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.

Background: In ISCHEMIA, an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular endpoints was myocardial infarction. Methods: ISCHEMIA prespecified that the primary and major secondary composite endpoints of the trial be analyzed using two MI definitions. For procedural MI, the primary MI definition used CK-MB as the preferred biomarker whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times URL for PCI and >10 times for CABG. Procedural MI definitions included (i) a category of elevated biomarker only events with much higher biomarker thresholds (ii) new ST segment depression of ≥ 1mm for the primary and ≥ 0.5 mm for the secondary definition and (iii) new coronary dissections ≥ NHLBI grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. Results: Procedural MI's accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive vs conservative strategy using the primary [2.7% vs. 1.1%; adjusted HR 2.98 (95% CI 1.87, 4.73)] and secondary [8.2% vs. 2.0%; adjusted HR 5.04 (95% CI 3.64, 6.97)] MI definitions. Type 1 MI's were less frequent with the invasive vs conservative strategy using the primary [3.40% vs. 6.89%; adjusted HR 0.53 (95% CI 0.41,0.69); p<0.0001], and secondary [3.48% vs 6.89%; adjusted HR 0.53 (95% CI 0.41, 0.69); p<0.0001] definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI compared to no MI using the primary [adjusted HR 3.38 (95% CI 2.03,5.61); p<0.001] or secondary MI definition [adjusted HR 3.52 (2.11, 5.88); p<0.001]. Conclusions: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and using the secondary MI definition. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01471522.

BACKGROUND:Psoriasis is associated with increased cardiovascular risk that is not captured by traditional pro-inflammatory biomarkers. OBJECTIVE:To investigate the relationship between psoriasis area and severity index (PASI), circulating pro-inflammatory biomarkers, and vascular health in psoriasis. METHODS:In psoriasis and age, sex-matched controls, 273 proteins were analyzed utilizing the OLINK platform, while vascular endothelial inflammation and health was measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS:= 48.18, p<0.001) in predicting vascular endothelial inflammation. LIMITATIONS/CONCLUSIONS:Our study was observational and does not allow for causal inference in the relationship between CCL20 and cardiovascular risk. CONCLUSION/CONCLUSIONS:We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.

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.

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:Platelets are increasingly recognized as immune cells. As such, they are commonly seen to induce and perpetuate inflammation, however, anti-inflammatory activities are increasingly attributed to them. Atherosclerosis is a chronic inflammatory condition. Similar to other inflammatory conditions, the resolution of atherosclerosis requires a shift in macrophages to an M2 phenotype, enhancing their efferocytosis and cholesterol efflux capabilities. OBJECTIVES/OBJECTIVE:To assess the effect of platelets on macrophage phenotype. METHODS:In several in vitro models employing murine (RAW264.7 and bone marrow derived macrophages) and human (THP-1 and monocyte-derived macrophages) cells, we exposed macrophages to media in which non-agonized human platelets were cultured for 60 minutes (platelet conditioned media; PCM) and assessed the impact on macrophage phenotype and function. RESULTS:). CONCLUSIONS:PCM induces an anti-inflammatory, pro-resolving phenotype in macrophages. Our findings suggest that therapies targeting hemostatic properties of platelets, while not influencing pro-resolving, immune-related activities, could be beneficial for the treatment of atherothrombotic disease.

Intracerebral hemorrhage (ICH) can be a devastating complication of coronavirus disease (COVID-19). We aimed to assess risk factors associated with ICH in this population. We performed a retrospective cohort study of adult patients admitted to NYU Langone Health system between March 1 and April 27 2020 with a positive nasopharyngeal swab polymerase chain reaction test result and presence of primary nontraumatic intracranial hemorrhage or hemorrhagic conversion of ischemic stroke on neuroimaging. Patients with intracranial procedures, malignancy, or vascular malformation were excluded. We used regression models to estimate odds ratios and 95% confidence intervals (OR, 95% CI) of the association between ICH and covariates. We also used regression models to determine association between ICH and mortality. Among 3824 patients admitted with COVID-19, 755 patients had neuroimaging and 416 patients were identified after exclusion criteria were applied. The mean (standard deviation) age was 69.3 (16.2), 35.8% were women, and 34.9% were on therapeutic anticoagulation. ICH occurred in 33 (7.9%) patients. Older age, non-Caucasian race, respiratory failure requiring mechanical ventilation, and therapeutic anticoagulation were associated with ICH on univariate analysis (p < 0.01 for each variable). In adjusted regression models, anticoagulation use was associated with a five-fold increased risk of ICH (OR 5.26, 95% CI 2.33-12.24, p < 0.001). ICH was associated with increased mortality (adjusted OR 2.6, 95 % CI 1.2-5.9). Anticoagulation use is associated with increased risk of ICH in patients with COVID-19. Further investigation is required to elucidate underlying mechanisms and prevention strategies in this population.

Mechanisms explaining the link between psoriasis, a proinflammatory condition, and cardiovascular disease are not fully known. PCSK9 is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism, and clinical trials targeting PCSK9 reduce cardiovascular disease. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict cardiovascular events. We used two separate human psoriasis cohorts and the K14-Rac1V12^-/+ murine model of psoriasis to investigate PCSK9 and cardiovascular risk in psoriasis. In both psoriasis cohorts (n = 88 and n = 20), PCSK9 levels were 20% and 13% higher than in age-, sex-, and cholesterol-matched controls, respectively (P < 0.05 for each comparison) and correlated with PASI (r = 0.43, P < 0.05). Despite no difference in hepatocyte expression, K14-Rac1V12^-/+ mice demonstrated skin-specific PCSK9 staining, which was confirmed in human psoriatic lesional skin. In patients with psoriasis, PCSK9 levels correlated with impaired endothelial vascular health (e.g., early atherosclerosis, β = 4.5, P < 0.01) and log converted coronary artery calcium score (β = 0.30, P = 0.01), which remained significant after adjustment for Framingham risk, body mass index, and active biologic use. Taken together, these findings suggest, independent of cholesterol, an association between circulating PCSK9 and early as well as advanced stages of atherosclerosis in psoriasis.