Faculty Bibliography

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: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.

Background Mendelian randomization studies suggest that lifelong modest reductions of LDL cholesterol are associated with fewer major adverse cardiovascular events (MACE). We explored the relationship between the magnitude of LDL reduction from lipid lowering therapy, the duration of time over which LDL was reduced, and risk of MACE. Methods Randomized controlled trials of guideline-recommended LDL lowering therapy with >1000 participants and >2 year follow-up were systematically identified. Cross products of net LDL reduction and duration of follow-up were calculated. MACE was defined as the composite endpoint of cardiovascular death, acute coronary syndrome, revascularization, and stroke as available for each trial. Correlations were performed using the Pearson test. Results A total of 33 RCTs enrolling 249,887 participants with 50-month median follow-up were included. Trials tested statins (n=29), ezetimibe (n=2), and PCSK9 inhibitors (n=2). The cross product of LDL reduction and duration of therapy correlated with the relative risk reduction of MACE (r²=0.15; p=0.03). This association was most robust in secondary prevention trials (r²=0.44; p=0.0003). A significant correlation was not observed between LDL lowering and MACE without the dimension of time. Conclusion Our findings suggest that the intensity and duration of LDL lowering is most strongly correlated with MACE. These findings suggest potential benefit of early initiation of lipid lowering therapy in at risk patients. [Formula presented]
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Background Adults hospitalized with coronavirus disease-2019 (COVID-19) are at increased risk for thrombosis. Relationships between age and sex and the incidence and outcomes of thrombosis in COVID-19 are unknown. Methods We included consecutive adults age >=18 years hospitalized with COVID-19 from March 1^st to April 17^th 2020 at a large New York health system. In-hospital thrombosis and all-cause mortality were determined. The incidence of death and thrombosis were evaluated in subgroups by age and sex. Multivariable logistic regression models were used to estimate the odds of an event adjusted for demographics and clinical covariates. Results Among 3334 COVID-19 patients, 61% were men. Men had a higher incidence of thrombosis (19% vs. 12%; aOR 1.60, 95% CI 1.30-1.97) and death or thrombosis (23% vs. 25%; aOR 1.18, 95% CI 1.00-1.41) than women. Sex differences in thrombotic risk were greatest in the youngest individuals and attenuated with older age (18-54 years: aOR 3.89, 95% CI 2.24-7.05; 55-74 years: aOR 1.69, 95% CI 1.21-2.41; >=75 years: aOR 1.07, 95% CI 0.74-1.54 for men versus women). In both sexes, COVID-19 with versus without thrombosis was associated with higher in-hospital mortality (43% vs. 21%, p<0.001; aOR 3.21, 95%CI 2.63-3.92). Conclusion Men hospitalized with COVID-19 have a greater risk of thrombosis than women. And sex differences were most pronounced among younger patients. Mechanisms of differential thrombotic risk by sex in COVID-19 are unknown and require further study. [Formula presented]
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OBJECTIVE:Hydroxychloroquine (HCQ) is a mainstay of therapy in the treatment of SLE. The effect of HCQ on platelets and vascular health is uncertain. We investigated the relationship between HCQ use and dose with platelet activity, platelet transcriptomics and vascular health in patients with SLE. METHODS:Platelet aggregation, platelet mRNA expression and vascular health (sublingual capillary perfused boundary region (PBR), red blood cell filling (RBCF) and brachial artery reactivity testing) were analysed by HCQ use and dose. RESULTS:Among 132 subjects with SLE (age: 39.7±12.9 years, 97% female), 108 were on HCQ. SLE disease activity was similar between subjects on and off HCQ. Platelet aggregation in response to multiple agonists was significantly lower in patients on HCQ. There were inverse relationships between HCQ dose and gene expression pathways of platelet activity. Gene expression of P-selectin (SELP) was inversely correlated with HCQ dose (r=-0.41, p=0.003), which was validated at the protein level. Subjects on HCQ had improved vascular function correlating with HCQ dose as measured by lower PBR (r=-0.52, p=0.007), higher RBCF (r=0.55, p=0.004) and greater brachial artery reactivity (r=0.43, p=0.056). CONCLUSION/CONCLUSIONS:HCQ use was associated with decreased platelet activation and activation-related transcripts and improved vascular health in SLE.

Thrombosis is a major concern in respiratory infections. Our aim was to investigate the magnitude and duration of risk for arterial and venous thrombosis following discharge after respiratory infection. Patients with respiratory infections were identified using the United States Nationwide Readmission Database from 2012 to 2014. Patients admitted with asthma or cellulitis served as comparators. Readmissions for acute myocardial infarction (MI) and venous thromboembolism (VTE) were evaluated at 30 to 180 days. The likelihood of a first thrombotic event after discharge was compared with a 30-day period prior to hospitalization. Among 5,271,068 patients discharged after a respiratory infection, 0.56% and 0.78% were readmitted within 30-days with MI and VTE, respectively. Relative to asthma and cellulitis, respiratory infection was associated with a greater age and sex-adjusted hazard of 30-day readmission for MI (adjusted HR [aHR] 1.48 [95% CI 1.42-1.54] vs. asthma; aHR 1.36 [95% CI 1.31-1.41] vs. cellulitis) and VTE (aHR 1.28 [95% CI 1.24-1.33] vs. asthma; aHR 1.26, [95% CI 1.22-1.30] vs. cellulitis). Risks of MI and VTE attenuated over time. In a crossover-cohort analysis, the odds of MI (OR 1.68 [95% CI 1.62-1.73]) and VTE (OR 3.30 [95% 3.19-3.41]) were higher in the 30 days following discharge after respiratory infection than during the 30-day baseline period. Hospitalization for respiratory infection was associated with increased risks of thrombosis that were highest in the first 30-days after discharge and declined over time.

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.

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.