via clamshell thoracotomy, recently the median sternotomy has emerged as a viable alternative. As the ideal surgical approach remains unclear, the aim of our study was to compare the short- and long-term outcomes of these 2 surgical approaches in DLT. Methods We retrospectively reviewed 192 consecutive adult patients who underwent primary DLT at our institution between 2012 and 2017 (sternotomy, n = 147; clamshell, n = 45). The impact of each surgical approach on post-transplant morbidity was investigated, and the overall survival probability analyses were performed. Results There were no significant differences in recipients’ baseline and donors’ characteristics and bilateral allograft ischemic time. Freedom from primary graft dysfunction, acute rejection episodes, postoperative prolonged ventilator support, tracheostomy, postoperative stroke, and airway dehiscence were comparable between these 2 groups. The duration of cardiopulmonary bypass and operative time were significantly longer in the clamshell thoracotomy group. Postoperative extracorporeal membrane oxygenation usage tended to be more frequent in the clamshell thoracotomy group than the median sternotomy group, despite no statistical significance. Length of hospital and intensive care unit stay were not influenced by the type of incision. There was no significant difference in overall survival between these 2 procedure groups (P = .61, log-rank test). Conclusions The median sternotomy approach in DLT decreases operative time and more importantly leads to a shorter duration of cardiopulmonary bypass. The type of surgical approach did not show any statistically significant impact on adult DLT recipients’ morbidity and survival.

Background: Heart-lung transplantation (HLTx) is an effective treatment for patients with advanced cardiopulmonary failure. However, no large multicenter study has focused on the relationship between donor and recipient risk factors and post-HLTx outcomes. Thus, we investigated this issue using data from the United Network for Organ Sharing database. Methods: All adult patients (age ≥18 years) registered in the United Network for Organ Sharing database who underwent HLTx between 1987 and 2017 were included (n=997). We stratified the cohort by patients who were alive without retransplant at 1 year (n=664) and patients who died or underwent retransplant within 1 year of HLTx (n=333). The primary outcome was the influence of donor and recipient characteristics on 1-year post-HLTx recipient death or retransplant. Kaplan-Meier curves were created to assess overall freedom from death or retransplant. To obtain a better effect estimation on hazard and survival time, the parametric Accelerated Failure Time model was chosen to perform time-to-event modeling analyses. Results: Overall graft survival at 1-year post-HLTx was 66.6%. Of donors, 53% were male, and the mean age was 28.2 years. Univariable analysis showed advanced donor age, recipient male sex, recipient creatinine, recipient history of prior cardiac or lung surgery, recipient extracorporeal membrane oxygenation support, transplant year, and transplant center volume were associated with 1-year post-HLTx death or retransplant. On multivariable analysis, advanced donor age (hazard ratio [HR], 1.017; P =0.0007), recipient male sex (HR, 1.701; P =0.0002), recipient extracorporeal membrane oxygenation support (HR, 4.854; P P P =0.0007) remained as significant predictors of death or retransplant. These predictors were incorporated into an equation capable of estimating the preliminary probability of graft survival at 1-year post-HLTx on the basis of preoperative factors alone. Conclusions: HLTx outcomes may be improved by considering the strong influence of donor age, recipient sex, recipient hemodynamic status, and transplant center volume. Marginal donors and recipients without significant factors contributing to poor post-HLTx outcomes may still be considered for transplantation, potentially with less impact on the risk of early postoperative death or retransplant.

Introduction The risk, cost, and adverse outcomes associated with packed red blood cell (RBC) transfusions in patients with cardiopulmonary failure requiring extracorporeal membrane oxygenation (ECMO) have raised concerns regarding the overutilization of RBC products. It is, therefore, necessary to establish optimal transfusion criteria and protocols for patients supported with ECMO. The goal of this study was to establish specific criteria for RBC transfusions in patients undergoing ECMO. Methods This was a retrospective cohort study conducted at Stanford University Hospital. Data on RBC utilization during the entire hospital stay were obtained, which included patients aged ≥18 years who received ECMO support between 1 January 2017, and 30 June 2020 ( n = 281). The primary outcome was in-hospital mortality. Results Hemoglobin (HGB) levels >10 g/dL before transfusion did not improve in-hospital survival. Therefore, we revised the HGB threshold to ≤10 g/dL to guide transfusion in patients undergoing ECMO. To validate this intervention, we prospectively compared the pre- and post-intervention cohorts for in-hospital mortality. Post-intervention analyses found 100% compliance for all eligible records and a decrease in the requirement for RBC transfusion by 1.2 units per patient without affecting the mortality. Conclusions As an institution-driven value-based approach to guide transfusion in patients undergoing ECMO, we lowered the threshold HGB level. Validation of this revised intervention demonstrated excellent compliance and reduced the need for RBC transfusion while maintaining the clinical outcome. Our findings can help reform value-based healthcare in this cohort while maintaining the outcome.

Background: Progressive aortic valve disease has remained a persistent cause of concern in patients with left ventricular assist devices. Aortic incompetence (AI) is a known predictor of both mortality and readmissions in this patient population and remains a challenging clinical problem. Methods: Ten left ventricular assist device patients with de novo aortic regurgitation and 19 control left ventricular assist device patients were identified. Three-dimensional models of patients’ aortas were created from their computed tomography scans, following which large-scale patient-specific computational fluid dynamics simulations were performed with physiologically accurate boundary conditions using the SimVascular flow solver. Results: The spatial distributions of time-averaged wall shear stress and oscillatory shear index show no significant differences in the aortic root in patients with and without AI (mean difference, 0.67 dyne/cm 2 [95% CI, −0.51 to 1.85]; P =0.23). Oscillatory shear index was also not significantly different between both groups of patients (mean difference, 0.03 [95% CI, −0.07 to 0.019]; P =0.22). The localized wall shear stress on the leaflet tips was significantly higher in the AI group than the non-AI group (1.62 versus 1.35 dyne/cm 2 ; mean difference [95% CI, 0.15–0.39]; P P =0.17). Conclusions: Computational fluid dynamics serves a unique role in studying the hemodynamic features in left ventricular assist device patients where 4-dimensional magnetic resonance imaging remains unfeasible. Contrary to the widely accepted notions of highly disturbed flow, in this study, we demonstrate that the aortic root is a region of relatively stagnant flow. We further identified localized hemodynamic features in the aortic root that challenge our understanding of how AI develops in this patient population.

Background The donor shortage poses a major limitation to use of heart transplantation. Novel strategies such as use of expanded-criteria donors with prolonged ischemia times are being employed to address this need. Recent developments in static hypothermia have allowed for the safe use of cardiac allografts with prolonged ischemic times. Case Report We present the case of a 68-year-old woman with valvular cardiomyopathy refractory to medical therapy who underwent orthotopic heart transplantation with a cardiac allograft exposed to elevated ischemic times. This was achieved through use of the federally approved SherpaPak Cardiac Transport System for transportation of the allograft. This method of static hypothermic organ preservation allowed for a 330-minute total ischemic time, including 283 minutes of storage within the preservation system. The patient tolerated the procedure well and was discharged on postoperative day 10, with excellent graft function and no evidence of rejection 3 months postoperatively. Conclusions Though traditionally ischemic times of 240 minutes or less are recommended for cardiac allografts, we demonstrate, to our knowledge, the longest reported ischemic time of 330 minutes via use of a novel method of static hypothermia for organ preservation. The recipient had an excellent outcome postoperatively, demonstrating the potential for this new organ preservation system to expand the donor pool and improve access and use of heart transplantation.

We aim to use computational fluid dynamics to investigate the hemodynamic conditions that may predispose to false lumen enlargement in this patient population. Nine patients who received surgical repairs of their type-A aortic dissections between 2017–2018 were retrospectively identified. Multiple contrast-enhanced post-operative CT scans were used to construct 3D models of aortic geometries. Computational fluid dynamics simulations of the models were run on a high-performance computing cluster using SimVascular – an open-source simulation package. Physiological pulsatile flow conditions (4.9 L/min) were used at the aortic true lumen inlet, and physiological vascular resistances were applied at the distal vascular ends. Exploratory analyses showed no correlation between rate of false lumen growth and blood pressure, immediate post-op aortic diameter, or the number of fenestrations (p = 0.2). 1-year post-operative CT scans showed a median false lumen growth rate of 4.31 (3.66, 14.67) mm/year Median (Interquartile range) peak systolic, mid-diastolic, and late diastolic velocity magnitudes were 0.90 (1.40); 0.10 (0.16); and 0.06 (0.06) cm/s respectively. Spearman's ranked correlations between fenestration velocity and 1-year false lumen growth rates were found to be statistically significant: Velocity magnitude at peak systolic (p = 0.025; rho = 0.75), mid diastolic (p = 0.025; rho = 0.75) and late diastolic phases of the cardiac cycle (p = 0.006; rho = 0.85). We have shown that false lumen growth is strongly correlated to fenestration flow velocity, which has potential implications for post-operative surveillance and risk stratification.

As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.

Non-invasive and cost effective in nature, the echocardiogram allows for a comprehensive assessment of the cardiac musculature and valves. Despite progressive improvements over the decades, the rich temporally resolved data in echocardiography videos remain underutilized. Human reads of echocardiograms reduce the complex patterns of cardiac wall motion, to a small list of measurements of heart function. Furthermore, all modern echocardiography artificial intelligence (AI) systems are similarly limited by design - automating measurements of the same reductionist metrics rather than utilizing the wealth of data embedded within each echo study. This underutilization is most evident in situations where clinical decision making is guided by subjective assessments of disease acuity, and tools that predict disease onset within clinically actionable timeframes are unavailable. Predicting the likelihood of developing post-operative right ventricular failure (RV failure) in the setting of mechanical circulatory support is one such clinical example. To address this, we developed a novel video AI system trained to predict post-operative right ventricular failure (RV failure), using the full spatiotemporal density of information from pre-operative echocardiography scans. We achieve an AUC of 0.729, specificity of 52% at 80% sensitivity and 46% sensitivity at 80% specificity. Furthermore, we show that our ML system significantly outperforms a team of human experts tasked with predicting RV failure on independent clinical evaluation. Finally, the methods we describe are generalizable to any cardiac clinical decision support application where treatment or patient selection is guided by qualitative echocardiography assessments., 12 pages, 3 figures