Sex differences in gene expression in response to ischemia in the human left ventricular myocardium.

Sex differences exist in the prevalence, presentation and outcomes of ischemic heart disease (IHD). Females have higher risk of heart failure post-myocardial infarction relative to males and are two to three times more likely to die after coronary artery bypass grafting surgery. We examined sex differences in human myocardial gene expression in response to ischemia. Left ventricular biopsies from 68 male/46 female patients undergoing aortic valve replacement surgery were obtained at baseline and after a median 74 min of cold cardioplegic arrest/ischemia. Transcriptomes were quantified by RNA-sequencing. Cell-type enrichment analysis was used to estimate the identity and relative proportions of different cell types in each sample. A sex-specific response to ischemia was observed for 271 genes. Notably, the expression FAM5C, PLA2G4E and CYP1A1 showed an increased expression in females compared to males due to ischemia and DIO3, MT1G and CMA1 showed a decreased expression in females compared to males due to ischemia. Functional annotation analysis revealed sex-specific modulation of the oxytocin signaling pathway and common pathway of fibrin clot formation. Expression quantitative trait locus (eQTL) analysis identified variant-by-sex interaction eQTLs, indicative of sex differences in the genotypic effects on gene expression. Cell-type enrichment analysis showed sex-bias in proportion of specific cell types. Common lymphoid progenitor cells and M2 macrophages were found to increase in female samples from pre- to post-ischemia, but no change was observed in male samples. These differences in response to myocardial ischemia provide insight into the sexual dimorphism of IHD and may aid in the development of sex-specific therapies that reduce myocardial injury.

Incidence and predictors of postoperative ischemic stroke after coronary artery bypass grafting.

BACKGROUND: Data on the incidence and outcomes of ischemic stroke in patients undergoing coronary artery bypass grafting (CABG) in the current era are limited. The goal of this study was to examine contemporary trends, predictors, and outcomes of ischemic stroke following CABG in a large nationally representative database over a 12-year-period. METHODS: The National Inpatient Sample was used to identify all adult (≥18 years) patients who underwent CABG between 2004 and 2015. The incidence and predictors of post-CABG ischemic stroke were assessed and in-hospital outcomes of patients with and without post-CABG stroke were compared. RESULTS: Out of 2 569 597 CABG operations, ischemic stroke occurred in 47 279 (1.8%) patients, with a rising incidence from 2004 (1.2%) to 2015 (2.3%) (P < .001). Patient risk profiles increased over time in both cohorts, with higher Charlson comorbidity scores observed amongst stroke patients. Stroke was independently associated with higher rates of in-hospital mortality (3-fold), longer lengths of hospital stay (~6 more days), and higher total hospitalisation cost (~$80 000 more). Age ≥60 years and female sex (OR 1.33, 95% CI 1.31-1.36) were the strongest predictors of stroke (both P < .001). Further, on-pump CABG was not an independent predictor of stroke (P = .784). CONCLUSION: In this nationally representative study we have shown that the rates of postoperative stroke complications following CABG have increased over time to commensurate with a parallel increase in overall baseline patient risks. Given the adverse impact of stroke on in-hospital morbidity and mortality after CABG, further studies are warranted to systematically delineate factors contributing to this striking trend.

Wound complications and 30-day readmissions after single and bilateral internal mammary grafting: Analysis of the Nationwide Readmissions Database.

BACKGROUND: This study compares the postoperative outcomes, 30-day readmission rates, and incidence of sternal wound infection-related readmissions between patients receiving bilateral internal mammary arteries (BIMA) and single internal mammary artery (SIMA) grafting during coronary artery bypass graft (CABG) surgery. METHODS: We utilized the weighted 2013-2014 National Readmission Database claims to identify all US adult patients who underwent CABG utilizing SIMA (n = 279,891) or BIMA (n = 11,651). Thirty-day overall and wound-related readmissions, in-hospital outcomes, costs, lengths of stay (LOS) at readmissions were compared between the two groups. Predictors of 30-day readmission were assessed using multivariable Cox proportional hazards analysis. RESULTS: After propensity matching (n = 10,339 pairs), there were no significant differences between the two groups during the index hospitalization, except for higher total hospital costs in the BIMA group (p = .02). The incidence of wound infections was also comparable between BIMA and SIMA (1.1% vs. 1.2%; p = .50). At 30-days, the overall readmission rate was elevated in SIMA patients (9.5% vs. 8.8%; p < .01), primarily impacted by cardiovascular causes. While the proportion of 30-day readmissions due to infections was significantly higher among BIMA versus SIMA patients (20.4% vs. 15.9%; p < .01), wound infections during the index hospitalization did not predict all-cause 30-day readmission among BIMA patients (p = .24) in the risk-adjusted analysis. Among the readmitted patients, LOS (6.4 vs. 6.2 days), costs ($14,440 vs. $16,461), and in-hospital mortality (2.4% vs. 1.7%) were comparable between the two groups (all p > .05). CONCLUSIONS: BIMA grafting is not an independent predictor of all-cause 30-day readmissions. Cardiovascular causes remain the primary driver of 30-day readmissions among SIMA and BIMA patients after CABG.

Novel and Annotated Long Noncoding RNAs Associated with Ischemia in the Human Heart.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart. METHODS AND RESULTS: RNA sequencing data gathered from 81 paired left ventricle samples from patients undergoing cardiopulmonary bypass was collected before and after a period of ischemia. Novel lncRNAs were validated with Oxford Nanopore Technologies long-read sequencing. Gene modules associated with an early ischemic response were identified and the subcellular location of selected lncRNAs was determined with RNAscope. A total of 2446 mRNAs, 270 annotated lncRNAs and one novel lncRNA differed in response to ischemia (adjusted p < 0.001, absolute fold change >1.2). The novel lncRNA belonged to a gene module of highly correlated genes that also included 39 annotated lncRNAs. This module associated with ischemia (Pearson correlation coefficient = -0.69, p = 1 × 10-23) and activation of cell death pathways (p < 6 × 10-9). A further nine novel cardiac lncRNAs were identified, of which, one overlapped five cis-eQTL eSNPs for the gene RWD Domain-Containing Sumoylation Enhancer (RWDD3) and was itself correlated with RWDD3 expression (Pearson correlation coefficient -0.2, p = 0.002). CONCLUSION: We have identified 10 novel lncRNAs, one of which was associated with myocardial ischemia and may have potential as a novel therapeutic target or early marker for myocardial dysfunction.

Myocardial preservation methods in isolated minimal invasive mitral valve surgery: Society of Thoracic Surgeons (STS) database outcomes.

OBJECTIVE: Minimal invasive mitral valve surgery (MIMVS) has become a commonly used approach for mitral valve surgery. Several techniques of myocardial preservation were described in patients undergoing MIMVS. We aim to evaluate preservation technique and short term outcomes. METHODS: A retrospective analysis of patients who underwent isolated MIMVS and were included in the Society of Thoracic Surgeons (STS) database. RESULTS: The final cohort included 4976 patients. Mean age was 63.1 years (SD, 12.5) and 42.6% were females. Antegrade delivery method (71.3% of the patients) was the most common, follow by antergrade/retrograde (19.9%). Blood, crystalloid solution, and combination of blood-crystalloid were used in 62.4%, 13.2%, and 13.7%, respectively. In multivariate analysis, cardioplegia technique was associated with mortality (P = .011), pleural effusion (P = .045), and length of ICU stay (P < .001). Antegrade-crystalloid (OR, 3.37; 95%CI, 1.70-6.68) and antegrade/retrograde-blood/crystalloid (OR, 3.28; 95%CI, 1.15-9.38) were associated with increased risk for mortality compared with antegrade-blood cardioplegia. Data on postoperative ejection fraction (EF), CPK-MB, and Troponin was available only in 30%, 9%, and 5% of the patients, respectively, and were not included in the analysis. CONCLUSIONS: Ante-grade-blood was the most common preservation technique in MIMVS. Ante-grade-crystalloid and ante-grade/retrograde-blood/crystalloid are associated with increased risk for mortality. The results suggest that using crystalloid solutions for cardioplegia should be carefully considered. The STS database as a source for MIMVS outcome analysis is lacking, both in detailed specification of different surgical technique aspects, and in actual data collection of already existing categories.

Transcatheter vs surgical aortic valve replacement in patients with interstitial lung disease.

BACKGROUND: Patients with underlying interstitial lung disease (ILD) who undergo cardiac surgery are at high risk of postoperative pulmonary complications. It remains unclear if transcatheter aortic valve replacement (TAVR) offers any benefit over surgical aortic valve replacement (SAVR) in ILD patients with severe aortic stenosis. METHODS: All adult patients with a diagnosis of ILD who underwent either a TAVR or isolated SAVR between January 2002 and December 2017 were retrospectively reviewed. Operative mortality, 30-day readmissions, and adjusted 1-year survival were compared between the two cohorts. RESULTS: The overall cohort included 52 TAVR and 74 SAVR patients. While TAVR patients were significantly older (77.2 vs 72.9 years) with higher Society of Thoracic Surgeons predicted risk of mortality (STS-PROM) scores compared with SAVR patients (6.29 vs 4.49; all P < .02), operative mortality was similar (5.8% vs 4.1%; P = .45). Rates of postoperative stroke, permanent pacemaker implantation, reintubation, and 30-day readmissions did not differ between the two groups (all P > .46). However, TAVR was associated with significantly shorter hospital and intensive care unit (ICU) length of stay, shorter ventilation times, and less requirement for ICU admission (all P < .05). Thirty-day readmissions and adjusted 1-year survival were also similar between the two groups (hazard ratio for TAVR vs SAVR = 1.34; 95% CI: 0.7-2.6). CONCLUSIONS: Among ILD patients with symptomatic aortic stenosis, TAVR was associated with comparable operative and risk-adjusted 1-year survival to SAVR. TAVR patients also had shorter ventilator times, ICU and hospital stay despite being at higher risk. Together, our findings suggest that TAVR may be a better option in this unique cohort.

Surgical pulmonary embolectomy and catheter-directed thrombolysis for treatment of submassive pulmonary embolism.

BACKGROUND: Acute pulmonary embolism (PE) with preserved hemodynamics but right ventricular dysfunction, classified as submassive PE, carries a high risk of mortality. We report the results for patients who did not qualify for medical therapy and required treatment of submassive PE with surgical pulmonary embolectomy and catheter-directed thrombolysis (CDT). METHODS: Between October 1999 and May 2015, 133 submassive PE patients underwent treatment with pulmonary embolectomy (71) and CDT (62). A multidisciplinary PE response team helped to determine the most appropriate treatment strategy on a case-by-case basis. The EkoSonic ultrasound-facilitated thrombolysis system (EKOS) was used for CDT, which was introduced in 2010. RESULTS: The mean age of submassive PE patients was 57.3 years, which included 36.8% females. PE risk factors included previous deep venous thrombosis (46.6%), immobility (36.1%), recent surgery (30.8%), and cancer (22.6%), P < 0.05. The most common indication for advanced treatment was right ventricular strain (42.9%), P = 0.03. The frequency of surgical pulmonary embolectomy remained stable even after incorporating the EKOS procedure into our treatment algorithm, with statistically similar operative mortality. Bleeding was observed in six CDT patients and one pulmonary embolectomy patient (P < 0.05). Follow-up echocardiography was available for 61% of the overall cohort, of whom 76.5% had no residual moderate or severe right ventricular dysfunction. CONCLUSIONS: Pulmonary embolectomy and CDT are important contemporary advanced treatment options for selected high-risk patients with submassive PE, who do not qualify for medical therapy.

Joint analysis of left ventricular expression and circulating plasma levels of Omentin after myocardial ischemia.

BACKGROUND: Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia. METHODS: A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled in this study. Plasma and left ventricular biopsy samples were taken at the beginning of cardiopulmonary bypass and after an average of 82 min of ischemic cross clamp time. The localization of ITLN1 in epicardial adipose tissue (EAT) was also further characterized with immunoassays and cell fate transition studies. RESULTS: mRNA expression of ITLN1 decreases in left ventricular tissue after acute ischemia in human patients (mean difference 280.48, p = 0.001) whereas plasma protein levels of ITLN1 increase (mean difference 5.24, p < 0.001). Immunohistochemistry localized ITLN1 to the mesothelium or visceral pericardium of EAT. Epithelial to mesenchymal transition in mesothelial cells leads to a downregulation of ITLN1 expression. CONCLUSIONS: Myocardial injury leads to a decrease in ITLN1 expression in the heart and a corresponding increase in plasma levels. These changes may in part be due to an epithelial to mesenchymal transition of the cells that express ITLN1 following ischemia. Trial Registration Clinicaltrials.gov ID: NCT00985049.

Integrated microRNA and mRNA responses to acute human left ventricular ischemia.

MicroRNAs (miRNAs) play a significant role in ischemic heart disease. Animal models of left ventricular (LV) ischemia demonstrate a unique miRNA profile; however, these models have limitations in describing human disease. In this study, we performed next-generation miRNA and mRNA sequencing on LV tissue from nine patients undergoing cardiac surgery with cardiopulmonary bypass and cardioplegic arrest. Samples were obtained immediately after aortic cross clamping (baseline) and before aortic cross clamp removal (postischemic). Of 1,237 identified miRNAs, 21 were differentially expressed between baseline and postischemic LV samples including the upregulated miRNAs miR-339-5p and miR-483-3p and the downregulated miRNA miR-139-5p. Target prediction analysis of these miRNAs was integrated with mRNA expression from the same LV samples to identify anticorrelated miRNA-mRNA pairs. Gene enrichment studies of candidate mRNA targets demonstrated an association with cardiovascular disease, cell death, and metabolism. Therapeutics that intervene on these miRNAs and their downstream targets may lead to novel mechanisms of mitigating the damage caused by ischemic insults on the human heart.

Using next-generation RNA sequencing to examine ischemic changes induced by cold blood cardioplegia on the human left ventricular myocardium transcriptome.

BACKGROUND: The exact mechanisms that underlie the pathological processes of myocardial ischemia in humans are unclear. Cardiopulmonary bypass with cardioplegic arrest allows the authors to examine the whole transcriptional profile of human left ventricular myocardium at baseline and after exposure to cold cardioplegia-induced ischemia as a human ischemia model. METHODS: The authors obtained biopsies from 45 patients undergoing aortic valve replacement surgery at baseline and after an average of 79 min of cold cardioplegic arrest. Samples were RNA sequenced and analyzed with the Partek Genomics Suite (Partek Inc., St. Louis, MO) for differential expression. Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, CA) and Biobase ExPlain (Biobase GmbH, Wolfenbuettel, Germany) systems were used for functional and pathway analyses. RESULTS: Of the 4,098 genes with a mean expression value greater than 5, 90% were down-regulated and 9.1% were up-regulated. Of those, 1,241 were significantly differentially expressed. Gene ontology analysis revealed significant down-regulation in immune inflammatory response and complement activation categories and highly consistent was the down-regulation of intelectin 1, proteoglycan, and secretory leukocyte peptidase inhibitor. Up-regulated genes of interest were FBJ murine osteosarcoma viral oncogene homolog and the hemoglobin genes hemoglobin α1 (HBA1) and hemoglobin ß. In addition, analysis of transcription factor-binding sites revealed interesting targets in factors regulating reactive oxygen species production, apoptosis, immunity, cytokine production, and inflammatory response. CONCLUSIONS: The authors have shown that the human left ventricle exhibits significant changes in gene expression in response to cold cardioplegia-induced ischemia during cardiopulmonary bypass, which provides great insight into the pathophysiology of ventricular ischemia, and thus, may help guide efforts to reduce myocardial damage during surgery.

The impact of a minimally invasive approach on reoperative aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: The advantages of minimally invasive aortic valve replacement (AVR) are well documented, but whether the benefits extend to subsequent reoperative aortic valve surgery and beyond is unknown. The study aim was to compare in-hospital outcomes and long-term survival following reoperative AVR between patients who had previous undergone either minimally invasive AVR (mini-AVR) or full sternotomy AVR (sAVR). METHODS: All reoperative, isolated AVRs performed between July 1997 and September 2013 at the authors' institution, with or without non-complex aortic surgery, were identified. Patients were excluded if AVR was not isolated, had occurred prior to July 1997, or if the initial AVR was performed before the patient was aged 18 years. All reoperations were performed through a full sternotomy. The main outcomes of interest were operative results and long-term survival. RESULTS: A total of 101 patients was identified, of which 34 had undergone previous mini-AVR and 67 previous sAVR. The time from the previous AVR was similar in both groups (median 7.6 years overall). Of previous valve implants, 57 were bioprostheses and 44 mechanical; structural valve degeneration was the most common indication for surgery (43/101). Mini-AVR and sAVR patients did not differ significantly with regards to patient demographics and preoperative risk factors. A strong trend towards shorter skin-to-skin operative times was observed for mini-AVR (330 min versus 356 min; p = 0.053). Postoperatively, mini-AVR patients had a shorter ventilation time (5.7 h versus 8.4 h; p = 0.005), intensive care unit stay (37 h versus 63 h; p ≤ 0.001) and hospital length of stay (6.5 days versus 8.0 days; p = 0.038). There was one operative mortality in the sAVR, and none in the mini-AVR group. Mid-term survival at one and five years for mini-AVR was 100% (95% CI 100-100) and 100% (95% CI 100-100), and for sAVR was 93.9% (95% CI 88.2-99.7) and 85.0% (95% CI 75.1-94.9), respectively (p = 0.041). CONCLUSION: Mini-AVR confers benefits during subsequent reoperative AVR, with shorter hospital stays and improved long-term survival. These findings suggest that mini-AVR should be considered for patients at risk for aortic valve reoperation, and describes a previously unreported advantage of this well-established technique.

Sex differences in the prevalence of diastolic dysfunction in cardiac surgical patients.

OBJECTIVES: The mortality from diastolic dysfunction is approximately 9% to 28%. In patients with ischemic heart disease, female sex and advanced age are associated with increases in ventricular diastolic stiffness. Clinical studies have found higher rates of diastolic dysfunction in women, despite higher ejection fractions, than in men post-myocardial infarction. Therefore, we hypothesized that female patients undergoing cardiac surgery have higher degrees of diastolic dysfunction and experience more adverse outcomes, such as prolonged hospitalization. METHODS: We prospectively enrolled 153 patients undergoing cardiac surgery. Diastolic function was assessed using early transmitral velocity (E) and early diastolic lateral mitral annular tissue velocity (e'). Left ventricular diastolic dysfunction was defined as binary and a continuous outcome (E/e'). RESULTS: Females were more likely than males to present with higher E/e' (11.5 vs. 7.9, p = 0.001) and higher left ventricular diastolic dysfunction (71% vs. 36%, p < 0.001). The addition of sex to the model for left ventricular diastolic dysfunction was significant. The relationship between sex and E/e' ratio showed the biggest difference between males and females in the 56-72-year-old age brackets, where women were much more likely to have a higher E/e' than males. CONCLUSIONS: We identified a significantly higher prevalence of diastolic dysfunction among females presenting for elective cardiac surgery compared to males. This finding is more pronounced with age. Additionally, we found that female sex is at higher risk of prolonged ICU and hospital length of stay.

The Use of Lidocaine Containing Cardioplegia in Surgery for Adult Acquired Heart Disease.

BACKGROUND: Del Nido cardioplegia, a crystalloid-based solution with lidocaine as a key element, is given as a single dose and has been used successfully in congenital cardiac surgery. HYPOTHESIS: We retrospectively compared a lidocaine containing "modified del Nido" solution with our standard whole blood cardioplegia to investigate its safety and efficacy in adult cardiac surgery. METHODS: From June 1, 2013 to December 30, 2013, we used a single dose of lidocaine containing cardioplegia (LC group) in 92 consecutive operations. Propensity matching analysis was undertaken to compare the outcomes of such patients with those who underwent their surgery by the same surgeon using standard whole blood cardioplegia (WB group), n = 396. Propensity score matching yielded 79 pairs of patients. RESULTS: After propensity matching, LC and WB groups were similar in baseline operative characteristics including cross-clamp time (LC: 65 minutes [range 54 to 89] vs. WB: 70 minutes [54 to 86], p = 0.993). Postoperative outcomes were similar including inotropic requirements (30.4% [24/72] vs. 25.3% [20/72], p < 0.60), median ventilation time (4.7 hours vs. 5.3, p < 0.74) and median length of stay was seven days for both groups (p < 0.82). Despite higher median postoperative, 24-hour CK-MB levels LC group (LC:22.3 ng/ml, range [15.6 to 40.3] vs. WB:18.4 ng/ml [13.9 to 28.2], p = 0.040), operative and one-year mortality were comparable among study groups (both p > 0.798). CONCLUSIONS: Lidocaine containing cardioplegia appears to be safe in adults undergoing cardiac procedure when administered for the first 60 minutes of aortic cross clamping. Higher CK-MB levels did not translate into adverse clinical outcomes.

The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL114-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.

Current trends in mitral valve repair techniques in North America.

BACKGROUND AND AIM OF THE STUDY: The current trends in the surgical technique of mitral valve repair (MVR) among North American medical centers participating in the Sorin Valve Repair Registry are described. METHODS: A total of 2,314 MVR procedures was performed and documented between 2003 and 2009 at 89 North American medical centers. Surgical procedure characteristics on all mitral valve annuloplasty and valve reconstructions were collected by participating surgeons, and documented in the registry. RESULTS: Early in the reporting period (between 2003 and 2007), posterior leaflet resection comprised 60% of all MVR procedures, but the percentage declined systematically through the years 2008 (56.1%) and 2009 (50.4%). A decrease over time was also observed in the frequency of sliding valvuloplasty procedures (from -30% in 2003 to 4.0% in 2009). Proportions of chordal repair techniques tended to increase towards the end of the reporting period, from a low of 15% in 2003 to a peak of 32% in 2008. CONCLUSION: This report documents important trends in current MVR techniques among a representative cohort of surgical centers across North America. The data obtained were consistent with a practical shift from the conventional surgical MVR techniques to methods that allow a greater leaflet preservation--and thus less resection--over the latter half of the reporting period.

The impact of hospital size on national trends and outcomes in isolated open proximal aortic surgery.

OBJECTIVE: To determine the impact of hospital size on national trend estimates of isolated open proximal aortic surgery for benchmarking hospital performance. METHODS: Patients age >18 years who underwent isolated open proximal aortic surgery for aneurysm and dissection from 2002 to 2014 were identified using the National Inpatient Sample. Concomitant valvular, vessel revascularization, re-do procedures, endovascular, and surgery for descending and thoracoabdominal aorta were excluded. Discharges were stratified by hospital size and analyzed using trend, multivariable regression, propensity-score matching analysis. RESULTS: Over a 13-year period, 53,657 isolated open proximal aortic operations were performed nationally. Although the total number of operations/year increased (∼2.9%/year increase) and overall in-hospital mortality decreased (∼4%/year; both P < .001 for trend), these did not differ by hospital size (P > .05). Large hospitals treated more sicker and older patients but had shorter length of stay and lower hospital costs (both P < .001). Even after propensity-score matching, large hospital continued to demonstrate superior in-hospital outcomes, although only statistically for major in-hospital cardiac complications compared with non-large hospitals. In our subgroup analysis of dissection versus non-dissection cohort, in-hospital mortality trends decreased only in the non-dissection cohort (P < .01) versus dissection cohort (P = .39), driven primarily by the impact of large hospitals (P < .01). CONCLUSIONS: This study demonstrates increasing volume and improving outcomes of isolated open proximal aortic surgeries nationally over the last decade regardless of hospital bed size. Moreover, the resource allocation of sicker patients to larger hospital resulted shorter length of stay and hospital costs, while maintaining similar operative mortality to small- and medium-sized hospitals.

Surgical Aortic Valve Replacement Outcomes in Non-Transcatheter Aortic Valve Replacement Centers: Implications for Tier-Based Systems of Care.

BACKGROUND: With wide expansion of transcatheter aortic valve replacement (TAVR) and dissemination of multidisciplinary-based approaches to care, societies are discussing the implementation of a tier system to valve centers. This study explores the impact of tier-based systems of care on surgical aortic valve replacement (SAVR) outcomes at institutions that perform SAVR only. METHODS: Medicare beneficiaries undergoing SAVR procedures from 2012 to 2015 were included. The SAVR hospitals were stratified into either tier A, valve centers with a TAVR program; or tier B, valve centers without a TAVR program. Adjusted survival, assessed by multivariable Cox regression, controlled for program type and patient risk profile. Time-dependent analysis accounted for hospitals that initiated a TAVR program during the study period. RESULTS: Overall, there were 562 tier A and 485 tier B SAVR hospitals. Tier A hospitals had significantly higher comorbidity burden compared with tier B hospitals (all P < .05) but had significantly lower rates of 30-day mortality (3.2% vs 4.1%) and 1-year mortality (8.1% vs 9.4%; both P < .05). After risk stratification, tier B hospitals had significantly worse 30-day mortality compared with tier A hospitals for all patient risk-profiles, except for the low-risk patients (P < .01). These findings persisted in the time-dependent analysis. Adjusted midterm survival was higher in tier A vs tier B hospitals. CONCLUSIONS: Low-risk patients can safely undergo SAVR in both tier level hospitals without compromising outcomes. Establishment of quality of care measures, especially in the SAVR-only hospitals, remains paramount and should be closely integrated when designing tier-based systems for aortic valve replacement care.

Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm.

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

Distinct Stress-Dependent Signatures of Cellular and Extracellular tRNA-Derived Small RNAs.

The cellular response to stress is an important determinant of disease pathogenesis. Uncovering the molecular fingerprints of distinct stress responses may identify novel biomarkers and key signaling pathways for different diseases. Emerging evidence shows that transfer RNA-derived small RNAs (tDRs) play pivotal roles in stress responses. However, RNA modifications present on tDRs are barriers to accurately quantifying tDRs using traditional small RNA sequencing. Here, AlkB-facilitated methylation sequencing is used to generate a comprehensive landscape of cellular and extracellular tDR abundances in various cell types during different stress responses. Extracellular tDRs are found to have distinct fragmentation signatures from intracellular tDRs and these tDR signatures are better indicators of different stress responses than miRNAs. These distinct extracellular tDR fragmentation patterns and signatures are also observed in plasma from patients on cardiopulmonary bypass. It is additionally demonstrated that angiogenin and RNASE1 are themselves regulated by stressors and contribute to the stress-modulated abundance of sub-populations of cellular and extracellular tDRs. Finally, a sub-population of extracellular tDRs is identified for which AGO2 appears to be required for their expression. Together, these findings provide a detailed profile of stress-responsive tDRs and provide insight about tDR biogenesis and stability in response to cellular stressors.

Enhanced Recovery After Cardiac Surgery: A Propensity-Matched Analysis.

Enhanced Recovery After Surgery (ERAS) pathways have improved clinical outcomes, cost-effectiveness, and patient satisfaction across multiple non-cardiac surgical specialties. Since the adaptation of ERAS in cardiac surgery is rapidly increasing yet still evolving, herein, we demonstrate early results of our implementation of ERAS cardiac guidelines. We retrospectively reviewed all patients who were managed with our institutional ERAS Cardiac Surgery guidelines between 5/2018 and 6/2019(N = 102). Postoperative primary outcomes (total ventilation times(hours), intensive-care unit(ICU) stay, and postoperative hospital length of stay (LOS)) were compared to 1:1 propensity matched controls from the pre ERAS era between January 2017 and March 2019. A total of 76 propensity-matched pairs were identified. Compared to the matched controls, ERAS patients had significantly shorter median ventilation times(3.5 vs. 5.3 hours, p = .01), ICU stays(median 28 vs 48 hours, p=.005) and postoperative hospital LOS (median 5 vs. 6 days, p = .03). There were no operative mortalities and no significant differences in 30-day readmission rates. There were also no significant differences in post-operative stroke, acute kidney injury, atrial fibrillation, and reoperation rates for bleeding. Two-year survival was also not statistically different between the two cohorts (p = .22). Our initial experience with implementation of ERAS protocols in cardiac surgery appear to demonstrate that these protocols are associated with shorter ventilation times, ICU stay, and hospital LOS without compromising patient outcomes. While these results are promising yet preliminary, further studies are warranted to demonstrate whether ERAS algorithms in cardiac surgery can consistently expedite postoperative recovery and improve outcomes.