Publications by authors named "Peter Libby"

506 Publications

Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development.

Circulation 2021 Apr 6. Epub 2021 Apr 6.

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Human Pathology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health, Moscow, Russian Federation.

Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The peroxisome proliferator-activated receptors (PPARs) pathway served as an example to substantiate our discovery platform. mouse experiments with macrophage-targeted PPARα siRNA and the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. experiments further included metabolomic profiling, qPCR, flow cytometry, metabolic assays, and single-cell RNA-sequencing on primary human and mouse macrophages. We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity. This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacologic treatment for this unmet medical need.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043724DOI Listing
April 2021

Targeted delivery of Protein Arginine Deiminase-4 inhibitors to limit arterial intimal NETosis and preserve endothelial integrity.

Cardiovasc Res 2021 Mar 5. Epub 2021 Mar 5.

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Aims: Recent evidence suggests that "vulnerable plaques," which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, anti-hypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion. Eroded plaques have a rich extracellular matrix, an intact fibrous cap, sparse lipid, and few mononuclear cells, but do harbor neutrophil extracellular traps (NETs). We recently reported that NETs amplify and propagate the endothelial damage at the site of arterial lesions that recapitulate superficial erosion in mice. We showed that genetic loss of protein arginine deiminase (PAD)-4 function inhibited NETosis and preserved endothelial integrity. The current study used systemic administration of targeted nanoparticles to deliver an agent that limits NETs formation to probe mechanisms of and demonstrate a novel therapeutic approach to plaque erosion that limits endothelial damage.

Methods And Results: We developed Collagen IV-targeted nanoparticles (Col IV NP) to deliver PAD4 inhibitors selectively to regions of endothelial cell sloughing and collagen IV-rich basement membrane exposure. We assessed the binding capability of the targeting ligand in vitro and evaluated Col IV NP targeting to areas of denuded endothelium in vivo in a mouse preparation that recapitulates features of superficial erosion. Delivery of the PAD4 inhibitor GSK484 reduced NET accumulation at sites of intimal injury and preserved endothelial continuity.

Conclusions: NPs directed to Col IV show selective uptake and delivery of their payload to experimentally eroded regions, illustrating their translational potential. Our results further support the role of PAD4 and NETs in superficial erosion.
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http://dx.doi.org/10.1093/cvr/cvab074DOI Listing
March 2021

The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis.

Nature 2021 Apr 17;592(7853):296-301. Epub 2021 Mar 17.

Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2 (JAK2) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2 selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2 lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2 lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2 macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.
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http://dx.doi.org/10.1038/s41586-021-03341-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038646PMC
April 2021

New Insights Into Plaque Erosion as a Mechanism of Acute Coronary Syndromes.

JAMA 2021 03;325(11):1043-1044

Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2021.0069DOI Listing
March 2021

Novel Lesional Transcriptional Signature Separates Atherosclerosis With and Without Diabetes in Yorkshire Swine and Humans.

Arterioscler Thromb Vasc Biol 2021 Apr 11;41(4):1487-1503. Epub 2021 Feb 11.

Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital (S.H., M.Z., G.S., A.U.C., M.A.C., D.A.G., A.K.W., A.P.A., X.S., G.K.S., I.A., E.R.E., P.L., P.H.S., M.W.F.), Harvard Medical School, Boston, MA.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.315896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990701PMC
April 2021

Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance.

Am Heart J 2020 Oct 24;235:104-112. Epub 2020 Oct 24.

Department of Cardiovascular Medicine, Cleveland Clinic and Cleveland Clinic Coordinating Center for Clinical Research.

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied. STUDY DESIGN: Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months. CONCLUSIONS: CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.
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http://dx.doi.org/10.1016/j.ahj.2020.10.060DOI Listing
October 2020

The cardiovascular-dialysis nexus: the transition to dialysis is a treacherous time for the heart.

Eur Heart J 2021 Mar;42(13):1244-1253

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, NRB-741-G, Boston, MA 02115, USA.

Chronic kidney disease (CKD) patients require dialysis to manage the progressive complications of uraemia. Yet, many physicians and patients do not recognize that dialysis initiation, although often necessary, subjects patients to substantial risk for cardiovascular (CV) death. While most recognize CV mortality risk approximately doubles with CKD the new data presented here show that this risk spikes to >20 times higher than the US population average at the initiation of chronic renal replacement therapy, and this elevated CV risk continues through the first 4 months of dialysis. Moreover, this peak reflects how dialysis itself changes the pathophysiology of CV disease and transforms its presentation, progression, and prognosis. This article reviews how dialysis initiation modifies the interpretation of circulating biomarkers, alters the accuracy of CV imaging, and worsens prognosis. We advocate a multidisciplinary approach and outline the issues practitioners should consider to optimize CV care for this unique and vulnerable population during a perilous passage.
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http://dx.doi.org/10.1093/eurheartj/ehaa1049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014523PMC
March 2021

Time-Restricted Salutary Effects of Blood Flow Restoration on Venous Thrombosis and Vein Wall Injury in Mouse and Human Subjects.

Circulation 2021 Mar 15;143(12):1224-1238. Epub 2021 Jan 15.

Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (W.L., C.W.K., M.O., L.W., A.T., F.A.J.).

Background: Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution.

Methods: First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes.

Results: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, <0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days.

Conclusions: Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988304PMC
March 2021

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials.

Eur Heart J 2021 Mar;42(9):896-903

Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiovascular Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02215, USA.

Aims: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy.

Methods And Results: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001).

Conclusion: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab.
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http://dx.doi.org/10.1093/eurheartj/ehaa1034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936519PMC
March 2021

Inflammation in Atherosclerosis-No Longer a Theory.

Authors:
Peter Libby

Clin Chem 2021 Jan;67(1):131-142

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Inflammation links to atherosclerosis and its complications in various experimental investigations. Animal studies have implicated numerous inflammatory mediators in the initiation and complication of atherosclerosis. Numerous studies in humans have shown associations of biomarkers of inflammation with cardiovascular events provoked by atheromata. Inflammatory status, determined by the biomarker C-reactive protein, can guide the allocation of statin therapy to individuals without elevated low-density lipoprotein (LDL) concentrations to prevent first ever adverse cardiovascular events.

Content: Until recently, no direct evidence has shown that an intervention that selectively limits inflammation can improve outcomes in patients with atherosclerosis. A recent study, based on decades of preclinical investigation, treated patients who had sustained a myocardial infarction and whose LDL was well-controlled on statin treatment with an antibody that neutralizes interleukin-1 beta. This trial, conducted in over 10 000 individuals, showed a reduction in major adverse cardiac events, establishing for the first time the clinical efficacy of an anti-inflammatory intervention in atherosclerosis. Two large subsequent studies have shown that colchicine treatment can also prevent recurrent events in patients recovering from an acute coronary syndrome or in the stable phase of coronary artery disease. These clinical trials have transformed inflammation in atherosclerosis from theory to practice.

Summary: Much work remains to optimize further anti-inflammatory interventions, minimize unwanted actions, and refine patient selection. This long road from discovery in the laboratory to successful clinical trials represents a victory for medical science, and opens a new avenue to reducing the risk that remains despite current treatments for atherosclerosis.
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http://dx.doi.org/10.1093/clinchem/hvaa275DOI Listing
January 2021

Eosinophils improve cardiac function after myocardial infarction.

Nat Commun 2020 12 16;11(1):6396. Epub 2020 Dec 16.

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Clinical studies reveal changes in blood eosinophil counts and eosinophil cationic proteins that may serve as risk factors for human coronary heart diseases. Here we report an increase of blood or heart eosinophil counts in humans and mice after myocardial infarction (MI), mostly in the infarct region. Genetic or inducible depletion of eosinophils exacerbates cardiac dysfunction, cell death, and fibrosis post-MI, with concurrent acute increase of heart and chronic increase of splenic neutrophils and monocytes. Mechanistic studies reveal roles of eosinophil IL4 and cationic protein mEar1 in blocking HO- and hypoxia-induced mouse and human cardiomyocyte death, TGF-β-induced cardiac fibroblast Smad2/3 activation, and TNF-α-induced neutrophil adhesion on the heart endothelial cell monolayer. In vitro-cultured eosinophils from WT mice or recombinant mEar1 protein, but not eosinophils from IL4-deficient mice, effectively correct exacerbated cardiac dysfunctions in eosinophil-deficient ∆dblGATA mice. This study establishes a cardioprotective role of eosinophils in post-MI hearts.
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http://dx.doi.org/10.1038/s41467-020-19297-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745020PMC
December 2020

Increased CHIP Prevalence Amongst People Living with HIV.

medRxiv 2020 Nov 7. Epub 2020 Nov 7.

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n=600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n=8,111) from blood DNA-derived exome sequences. We observed that HIV is associated with increased CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p=0.005). Additionally, unlike in ARIC, ASXL1 was the most commonly implicated mutated CHIP gene. We propose that CHIP may be one mechanism through which PLWH are at increased risk for CAD. Larger prospective studies should evaluate the hypothesis that CHIP contributes to the excess cardiovascular risk in PLWH.
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http://dx.doi.org/10.1101/2020.11.06.20225607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654930PMC
November 2020

Endotoxinemia Accelerates Atherosclerosis Through Electrostatic Charge-Mediated Monocyte Adhesion.

Circulation 2021 Jan 10;143(3):254-266. Epub 2020 Nov 10.

Institute for Cardiovascular Prevention (IPEK), LMU Munich Hospital, Germany (A.S., A.O.-G., C.W., P. Lemnitzer, J.R.V., C.P., L.P.O., J.W., Y.D., O.S.).

Background: Acute infection is a well-established risk factor of cardiovascular inflammation increasing the risk for a cardiovascular complication within the first weeks after infection. However, the nature of the processes underlying such aggravation remains unclear. Lipopolysaccharide derived from Gram-negative bacteria is a potent activator of circulating immune cells including neutrophils, which foster inflammation through discharge of neutrophil extracellular traps (NETs). Here, we use a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation Methods: Acute infection was mimicked by injection of a single dose of lipopolysaccharide into hypercholesterolemic mice. Atherosclerosis burden was studied by histomorphometric analysis of the aortic root. Arterial myeloid cell adhesion was quantified by intravital microscopy.

Results: Lipopolysaccharide treatment rapidly enhanced atherosclerotic lesion size by expansion of the lesional myeloid cell accumulation. Lipopolysaccharide treatment led to the deposition of NETs along the arterial lumen, and inhibition of NET release annulled lesion expansion during endotoxinemia, thus suggesting that NETs regulate myeloid cell recruitment. To study the mechanism of monocyte adhesion to NETs, we used in vitro adhesion assays and biophysical approaches. In these experiments, NET-resident histone H2a attracted monocytes in a receptor-independent, surface charge-dependent fashion. Therapeutic neutralization of histone H2a by antibodies or by in silico designed cyclic peptides enables us to reduce luminal monocyte adhesion and lesion expansion during endotoxinemia.

Conclusions: Our study shows that NET-associated histone H2a mediates charge-dependent monocyte adhesion to NETs and accelerates atherosclerosis during endotoxinemia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914394PMC
January 2021

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

Circulation 2021 Feb 9;143(5):410-423. Epub 2020 Nov 9.

Cardiology Division (M.C.H., J.P.P., P.N.), Massachusetts General Hospital, Harvard Medical School, Boston.

Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.

Methods: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.

Results: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; =0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; =0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; =0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; <0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; =0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; =0.005).

Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911856PMC
February 2021

Eosinophils Protect Mice From Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm.

Circ Res 2021 Jan 6;128(2):188-202. Epub 2020 Nov 6.

Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, China (C.L., Y.W., J.Z., G.-P.S.).

Rationale: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease.

Objective: To test whether and how eosinophils affect AAA growth.

Methods And Results: Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 10/L, <0.001). Univariate (odds ratio, 1.381, <0.001) and multivariate (odds ratio, 1.237, =0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in and eosinophil-deficient ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11bLy6C monocytes, and increased CD11bLy6C monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and mice, but not eosinophil from mice, blocked AAA growth in ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells.

Conclusions: Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855167PMC
January 2021

Remembering Dr. James T. Willerson.

JACC Basic Transl Sci 2020 Oct 26;5(10):1054-1055. Epub 2020 Oct 26.

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http://dx.doi.org/10.1016/j.jacbts.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591926PMC
October 2020

A tale of two therapies lipid-lowering vs anti-inflammatory therapy - a false dichotomy?

Eur Heart J Cardiovasc Pharmacother 2020 Nov 2. Epub 2020 Nov 2.

The University of Helsinki and Helsinki University Hospital, Helsinki, Finland, and University of Oulu, Center for Life Course Health Research, Oulu, Finland (T.E.S.).

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http://dx.doi.org/10.1093/ehjcvp/pvaa131DOI Listing
November 2020

Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study.

Eur Heart J 2020 10;41(37):3549-3560

Department of Cardiology, University Heart Centre Berlin and Charité University Medicine Berlin, Campus Benjamin-Franklin (CBF), Hindenburgdamm 30, Berlin D-12203, Germany.

Aims: Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping.

Methods And Results: The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS.

Conclusions: The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC.

Trial Registration: The study was registered at clinicalTrials.gov (NCT03129503).
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http://dx.doi.org/10.1093/eurheartj/ehaa703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780480PMC
October 2020

COVID-19 - A vascular disease.

Trends Cardiovasc Med 2021 01 14;31(1):1-5. Epub 2020 Oct 14.

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to multi-system dysfunction with emerging evidence suggesting that SARS-CoV-2-mediated endothelial injury is an important effector of the virus. Potential therapies that address vascular system dysfunction and its sequelae may have an important role in treating SARS-CoV-2 infection and its long-lasting effects.
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http://dx.doi.org/10.1016/j.tcm.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556303PMC
January 2021

LncRNA VINAS regulates atherosclerosis by modulating NF-κB and MAPK signaling.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Long noncoding RNAs (lncRNAs) play important roles in regulating diverse cellular processes in the vessel wall, including atherosclerosis. RNA-Seq profiling of intimal lesions revealed a lncRNA, VINAS (Vascular INflammation and Atherosclerosis lncRNA Sequence), that is enriched in the aortic intima and regulates vascular inflammation. Aortic intimal expression of VINAS fell with atherosclerotic progression and rose with regression. VINAS knockdown reduced atherosclerotic lesion formation by 55% in LDL receptor-deficient (LDLR-/-) mice, independent of effects on circulating lipids, by decreasing inflammation in the vessel wall. Loss- and gain-of-function studies in vitro demonstrated that VINAS serves as a critical regulator of inflammation by modulating NF-κB and MAPK signaling pathways. VINAS knockdown decreased the expression of key inflammatory markers, such as MCP-1, TNF-α, IL-1β, and COX-2, in endothelial cells (ECs), vascular smooth muscle cells, and bone marrow-derived macrophages. Moreover, VINAS silencing decreased expression of leukocyte adhesion molecules VCAM-1, E-selectin, and ICAM-1 and reduced monocyte adhesion to ECs. DEP domain containing 4 (DEPDC4), an evolutionary conserved human ortholog of VINAS with approximately 74% homology, showed similar regulation in human and pig atherosclerotic specimens. DEPDC4 knockdown replicated antiinflammatory effects of VINAS in human ECs. These findings reveal a potentially novel lncRNA that regulates vascular inflammation, with broad implications for vascular diseases.
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http://dx.doi.org/10.1172/jci.insight.140627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710319PMC
November 2020

Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial.

J Am Coll Cardiol 2020 10;76(14):1660-1670

Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: Inflammation reduction with the interleukin (IL)-1β inhibitor canakinumab significantly reduces the first major adverse cardiovascular event in patients with prior myocardial infarction (MI) and residual inflammatory risk (high-sensitivity C-reactive protein ≥ 2 mg/l). However, the effect of canakinumab on the total number of cardiovascular events, including recurrent events collected after a first event, is unknown.

Objectives: This study sought to determine whether randomly allocated canakinumab would reduce the total burden of serious cardiovascular events.

Methods: We randomized 10,061 patients to placebo or canakinumab 50 mg, 150 mg, or 300 mg once every 3 months and compared the rates of the composite of all serious cardiovascular events (MI, stroke, coronary revascularization, and cardiovascular death) in active versus placebo groups. We used negative binomial regression to account for correlations among repeated events in the same person and to estimate rate ratios and 95% confidence intervals.

Results: During a median of 3.7 years of follow-up, 3,417 total serious cardiovascular events occurred in 2,003 individuals among the 10,061 unique patients randomized. Canakinumab reduced the rates of total serious cardiovascular events, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 10.4, 8.4, 8.3, and 8.2, respectively. The corresponding rate ratios (95% confidence intervals) compared with placebo were 0.80 (0.69 to 0.93) for 50 mg, 0.79 (0.68 to 0.92) for 150 mg, and 0.78 (0.67 to 0.91) for 300 mg.

Conclusions: Anti-inflammatory therapy with canakinumab significantly reduced the total number of cardiovascular events in patients with prior MI and evidence of residual inflammatory risk. (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events] (CANTOS); NCT01327846.
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http://dx.doi.org/10.1016/j.jacc.2020.08.011DOI Listing
October 2020

Annexin A1-dependent tethering promotes extracellular vesicle aggregation revealed with single-extracellular vesicle analysis.

Sci Adv 2020 Sep 16;6(38). Epub 2020 Sep 16.

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Extracellular vesicles (EVs) including plasma membrane-derived microvesicles and endosomal-derived exosomes aggregate by unknown mechanisms, forming microcalcifications that promote cardiovascular disease, the leading cause of death worldwide. Here, we show a framework for assessing cell-independent EV mechanisms in disease by suggesting that annexin A1 (ANXA1)-dependent tethering induces EV aggregation and microcalcification. We present single-EV microarray, a method to distinguish microvesicles from exosomes and assess heterogeneity at a single-EV level. Single-EV microarray and proteomics revealed increased ANXA1 primarily on aggregating and calcifying microvesicles. ANXA1 vesicle aggregation was suppressed by calcium chelation, altering pH, or ANXA1 neutralizing antibody. knockdown attenuated EV aggregation and microcalcification formation in human cardiovascular cells and acellular three-dimensional collagen hydrogels. Our findings explain why microcalcifications are more prone to form in vulnerable regions of plaque, regulating critical cardiovascular pathology, and likely extend to other EV-associated diseases, including autoimmune and neurodegenerative diseases and cancer.
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http://dx.doi.org/10.1126/sciadv.abb1244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494353PMC
September 2020

COVID-19 is, in the end, an endothelial disease.

Eur Heart J 2020 09;41(32):3038-3044

Heart Division, Royal Brompton & Harefield Hospital and National Heart and Lung Institute, Imperial College, London, UK.

The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.
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http://dx.doi.org/10.1093/eurheartj/ehaa623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470753PMC
September 2020

The European Heart Journal: leading the fight to reduce the global burden of cardiovascular disease.

Eur Heart J 2020 09;41(33):3113-3116

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK Copenhagen, Denmark.

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http://dx.doi.org/10.1093/eurheartj/ehaa674DOI Listing
September 2020

Role for Anti-Cytokine Therapies in Severe Coronavirus Disease 2019.

Crit Care Explor 2020 Aug 10;2(8):e0178. Epub 2020 Aug 10.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA.

The causative agent for coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, appears exceptional in its virulence and immunopathology. In some patients, the resulting hyperinflammation resembles a cytokine release syndrome. Our knowledge of the immunopathogenesis of coronavirus disease 2019 is evolving and anti-cytokine therapies are under active investigation. This narrative review summarizes existing knowledge of the immune response to coronavirus infection and highlights the current and potential future roles of therapeutic strategies to combat the hyperinflammatory response of patients with coronavirus disease 2019.

Data Sources: Relevant and up-to-date literature, media reports, and author experiences were included from Medline, national newspapers, and public clinical trial databases.

Study Selection: The authors selected studies for inclusion by consensus.

Data Extraction: The authors reviewed each study and selected approrpriate data for inclusion through consensus.

Data Synthesis: Hyperinflammation, reminiscent of cytokine release syndromes such as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, appears to drive outcomes among adults with severe coronavirus disease 2019. Cytokines, particularly interleukin-1 and interleukin-6, appear to contribute importantly to such systemic hyperinflammation. Ongoing clinical trials will determine the efficacy and safety of anti-cytokine therapies in coronavirus disease 2019. In the interim, anti-cytokine therapies may provide a treatment option for adults with severe coronavirus disease 2019 unresponsive to standard critical care management, including ventilation.

Conclusions: This review provides an overview of the current understanding of the immunopathogenesis of coronavirus disease 2019 in adults and proposes treatment considerations for anti-cytokine therapy use in adults with severe disease.
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http://dx.doi.org/10.1097/CCE.0000000000000178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419062PMC
August 2020

Paclitaxel Drug-Coated Balloon Angioplasty Suppresses Progression and Inflammation of Experimental Atherosclerosis in Rabbits.

JACC Basic Transl Sci 2020 Jul 10;5(7):685-695. Epub 2020 Jun 10.

Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Paclitaxel drug-coated balloons (DCBs) reduce restenosis, but their overall safety has recently raised concerns. This study hypothesized that DCBs could lessen inflammation and reduce plaque progression. Using 25 rabbits with cholesterol feeding- and balloon injury-induced lesions, DCB-percutaneous transluminal angioplasty (PTA), plain PTA, or sham-PTA (balloon insertion without inflation) was investigated using serial intravascular near-infrared fluorescence-optical coherence tomography and serial intravascular ultrasound. In these experiments, DCB-PTA reduced inflammation and plaque burden in nonobstructive lesions compared with PTA or sham-PTA. These findings indicated the potential for DCBs to serve safely as regional anti-atherosclerosis therapy.
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http://dx.doi.org/10.1016/j.jacbts.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393431PMC
July 2020

Oxidized Low-Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles.

J Am Heart Assoc 2020 08 31;9(15):e015878. Epub 2020 Jul 31.

Cardiovascular Division Department of Medicine Brigham and Women's HospitalHarvard Medical School Boston MA.

Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage-derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low-density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration-dependent manner (293% increase; <0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (<0.05), and oxLDL-induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL-induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (<0.01) and caspase 3/7 activation increased MΦMP production by 208% (<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL-induced caspase 3/7 activation and attenuated oxLDL-stimulated MΦMP production and tissue factor content by 60% (<0.01) and 43% (<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.
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http://dx.doi.org/10.1161/JAHA.120.015878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792235PMC
August 2020

Postischemic Administration of IL-1α Neutralizing Antibody Reduces Brain Damage and Neurological Deficit in Experimental Stroke.

Circulation 2020 Jul 13;142(2):187-189. Epub 2020 Jul 13.

Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland (L.L, N.R.B., Y.M.P., L.S., A.A., J.H.B., T.F.L., G.G.C.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046301DOI Listing
July 2020

Prospective Evaluation of Clinico-Pathological Predictors of Postoperative Atrial Fibrillation: An Ancillary Study From the OPERA Trial.

Circ Arrhythm Electrophysiol 2020 08 12;13(8):e008382. Epub 2020 Jul 12.

Brigham and Women's Hospital, Boston, MA (D.M.).

Background: Postoperative atrial fibrillation (POAF) occurs in 30% to 50% of patients undergoing cardiac surgery and is associated with increased morbidity and mortality. Prospective identification of structural/molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict risk of POAF may identify new molecular pathways and targets for prevention of this common morbid complication.

Methods: Right atrial appendage samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation), fixed in 10% buffered formalin, and embedded in paraffin for histology. We assessed general tissue morphology, cardiomyocyte diameters, myocytolysis (perinuclear myofibril loss), accumulation of perinuclear glycogen, interstitial fibrosis, and myocardial gap junction distribution. We also assayed NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT, CRP (C-reactive protein), and circulating oxidative stress biomarkers (F2-isoprostanes, F3-isoprostanes, isofurans) in plasma collected before, during, and 48 hours after surgery. POAF was defined as occurrence of postcardiac surgery atrial fibrillation or flutter of at least 30 seconds duration confirmed by rhythm strip or 12-lead ECG. The follow-up period for all arrhythmias was from surgery until hospital discharge or postoperative day 10.

Results: Thirty-five percent of patients experienced POAF. Compared with the non-POAF group, they were slightly older and more likely to have chronic obstructive pulmonary disease or heart failure. They also had a higher European System for Cardiac Operative Risk Evaluation and more often underwent valve surgery. No differences in left atrial size were observed between patients with POAF and patients without POAF. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen score or Cx43 distribution at the time of surgery was not significantly associated with incidence of POAF. None of these histopathologic abnormalities were correlated with levels of NT-proBNP, hs-cTnT, CRP, or oxidative stress biomarkers.

Conclusions: In sinus rhythm patients undergoing cardiac surgery, histopathologic changes in the right atrial appendage do not predict POAF. They also do not correlate with biomarkers of cardiac function, inflammation, and oxidative stress. Graphic Abstract: A graphic abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCEP.120.008382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457312PMC
August 2020