The Obesity Mortality Paradox in Patients with Pulmonary Embolism: Insights from a Tertiary Care Center.

Background: While obesity is associated with an increased risk of venous thromboembolism (VTE), there is some data to suggest that higher BMI is also associated with decreased all-cause mortality in patients with a pulmonary embolism (PE). Methods: Using PE Response Team (PERT) activation data from a large tertiary hospital between 27 October 2020 and 28 August 2023, we constructed a multivariate Cox proportional hazards model to assess the association between obesity as a dichotomous variable (defined as BMI ≥ 30 vs. BMI 18.5-29.9), BMI as a continuous variable, and 30-day PE-related mortality. Results: A total of 248 patients were included in this analysis (150 with obesity and 98 who were in the normal/overweight category). Obesity was associated with a lower risk of 30-day PE-related mortality (adjusted HR 0.29, p = 0.036, 95% CI 0.09-0.92). A higher BMI was paradoxically associated with a lower risk of PE-related mortality (HR = 0.91 per 1 kg/m2 increase, p = 0.049, 95% CI 0.83-0.999). Conclusions: In our contemporary cohort of patients with a PERT activation, obesity was associated with a lower risk of PE-related mortality.

Dysregulated platelet function in patients with postacute sequelae of COVID-19.

BACKGROUND: Postacute sequelae of COVID-19 (PASC), also referred to as "Long COVID", sometimes follows COVID-19, a disease caused by SARS-CoV-2. Although SARS-CoV-2 is well known to promote a prothrombotic state, less is known about the thrombosis risk in PASC. Our objective was to evaluate platelet function and thrombotic potential in patients following recovery from SARS-CoV-2, but with clear symptoms of patients with PASC. METHODS: patients with PASC and matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by light transmission aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under shear stress conditions. RESULTS: A mild increase in platelet aggregation in patients with PASC through the thromboxane receptor was observed, and platelet activation through the glycoprotein VI (GPVI) receptor was decreased in patients with PASC compared to age- and sex-matched healthy controls. Thrombosis under shear conditions as well as Factor Xa activity were reduced in patients with PASC. Plasma from patients with PASC was an extremely potent activator of washed, healthy platelets - a phenomenon not observed when stimulating healthy platelets after incubation with plasma from healthy individuals. CONCLUSIONS: patients with PASC show dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating molecule that promotes thrombosis. A hitherto undescribed protective response appears to exist in patients with PASC to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.

Venous thromboembolic outcomes in patients with lymphedema and lipedema: An analysis from the National Inpatient Sample.

BACKGROUND: Patients with lymphedema and lipedema share physical exam findings that may lead to misdiagnosis. Poor mobility is common in patients with obesity and patients with lymphedema and lipedema. This may constitute a risk factor for venous thromboembolism (VTE). Our objective was to evaluate the association of VTE in obese patients with lymphedema and lipedema. METHODS: The National Inpatient Sample (NIS) was searched from 2016 to 2020 to identify hospital admissions of obese female patients with lymphedema and lipedema. Patients were analyzed in the context of presence or absence of VTE while adjusting for complex cluster sampling techniques. Predictors of VTE were accessed by multivariable regression. RESULTS: Lymphedema was identified in 189,985 patients and lipedema in 50,645 patients. VTE was observed in 3.12% (n = 374,210) of patients with obesity. In patients with obesity, VTE was more common in patients with lymphedema than without (2.6% vs 1.6%; p < 0.01). Similarly, VTE was more common in patients with lipedema than without (0.6% vs 0.4%; p < 0.01). After multivariable logistic regression, VTE events in obese patients with lymphedema were higher versus without (OR 1.6; CI 1.08-2.43; p = 0.02). Similarly, VTE events were more common in obese patients with lipedema versus obese patients without lipedema (OR 1.20; CI 1.03-1.41; p = 0.02). CONCLUSIONS: In this hypothesis-generating study, lymphedema and lipedema show a positive association with VTE after adjusting for baseline patient characteristics such as obesity, which is a known independent risk factor for VTE. Mechanisms whereby lymphedema and lipedema are associated with VTE should be investigated.

Carotid Duplex Ultrasonography to Assess Severity of Low-Flow Low-Gradient Aortic Stenosis.

BACKGROUND: Patients with low-flow, low-gradient aortic valve stenosis constitute a substantial subset of all severe aortic stenosis patients. However, assessment of true severity of these patients can be challenging. In this analysis, we study the utility of the common carotid artery waveforms to distinguish true from pseudo-severe low-flow low-gradient aortic stenosis. METHODS: This is an observational analysis that included patients who underwent a transthoracic echocardiogram (TTE) and duplex carotid ultrasonography (DCUS) and had low-flow, low-gradient aortic stenosis with reduced left ventricular ejection fraction (LVEF) on the index TTE (LVEF <50%, calculated aortic valve area [AVA] of ≤1.0 cm2, mean and peak gradient of <40 and <64 mm Hg, respectively, and stroke volume index <35 mL/m2). Patients were classified as pseudo-severe and true-severe aortic stenosis based on additional subsequent testing. Differences in various TTE and DCUS waveform parameters across the aortic valve and the common carotid artery were compared between the 2 groups. RESULTS: The study included 30 patients (60 carotid arteries). Fifteen patients were categorized as pseudo-severe and 15 as true severe aortic stenosis. There were no significant differences in calculated AVA, LVEF, stroke volume/stroke volume index, and Doppler Velocity Index in the 2 groups. Mean and peak gradient were higher in patients with true-severe aortic stenosis. Carotid acceleration time (cAT) was significantly prolonged in patients with true-severe compared with pseudo-severe aortic stenosis. A cAT ≥80 ms was 83.3% sensitive and 83.3% specific for true-severe aortic stenosis. CONCLUSION: cAT acceleration time may be used to distinguish true from pseudo-severe low-flow, low-gradient aortic valve stenosis.

Antiplatelet Therapy, Abdominal Aortic Aneurysm Progression, and Clinical Outcomes.

Importance: Preclinical studies suggest a potential role for aspirin in slowing abdominal aortic aneurysm (AAA) progression and preventing rupture. Evidence on the clinical benefit of aspirin in AAA from human studies is lacking. Objective: To investigate the association of aspirin use with aneurysm progression and long-term clinical outcomes in patients with AAA. Design, Setting, and Participants: This was a retrospective, single-center cohort study. Adult patients with at least 2 available vascular ultrasounds at the Cleveland Clinic were included, and patients with history of aneurysm repair, dissection, or rupture were excluded. All patients were followed up for 10 years. Data were analyzed from May 2022 to July 2023. Main Outcomes and Measures: Clinical outcomes were time-to-first occurrence of all-cause mortality, major bleeding, or composite of dissection, rupture, and repair. Multivariable-adjusted Cox proportional-hazard regression was used to estimate hazard ratios (HR) for all-cause mortality, and subhazard ratios competing-risk regression using Fine and Gray proportional subhazards regression was used for major bleeding and composite outcome. Aneurysm progression was assessed by comparing the mean annualized change of aneurysm diameter using multivariable-adjusted linear regression and comparing the odds of having rapid progression (annual diameter change >0.5 cm per year) using logistic regression. Results: A total of 3435 patients (mean [SD] age 73.7 [9.0] years; 2672 male patients [77.5%]; 120 Asian, Hispanic, American Indian, or Pacific Islander patients [3.4%]; 255 Black patients [7.4%]; 3060 White patients [89.0%]; and median [IQR] follow-up, 4.9 [2.5-7.5] years) were included in the final analyses, of which 2150 (63%) were verified to be taking aspirin by prescription. Patients taking aspirin had a slower mean (SD) annualized change in aneurysm diameter (2.8 [3.0] vs 3.8 [4.2] mm per year; P = .001) and lower odds of having rapid aneurysm progression compared with patients not taking aspirin (adjusted odds ratio, 0.64; 95% CI, 0.49-0.89; P = .002). Aspirin use was not associated with risk of all-cause mortality (adjusted HR [aHR], 0.92; 95% CI, 0.79-1.07; P = .32), nor was aspirin use associated with major bleeding (aHR, 0.88; 95% CI, 0.76-1.03; P = .12), or composite outcome (aHR, 1.16; 95% CI, 0.93-1.45; P = .09) at 10 years. Conclusions: In this retrospective study of a clinical cohort of 3435 patients with objectively measured changes in aortic aneurysm growth, aspirin use was significantly associated with slower progression of AAA with a favorable safety profile.

Dysregulated Platelet Function in Patients with Post-Acute Sequelae of COVID-19.

Background: Post-acute sequelae of COVID-19 (PASC), also referred as Long-COVID, sometimes follows COVID-19, a disease caused by SARS-CoV-2. While SARS-CoV-2 is well-known to promote a prothrombotic state, less is known about the thrombosis risk in PASC. Aim: Our objective was to evaluate the platelet function and thrombotic potential in patients following recovery from SARS-CoV-2 with clear symptoms of PASC. Methods: PASC patients and matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by Light Transmission Aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under shear stress conditions. Results: A mild increase in platelet aggregation in PASC patients through the thromboxane receptor was observed and platelet activation through the glycoprotein VI (GPVI) receptor was decreased in PASC patients compared to age- and sex-matched healthy controls. Thrombosis under shear conditions as well as Factor Xa activity were reduced in PASC patients. Plasma from PASC patients was an extremely potent activator of washed, healthy platelets - a phenomenon not observed when stimulating healthy platelets after incubation with plasma from healthy individuals. Conclusions: PASC patients show dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating molecule that promotes thrombosis. A hitherto undescribed protective response appears to exists in PASC patients to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.

Protection of ß2GPI Deficient Mice from Thrombosis Reflects a Defect in PAR3-facilitated Platelet Activation.

Background: Antibodies to ß2-glycoprotein I (ß2GPI) cause thrombosis in antiphospholipid syndrome, however the role of ß2GPI itself in regulation of coagulation pathways in vivo is not well understood. Methods: We developed ß2GPI-deficient mice (Apoh -/- ) by deleting exon 2 and 3 of Apoh using CRISPR/Cas9 and compared the propensity of wild-type (WT) and Apoh -/- mice to develop thrombosis using rose bengal and FeCl 3 -induced carotid thrombosis, laser-induced cremaster arteriolar injury, and inferior vena cava (IVC) stasis models. We also compared tail bleeding times and assessed platelet activation in WT and Apoh -/- mice in the absence and presence of exogenous ß2GPI. Results: Compared to WT littermates, Apoh -/- mice demonstrated a prolonged time to occlusion of the carotid artery after exposure to rose bengal or FeCl 3 , and reduced platelet and fibrin accumulation in cremasteric arterioles after laser injury. Similarly, significantly smaller thrombi were retrieved from the IVC of Apoh -/- mice 48 hours after IVC occlusion. The activated partial thromboplastin time (aPTT) and prothrombin time, as well as aPTT reagent- and tissue factor-induced thrombin generation times using plasma from Apoh -/- and WT mice revealed no differences. However, we observed significant prolongation of tail bleeding in Apoh -/- mice, and reduced P-selectin expression and binding of fibrinogen to the activated α2bß3 integrin on platelets from these mice after stimulation with low thrombin concentrations; these changes were reversed by exogenous ß2GPI. An antibody to PAR3 blocked thrombin-induced activation of WT, but not Apoh -/- platelets, as well as the ability of ß2GPI to restore the activation response of Apoh -/- platelets to thrombin. ß2GPI deficiency did not affect platelet activation by a PAR4-activator peptide, or ADP. Conclusions: In mice, ß2GPI may mediate procoagulant activity by enhancing the ability of PAR3 to present thrombin to PAR4, promoting platelet activation at low thrombin concentrations. Key Points: ß2GPI deficient mice are protected from experimental arterial, venous, and microvascular thrombosis.ß2GPI deficient mice display prolonged tail bleeding times and reduced PAR3-facilitated platelet activation by low concentrations of thrombin.

Temporal trends in the utilization of advanced therapies among patients with acute pulmonary embolism: insights from a national database.

There is a paucity of data regarding the contemporary temporal trends in the adoption of advanced pulmonary embolism (PE) therapies in the United States as well as the parallel trends in outcomes of patients with acute PE. Therefore, we queried the Nationwide Readmissions Database (years 2016-2020) to report the temporal trends in utilization of advanced PE therapies. Our final analysis included 920 770 hospitalizations with acute PE. We demonstrated an increase in the proportion of patients diagnosed with high-risk PE during the study years. Overall, there was an increase in the use of advanced PE therapies, which was mainly due to the increase in the utilization of systemic thrombolytics, and catheter-directed therapies. Also, extracorporeal membrane oxygenation cannulation showed an incremental increase over the study years. The use of inferior vena cava filter has declined, while the use of surgical embolectomy did not change during the study years. The use of advanced therapies has increased among urban teaching, but not among urban non-teaching hospitals. During the study years, there was no change in unadjusted or adjusted in-hospital mortality rates among patients with acute PE, while the 90-day unplanned readmission rate has declined.

Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist. KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.

Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response. SIGNIFICANCE: Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949.

A Post-Pandemic Enigma: The Cardiovascular Impact of Post-Acute Sequelae of SARS-CoV-2.

COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena. This review will highlight the suspected pathophysiology of postacute sequelae of SARS-CoV-2, its influence on the cardiovascular system, and potential treatment strategies.

Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms.

BACKGROUND: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. METHODS: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr-/-) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3-/-). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. RESULTS: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3-/- mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK. CONCLUSIONS: These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.

Psychological distress in pulmonary embolism survivors in a pulmonary embolism response team clinic: Protocol for a prospective observational study.

Background: Pulmonary embolism (PE) is a leading cause of cardiovascular death. Psychological distress in PE is understudied and underrecognized. Objectives: The primary aim of this proposed protocol was to describe the incidence of psychological distress symptoms (anxiety, depression, posttraumatic stress, and fear of recurrence) in the survivors of PE after discharge from hospitalization. The secondary aim was to assess the influence of acute disease, etiology, and treatment of PE on psychological distress. Methods: This is a prospective observational cohort study in a large tertiary care referral center. The participants are adult patients presenting to the hospital with PE fulfilling objective pulmonary embolism response team (PERT) activation criteria. After discharge, patients complete a series of validated measures of psychological distress (anxiety, depression, posttraumatic stress, and fear of recurrence) and quality of life at follow-ups approximately 1, 3, 6, and 12 months after diagnosis and treatment of their PE. Factors influencing each type of distress are evaluated. Conclusion: This protocol aims to identify the unmet needs of patients experiencing psychological distress following PE. It will describe anxiety, depression, fear of recurrence, and posttraumatic symptoms in PE survivors during the first year of outpatient follow-up in a PERT clinic.