Faculty Bibliography

BACKGROUND:Real-world data on the clinical outcomes of heart failure (HF) across the spectrum of ejection fraction (EF) and the prognostic value of B-type natriuretic peptide (BNP) have not been well examined. HYPOTHESIS/OBJECTIVE:The real-world association between the clinical outcomes of HF and EF or BNP levels may differ across different EF or BNP values. METHODS:The Optum Integrated Claims-Clinical data (07/2009-09/2016) was used to identify adult patients with ≥1 HF diagnosis during a hospitalization or emergency room visit. Three EF cohorts were formed: reduced (rEF; EF<40%), mid-range (mrEF; EF 40%-49%), and preserved EF (pEF; EF≥50%). Stratifications by BNP levels were performed using median BNP as cutoff between high versus low BNP (H-BNP vs. L-BNP). RESULTS:In total, 7,005 HF patients with EF measurements (2,456 patients with both HF and BNP measurements) were identified. rEF patients had higher risk of stroke (HR=1.57, P=0.010) and AMI (HR=2.42, P<0.001) compared to pEF patients. H-BNP was associated with a significantly higher risk of mortality (P<0.001). rEF patients with H-BNP had a significantly higher risk of stroke than those with L-BNP. CONCLUSIONS:Patients with rEF had a significantly higher rate of stroke and AMI versus pEF patients, as did patients with H-BNP versus L-BNP. This study is the first to show the real-world association of EF and BNP (alone and in combination) with clinical outcomes, further supporting the recommendation to use these markers in clinical practice. These results may help guide future recommendations and improve the clinical management of HF.

BACKGROUND:Coronary artery disease accelerates heart failure progression, leading to poor prognosis and a substantial increase in morbidity and mortality. This study was aimed to assess the impact of coronary artery disease on all-cause mortality, myocardial infarction (MI), and ischemic stroke (IS) among hospitalized newly-diagnosed heart failure (HF) patients with left ventricular systolic dysfunction (LVSD). METHODS:This retrospective cohort study included Medicare patients (aged ≥65 years) with ≥1 inpatient heart failure claim (index date = discharge date) during 01JAN2007-31DEC2013. Patients were required to have continuous enrollment for ≥1-year pre-index date (baseline: 1-year pre-index period) without a prior heart failure claim (in the 1 year pre-index prior to the index hospital admission); follow-up ran from the index date to death, disenrollment from the health plan, or the end of the study period, whichever occurred first. HF with LVSD patients, identified with diagnosis codes of systolic dysfunction (excluding baseline atrial fibrillation), were stratified based on prevalent coronary artery disease at baseline into coronary artery disease and non-coronary artery disease cohorts. Main outcomes were occurrence of major adverse cardiovascular events including all-cause mortality, myocardial infarction, and ischemic stroke. Propensity score matching (PSM) was used to balance patient characteristics. Kaplan-Meier curves of ACM and cumulative incidence distribution of MI/IS were presented. RESULTS:Of 22,230 HF with LVSD patients, 15,827 (71.2%) had coronary artery disease and were overall more likely to be younger (79.8 vs 80.9 years), male (49.6% vs. 35.6%), white (86.2% vs 81.4%), with more prevalent comorbidities including hypertension (80.7% vs 74.3%), hyperlipidemia (67.7% vs 46.7%), and diabetes (46.3% vs 35.8%) (all p < 0.0001). After propensity score matching, cohorts included 5792 patients each. The coronary artery disease cohort had significantly higher cumulative incidence of myocardial infarction and ischemic stroke at the end of 7-year follow-up vs non-coronary artery disease (myocardial infarction = 50.0% vs 18.0%; ischemic stroke = 23.3% vs 18.7%; all p < 0.0001). Follow-up all-cause mortality rates were similar between the two cohorts. CONCLUSIONS:HF with LVSD patients with coronary artery disease had significantly higher incidence of ischemic stroke and myocardial infarction, but similar all-cause mortality compared to those without coronary artery disease.

BACKGROUND AND AIMS/OBJECTIVE:Platelets are a major culprit in the pathogenesis of cardiovascular disease (CVD). Circulating monocyte-platelet aggregates (MPA) represent the crossroads between atherothrombosis and inflammation. However, there is little understanding of the platelets and monocytes that comprise MPA and the prevalence of MPA in different CVD phenotypes. We aimed to establish (1) the reproducibility of MPA over time in circulating blood samples from healthy controls, (2) the effect of aspirin, (3) the relationship between MPA and platelet activity and monocyte subtype, and (4) the association between MPA and CVD phenotype (coronary artery disease, peripheral artery disease [PAD], abdominal aortic aneurysm, and carotid artery stenosis). METHODS AND RESULTS/RESULTS:platelets in healthy subjects and in patients with CVD. We found that MPA did not significantly differ over time in healthy controls, nor altered by aspirin use. Compared with healthy controls, MPA were significantly higher in CVD (9.4% [8.2, 11.1] vs. 21.8% [11.5, 44.1], p < 0.001) which remained significant after multivariable adjustment (β = 9.1 [SER = 3.9], p = 0.02). We found PAD to be associated with a higher MPA in circulation (β = 19.3 [SER = 6.0], p = 0.001), and among PAD subjects, MPA was higher in subjects with critical limb ischemia (34.9% [21.9, 51.15] vs. 21.6% [15.1, 40.6], p = 0.0015), and significance remained following multivariable adjustment (β = 14.77 (SE = 4.35), p = 0.001). CONCLUSIONS:Circulating MPA are a robust marker of platelet activity and monocyte inflammation, unaffected by low-dose aspirin, and are significantly elevated in subjects with CVD, particularly those with PAD.

Background/UNASSIGNED:Perioperative cardiovascular outcomes of transplant surgery are not well defined. We evaluated the incidence of perioperative major cardiovascular and cerebrovascular events (MACCE) after non-cardiac transplant surgery from a large database of hospital admissions from the United States. Methods/UNASSIGNED:Patients ≥18 years of age undergoing non-cardiac solid organ transplant surgery from 2004 to 2014 were identified from the Healthcare Cost and Utilization Project's (HCUP) National Inpatient Sample (NIS). The primary outcome was perioperative MACCE, defined as in-hospital death, myocardial infarction (MI), or ischemic stroke. Results/UNASSIGNED:A total of 49,978 hospitalizations for transplant surgery were identified. Renal (67.3%), liver (21.6%), and lung (6.7%) transplantation were the most common surgeries. Perioperative MACCE occurred in 1,539 transplant surgeries (3.1%). Recipients of organ transplantation were more likely to have perioperative MACCE in comparison to non-transplant, non-cardiac surgery (3.1% vs. 2.0%, p < 0.001; adjusted OR [aOR] 1.29, 95% CI 1.22-1.36). MACCE after transplant surgery were driven by increased mortality (1.7% vs. 1.1%, p < 0.001; aOR 1.15, 95% CI 1.07-1.23) and MI (1.2% vs. 0.6%, p < 0.001; aOR 2.26, 95% CI 2.09-2.46) versus non-transplant surgery, with lower rates of stroke (0.3% vs. 0.5%, p < 0.001; aOR 0.56, 95% CI 0.47-0.65). Among patients hospitalized for renal, liver, and lung transplantation, MACCE occurred in 1.7%, 5.6%, and 7.5%, respectively, with no difference in the frequency of MI by surgery type. Conclusions/UNASSIGNED:Cardiovascular outcomes of transplant surgery vary by surgical subtype and are largely driven by increased perioperative death and MI. Efforts to reduce cardiovascular risks of non-cardiac organ transplant surgery are necessary.

Importance/UNASSIGNED:Patients with peripheral artery disease (PAD) are at high risk for myocardial infarction (MI). Objective/UNASSIGNED:To characterize the incidence and types of MI in a PAD population, identify factors associated with MI, and determine the association of MI with cardiovascular mortality and acute limb ischemia. Design, Setting, and Participants/UNASSIGNED:The Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) was a double-blind randomized clinical trial conducted at 811 sites in 28 countries that randomized 13 885 patients with symptomatic PAD to monotherapy with ticagrelor or clopidogrel. Participants had an ankle-brachial index (ABI) of 0.80 or less or previous lower extremity revascularization. Median follow-up was 30 months. For these analyses, patients were evaluated for MI occurrence during follow-up irrespective of treatment. Data were analyzed from June 2017 to September 2018. Main Outcomes and Measures/UNASSIGNED:An adjudication clinical events committee classified MI as type 1 (spontaneous), type 2 (secondary), type 3 (sudden cardiac death), type 4a (less than 48 hours after percutaneous coronary intervention), type 4b (definite stent thrombosis), or type 5 (less than 72 hours after coronary artery bypass graft). A multivariate regression model was developed by stepwise selection to identify factors associated with MI, and a time-dependent multivariate Cox regression analysis was performed to determine the association of MI with cardiovascular death and acute limb ischemia requiring hospitalization. Results/UNASSIGNED:Of the 13 885 patients included in this analysis, 9997 (72.0%) were male, and the median (interquartile range) age was 66 (60-73) years. Myocardial infarction occurred in 683 patients (4.9%; 2.4 events per 100 patient-years) during a median follow-up of 30 months. Patients experiencing MI were older (median [interquartile range] age, 69 [62-75] vs 66 [60-72] years), more likely to have diabetes (349 of 683 [51.1%] vs 4996 of 13 202 [37.8%]) or a previous lower extremity revascularization (466 of 683 [68.2%] vs 7409 of 13 202 [56.1%]), and had a lower ABI (if included by ABI) compared with censored patients. Of the 683 patients with MI during follow-up, the most common MI type was type 1 (405 [59.3%]), followed by type 2 (236 [34.6%]), type 4a (14 [2.0%]), type 3 (12 [1.8%]), type 4b (11 [1.6%]), and type 5 (5 [0.7%]). Postrandomization MI was independently associated with cardiovascular death (adjusted hazard ratio, 9.0; 95% CI, 7.3-11.2; P < .001) and acute limb ischemia requiring hospitalization (adjusted hazard ratio, 2.5; 95% CI, 1.3-5.0; P = .008). Conclusions and Relevance/UNASSIGNED:Approximately 5% of patients with symptomatic PAD had an MI during a median follow-up of 30 months. Type 1 MI (spontaneous) was the most common MI type; however, one-third of MIs were type 2 MI (secondary). More research is needed to identify therapies to reduce the risk of MI in patients with PAD and to improve management of type 2 MI. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01732822.

Chronic inflammation drives many obesity-associated conditions, including atherosclerosis. GlycA, a marker of systemic inflammation with lower intraindividual variability than hsCRP, is independently associated with incident cardiovascular events and mortality. Although GlycA is elevated in obesity, correlations with anthropometric measures are modest and the effect of weight loss on GlycA is untested. Obese (BMI 44.6±6.6kg/m² ), non-diabetic women (33.7±8.2 years) undergoing Roux-en-Y gastric bypass (n=23) or sleeve gastrectomy (n=31) were prospectively studied at baseline, 6 and 12 months post-procedure. Women with normal BMI (n=14) served as controls. Bariatric surgery significantly reduced GlycA by 6 months (451±47umol/L vs 383±50umol/L; p<0.001) with further reduction at 12 months (348±41umol/L; p<0.001) and no difference between procedures. At 12 months, despite 41% of surgical subjects maintaining BMI >30kg/m² , GlycA levels did not differ between surgical and control subjects (p=0.13). Increased HDL particle size was strongly associated with reduced GlycA (r=-0.49; p<0.001) and was found to mediate up to 43% of its weight-loss-associated fall. This is the first study to demonstrate that surgical weight loss markedly reduces levels of GlycA.

The human genome encodes thousands of long non-coding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, that regulates cellular and systemic cholesterol homeostasis. LncRNA CHROME expression is influenced by dietary and cellular cholesterol via the sterol-activated liver X receptor transcription factors, which control genes mediating responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and HDL biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. CHROME knockdown in human hepatocytes and macrophages increases levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing expression of their overlapping target gene networks and associated biologic functions. In particular, cells lacking CHROME show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify CHROME as a central component of the non-coding RNA circuitry controlling cholesterol homeostasis in humans.