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.

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.

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.

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.

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.

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.

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.

Long-term Outcomes of Aortic Valve Replacement With Aortic Homograft: 27 Years Experience.

BACKGROUND: Aortic homografts have been used in young patients requiring aortic valve replacement. Currently, these grafts are generally reserved for aortic valve endocarditis with or without root abscess; however, longitudinal data are lacking. Our aim was to assess the long-term safety and durability of homograft implantation. METHODS: All adult patients undergoing aortic homograft implantation at a single institution from 1992 to 2019 were included. Outcomes of interest included all-cause mortality and aortic valve reoperation, studied over a median follow-up duration of 19 years. RESULTS: In all, 252 patients with a mean age of 49 years were included. Infective endocarditis was the primary indication for surgery in 95 patients (38%). The endocarditis group, compared with the no-endocarditis group, had a higher prevalence of New York Heart Association class III-IV (56% vs 26%), chronic kidney disease (22% vs 1%), prior cardiac surgery (40% vs 10%), and emergency status (7% vs 0%; all P < .001). Operative mortality was higher among endocarditis patients (16% vs 0.6%, P < .001), which persisted after risk adjustment. Among patients who survived to discharge, however, there was no difference in long-term survival between the endocarditis group and no-endocarditis group. Overall survival and freedom from reoperation were 88.3% and 80% at 15 years and 87.2% and 78% at 25 years, respectively. Indications for reoperation included structural valve deterioration (83%), endocarditis (12%), and mitral valve disease (5%). Reoperative mortality occurred in 2 patients (4.9%). CONCLUSIONS: Aortic homografts are associated with good long-term survival and admissible freedom from reoperation. Operative mortality is high among patients with endocarditis; however, for those who survive to discharge, long-term survival and durability are the same as for patients without endocarditis.

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.