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Background Frailty is prevalent in older adults with heart failure and is associated with poor outcomes; however, there remains uncertainty on how to measure frailty in clinical practice. Methods and Results A multicentric prospective cohort study was assembled at 4 heart failure clinics to compare the prognostic value of 3 physical frailty scales in ambulatory patients with heart failure. Outcomes were all‐cause death or hospitalization and health‐related quality of life using the 36‐Item Short Form survey questionnaire (SF‐36) at 3 months. Multivariable regression was adjusted for age, sex, Meta‐Analysis Global Group in Chronic Heart Failure score, and baseline SF‐36 score. The cohort included 215 patients (mean age 77.6 years). All 3 frailty scales were independently associated with death or hospitalization at 3 months; the adjusted odds ratios standardized per 1 SD worsening of the Short Physical Performance Battery; Fried, and strength, assistance with walking, rising from a chair, climbing stairs, and falls scales were 1.67 (95% CI, 1.09–2.55), 1.60 (95% CI, 1.04–2.46), and 1.55 (95% CI, 1.03–2.35), respectively, with C statistics of 0.77 to 0.78. All 3 frailty scales were independently associated with worsening SF‐36 scores, especially the Short Physical Performance Battery, for which 1 SD worsening of frailty translated to a decrement of −5.86 (−8.55 to −3.17) and −5.51 (−7.82 to −3.21) points in the Physical Component Score and Mental Component Score. Conclusions All 3 physical frailty scales were associated with death, hospitalization, and reduced health‐related quality of life in ambulatory patients with heart failure. Questionnaire or performance‐based physical frailty scales can be used to offer prognostic value and a therapeutic target in this vulnerable population. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03887351.

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

Background: Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these drugs on cardiovascular outcomes among patients with heart failure (HF) and diabetes is unclear. Methods: We evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-HF Registry between 2006 and 2014 who had diabetes and Part D prescription coverage (n=29,181). Patients with glomerular filtration rate 2 or prescribed metformin or sulfonylurea prior to admission were excluded. In separate analyses for metformin and sulfonylurea, patients filling new prescriptions for each therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between therapy and mortality and hospitalization for HF (HHF) outcomes over the following 12 months. Secondary analyses were stratified by ejection fraction (EF) ≤40% vs >40%. Results: Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was associated with reduced risk of composite mortality/HHF, but not individual components (Table) . Associations with mortality/HHF and HHF endpoints were driven by reduced risk among patients with EF>40% (all p for interaction ≤0.04). Sulfonylurea prescription was independently associated with increased risk of mortality, HHF, and the composite. Associations between sulfonylurea prescription and endpoints were consistent regardless of EF (all p for interaction >0.12). Conclusion: Among US patients hospitalized for HF with comorbid diabetes, initiation of metformin was independently associated with improved clinical outcomes, driven by improvements among patients with preserved EF. In contrast, sulfonylurea initiation was associated with adverse clinical outcomes regardless of EF.

Introduction: Coronary Computed Tomography Angiography (CCTA) and SPECT myocardial perfusion imaging (SPECT-MPI) are equally safe in evaluating patients presenting to the emergency department with acute chest pain. However, no study has compared the use of CCTA with Fractional Flow Reserve (FFR-CT) to SPECT-MPI in a chest pain observation unit (OU). We compared the performance of CCTA (with FFR-CT as needed) to SPECT-MPI for change in coronary artery disease (CAD) specific treatment (statins, antianginals, antiplatelets, and coronary revascularization) as well its impact on length of hospital stay (LOS). Methods: In 2020, our institution implemented an algorithm-based protocol in the OU to select patients appropriate for CCTA with explicit guidelines for management based on the results. We performed a retrospective analysis of 105 patients (52 SPECT-MPI patients from the period prior to initiation of the OU CCTA protocol who met criteria for CCTA, and 53 CCTA patients after CCTA protocol initiation). We performed two-tailed t-tests and chi-squared analyses to compare changes in treatment and LOS in both groups. Results: Patients in the CCTA group were younger (61 vs. 67 years, p=0.007), but there were no significant differences in CAD risk factors amongst the two groups. CCTA led to significant increase in statin, antianginal, and antiplatelet therapies, cardiac catheterization and revascularization within 6 months. There was no increase in LOS. Finally, CCTA did not increase acute kidney injury at follow up (Table 1). Conclusion: CCTA with FFR-CT significantly improved patient care by increasing appropriate preventative CAD treatment compared to SPECT-MPI while increasing the rate of revascularization without compromising length of stay or kidney function. In conclusion, protocol-based use of CCTA with FFR-CT is a more effective tool when compared to SPECT-MPI for chest pain patients admitted to the OU.

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Background: The effect of menopausal status on the risk factors of cardiovascular (CV) disease is not well ascertained. We aimed to evaluate the impact of menopause on several traditional and non-traditional cardiovascular (CV) risk factors. Methods: The CARTaGENE study was a prospective cohort study with random sampling of individuals in Quebec, Canada. We completed a seven-year follow-up in 2016. For this analysis, we included only subjects without prior cardiovascular (CV) events (CVE) or CV interventions (CVI). We defined the primary endpoint as CVE which can be any of the following events: acute coronary syndromes, heart failure, strokes, CV deaths, and peripheral vascular events. The secondary endpoint was CVI which included coronary, carotid, or peripheral artery revascularization. We used Cox proportional hazard stepwise multivariate analyses to identify independent predictors of the primary endpoint separately in pre- and post-menopausal women. Results Of 9,529 women without prior CV disease, 57% were post-menopausal. The mean age was 47.4 years and 58.6 years for pre-menopausal and post-menopausal women, respectively. There were 793 CVEs and 83 CVIs with a median time to event of 6.6 years. Hypertension, active smoking, increased waist to hip ratio, and glycosylated hemoglobin were independent predictors of the primary endpoint in both pre- and post-menopausal women. Furthermore, advanced age, family history of myocardial infarction, prior cancer, increased gamma-glutamyl transferase, and hyperuricemia also predicted increased riks of the primary endpoint in post-menopausal women. Conclusion: Hypertension, active smoking, increased waist to hip ratio, and high glycosylated hemoglobin were associated with increased CV risk in pre-menopausal women. The impact of hypertension was markedly amplified in pre-menopausal women compared to postmenopausal women. Intensive blood pressure control should be considered in pre-menopausal women.

Background: Patients with type 2 diabetes mellitus (T2DM) are at an increased risk for developing heart failure (HF), and clinical models are needed to identify patients with a greater risk for HF hospitalization (HHF). The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM) was recently developed and validated to predict HHF in patients with T2DM in two large clinical trials (SAVOR-TIMI 53 and DECLARE-TIMI 58). We aimed to validate the TRS-HFDM in another cohort of patients with T2DM. Methods: We validated the TRS-HFDM score in 5,123 patients with T2DM for fatal or non-fatal HHF in the placebo arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes Study Group). The TRS-HFDM included: prior HF, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. We evaluated discrimination with the Harrell C index, and calibration by comparing observed event rates for HHF with predicted risk, and the Nam-D’Agostino statistic. Results: During a mean follow up of 4.8 years, 212 patients (4.14%) experienced at least one HHF. The mean age was 63 ±6.7 years, and 38% were female. The baseline hemoglobin A1C was 8.3%, and 36% were on insulin. The ACCORD patients had less comorbidities with a lower proportion of patients with renal dysfunction (8% vs. 16% vs. 17%), established cardiovascular disease (35% vs.79% vs. 41%) and pre-existing HF (5% vs. 13% vs. 10%) compared to patients enrolled in the SAVOR-TIMI 53 and DECLARE TIMI-58 trials respectively. In our cohort, the TRS-HFDM score predicted well HHF events with a Harrel C index of 0.78. The integer-based score was well calibrated, with the observed Kaplan-Meier HHF rates closely predicting the Kaplan-Meier event rates at the end follow up (Nam D`Agostino test: 65.39 (p Discussion: Our findings confirm the applicability of the TRS-HFDM in a large cohort of patients with T2DM with less high-risk features than the SAVOR-TIMI 53 and DECLARE-TIMI 58 populations. Future validation of this risk score in observational cohort studies is needed to evaluate its external validity in a general clinical setting.

Background There are conflicting data regarding the benefit of primary prevention implantable cardioverter‐defibrillators ( ICD s) in patients with diabetes mellitus and heart failure (HF) with reduced ejection fraction. We aimed to assess the comparative effectiveness of ICD placement in patients with diabetes mellitus and HF with reduced ejection fraction. Methods and Results Data were obtained from the Get With the Guidelines–Health Failure registry, linked with claims from the Centers for Medicare & Medicaid Services. We used a Cox proportional hazards model censored at 5 years with propensity score matching. Of the 17 186 patients with HF with reduced ejection fraction from the Centers for Medicare & Medicaid Services claims database (6540 with diabetes mellitus; 38%), 1677 (646 with diabetes mellitus; 39%) received an ICD during their index HF hospitalization or were prescribed an ICD at discharge. Patients with diabetes mellitus and an ICD (n=646), as compared with those without an ICD (n=1031), were more likely to be younger (74 versus 78 years of age) and have coronary artery disease (68% versus 60%). After propensity matching, ICD use among patients with diabetes mellitus, as compared with those without an ICD , was associated with a reduced risk of all‐cause mortality at 5 years after HF discharge (54% versus 59%; multivariable hazard ratio, 0.73; 95% CI , 0.64–0.82; P ICD use and all‐cause mortality ( P =0.95 for interaction). Similar results were seen in patients without diabetes mellitus. Conclusions Primary prevention ICD use among older patients with HF with reduced ejection fraction and diabetes mellitus was associated with a reduced risk of all‐cause mortality. Our analysis supports current guideline recommendations for implantation of primary prevention ICD s among older patients with diabetes mellitus and HF with reduced ejection fraction.

Background and Purpose: Chronic remote ischemic conditioning (C-RIC) is effective at improving cerebral blood flow (CBF) inducing vascular remodeling, and improving cognition in a bilateral carotid artery stenosis (BCAS) mouse model, a model for Vascular Cognitive Impairment and Dementia (VCID). This effect is lost in NOS3-KO mice. We wanted to determine if the beneficial effect of C-RIC can be restored by bone marrow cell-derived NOS3. Methods: We prepared BM chimera from adult WT (B6.SJL-Ptprc a ; CD45.1) to adult NOS3-KO (B6.129; CD45.2) & vice versa in male mice (5-6 months) following confirmation for BM engrafting with flow cytometry at 2 weeks. Microcoil (0.18 mm) induced BCAS model was used to induce chronic hypoperfusion. Mice were randomly assigned to 3-groups: (1) Sham (2) BCAS and (3) BCAS+RIC. RIC was started 7d post-surgery daily for 3-4 weeks. Behavioral test and CBF was performed before termination. Functional outcomes were assessed using novel object recognition (NOR) test for non-spatial working memory, and hanging wire and beam walk test for motor/muscular impairment. We measured whole blood P-NOS3, P-AMPK and VEGFR2/CD31 by flow cytometry. Results: C-RIC-therapy for 3-4 weeks improves CBF in engrafted BM of WT into NOS3-KO in the BCAS+RIC groups at both 2 weeks and 4 weeks compared to BCAS (Sham RIC groups).No effect of C-RIC was shown in engrafted BM of NOS3 into WT. There was significant change between the BCAS and BCAS+RIC groups in the functional outcomes and histopathological evidences also reflects major changing in the groups in the BM of WT into NOS3-KO mice. Whole blood P-NOS3, P-AMPK and VEGFR2/CD31 was increased by C-RIC. However, no effect was shown in the NOS3-KO into WT chimera. Conclusions: The Beneficial effect of C-RIC is dependent upon bone marrow derived NOS3.Further studies are needed to determine if the red blood cell is the key cell carrying NOS3

Background Improved heart failure ( HF ) risk stratification after a recent acute coronary syndrome may identify those who can benefit from therapies that reduce HF risk. We aimed to identify clinical and biomarker predictors for expanded HF outcomes in patients with type 2 diabetes mellitus after recent acute coronary syndrome. Methods and Results The EXAMINE ( Ex amination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial was a multicenter, non‐inferiority, double‐masked, placebo‐controlled study which randomized 5380 patients with type 2 diabetes mellitus after recent acute coronary syndrome to alogliptin or placebo. Baseline biomarkers were measured in 5154 patients: NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), high‐sensitivity troponin I, adiponectin, growth‐differentiation‐factor‐15, and galectin‐3. Our primary outcome was cardiovascular) death, HF hospitalization, elevated NT‐proBNP during follow‐up, or loop diuretics initiation. The association between clinical variables, biomarkers, and outcomes were assessed using Cox regression models. In the study population, the median age was 61.0 years, 67.7% were men, and 28.0% had baseline HF (median follow‐up was 18 months). In multivariable analyses, NT‐proBNP had the strongest association with the primary outcome (per log 2 , hazard ratio 1.24; Wald χ 2 67.4; P HF history (hazard ratio 1.42; Wald χ 2 20.8; P HF outcomes (C‐statistic=0.72). Discrimination results were similar for cardiovascular death or HF hospitalization. Conclusions Among patients with type 2 diabetes mellitus after recent acute coronary syndrome, the use biomarkers such as N‐terminal pro‐B‐type natriuretic peptide and clinical variables enables risk stratification for expanded HF outcomes. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00968708.

Background: Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown. Methods: The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death. Results: In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P P P =0.028). Prior stroke/systemic embolism (HR, 2.58; P >0.001) followed by troponin T (HR, 1.45; P Conclusions: Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients’ risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Zenker's diverticulum (ZD), a pulsion diverticulum of hypopharynx is a rare but treatable cause of morbidity in geriatric population. Traditionally a surgical disease but due to its associated high morbidity, flexible endoscopy has become a lucrative option. We reviewed 997 patients from 23 original studies who underwent flexible endoscopic diverticulotomy (FED) of ZD. Composite technical and clinical success rate for the study cohort was 99.4% and 87.9%, respectively. Composite failure rate was 10.0% but close to half of them (45.3%) had success with repeat endoscopic intervention. Composite rate for symptom recurrence after long-term follow-up was 13.6% but more than half (61.8%) had success with repeat endoscopic intervention. Bleeding (6.6%) and perforation (5.3%) were 2 most common complications of FED. All bleeding events were successfully managed with observation or endoscopic therapy. Majority of perforation events (4.4%) were successfully managed with conservative care and only 0.9% required invasive management. No mortality was reported. Efficacy and safety of FED of ZD remained same irrespective of diverticulum size or prior surgical/endoscopic treatment. FED with diverticuloscope (FEDD) and FED with cap (FEDC) had comparable technical success rate (99.6% vs. 100.0%) but FEDD had higher clinical success rate compared with FEDC (86.8% vs. 75.4%). FEDD had twice the risk of symptom recurrence than FEDC (16.5% vs. 9.5%). FEDD had a comparable bleeding risk to FEDC (3.3% vs. 4.0%) but a much lower perforation rate (2.3% vs. 10.3%). Upper esophageal sphincterotomy and adequate length of septotomy are the cornerstones of FED. FED can be considered a safe and efficacious treatment modality for patients with ZD.

The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency.The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation20% at the end of the study.The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16.This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.

Background Antihyperglycemic therapies may increase the risk of cardiovascular events including hospitalization for heart failure. There is a paucity of data evaluating the cardiovascular safety of antihyperglycemic therapies in the high‐risk period following an acute coronary syndrome ( ACS ). Methods and Results The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial randomized 5380 patients who were 15 to 90 days post ACS to the dipeptidyl dipeptidase‐IV ( DPP ‐ IV ) inhibitor alogliptin versus placebo; mean follow‐up was 18 months. Using a landmark analysis, we assessed the (1) burden of cardiovascular events from randomization to 6 months (early period) and from 6 months to the end of follow‐up (late period) and (2) the risk of cardiovascular events associated with early (up to 6 months) and chronic (6 months to end of follow‐up) DPP ‐ IV inhibition with alogliptin. Patients with early versus late events had similar baseline demographic profiles. Overall, 42.1% of the composite of cardiovascular death/myocardial infarction/stroke and 47.5% of hospitalization for heart failure occurred in the early period. Early DPP ‐ IV inhibition did not increase the risk of early cardiovascular death/myocardial infarction/stroke (hazard ratio 0.96, 95% confidence interval, 0.76–1.21) or hospitalization for heart failure (1.23, 95% confidence interval, 0.84–1.82). Similarly, chronic DPP ‐ IV inhibition did not increase the risk of late cardiovascular death/myocardial infarction/stroke (hazard ratio 1.03, 95% confidence interval, 0.89–1.26) or hospitalization for heart failure (hazard ratio 1.02, 95% confidence interval, 0.85–1.22). Conclusions Early after an ACS , patients with type 2 diabetes mellitus experience a significant burden of HF events and recurrent ACS . DPP ‐ IV inhibition with alogliptin appears to be safe even in the high‐risk period following an ACS .

Background: The increase in medical complexity among patients hospitalized with heart failure (HF) may be reflected by an increase in concomitant noncardiovascular comorbidities. Among patients hospitalized with HF, the temporal trends in the prevalence of noncardiovascular comorbidities have not been well described. Methods and Results: We used data from 207 984 patients in the Get With The Guidelines–Heart Failure registry (from 2005 to 2014) to evaluate the prevalence and trends of noncardiovascular comorbidities (chronic obstructive pulmonary disorder/asthma, anemia, diabetes mellitus, obesity [body mass index ≥30 kg/m 2 ], and renal impairment) among patients hospitalized with HF. Medicare beneficiaries aged ≥65 years were used to assess 30-day mortality. The prevalence of 0, 1, 2, and ≥3 noncardiovascular comorbidities was 18%, 30%, 27%, 25%, respectively. From 2005 to 2014, there was a decline in patients with 0 noncardiovascular comorbidities (22%–16%; P P P P P Conclusions: Patients admitted in hospital for HF have an increasing number of noncardiovascular comorbidities over time, which are associated with worse outcomes. Strategies addressing the growing burden of noncardiovascular comorbidities may represent an avenue to improve outcomes and should be included in the delivery of in-hospital HF care.

Introduction: Patients with diabetes mellitus (DM) and heart failure with reduced ejection fraction (HFrEF) are at increased risk of sudden death. However, given the burden of competing causes of death in patients with DM, therapies to reduce the risk of sudden death may have reduced efficacy. We aimed to assess the effectiveness of implantable cardioverter-defibrillators (ICDs) in a large US registry. Methods: We linked data from the GWTG-HF registry to the Centers for Medicare/Medicaid Services claims (January 2010 to December 2014). Using Cox proportional hazard models with propensity score matching for baseline covariates, among patients with and without DM, we compared patients who received an ICD (or were prescribed an ICD at discharge) to those without an ICD. The primary outcome was all-cause mortality. Results: Among the 17,186 patients in our study cohort, 6683 (38%) had DM. For patients with DM, those with an ICD (n=663), compared to those without and ICD, were younger (74.0 vs. 78.0 years of age), more likely to be male (66.3% vs. 55.7%) and more likely to have coronary disease (67.8% vs. 60.4%) Similar trends were seen among patients without DM (n=1,031). Among patients with DM, in matched cohorts, an ICD was associated with a reduced risk of mortality (54.4% vs. 60.0%; adjusted HR [aHR] 0.74, 95% CI 0.65-0.83; figure panel A). Similar results for mortality were seen in patients without DM (47.4% vs. 57.0%; aHR 0.68, 95% CI 0.61-0.75; figure panel B). Diabetes did not modify the relationship between ICD and mortality (interaction p-value = 0.24). Conclusion: Among patients with HFrEF, primary prevention ICD was associated with reduced mortality in patients with and without diabetes. These findings support current guideline recommendation for primary prevention ICDs among eligible patients with DM.

Background: We previously demonstrated the presence and localization of hepatic apoB100 and intestinal apoB48 in human carotid atherosclerotic plaques by immunoperoxidase, immunofluorescence (IF), immunoelectron microscopy, and western blot; however, co-localization of apoB48 and apoB100 with macrophages has not been shown. Methods: In 3 patients undergoing carotid endarterectomy (CEA), plaques were stained for apoB100/CD68 and apoB48/CD68 dual stain (DS)-IF. CD68 was used to localize macrophages. Slides were processed for antigen retrieval and incubated with primary antibodies(ApoB100: ab50069-100 rabbit polyclonal antibody recognizing the C-terminal; apoB48:Shibayagi AKHB48E goat monoclonal antibody recognizing the C-terminal; CD68: Santa Cruz Biotechnologies SC-20060 mouse monoclonal antibody) and species-specific secondary antibodies (Invitrogen;A21447,A21235,A21244, or A11010 ).Confocal microscopy was used to visualize DS-IF. Results: There is intense CD68 staining throughout the plaques, demonstrating the presence of macrophages(B,E). As previously demonstrated, both apoB100 and apoB48 are present in plaques(A,D). Importantly, while CD68 staining is present throughout the plaque and in areas independent of apoB100 and apoB48, both apoB100 and apoB48 are always co-localized with CD68(C,F). Conclusions: This is the first demonstration that both hepatic apoB100 and intestinal apoB48 co-localize with macrophages in human carotid atherosclerotic plaques.