Faculty Bibliography

BACKGROUND:There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). METHODS:We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. RESULTS:Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. CONCLUSIONS:We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

Background Psoriasis is an inflammatory disease of the skin associated with heightened cardiovascular (CV) disease. Serum levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) associates with future CV risk and vascular dysfunction. We aimed to identify the relationship between pro-inflammatory pathways, circulating PCSK9, and vascular health in psoriasis. Methods Whole blood transcriptomics and serum proteomics was performed in 20 patients with psoriasis (mean age 42 +/- 14 years, 55% male, psoriasis area and severity index [PASI] 5 [3 - 11]) and 15 controls (mean age 41 +/- 14 years, 53% male) recruited into a clinical trial to assess vascular health in psoriasis (NCT03228017). Vascular health was assessed through flow mediated dilatation (FMD) and harvesting and analysis of brachial vein endothelial cells. Results Circulating PCSK9 was found to be 1.13-fold higher in psoriasis compared to controls (p=0.02) despite no difference in LDL-C (108 +/- 38 mg/dl vs. 90 +/- 25 mg/dl, respectively p=0.31). Circulating PCSK9 was correlated with psoriasis area severity index (PASI score, r=0.43, p=0.04) even after adjustment for age, gender, BMI and LDL-C (beta=0.02, p=0.03). Integration of the whole blood transcriptome yielded 322 transcripts which correlated with circulating PCSK9 (FDR<0.05). Network analysis of these transcripts highlighted interferon signaling (p=7.2x10^-6), a known pathogenic process in psoriasis, as a key regulator of PCSK9. Finally, circulating PCSK9 positively correlated with brachial vein endothelial expression of the pro-inflammatory transcripts CXCL10 (r=0.69, p<0.001), ICAM1 (r=0.49, p=0.02) and IL1beta (r=0.38, p<0.01) and inversely correlated with the functional measure of endothelial health, FMD (r=-0.52, p=0.03). Conclusion Circulating PCSK9 is elevated in psoriasis and associated with impaired vascular health. Analysis of the relationship between PCSK9 and systemic pathways revealed prominent interactions between PCSK9 and interferon signaling. Further research to better characterize these transcriptome and proteome variations and how it impacts vascular health in psoriasis may help elucidate new targets for therapeutic interventions.
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Importance/UNASSIGNED:While many features of stable ischemic heart disease vary by sex, differences in ischemia, coronary anatomy, and symptoms by sex have not been investigated among patients with moderate or severe ischemia. The enrolled ISCHEMIA trial cohort that underwent coronary computed tomographic angiography (CCTA) was required to have obstructive coronary artery disease (CAD) for randomization. Objective/UNASSIGNED:To describe sex differences in stress testing, CCTA findings, and symptoms in ISCHEMIA trial participants. Design, Setting, and Participants/UNASSIGNED:This secondary analysis of the multicenter ISCHEMIA randomized clinical trial analyzed baseline characteristics of patients with stable ischemic heart disease. Individuals were enrolled from July 2012 to January 2018 based on local reading of moderate or severe ischemia on a stress test, after which blinded CCTA was performed in most. Core laboratories reviewed stress tests and CCTAs. Participants with no obstructive CAD or with left main CAD of 50% or greater were excluded. Those who met eligibility criteria including CCTA (if performed) were randomized to a routine invasive or a conservative management strategy (N = 5179). Angina was assessed using the Seattle Angina Questionnaire. Analysis began October 1, 2018. Interventions/UNASSIGNED:CCTA and angina assessment. Main Outcomes and Measures/UNASSIGNED:Sex differences in stress test, CCTA findings, and symptom severity. Results/UNASSIGNED:Of 8518 patients enrolled, 6256 (77%) were men. Women were more likely to have no obstructive CAD (<50% stenosis in all vessels on CCTA) (353 of 1022 [34.4%] vs 378 of 3353 [11.3%]). Of individuals who were randomized, women had more angina at baseline than men (median [interquartile range] Seattle Angina Questionnaire Angina Frequency score: 80 [70-100] vs 90 [70-100]). Women had less severe ischemia on stress imaging (383 of 919 [41.7%] vs 1361 of 2972 [45.9%] with severe ischemia; 386 of 919 [42.0%] vs 1215 of 2972 [40.9%] with moderate ischemia; and 150 of 919 [16.4%] vs 394 of 2972 [13.3%] with mild or no ischemia). Ischemia was similar by sex on exercise tolerance testing. Women had less extensive CAD on CCTA (205 of 568 women [36%] vs 1142 of 2418 men [47%] with 3-vessel disease; 184 of 568 women [32%] vs 754 of 2418 men [31%] with 2-vessel disease; and 178 of 568 women [31%] vs 519 of 2418 men [22%] with 1-vessel disease). Female sex was independently associated with greater angina frequency (odds ratio, 1.41; 95% CI, 1.13-1.76). Conclusions and Relevance/UNASSIGNED:Women in the ISCHEMIA trial had more frequent angina, independent of less extensive CAD, and less severe ischemia than men. These findings reflect inherent sex differences in the complex relationships between angina, atherosclerosis, and ischemia that may have implications for testing and treatment of patients with suspected stable ischemic heart disease. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01471522.

Background Heart failure (HF) and chronic kidney disease (CKD) commonly co-exist, and are associated with adverse postoperative cardiovascular outcomes. The impact of CKD in HF patients undergoing noncardiac surgery is uncertain. Methods Patients with HF undergoing non-cardiac surgery were identified from the National Surgical Quality Improvement Program between 2009-2015. Patients were classified into 5 groups based on estimated glomerular filtration rate (eGFR) and requirement of dialysis and were followed prospectively for the primary outcome of death and major adverse cardiovascular events (MACE; a composite of death, myocardial infarction (MI), and stroke) within 30-days post-operatively. Multivariable logistic regression models adjusted for age, sex, race, surgery type, and clinical history and surgery type were generated to estimate the association between CKD stage and outcomes. Results Among 27,612 HF patients undergoing surgery, 65.1% had CKD (19.7% with eGFR 45-60, 20.3% eGFR 30-45, and 25.1% eGFR < 30 with or without dialysis). The incidence of postoperative death and MACE increased with worsening CKD (Table). After multivariable adjustment, eGFR <60 was associated with increased odds of MI and cardiac arrest and eGFR <45 was associated with postoperative mortality. No association was observed between CKD and stroke. Conclusion Among HF patients, the presence of CKD is common and is associated with increased risk for postoperative mortality and MACE. [Figure presented]
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Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening complication of heparin exposure. Here, we review the pathogenesis, incidence, diagnosis, and management of HIT. The first step in thwarting devastating complications from this entity is to maintain a high index of clinical suspicion, followed by an accurate clinical scoring assessment using the 4Ts. Next, appropriate stepwise laboratory testing must be undertaken in order to rule out HIT or establish the diagnosis. In the interim, all heparin must be stopped immediately, and the patient administered alternative anticoagulation. Here we review alternative anticoagulation choice, therapy alternatives in the difficult-to-manage patient with HIT, and the problem of overdiagnosis.

Variability in daily sleep patterns is an emerging factor linked to metabolic syndrome. However, whether reducing bedtime variability improves markers of disease risk has not been tested. Here, we assessed whether body composition and inflammation were impacted by changes in bedtime variability over a 6-week period, during which, women were instructed to maintain healthy, habitual sleep (HS) patterns (one arm of a randomized trial). Data were available for 37 women (age 34.9 ± 12.4 years, BMI 24.7 ± 2.9 kg/m², sleep duration 7.58 ± 0.49 h/night). Body composition and leukocyte platelet aggregates (LPA) were measured at baseline and endpoint using magnetic resonance imaging and flow cytometry, respectively. Sleep data were collected daily using wrist actigraphy. Change in bedtime variability was calculated as the difference in the standard deviation (SD) of bedtimes measured during the 2-week screening period and the 6-week intervention period. Results showed that women who reduced their bedtime variability (n = 29) during the intervention had reductions in total (P < 0.001) and subcutaneous adipose tissue (P < 0.001) relative to women who increased/maintained (n = 8) bedtime variability. Similar effects were observed for LPA levels between women who reduced vs increased/maintained bedtime variability (P = 0.011). Thus, reducing bedtime variability, without changing sleep duration, could improve cardiometabolic health by reducing adiposity and inflammation.

Background/UNASSIGNED:Critical limb ischemia (CLI) is a severe stage of peripheral arterial disease and has a substantial disease and economic burden not only to patients and families, but also to the society and healthcare systems. We aim to develop a personalized prediction model that utilizes baseline patient characteristics prior to CLI diagnosis to predict subsequent 1-year all-cause hospitalizations and total annual healthcare cost, using a novel Bayesian machine learning platform, Reverse Engineering Forward Simulation™ (REFS™), to support a paradigm shift from reactive healthcare to Predictive Preventive and Personalized Medicine (PPPM)-driven healthcare. Methods/UNASSIGNED:Patients ≥ 50 years with CLI plus clinical activity for a 6-month pre-index and a 12-month post-index period or death during the post-index period were included in this retrospective cohort of the linked Optum-Humedica databases. REFS™ built an ensemble of 256 predictive models to identify predictors of all-cause hospitalizations and total annual all-cause healthcare costs during the 12-month post-index interval. Results/UNASSIGNED:The mean age of 3189 eligible patients was 71.9 years. The most common CLI-related comorbidities were hypertension (79.5%), dyslipidemia (61.4%), coronary atherosclerosis and other heart disease (42.3%), and type 2 diabetes (39.2%). Post-index CLI-related healthcare utilization included inpatient services (14.6%) and ≥ 1 outpatient visits (32.1%). Median annual all-cause and CLI-related costs per patient were $30,514 and $2196, respectively. REFS™ identified diagnosis of skin and subcutaneous tissue infections, cellulitis and abscess, use of nonselective beta-blockers, other aftercare, and osteoarthritis as high confidence predictors of all-cause hospitalizations. The leading predictors for total all-cause costs included region of residence and comorbid health conditions including other diseases of kidney and ureters, blindness of vision defects, chronic ulcer of skin, and chronic ulcer of leg or foot. Conclusions/UNASSIGNED:REFS™ identified baseline predictors of subsequent healthcare resource utilization and costs in CLI patients. Machine learning and model-based, data-driven medicine may complement physicians' evidence-based medical services. These findings also support the PPPM framework that a paradigm shift from post-diagnosis disease care to early management of comorbidities and targeted prevention is warranted to deliver a cost-effective medical services and desirable healthcare economy.

OBJECTIVE:=0.02). CONCLUSIONS:In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation, which suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.

In the original article. The third author name is incorrect. The correct name is Nicholas J. Leeper.