Citations

In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBPβ-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.

AbstractBackgroundThe incidence and impact of noise in a subcutaneous implantable cardioverter defibrillator (S‐ICD) after left ventricular assist device (LVAD) implantation is not well established.MethodsWe performed a retrospective study of patients implanted with LVAD and with a pre‐existing S‐ICD between January 2005 and December 2020 at the three Mayo Clinic centers (Minnesota, Arizona, and Florida).ResultsOf the 908 LVAD patients, a pre‐existing S‐ICD was present in 9 patients (mean age 49.1 ± 13.7 years, 66.7% males), 100% with Boston Scientific third‐generation EMBLEM MRI S‐ICD, 11% with HeartMate II (HM II), 44% with HeartMate 3 (HM 3), and 44% with HeartWare (HW) LVAD. The incidence of noise from LVAD‐related electromagnetic interference (EMI) was 33% and was only seen with HM 3 LVAD. Multiple measures attempted to resolve noise, including using alternative S‐ICD sensing vector, adjusting S‐ICD time zone, and increasing LVAD pump speed, were unsuccessful, necessitating S‐ICD device therapies to be turned off permanently.ConclusionsThe incidence of LVAD‐related S‐ICD noise is high in patients with concomitant LVAD and S‐ICD with significant impact on device function. As conservative management failed to resolve the EMI, the S‐ICDs had to be programmed off to avoid inappropriate shocks. This study highlights the importance of awareness of LVAD‐SICD device interference and the need to improve S‐ICD detection algorithms to eliminate noise.

Background: Cerebral cavernous angiomas with symptomatic hemorrhage (CASH) carry highest rebleed rates and are targeted for novel interventions. A multisite clinical trial readiness project (clinicaltrials.gov NCT03652181) aims to identify clinical and functional changes over time in trial eligible CASH patients. Methods: Adult patients from 5 high volume centers with a CASH in the prior year and no planned surgical intervention were enrolled. In addition to demographic, clinical, and imaging review, patients underwent baseline, 1 year and 2 year NIH-stroke scale (NIHSS), modified Rankin scale (mRS), Euro-QOL 5D-3L (EQ-5D-3L) and EQ VAS (visual analog score), and PROMIS 29 assessments. Recurrent symptomatic hemorrhages (SH) were verified. We assessed the hemorrhage rate, change in scores/scales over time, and determined which scales/scores were most affected in patients with SH. Results: 123 patients completed baseline assessments and were prospectively followed (60.9% female; mean age 44.1 years; 39.1% familial; 41.5% brainstem location). As of reporting date, 89 of 104 (86%) and 58 of 76 (76%) cases have completed assessments. There were 16 SHs during 147 patient-years of follow up (10.9% per patient year). At baseline, 111 (90.2%) of patients had NIHSS 0-2 and 77 (62.6%) patients had mRS baseline 0-1 which improved to 40 (95.2 %) and 43 (75.4%) at 2 years. At baseline, 54 (43.9%) of patients had at least one moderate to severely abnormal PROMIS-29 domain compared to 13 (26.5%) at 2 years. EQ-5D-3L baseline demonstrated a moderate proportion of patients reporting some difficulty with pain (48.8%), anxiety (41.5%), and activity (41.5%) which improved to 28%, 30%, and 34% respectively at 2 years. Patients with a prospective SH were more likely than those without recurrent SH at 2 years to display mild functional decline (0.5 SD) of most PROMIS-29 domains, a mRS of 2 or higher and an abnormal EQ- self-care (P<0.05). Other scales/scores were not significantly different between the groups. Conclusion: We report SH rate and functional outcome at baseline and rates of changes during 2 years in trial eligible CASH patients. The PROMIS-29, mRS, and EQ-self-care domains were most discriminative in patients with recurrent SH. No test was 100% specific.

Background: Quantitative susceptibility mapping (QSM) is a measure of iron content, and ≥6% increase in QSM has been correlated with new hemorrhage in previously stable cavernous angiomas. Longitudinal changes in QSM are not known in cavernous angiomas with symptomatic hemorrhage (CASH) with high rates of rebleeding and are the targets of novel pharmacotherapies. In a prospective multisite Trial Readiness project (clinicaltrials.gov NCT03652181), QSM is longitudinally assessed. Methods: Trial eligible subjects with CASH in the prior year and not undergoing lesion resection or radiation, were enrolled. Mean QSM of CASH lesion was acquired at baseline and at 1 and 2 year planned follow-ups. Relative change in mean lesional QSM during each follow-up year was assessed, and any symptomatic hemorrhage (SH), asymptomatic changes (AC; defined as subclinical bleed or growth) in the lesion during the same epoch. Results: Paired QSM assessments were completed to date in 99 CASH lesions (67 year 1, and 32 year 2) and are reported herein. Four SH and 6 ACs occurred during 1 st follow-up year, and 3 SH during 2 nd year. QSM increased in 54 lesion-years, decreased in 44, and remained stable in 1. The % lesional QSM change in year 1 was significantly higher than that observed in year 2 (mean +9.33, SD 37.52 vs. +5.20; SD= 24.86; p=0.05; Spearman correlation ρ -0.36). CAs with clinical SH or AC had a significantly higher % QSM change than lesions without (mean +28.03, SD 17.77 vs. +4.97, SD= 34.75; p=0.0014). All 13 lesions with SH/AC demonstrated a QSM increase ≥6% while 31 of 86 (36%) lesions with no clinical events had a ≥6% QSM increase. Conclusion: QSM change of ≥6% is present in every CASH lesion manifesting a new SH or AC (100% specificity), and is more common than clinical events (3.4X higher sensitivity). The biomarker can hence be used as a more sensitive categorical outcome than SH or AC in clinical trials of novel therapies aimed at bleeding in CASH lesions. Effect of an intervention on % QSM change may also be proposed as a time-averaged difference between 2 arms using a repeated measures analysis implemented as an unadjusted linear mixed model. These results are the basis of application for certification by the U.S F.D.A. of QSM as a monitoring biomarker of drug effect in CASH.

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P &lt; .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P &lt; .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P &amp;lt; .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P &amp;lt; .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P &amp;lt; .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Background and Objectives: Cancer and coronary artery disease (CAD) often coexist. Compared to quantitative coronary angiography (QCA), fractional flow reserve (FFR) has emerged as a more reliable method of identifying significant coronary stenoses. We aimed to assess the specific management, safety and outcomes of FFR-guided percutaneous coronary intervention (PCI) in cancer patients with stable CAD. Materials and Methods: FFR was used to assess cancer patients that underwent coronary angiography for stable CAD between September 2008 and May 2016, and were found to have ≥50% stenosis by QCA. Patients with lesions with an FFR > 0.75 received medical therapy alone, while those with FFR ≤ 0.75 were revascularized. Procedure-related complications, all-cause mortality, nonfatal myocardial infarction, or urgent revascularizations were analyzed. Results: Fifty-seven patients with stable CAD underwent FFR on 57 lesions. Out of 31 patients with ≥70% stenosis as measured by QCA, 14 (45.1%) had an FFR ≥ 0.75 and lesions were reclassified as moderate and did not receive PCI nor DAPT. Out of 26 patients with <70% stenosis as measured by QCA, 6 (23%) had an FFR < 0.75 and were reclassified as severe and were treated with PCI and associated DAPT. No periprocedural complications, urgent revascularization, acute coronary syndromes, or cardiovascular deaths were noted. There was a 22.8% mortality at 1 year, all cancer related. Patients who received a stent by FFR assessment showed a significant association with decreased risk of all-cause death (HR: 0.37, 95% CI 0.15–0.90, p = 0.03). Conclusions: Further studies are needed to define the optimal therapeutic approach for cancer patients with CAD. Using an FFR cut-off point of 0.75 to guide PCI translates into fewer interventions and can facilitate cancer care. There was an overall reduction in mortality in patients that received a stent, suggesting increased resilience to cancer therapy and progression.

Introduction: Atrial flutter (AFL) with figure-of-eight reentry (FOER) is effectively terminated by catheter ablation (CA) of the shared isthmus. Case: A 50-year-old man with prior mitral valve (MV) repair presented to our hospital with palpitations for 9 months refractory to metoprolol. ECG showed coarse atrial fibrillation at 61 bpm. Echocardiography showed left ventricular LVEF of 45%. Electrophysiology study revealed AFL (cycle length, TCL 290 msec) with a concentric activation pattern on the coronary sinus (CS) catheter, and a chevron pattern on the Halo catheter placed against the lateral tricuspid annulus (TA). Entrainment map revealed a near equal post-pacing interval and TCL in proximal CS, low lateral right atrium (RA), and CTI. Incomplete line of block was noted in the anterior wall of RA near the superior vena cava (SVC), likely from prior atriotomy scar. Double loop reentry (DLR) was demonstrated with one wavefront (WV) traveling counterclockwise around the TA using the CTI, and the other WV traveling posteriorly around the SVC (Figure). After CTI ablation, TCL changed from 290 msec to 330 msec suggesting blocked CTI. Now, the WV was a single loop around the SVC, confirmed by repeat activation mapping. Linear ablation from anterior TA to the anterior aspect of the SVC terminated the AFL. Differential pacing from either side of the anterior line and the CTI demonstrated a conduction time of > 200 msec and 150 msec in either direction, respectively. Decremental atrial pacing was unable to induce any arrhythmias. Discussion: FOER in this case is suggested by fusion of WVs in the lateral RA. The 2 circuits each had their own conduction gap, in the CTI and anterior RA wall near the SVC, respectively. DLR was proven by entrainment as well as activation mapping. The faster CTI-dependent AFL was entraining the upper loop reentry circuit. Conclusion: Atypical right AFL with DLR mimicking FOER was successfully terminated by CA of CTI and anterior line of ablation from TA to SVC.

Background: Elevated intracranial pressure (ICP) is one proposed mechanism leading to poor outcomes in patients with spontaneous intraventricular hemorrhage (IVH). We characterized occurrence and significance of intracranial hypertension in severe IVH requiring extraventricular drainage (EVD). Methods: Prospective analysis of ICP in the first 400 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing EVD plus intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD plus placebo for treatment of IVH in patients with obstructive IVH and intracerebral hemorrhage (ICH) volume <30cc. Maximum and minimum ICP was recorded every 4 hours in all patients until 7 days post randomization. ICP readings were analyzed at pre-defined thresholds and proportion of high ICP events compared by clinical/radiological variables. Impact on 30 day mortality was assessed. Results: of 17,593 ICP readings, maximum ICP ranged from -4 to 115 mm Hg (median, interquartile range; 11,8); 90.2% (15,861) were ≤ 20 mm Hg, 2.0% were >30, 0.5% were >40, and 0.2% were > 50 mm Hg. Proportion of threshold events > 20 and > 30 mm Hg were more frequent in patients with persistent closure of the lower ventricular system after day 3 (p=0.047 and p=0.04, respectively), but were not correlated with initial or end of treatment (72 hours after last dose of study agent) ICH or IVH volumes. ICP elevation > 20 mm Hg occurred during a required 1 hr EVD closure time after study agent injection in 507/3364 (15.1%) injections although early re-opening of EVDs occurred in only 3.9%. Shunting for hydrocephalus was required in 18% of patients over 1 yr follow-up and was not associated with high ICP events. Percentage of ICP readings per patient > 30 mmHg and ICH/IVH volumes were independent predictors of 30 day mortality after adjustment for other outcome predictors (p=0.01; p=0.04; p<0.001, respectively). Conclusions: ICP is not frequently elevated during monitoring and drainage with an EVD in patients with severe IVH. ICP > 30 mm Hg predicts higher short-term mortality. Early opening of the lower ventricular system may reduce frequency of high ICP events. Injection of thrombolytics can be performed without additional ICP management in the majority of patients.