cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism in vitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use in vivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth in vivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell-dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

Transforming Growth Factor-ß Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy.

BACKGROUND & AIMS: Transforming growth factor-b (TGFb) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating CD8 T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFb inhibition has shown limited efficacy against pancreatic cancer in mice or humans. METHODS: We evaluated the TGFß-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment. RESULTS: Blockade of TGFß with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFß blockade was preserved in CD8-depleted or recombination activating gene 2 (RAG2-/-) mice. TGFß blockade decreased total α-smooth muscle actin-positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex vivo revealed that tumor cells treated with TGFß blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFß blockade increased chemotherapy-induced cell death in vivo. CONCLUSIONS: TGFß regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFß blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.

Elevated myocardial extracellular volume fraction is associated with the development of conduction pathway defects following transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become an established method of aortic stenosis treatment but suffers from the risk of heart block and pacemaker requirement. Risk stratification for patients who may develop heart block remains imperfect. Simultaneously, myocardial fibrosis as measured by cardiac magnetic resonance imaging (CMR) has been demonstrated as a prognostic indicator of ventricular recovery and mortality following TAVR. However, the association of CMR-based measures of myocardial fibrosis with post-TAVR conduction disturbances has not yet been explored. AIMS: We evaluated whether myocardial fibrosis, as measured by late gadolinium enhancement and extracellular volume (ECV) from CMR would be associated with new conduction abnormalities following TAVR. METHODS: One hundred seventy patients who underwent CMR within 2 months before TAVR were retrospectively reviewed. Septal late gadolinium enhancement (LGE) and ECV measurements were made as surrogates for replacement and interstitial fibrosis respectively. New conduction abnormalities were defined by the presence of transient or permanent atrioventricular block, new bundle branch blocks, and need for permanent pacemaker. Association of myocardial fibrosis and new conduction derangements were tested using receiver operator curve (ROC) and regression analysis in patients with and without pre-existing conduction issues. RESULTS: Forty-six (27.1%) patients developed post-TAVR conduction deficits. ECV was significantly higher among patients who experienced new conduction defects (26.2 ± 3.45% vs. 24.7% ± 4.15%, p value: 0.020). A greater fraction of patients that had new conduction defects had an elevated ECV of ≥26% (54.3% vs. 36.3%, p value: 0.026). ECV ≥ 26% was independently associated with the development of new conduction defects (odds ratio [OR]: 2.364, p value: 0.030). ROC analysis revealed a significant association of ECV with new conduction defects with an area under the receiver operating characteristic curve (AUC) of 0.632 (95% confidence interval: 0.555-0.705, p value: 0.005). The combination of prior right bundle branch block (RBBB) and ECV revealed a greater AUC of 0.779 (0.709-0.839, p value: <0.001) than RBBB alone (Delong p value: 0.049). No association of LGE/ECV with new conduction defects was observed among patients with pre-existing conduction disease. Among patients without baseline conduction disease, ECV was independently associated with the development of new conduction deficits (OR: 3.685, p value: 0.008). CONCLUSION: The present study explored the association of myocardial fibrosis, as measured by LGE and ECV with conduction deficits post-TAVR. Our results demonstrate an association of ECV, and thereby interstitial myocardial fibrosis, with new conduction derangement post-TAVR and introduce ECV as a potentially new risk stratification tool to identify patients at higher risk for needing post-TAVR surveillance and/or permanent pacemaker.

Clinical impact of right ventricular pacing burden in patients with post-transcatheter aortic valve replacement permanent pacemaker implantation.

AIMS: Patients who undergo permanent pacemaker (PPM) implantation after transcatheter aortic valve replacement (TAVR) have a worse outcome. The aim of this study was to identify risk factors of worse outcomes in patients with post-TAVR PPM implantation. METHODS AND RESULTS: This is a single-centre, retrospective study of consecutive patients who underwent post-TAVR PPM implantation from 11 March 2011 to 9 November 2019. Clinical outcomes were evaluated by landmark analysis with cut-off at 1 year after the PPM implantation. Of the 1389 patients underwent TAVR during the study duration and a total of 110 patients were included in the final analysis. Right ventricular pacing burden (RVPB) ≥ 30% at 1 year was associated with a higher likelihood of heart failure (HF) readmission [adjusted hazard ratio (aHR): 6.333; 95% confidence interval [CI]: 1.417-28.311; P = 0.016] and composite endpoint of overall death and/or HF (aHR: 2.453; 95% CI: 1.040-5.786; P = 0.040). The RVPB ≥30% at 1 year was associated with higher atrial fibrillation burden (24.1 ± 40.6% vs. 1.2 ± 5.3%; P = 0.013) and a decrease in left ventricular ejection fraction (-5.0 ± 9.8% vs. + 1.1 ± 7.9%; P = 0.005). The predicting factors of the RVPB ≥30% at 1 year were the presence of RVPB ≥40% at 1 month and the valve implantation depth measured from non-coronary cusp ≥4.0 mm (aHR: 57.808; 95% CI: 12.489-267.584; P < 0.001 and aHR: 6.817; 95% CI: 1.829-25.402; P = 0.004). CONCLUSIONS: The RVPB ≥30% at 1 year was associated with worse outcomes. Clinical benefit of minimal RV pacing algorithms and biventricular pacing needs to be investigated.

Transcatheter Mitral Valve Replacement After Surgical Repair or Replacement: Comprehensive Midterm Evaluation of Valve-in-Valve and Valve-in-Ring Implantation From the VIVID Registry.

BACKGROUND: Mitral valve-in-valve (ViV) and valve-in-ring (ViR) are alternatives to surgical reoperation in patients with recurrent mitral valve failure after previous surgical valve repair or replacement. Our aim was to perform a large-scale analysis examining midterm outcomes after mitral ViV and ViR. METHODS: Patients undergoing mitral ViV and ViR were enrolled in the Valve-in-Valve International Data Registry. Cases were performed between March 2006 and March 2020. Clinical endpoints are reported according to the Mitral Valve Academic Research Consortium (MVARC) definitions. Significant residual mitral stenosis (MS) was defined as mean gradient ≥10 mm Hg and significant residual mitral regurgitation (MR) as ≥ moderate. RESULTS: A total of 1079 patients (857 ViV, 222 ViR; mean age 73.5±12.5 years; 40.8% male) from 90 centers were included. Median STS-PROM score 8.6%; median clinical follow-up 492 days (interquartile range, 76-996); median echocardiographic follow-up for patients that survived 1 year was 772.5 days (interquartile range, 510-1211.75). Four-year Kaplan-Meier survival rate was 62.5% in ViV versus 49.5% for ViR (P<0.001). Mean gradient across the mitral valve postprocedure was 5.7±2.8 mm Hg (≥5 mm Hg; 61.4% of patients). Significant residual MS occurred in 8.2% of the ViV and 12.0% of the ViR patients (P=0.09). Significant residual MR was more common in ViR patients (16.6% versus 3.1%; P<0.001) and was associated with lower survival at 4 years (35.1% versus 61.6%; P=0.02). The rates of Mitral Valve Academic Research Consortium-defined device success were low for both procedures (39.4% total; 32.0% ViR versus 41.3% ViV; P=0.01), mostly related to having postprocedural mean gradient ≥5 mm Hg. Correlates for residual MS were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual MR was ViR. Significant residual MS (subhazard ratio, 4.67; 95% CI, 1.74-12.56; P=0.002) and significant residual MR (subhazard ratio, 7.88; 95% CI, 2.88-21.53; P<0.001) were both independently associated with repeat mitral valve replacement. CONCLUSIONS: Significant residual MS and/or MR were not infrequent after mitral ViV and ViR procedures and were both associated with a need for repeat valve replacement. Strategies to improve postprocedural hemodynamics in mitral ViV and ViR should be further explored.

Interleukin-1 (IL-1) and the inflammasome in cancer.

Numerous preclinical and clinical studies have demonstrated the significant contribution of inflammation to the development and progression of various types of cancer. Inflammation in the tumor microenvironment mediates complex interactions between innate immunity, adaptive immunity, microbiomes and stroma, and ultimately alters the overall fitness of tumor cells at multiple stages of carcinogenesis. Malignancies are known to arise in areas of chronic inflammation and inflammation in the tumor microenvironment (often called tumor-promoting inflammation) is believed to allow cancer cells to evade immunosurveillance while promoting genetic instability, survival and progression. Among the strongest data suggesting a causal role for inflammation in cancer come from the recent CANTOS trial which demonstrated that interleukin-1ß (IL-1ß) inhibition with canakinumab leads to a significant, dose-dependent decrease in incident lung cancer. This observation has launched a series of additional clinical studies to understand the role of IL-1ß and the inflammasome in cancer, and the clinical utility of IL-1ß inhibition in different stages of lung cancer. In this article we will review recent data implicating IL-1ß signaling and its upstream regulator NLRP3 in both solid tumor and hematologic malignancies. We will discuss the key preclinical observations and the current clinical landscape, and describe the pharmacologic tools which will be used to evaluate the effects of blocking tumor-promoting inflammation clinically.

Redo-transcatheter aortic valve replacement with the supra-annular, self-expandable Evolut platform: Insights from the Transcatheter valve Therapy Registry.

OBJECTIVES: To assess the safety profile of redo-TAVR procedures from patients in the transcatheter valve therapy (TVT) Registry. BACKGROUND: The use of transcatheter aortic valves (TAV) to treat previously implanted failing TAVS (TAV-in-TAV) has been an increasingly important topic as indications for TAVR move to younger and lower-risk patients, but data on the safety and efficacy of redo-TAVR is limited. METHODS: Patients undergoing redo-TAVR procedures using the Evolut R, Evolut PRO or Evolut PRO+ valve in the TVT Registry between April 2015 and March 2020 were included. In-hospital, 30-day and 1-year outcomes were analyzed. RESULTS: Redo-TAVR was performed in 292 patients (213 patients received the Evolut R valve and 79 received the Evolut PRO or PRO+ valve). Device success was achieved in 94.5%. In-hospital mortality was 2.1%, stroke occurred in 2.7%, and 77.2% of patients were discharged home. There were no cases of coronary compression/obstruction or myocardial infarction that occurred in index hospitalization. Mean gradient at 30-days was 11.9 ± 6.9 mmHg, and 73.1% had none/trace total aortic regurgitation. CONCLUSIONS: Results from the TVT Registry demonstrate good short-term outcomes after redo-TAVR with the supra-annular, self-expandable Evolut platform. Long-term follow-up is necessary to further expand understanding this complex scenario.

Percutaneous mechanical thrombectomy and extracorporeal membranous oxygenation: A case series.

BACKGROUND: Massive or high-risk pulmonary embolism (PE) is a potentially life-threatening diagnosis with significant morbidity and mortality if treatment is delayed. Extracorporeal membrane oxygenation (ECMO) and large bore thrombectomy (LBT) in isolation have been used to stabilize and treat patients with massive PE, however, literature describing the combination of both modalities is lacking. We present a case series involving 9 patients who underwent combined ECMO and LBT and their outcomes. METHODS: This was a retrospective chart review of patients with confirmed PE, who underwent LBT and ECMO. We retrospectively captured clinical, therapeutic, and outcome data at the time of pulmonary embolism response team (PERT) activation and during the follow-up period for up to 90 days. RESULTS: Nine patients who had PERT activation with confirmed PE diagnosis have undergone combined LBT and ECMO initiation since the advent of our PERT program. The median age was 57 (range 28-68) years. Six patients out of 9 (55%) had cardiac arrest before therapy. All patients exhibited right heart strain on computed tomography and echocardiogram. The median ECMO duration was 5 days (range 2.3-11.6 days), with mean hospitalization of 16.1 days (range 1.5-30.9). Mortality was 22% at 90-day follow-up period. CONCLUSION: Patients with massive pulmonary embolism who suffer cardiac arrest have significant morbidity and mortality. ECMO in combination with LBT is a viable treatment option for patients with significant hemodynamic compromise.

Idiopathic posterior papillary muscle rupture; a case report.

BACKGROUND: Papillary muscle rupture is a rare condition. Its clinical presentation, diagnosis and management can be very challenging for the clinician. CASE PRESENTATION: A 73-year-old woman with hypertension presented with chest pain, ST-segment changes, and elevated serum troponin levels. Coronary angiography was normal. Echocardiography revealed normal ventricular function, flail posterior mitral leaflet, and severe mitral regurgitation. She underwent emergent mitral valve replacement. CONCLUSION: The diagnostic and management strategies of this uncommon presentation are discussed.

Safety-net hospitals versus non-safety centers and clinical outcomes after trans-catheter aortic valve replacement.

OBJECTIVE: To compare post-procedural outcomes of trans-catheter valve replacement (TAVR) among safety-net (SNH) and non-safety net hospitals (non-SNH). BACKGROUND: SNH treat a large population of un-insured and low income patients; prior studies report worse outcome at these centers. Results of TAVR at these centers is limited. METHODS: Adults undergoing TAVR at hospitals in the US participating in the National In-patient sample (NIS) database from January 2014 to December 2015 were included. A 1:1 propensity-matched cohort of patients operated at SNH and non-SNH institutions was analyzed, on the basis of 16 demographic and clinical co-variates. Main outcome was all-cause post-procedural mortality. Secondary outcomes included stroke, acute kidney injury and length of post-operative stay. RESULTS: Between 2014 and 2015, 41,410 patients (mean age 80 ± 0.11 years, 46% female) underwent TAVR at 731 centers; 6,996 (16.80%) procedures were performed at SNH comprising 135/731 (18.4%) of all centers performing TAVR. SNH patients were more likely to be female (49% vs. 46%, p < .001); admitted emergently (31% vs. 21%; p < .001; at the lowest quartile for household income (25% % vs. 20%; p < .001) and from minorities (Blacks 5.9% vs. 3.9%; Hispanic 7.2% vs. 3.2%).Adjusted logistic regression was performed on 6,995 propensity-matched patient pairs. Post-procedural mortality [OR 0.99(0.98-1.007); p = .43], stroke [OR 1.009(0.99-1.02); p = .08], acute kidney injury [OR 0.99(0.96-1.01); p = .5] and overall length of stay (6.9 ± 0.1 vs. 7.1 ± 0.2 days; p = .57) were comparable in both cohorts. CONCLUSION: Post-procedural outcomes after TAVR at SNH are comparable to national outcomes and wider adoption of TAVR at SNH may not adversely influence outcomes.

Acute kidney injury in renal transplant recipients undergoing cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is a key risk factor for chronic kidney disease in the general population, but has not been investigated in detail among renal transplant recipients (RTRs). We investigated the incidence, severity and risk factors for AKI following cardiac surgery among RTRs compared with non-RTRs with otherwise similar clinical characteristics. METHODS: We conducted a retrospective cohort study of RTRs (n = 83) and non-RTRs (n = 83) who underwent cardiac surgery at two major academic medical centers. Non-RTRs were matched 1:1 to RTRs by age, preoperative (preop) estimated glomerular filtration rate and type of cardiac surgery. We defined AKI according to Kidney Disease: Improving Global Outcomes criteria. RESULTS: RTRs had a higher rate of AKI following cardiac surgery compared with non-RTRs [46% versus 28%; adjusted odds ratio 2.77 (95% confidence interval 1.36-5.64)]. Among RTRs, deceased donor (DD) versus living donor (LD) status, as well as higher versus lower preop calcineurin inhibitor (CNI) trough levels, were associated with higher rates of AKI (57% versus 33% among DD-RTRs versus LD-RTRs; P = 0.047; 73% versus 36% among RTRs with higher versus lower CNI trough levels, P = 0.02). The combination of both risk factors (DD status and higher CNI trough level) had an additive effect (88% AKI incidence among patients with both risk factors versus 25% incidence among RTRs with neither risk factor, P = 0.004). CONCLUSIONS: RTRs have a higher risk of AKI following cardiac surgery compared with non-RTRs with otherwise similar characteristics. Among RTRs, DD-RTRs and those with higher preop CNI trough levels are at the highest risk.

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.

Variability in opioid prescribing practices among cardiac surgeons and trainees.

BACKGROUND AND AIM: The opioid epidemic has become a major public health crisis in recent years. Discharge opioid prescription following cardiac surgery has been associated with opioid use disorder; however, ideal practices remain unclear. Our aim was to examine current practices in discharge opioid prescription among cardiac surgeons and trainees. METHODS: A survey instrument with open- and closed-ended questions, developed through a 3-round Delphi method, was circulated to cardiac surgeons and trainees via the Canadian Society of Cardiac Surgeons. Survey questions focused on routine prescription practices including type, dosage and duration. Respondents were also asked about their perceptions of current education and guidelines surrounding opioid medication. RESULTS: Eighty-one percent of respondents reported prescribing opioids at discharge following routine sternotomy-based procedures, however, there remained significant variability in the type and dose of medication prescribed. The median (interquartile range) number of pills prescribed was 30 (20-30) with a median total dose of 135 (113-200) Morphine Milligram Equivalents. Informal teaching was the most commonly reported primary influence on prescribing habits and a lack of formal education regarding opioid prescription was associated with a higher number of pills prescribed. A majority of respondents (91%) felt that there would be value in establishing practice guidelines for opioid prescription following cardiac surgery. CONCLUSIONS: Significant variability exists with respect to routine opioid prescription at discharge following cardiac surgery. Education has come predominantly from informal sources and there is a desire for guidelines. Standardization in this area may have a role in combatting the opioid epidemic.

The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest.

BACKGROUND: Cerebral edema after cardiac arrest (CA) is associated with increased mortality and unfavorable outcome in children and adults. Aquaporin-4 mediates cerebral water movement and its absence in models of ischemia improves outcome. We investigated early and selective pharmacologic inhibition of aquaporin-4 in a clinically relevant asphyxial CA model in immature rats in a threshold CA insult that produces primarily cytotoxic edema in the absence of blood-brain barrier permeability. METHODS: Postnatal day 16-18 Sprague-Dawley rats were studied in our established 9-min asphyxial CA model. Rats were randomized to aquaporin-4 inhibitor (AER-271) vs vehicle treatment, initiated at return of spontaneous circulation. Cerebral edema (% brain water) was the primary outcome with secondary assessments of the Neurologic Deficit Score (NDS), hippocampal neuronal death, and neuroinflammation. RESULTS: Treatment with AER-271 ameliorated early cerebral edema measured at 3 h after CA vs vehicle treated rats. This treatment also attenuated early NDS. In contrast to rats treated with vehicle after CA, rats treated with AER-271 did not develop significant neuronal death or neuroinflammation as compared to sham. CONCLUSION: Early post-resuscitation aquaporin-4 inhibition blocks the development of early cerebral edema, reduces early neurologic deficit, and blunts neuronal death and neuroinflammation post-CA.

Transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis in people with low surgical risk.

BACKGROUND: Severe aortic valve stenosis (AS) is a major cause of morbidity and mortality worldwide. The definitive management for severe AS is aortic valve replacement (AVR). The choice of transcatheter approach versus open-heart surgery for AVR in people with severe AS and low surgical risk remains a matter of debate. OBJECTIVES: To assess the benefits and harms of transcatheter aortic valve implantation (TAVI) compared to surgical aortic valve replacement (SAVR) in people with severe AS and low surgical risk. SEARCH METHODS: We searched the following databases for randomised controlled trials (RCTs) on 29 April 2019: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science Core Collection. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We searched all databases from inception to present and imposed no restriction on language or date of publication. SELECTION CRITERIA: We included RCTs that compared TAVI and SAVR in adults (18 years of age or older) with severe AS and low surgical risk. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Two authors independently screened titles and abstracts for inclusion, performed data extraction, and assessed risk of bias in the studies included. We analysed dichotomous data using the risk ratio (RR) and continuous data using the mean difference (MD), with respective 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach. Our outcomes of interest were assessed in the short term (i.e. during hospitalisation and up to 30 days of follow-up). Primary outcomes were all-cause mortality, stroke, and rehospitalisation. Secondary outcomes were myocardial infarction (MI), cardiac death, length of hospital stay (LOS), permanent pacemaker (PPM) implantation, new-onset atrial fibrillation, acute kidney injury (AKI), and any bleeding. MAIN RESULTS: We identified four studies (13 reports), with 2818 participants, and one ongoing study. Overall certainty of evidence ranged from high to very low. There is probably little or no difference between TAVI and SAVR for the following short-term outcomes: all-cause mortality (RR 0.69, 95% CI 0.33 to 1.44; SAVR 11 deaths per 1000, TAVI 8 deaths per 1000 (95% CI 4 to 16); 2818 participants; 4 studies; moderate-certainty evidence); stroke (RR 0.73, 95% CI 0.42 to 1.25; SAVR 21 strokes per 1000, TAVI 16 strokes per 1000 (95% CI 9 to 27); 2818 participants; 4 studies; moderate-certainty evidence); MI (RR 0.82, 95% CI 0.42 to 1.58; SAVR 14 MI per 1000, TAVI 11 MI per 1000 (95% CI 6 to 21); 2748 participants; 3 studies; moderate-certainty evidence); and cardiac death (RR 0.71, 95% CI 0.32 to 1.56; SAVR 10 cardiac deaths per 1000, TAVI 7 cardiac deaths per 1000 (95% CI 3 to 16); 2818 participants; 4 studies; moderate-certainty evidence). TAVI may reduce the risk of short-term rehospitalisation, although the confidence interval also includes the possibility of no difference in risk between groups (RR 0.64, 95% CI 0.39 to 1.06; SAVR 30 cases per 1000, TAVI 19 cases per 1000 (95% CI 12 to 32); 2468 participants; 2 studies; low-certainty evidence). TAVI, compared with SAVR, probably increases the risk of PPM implantation (RR 3.65, 95% CI 1.50 to 8.87; SAVR 47 per 1000, TAVI 170 cases per 1000 (95% CI 70 to 413); number needed to treat for an additional harmful outcome (NNTH) = 7; 2683 participants; 3 studies; moderate-certainty evidence). We are uncertain whether TAVI, compared with SAVR, affects the LOS in days, although it appears to be associated with shorter LOS. TAVI, compared with SAVR, reduces the risk of atrial fibrillation (RR 0.21, 95% CI 0.15 to 0.30; 2683 participants; 3 studies), AKI (RR 0.30, 95% CI 0.16 to 0.58; 2753 participants; 4 studies), and bleeding (RR 0.31, 95% CI 0.16 to 0.62; 2753 participants; 4 studies) (all high-certainty evidence). AUTHORS' CONCLUSIONS: Our meta-analysis indicates that, in the short term, TAVI probably has little or no mortality difference compared to SAVR for severe AS in individuals with low surgical risk. Similarly, there is probably little or no difference in risk of stroke, MI, and cardiac death between the two approaches. TAVI may reduce the risk of rehospitalisation, but we are uncertain about the effects on LOS. TAVI reduces the risk of atrial fibrillation, AKI, and bleeding. However, this benefit is offset by the increased risk of PPM implantation. Long-term follow-up data are needed to further assess and validate these outcomes, especially durability, in the low surgical risk population.

Chronic opioid use after coronary bypass surgery.

BACKGROUND: Opioid dependence has become a major health care issue. Pain management of invasive surgical procedures with opioids may potentially contribute to this epidemic. We sought to determine the association of opioid-prescribing patterns with chronic opioid use. METHODS: We retrospectively reviewed all patients undergoing isolated coronary artery bypass graft (CABG) procedures during 2016 at a single institution. Prescribing patterns and medication usage were compared between opioid-naïve and opioid-exposed patients (patients with reported opioid use within 30 days prior to surgery). Chronic opioid dependence was defined as opioid usage beyond 90 days after discharge. RESULTS: We included 284 opioid-naïve and 46 opioid-exposed patients. Although overall prescribing patterns were similar between groups, a higher proportion of opioid-exposed patients were prescribed a total dose >150 mg of oxycodone per discharge prescription (15.2% vs 4.9%; P = 0.024), and had a higher proportion of refills within 30 days (28.3% vs 10.9%; relative risk [RR] 3.2 [95% confidence interval (CI): 1.5-6.8]; all P < 0.05). The incidence of chronic opioid dependence was higher among opioid-exposed patients compared to opioid-naïve patients (21.7% vs 3.2%; RR 8.5 [95%CI: 3.2-22.3]; P = 0.001). CONCLUSIONS: Ongoing opioid use 3 months after CABG is present in 21.7% of opioid-exposed patients and 3.2% of opioid-naïve patients. These preliminary findings highlight the burden of prescribing patterns on the overall opioid epidemic and the need to develop alternative pain management strategies.

Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia.

Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8 hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor-reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants.

Impact of flow, gradient, and left ventricular function on outcomes after transcatheter aortic valve replacement.

OBJECTIVES: To assess the impact of low flow with and without preserved left ventricular ejection fraction (LVEF) on outcomes after transcatheter aortic valve replacement (TAVR). BACKGROUND: Prior studies have shown that patients with low flow, AVG, and LVEF have worse outcomes after TAVR. It is unclear whether low AVG and LVEF remain prognostic after adjusting for flow, and how the outcomes of patients with low flow with and without preserved LVEF compare after TAVR. The goal of this study was to provide insight into these open questions. METHODS: Data from 340 TAVR patients at Brigham and Women's Hospital from 2011 through 2015 were analyzed. Low flow was defined as stroke volume index (SVI) ≤35 mL/m2 , low AVG as mean gradient < 40 mmHg, and reduced LVEF as < 50%. RESULTS: Low flow was present in 96 (28.2%) patients, 48 (50.0%) of whom also had reduced LVEF. At 1 year, low flow was associated with increased mortality (21.9 vs 7.4%; P = 0.0002) and heart failure (HF) (20.8 vs 5.3%; P = 0.0113). Among patients with low flow, those with preserved LVEF had increased mortality (HR 5.17, 95% CI 2.73-9.80; P < 0.001) and HF (HR 7.69, 95% CI 3.86-15.31; P < 0.001). After adjusting for clinical factors, patients with low flow had increased mortality (HR 6.51, 95% CI 2.98-14.22; P < 0.001) and HF (HR 5.52, 95% CI 2.34-12.98; P < 0.001), while neither low AVG nor low LVEF were associated with increases in mortality or HF. CONCLUSIONS: In patients undergoing TAVR, low flow was an independent predictor of 1-year mortality and HF, and a stronger predictor than either low AVG or LVEF. Patients with low flow and preserved EF had increased mortality and HF at 1-year, while those with low flow and reduced EF had outcomes similar to patients with normal flow.

Clinical Significance of Greater Implantation Height with SAPIEN 3 Transcatheter Heart Valve.

BACKGROUND: A lower rate of permanent pacemaker (PPM) has been linked to a target aortic implantation height (AIH) >0.70, following transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve. Based on clinical experience, it was hypothesized that a higher AIH (≥0.85) would lower the rate of PPM implantation. METHODS: A total of 127 patients (66 females, 61 males; mean age 82 ± 8 years) underwent TAVR with the SAPIEN 3 valve between May 2015 and July 2016. AIH was defined as the proportion of the valve frame above the aortic annulus in the post-deployment aortogram. A target AIH (≥0.70) was achieved in 113 patients (89%). Cases were stratified into a High Implantation (HI) group (AIH ≥0.85; 33 patients) or a Standard Implantation (SI) group (AIH <0.85; 94 patients). RESULTS: The mean Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score of all patients was 6.4 ± 3.5%. Preoperative right bundle branch block (RBBB) was prevalent in 13% of SI patients, and in 18% of HI patients (p = 0.56). There were no significant differences in operative mortality (3.2% versus 0%), median length of stay (2 days versus 3 days) and incidence of moderate-to-severe paravalvular leak (3.2% versus 0%; all p >0.410) between SI and HI patients, respectively. Likewise, the incidence of new PPM did not differ between the two groups (12% in HI versus 13% in SI; p ≥0.99). The mean AIH was similar for patients with PPM implantation (0.80 ± 0.08) compared to those without (0.78 ± 0.06; p = 0.520). Preoperative RBBB was significantly associated with PPM implantation (odds ratio (OR) 10.1; p = 0.002), and patients who underwent PPM implantation had a higher operative mortality (12.5% versus 1%; p = 0.040). CONCLUSIONS: Among TAVR patients who received the SAPIEN 3 heart valve, a higher AIH (≥0.85) was not associated with a lower rate of PPM implantation or increased operative mortality. Prior RBBB was the only independent risk factor for new PPM implantation. Long-term follow up is crucial in determining the clinical significance of PPM implantation.