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Introduction: Collateral circulation plays a crucial role in determining the extent of brain tissue ischemia and functional outcome in large vessel occlusive (LVO) stroke. Heart failure (HF) is known to cause cerebral hypoperfusion, yet the relationship between HF and robustness of collateral flow has not been well described. Here we hypothesized that HF is associated with poor collateral flow and functional outcome in patients presenting with LVO treated with mechanical thrombectomy (MT). Methods: A single center retrospective study of patients presenting with LVO ischemic stroke who underwent MT between 2012-2020 was done. Single-phase CTA of head prior to MT was used to assess collateral status with poor status defined as ≤ 50% filling and good status as >50% filling. Classification of HF by left ventricular ejection fraction (LVEF) on echocardiogram was used where HF with reduced ejection fraction (HFrEF) had LVEF ≤40%, HF with preserved EF (HFpEF) had LVEF ≥50% with evidence of structural heart disease, and no HF was LVEF≥50% without structural heart disease. Functional outcome was modified Rankin scale (mRS) at 90 days with scores of 0-2 representing good outcome and 3-6 representing poor outcome. Multivariable logistic regression analyses were performed to evaluate the association between HF and poor collaterals after adjusting for vascular risk factors. Results: We identified 235 patients, mean age was 69 ±15 years, median NIHSS was 18, and 45.5% had HF (HFrEF 12.8%, HFmrEF 4.7%, HFpEF 28.1%) while 54.5% had no HF. Poor collaterals were seen in 47.7%, and those with HF were likely to have poor collaterals compared to those without HF (56.1% vs 35.1%, P=.001). There was a dose-dependent relationship between severity of HF and poor collaterals: adjusted odds of poor collaterals were 1.63 and 2.45 in HFpEF and HFrEF, compared to those without HF (trend p=.018). Patients with poor collaterals were likely to have poor outcome at 3 months compared to those with good collaterals (75.0% vs 57.8%; p=.015). Conclusion: Patients with HFrEF were twice as likely to have poor collaterals. This study demonstrated a likely mechanism for poor outcomes seen in ischemic stroke with HF, future studies may explore whether optimization of HF may augment collaterals to improve outcomes.

ImportanceTafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms.ObjectiveTo evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms.Design, Setting, and ParticipantsThis randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries.InterventionsTafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo.Main Outcomes and MeasuresEstablished thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class.ResultsAmong 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P < .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo.Conclusions and RelevanceIn ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT01994889

Background. End-stage kidney disease patients with concomitant heart failure (HF) with reduced ejection fraction are often denied kidney transplantation. The aims of this study were to explore factors predictive of suitability for kidney transplant and to assess cardiovascular outcomes in patients with impaired left ventricular ejection fraction (LVEF) after transplant. Methods. We evaluated 109 consecutive adults with LVEF ≤40% at the time of initial kidney transplant evaluation between 2013 and 2018. Posttransplant cardiovascular outcomes were defined as nonfatal myocardial infarction (MI), admission for HF, cardiovascular death, and all-cause mortality. Results. A cardiologist participated in kidney transplant evaluation for 87% of patients and was present at 49% of transplant selection conferences. Twenty-four patients (22%) were denied by a cardiologist for kidney transplant‚ and 59 (54%) were denied by the selection committee, of whom 43 were because of cardiovascular risk. Forty-two (38%) patients were approved for kidney transplant. On univariate analysis, the variables associated with denial for kidney transplant included cardiologist denial, higher cardiac troponin T, prior coronary intervention, cardiovascular event, positive stress study, lower ejection fraction, and lower VO2 max (all P < 0.05). Cardiologist denial was the most significant predictor of denial for kidney transplant in different multivariate models. At a median follow-up of 15 mo, 5 (5%) suffered nonfatal MI, 13 (12%) were hospitalized for HF exacerbation, and 17 (16%) died. Only 22 patients, 52% of those approved, underwent kidney transplant. After kidney transplant, there was 1 death, 1 nonfatal MI, and 3 hospitalizations for HF. Median LVEF improved from 38% before listing to 55% posttransplant. Conclusions. Cardiologist denial was the primary predictor of rejection for kidney transplant. Despite careful selection, prevalence of cardiovascular events and mortality after kidney transplant was 23%. There is need for a structured multidisciplinary approach for patients with impaired LVEF.

Background: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer’s disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. Objective: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1–6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. Methods: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Results: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Conclusion: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

Extradural malignant primary spinal tumors are rare and outcome data, especially for younger patients, is limited. In a worldwide (11 centers) study (Predictors of Mortality and Morbidity in the Surgical Management of Primary Tumors of the Spine study; ClinicalTrials.gov Identifier NCT01643174) by the AO Spine Knowledge Forum Tumor, patients surgically treated for primary tumors of the spine between 1992 and 2012, were retrospectively analyzed from a prospective database of their medical history. Medical history, tumor characteristics, diagnostics, treatments, cross-sectional survival, and local recurrences were analyzed. Sixty-eight cases (32 f; 36 m), at an average age of 18.6 ± 4.7 years at the time of diagnosis, were identified (median follow-up 2.9 years). The most common entities were Ewing’s sarcoma (42.6%). Of the patients, 28% had undergone previous spine tumor surgery in another center (84% with intralesional margins). Resection was considered “Enneking appropriate” (EA) in 47.8% of the cases. Of the patients, 77.9% underwent chemotherapy and 50% radiotherapy. A local recurrence occurred in 36.4%. Over a third of patients died within a 10-year follow-up period. Kaplan-Meier-analysis demonstrated statistically significant overall survival (p = 0.007) and local recurrence rates (p = 0.042) for tumors treated with EA surgery versus Enneking inappropriate surgery. Aggressive resection of extradural primary malignant spinal tumors combined with adjuvant therapy reveals low local recurrence rates and better outcomes overall in younger patients.

Background: Improvement in renal function (IRF) in acute decompensated heart failure is associated with adverse outcomes. The mechanisms driving this paradox remain undefined. Methods: Using the ROSE-AHF study (Renal Optimization Strategies Evaluation–Acute Heart Failure), 277 patients were grouped according to renal function, with IRF defined by a ≥20% increase (N=75), worsening renal function by a ≥20% decline (N=53), and stable renal function (SRF) by a <20% change (N=149) in estimated glomerular filtration rate between baseline and 72 hours. Three well-validated renal tubular injury markers, NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetyl-β-d-glucosaminidase), and KIM-1 (kidney injury molecule 1), were evaluated at baseline and 72 hours. Patients were also classified by the pattern of change in these markers. Results: Patients with IRF had the lowest admission estimated glomerular filtration rate (IRF, 37 [28 to 51] mL/min per 1.73 m 2 ; worsening renal function, 43 [35 to 55] mL/min per 1.73 m 2 ; and SRF, 43 [32 to 55] mL/min per 1.73 m 2 ; P trend =0.032) but greater cumulative urine output (IRF, 8780 [7025 to 11 208] mL; worsening renal function, 7860 [5555 to 9765] mL; and SRF, 8150 [6325 to 10 456] mL; P trend =0.024) and weight loss (IRF, –9.0 [–12.4 to –5.3] lb; worsening renal function, –5.1 [–8.1 to –1.3] lb; and SRF, –7.1 [–11.9 to –3.2] lb; P trend <0.001) despite similar diuretic doses ( P trend =0.16). There were no differences in the relative change in NGAL, NAG, or KIM-1 between renal function groups ( P trend >0.19 for all). Patients with IRF had worse survival than patients with SRF (27% versus 54%; hazard ratio, 1.98 [1.10–3.58]; P =0.024). Conclusions: IRF during decongestive therapy for acute decompensated heart failure was not associated with improved markers of renal tubular injury and was associated with worsened survival, likely driven by the presence of greater underlying cardiorenal dysfunction and more severe congestion.

464 Background: A larger proportion of Hispanic gastric cancer patients are diagnosed at a young age than patients of other ethnicities. Despite diagnosis at an early age, young Hispanic patients also present more frequently with advanced disease. Whether there are molecular differences between tumors from young and old Hispanic gastric cancer patients is unknown. Methods: We performed RNA-sequencing on pre-treatment tumor samples of gastric cancer patients of self-identified Hispanic ethnicity. We stratified patients into two groups: <50 years and ≥50 years. Differentially expressed genes between groups were detected using the DESeq2 package (RStudio). We performed Gene Set Enrichment Analysis (GSEA) to identify pathways that were uniquely overexpressed in each age group. Results: 57 patients were included in our study. 23 patients were <50 years and 33 patients were ≥50 years. Comparison of the top 10% most differentially expressed genes showed no clustering based on age. However, visual inspection of the top 40 most differentially expressed genes revealed 2 distinct patterns of gene expression between age groups. GSEA revealed upregulation of DNA replication, cell cycle, and DNA repair pathways in the younger patients The tumors in younger patients also had upregulation of multiple immune activation pathways. Cancers from older patients had upregulation of programmed cell death pathways. Conclusions: Early-onset gastric cancer in Hispanic patients may represent a distinct biologic process.

Extradural primary spinal tumors were retrospectively analyzed from a prospective database of 1495 cases. All subjects with benign primary tumors under the age of 25 years, who were enrolled between 1990 and 2012 (Median FU was 2.4 years), were identified. Patient- and case-related characteristics were collected and statistically analyzed. Results: 161 patients (66f;95m; age 17.0 ± 4.7 years at time of diagnosis) were identified. The most common tumors were osteoblastomas n = 53 (32.9%), osteoid osteomas n = 45 (28.0%), and aneurysmal bone cysts n = 32 (19.9%). The tumor grade, according to the Enneking Classification S1/S2/S3, was 14/73/74 (8.7/45.3/46.0%), respectively. Tumor-related pain was present in 156 (96.9%) patients. Diagnosis was achieved by biopsies in 2/3 of the cases. Spinal fixation was used in >50% of the cases. Resection was Enneking appropriate in n = 100 (62.1%) of cases. Local recurrence occurred in 21 (13.1%) patients. Two patients died within a 10-year follow-up period. Conclusion: This is one of the largest international multicenter cohorts of young patients surgically treated for benign spinal tumors. The heterogenic young patient cohort presented at a mid-term follow-up without a correlation between the grade of aggressiveness in resection and local recurrence rates. Further prospective data are required to identify prognostic factors that determine oncological and functional outcomes for young patients suffering from these rare tumors.