Faculty Bibliography

BACKGROUND:A systemic inflammatory response is observed in coronavirus disease 2019 (COVID-19). Elevated serum levels of C-reactive protein (CRP), a marker of systemic inflammation, are associated with severe disease in bacterial or viral infections. We aimed to explore associations between CRP concentration at initial hospital presentation and clinical outcomes in patients with COVID-19. METHODS AND RESULTS/RESULTS:Consecutive adults aged ≥18 years with COVID-19 admitted to a large New York healthcare system between 1 March and 8 April 2020 were identified. Patients with measurement of CRP were included. Venous thrombo-embolism (VTE), acute kidney injury (AKI), critical illness, and in-hospital mortality were determined for all patients. Among 2782 patients hospitalized with COVID-19, 2601 (93.5%) had a CRP measurement [median 108 mg/L, interquartile range (IQR) 53-169]. CRP concentrations above the median value were associated with VTE [8.3% vs. 3.4%; adjusted odds ratio (aOR) 2.33, 95% confidence interval (CI) 1.61-3.36], AKI (43.0% vs. 28.4%; aOR 2.11, 95% CI 1.76-2.52), critical illness (47.6% vs. 25.9%; aOR 2.83, 95% CI 2.37-3.37), and mortality (32.2% vs. 17.8%; aOR 2.59, 95% CI 2.11-3.18), compared with CRP below the median. A dose response was observed between CRP concentration and adverse outcomes. While the associations between CRP and adverse outcomes were consistent among patients with low and high D-dimer levels, patients with high D-dimer and high CRP have the greatest risk of adverse outcomes. CONCLUSIONS:Systemic inflammation, as measured by CRP, is strongly associated with VTE, AKI, critical illness, and mortality in COVID-19. CRP-based approaches to risk stratification and treatment should be tested.

Contemporary approaches to cardiovascular risk stratification before noncardiac surgery focus on macrovascular atherosclerotic disease and risk factors. We sought to determine the prevalence of microvascular disease (MVD) and its associated perioperative outcomes. Adults ≥18 years old undergoing noncardiac surgery between 2004 and 2014 were identified using the Nationwide Inpatient Sample (NIS). Prevalent MVD (retinopathy, neuropathy, and nephropathy) was identified by ICD-9 diagnosis codes. The primary outcomes were all-cause in-hospital mortality and the composite of major adverse cardiac events (MACE; death, myocardial infarction, and ischemic stroke). Multivariable logistic regression models were used to estimate associations between MVD and outcomes after adjusting for demographics and clinical covariates. Among 81,297,003 hospitalizations for noncardiac surgery, 4,236,932 (5.0%) had a diagnosis of MVD. Patients with MVD were older and more likely to have traditional cardiovascular risk factors. In-hospital perioperative MACE (4.1% vs. 1.9%; adjusted odds ratio [aOR] 1.15, 95% confidence interval [CI] 1.13 to 1.17) and mortality (2.0% vs. 1.1%; aOR 1.15, 95% CI 1.12 to 1.17) were greater in hospitalizations with MVD compared with those without. Microvascular disease was associated with postoperative outcomes in when stratified by age, sex, and coronary artery disease (CAD). Compared with surgical hospitalizations without CAD or MVD, MVD alone (aOR 1.12; 95% CI 1.11 to 1.14), CAD alone (aOR 1.44; 95% CI 1.42 to 1.46), and MVD with CAD (aOR 2.01; 95% CI 1.96 to 2.06) were associated with perioperative MACE. In conclusion, microvascular disease was present in 1 in 20 hospitalizations for noncardiac surgery, and was associated with perioperative mortality and MACE independent of macrovascular disease and traditional risk factors.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 6-15% of MI and disproportionately affects women. Scientific statements recommend multi-modality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance imaging (CMR) to assess mechanisms of MINOCA. Methods: In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of MI. If invasive coronary angiography revealed <50% stenosis in all major arteries, multi-vessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and/or T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and non-ischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible. Results: Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intra-plaque cavity or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% of participants undergoing CMR (62/116). A non-ischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome or non-ischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% of the women with multi-modality imaging (98/116), higher than with OCT alone (p<0.001) or CMR alone (p=0.001). An ischemic etiology was identified in 63.8% of women with MINOCA (74/116), a non-ischemic etiology was identified in 20.7% (24/116), and no mechanism was identified in 15.5% (18/116). Conclusions: Multi-modality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, three-quarters of which were ischemic and one-quarter of which were non-ischemic, alternate diagnoses to MI. Identification of the etiology of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02905357.

OBJECTIVE:To better characterize COVID-19 patients most at risk for severe, outpatient thrombosis by defining patients hospitalized with COVID-19 with an arterial or venous thrombosis diagnosed at admission METHODS AND RESULTS: We conducted a single center retrospective analysis of COVID-19 patients. There was a shift in the proportions of thrombosis subtypes from 2019 to 2020, with declines in STEMI (from 22.0% to 10.1% of thrombotic events) and stroke (from 48.6% to 37.2%), and an increase in the proportion of patients with VTE (29.4% to 52.7%). COVID-associated thrombosis were younger (58 years vs. 64 years, p=0.043), trended to be less frequently female (31.3% vs. 43.9%, p =0.16), but there was no difference body mass index or major comorbidities between those with and without COVID-19. COVID-19-associted thrombosis was correlated with a higher mortality (15.2% vs. 4.3%, p=0.016). The biometric profile of patients admitted with COVID-associated thrombosis compared to regular thrombosis had significant changes in the complete blood count, liver function tests, d-dimer, c-related protein, ferritin, and coagulation panels. CONCLUSIONS:Outpatients with COVID-19 who developed thrombosis requiring hospitalization have an increased mortality over non-COVID-19 outpatients who develop thrombosis requiring hospitalization. Given the significantly higher inflammatory markers, it is possible this is related to different mechanisms of thrombotic disease in these patients. The inflammation may be a target to reduce the risk of or aid in the treatment of thrombosis. We call for more studies elucidating the role immunothrombosis maybe playing in COVID.

BACKGROUND:Perioperative cardiovascular events are a leading cause of morbidity and mortality after non-cardiac surgery. We propose a simplified method for perioperative risk stratification. METHODS:A retrospective cohort study identified patients undergoing non-cardiac surgery between 2009-2015 in the United States National Surgical Quality Improvement Program. Multivariable logistic regression models adjusted for age, sex, race and surgery type were generated to estimate the impact of traditional cardiovascular risk factors (hypertension, diabetes mellitus, current smoking) on odds of perioperative myocardial infarction (MI). Time to event analysis was conducted using competing risk analysis, with MI as the outcome event and death as the competing risk. RESULTS:A total of 3,848,501 non-cardiac surgeries were identified. Post-operative MI occurred in 0.37% of patients and 1.04% of patients died. The 30-day event rate of perioperative MI increased in a stepwise fashion with additional risk factors (0.41% for one, 0.81% for two, and 1.07% for three; P-for-trend < 0.001) after accounting for the competing risk of death. In comparison to those with no risk factors, patients with one, two and three risk factors had increased odds of MI (aOR 2.07; 95% CI 1.96-2.19; aOR 3.63 95% CI 3.43-3.85; aOR 5.54 95% CI 5.09-6.04). Perioperative MI was rare (0.10%) in patients without risk factors. CONCLUSIONS:Patients with cardiovascular risk factors are at increased risk of perioperative MI, those without risk factors are at low risk. Further evaluation is needed to determine the impact of a simplified risk score in the perioperative setting.

BACKGROUND:Heart failure (HF) affects ∼5.7 million United States adults and many of these patients develop non-cardiac disease that requires surgery. The aim of this study was to determine perioperative outcomes associated with HF in a large cohort of patients undergoing in-hospital non-cardiac surgery. METHODS:Adults ≥18 years old undergoing non-cardiac surgery between 2012-2014 were identified using the HCUP National Inpatient Sample. Patients with HF were identified by ICD-9 diagnosis codes. The primary outcome was all-cause in-hospital mortality. Multivariable logistic regression models were used to estimate associations between HF and outcomes. RESULTS:A total of 21,560,996 surgical hospitalizations were identified, of which 1,063,405 (4.9%) had a diagnosis of HF. Among hospitalizations with HF, 4.7% had acute HF, 11.3% had acute on chronic HF, 27.8% had chronic HF, and 56.2% had an indeterminate diagnosis code that did not specify temporality. In-hospital perioperative mortality was more common with a diagnosis of any HF compared to without HF (4.8% vs. 0.78%, p < 0.001; adjusted OR [aOR] 2.15 [95% CI 2.09-2.22]), and the association between HF and mortality was greatest at small and non-teaching hospitals. Acute HF without chronic HF was associated with 8.0% mortality. Among patients with a chronic HF diagnosis, perioperative mortality was greater in those with acute on chronic HF compared to chronic HF alone (7.8% vs. 3.9%, p < 0.001; aOR 1.78, 95% CI 1.67-1.90). CONCLUSION/CONCLUSIONS:In patients hospitalized for non-cardiac surgery, HF was common and was associated with increased risk of perioperative mortality. The greatest risks were in patients with acute HF.

Background/Purpose: Patients with systemic lupus erythematosus (SLE) are at increased risk of premature atherosclerosis and thrombosis. Hydroxychloroquine (HCQ) is widely used in the treatment of SLE and has been considered of benefit for overall vascular health albeit studies to address this benefit at the cellular level have been limited. Accordingly, this study was initiated to investigate the relationship between HCQ use and dose with platelet activity, the platelet transcriptome, and vascular functional readouts.
Method(s): Patients fulfilling ACR or SLICC criteria for SLE were consecutively recruited for platelet evaluation with the only exclusion being on nonsteroidal anti-inflammatory medications, aspirin or anticoagulants. At enrollment, blood was collected for hematology analysis using the Sysmex XN-1000 analyzer, platelet aggregation via the Helena AggRAMTM system, and platelet RNA isolation and storage. Microvascular function was assessed via sublingual sidestream darkfield imaging. Brachial artery reactivity testing was used to evaluate large vessel function. Stored platelet RNA was isolated and analyzed by RNA sequencing (Illumina HiSeq4000 Sequencing).
Result(s): Among 132 SLE subjects, 108 were on HCQ. Mean age was 39.9 +/- 13.0 and 97% were female. Lupus disease activity at the time of blood draw assessed by the SELENA-SLEDAI activity index was 3.44 (range 0-20). Demographics and SLE disease activity did not differ between those on versus off HCQ (Table 1). Platelet count and size were not different between groups (Figure 1A). Platelet aggregation in response to submaximal ADP at multiple concentrations was lower in participants on HCQ (Figure 1B). Consistently, there was an inverse relationship between HCQ dosing and platelet aggregation in response to ADP (2uM: R=-0.213, P=0.037; 1uM: R=-0.310, P=0.0025; 0.4uM: R=-0.376, P=0.00018; Figure 1C). Since no subjects were on aspirin (or any other antiplatelet therapy at enrollment), aggregation in response to arachidonic acid (AA) was robust and similar between groups. However, after incubating platelets with aspirin (3mM) in vitro, platelet aggregation in response to AA was lower in the HCQ group compared to non-HCQ group (P=0.035, Figure 1B). To investigate the potential mechanisms of HCQ induced lower platelet aggregation, we evaluated platelet RNA sequencing in 49 subjects (8 no HCQ, 41 on HCQ). Positive regulation of pathways related to platelet activation (and in particular, P-selectin expression) was inversely related to HCQ, especially with higher doses (Figure 1E). In terms of vascular function, subjects on HCQ had improved microvascular function as noted by an increased proportion of sublingual capillaries filled with RBCs (P=0.011) and smaller perfused boundary region (PBR, P=0.010). HCQ dosing correlated with PBR (R=-0.599, P=0.002, Figure 1H) and RBC Filling (R=-0.592, P=0.002, Figure 1I). BART also trended positively with HCQ dose (R=0.385, P=0.094; Figure 1J).
Conclusion(s): These findings suggest that HCQ may provide benefit for vascular health in SLE as supported by ex vivo experiments demonstrating decreased platelet aggregation and downregulation of platelet functional pathways as well as improved vascular readouts