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Microvascular endothelial glycocalyx thickness is associated with brachial artery flow-mediated dilation [Letter]

Smilowitz, Nathaniel R; Luttrell-Williams, Elliot; Golpanian, Michael; Engel, Alexis; Buyon, Jill P; Katz, Stuart D; Berger, Jeffrey S
PMID: 34278881
ISSN: 1477-0377
CID: 4947892

Thrombosis at Hospital Presentation in Patients with and without COVID-19

Brosnahan, Shari B; Smilowitz, Nathaniel R; Amoroso, Nancy E; Barfield, Michael; Berger, Jeffery S; Goldenberg, Ronald; Ishida, Koto; Talmor, Nina; Torres, Jose; Yaghi, Shadi; Yuriditsky, Eugene; Maldonado, Thomas
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.
PMID: 33186750
ISSN: 2213-3348
CID: 4672082

Perioperative cardiovascular outcomes among older adults undergoing in-hospital noncardiac surgery

Banco, Darcy; Dodson, John A; Berger, Jeffrey S; Smilowitz, Nathaniel R
BACKGROUND:Older adults undergoing noncardiac surgery have a high risk of major adverse cardiovascular events (MACE). This study aims to estimate the magnitude of increased perioperative risk, and examine national trends in perioperative MACE following in-hospital noncardiac surgery in older adults compared to middle-aged adults. DESIGN/METHODS:Time-series analysis of retrospective longitudinal data. SETTING/METHODS:The United States Agency for Healthcare Research and Quality National Inpatient Sample (NIS). PARTICIPANTS/METHODS:Hospitalizations for major noncardiac surgery among adults age ≥45 years between January 2004 and December 2014. MEASUREMENTS/METHODS:Inpatient perioperative MACE was defined as a composite of in-hospital death, myocardial infarction (MI), and ischemic stroke. In hospital death was determined from the NIS discharge disposition. MI and ischemic stroke were defined by International Classification of Diseases, Ninth Revision codes. RESULTS:Of an estimated 55,349,978 surgical hospitalizations, 26,423,039 (47.7%) were for adults age 45-64, 14,231,386 (25.7%) age 65-74, 10,621,029 (19.2%) age 75-84 years, and 4,074,523 (7.4%) age ≥85 years. MACE occurred in 1,601,022 surgical hospitalizations (2.9%). Adults 65-74 (2.8%; aOR 1.16, 95% CI 1.14-1.17), 75-84 years (4.5%; aOR 1.30, 95% CI 1.28-1.32), and ≥85 years (6.9%; aOR 1.55, 95% CI 1.52-1.57) had greater risk of MACE than those 45-64 years (1.7%). From 2004 to 2014, MACE declined among adults 65-74 (3.1-2.5%, p < 0.001), 75-85 years (4.9-3.9%, p < 0.001), and ≥85 years (7.7-6.1%, p < 0.001), but was unchanged for adults age 45-64. Declines in MACE were driven by decreased MI and mortality despite increased stroke. CONCLUSION/CONCLUSIONS:Older adults accounted for half of hospitalizations, but experienced the majority of MACE. Older adults had greater adjusted odds of MACE than younger individuals. The proportion of perioperative MACE declined over time, despite increases in ischemic stroke. These data highlight risks of noncardiac surgery in older adults that warrant increased attention to improve perioperative outcomes.
PMID: 34176124
ISSN: 1532-5415
CID: 4965592

C-reactive protein and clinical outcomes in patients with COVID-19

Smilowitz, Nathaniel R; Kunichoff, Dennis; Garshick, Michael; Shah, Binita; Pillinger, Michael; Hochman, Judith S; Berger, Jeffrey S
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.
PMID: 33448289
ISSN: 1522-9645
CID: 4785432


Redel-Traub, G; Smilowitz, N; Weintraub, H; Schwartzbard, A; Berger, J
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]
ISSN: 0735-1097
CID: 4884632


Wilcox, T; Smilowitz, N; Berger, J
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 1st to April 17th 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]
ISSN: 0735-1097
CID: 4884292

Multiple Biomarker Approach to Risk Stratification in COVID-19 [Letter]

Smilowitz, Nathaniel R; Nguy, Vuthy; Aphinyanaphongs, Yindalon; Newman, Jonathan D; Xia, Yuhe; Reynolds, Harmony R; Hochman, Judith S; Fishman, Glenn I; Berger, Jeffrey S
PMID: 33587646
ISSN: 1524-4539
CID: 4786532

Hydroxychloroquine is associated with lower platelet activity and improved vascular health in systemic lupus erythematosus

Cornwell, MacIntosh Grant; Luttrell-Williams, Elliot S; Golpanian, Michael; El Bannoudi, Hanane; Myndzar, Khrystyna; Izmirly, Peter; Belmont, H Michael; Katz, Stuart; Smilowitz, Nathaniel R; Engel, Alexis; Clancy, Robert; Ruggles, Kelly; Buyon, Jill P; Berger, Jeffrey S
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.
PMID: 33737451
ISSN: 2053-8790
CID: 4818092

Risk of thrombotic events after respiratory infection requiring hospitalization

Smilowitz, Nathaniel R; Subashchandran, Varun; Newman, Jonathan; Barfield, Michael E; Maldonado, Thomas S; Brosnahan, Shari B; Yuriditsky, Eugene; Horowitz, James M; Shah, Binita; Reynolds, Harmony R; Hochman, Judith S; Berger, Jeffrey S
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.
PMID: 33602977
ISSN: 2045-2322
CID: 4787172

Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of MINOCA in Women

Reynolds, Harmony R; Maehara, Akiko; Kwong, Raymond Y; Sedlak, Tara; Saw, Jacqueline; Smilowitz, Nathaniel R; Mahmud, Ehtisham; Wei, Janet; Marzo, Kevin; Matsumura, Mitsuaki; Seno, Ayako; Hausvater, Anais; Giesler, Caitlin; Jhalani, Nisha; Toma, Catalin; Har, Bryan; Thomas, Dwithiya; Mehta, Laxmi S; Trost, Jeffrey; Mehta, Puja K; Ahmed, Bina; Bainey, Kevin R; Xia, Yuhe; Shah, Binita; Attubato, Michael; Bangalore, Sripal; Razzouk, Louai; Ali, Ziad A; Bairey-Merz, C Noel; Park, Ki; Hada, Ellen; Zhong, Hua; Hochman, Judith S
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: Unique Identifier: NCT02905357.
PMID: 33191769
ISSN: 1524-4539
CID: 4672212