Publications by authors named "Karlheinz Peter"

223 Publications

Platelets, coagulation and the vascular wall The quest to better understand and smarten up our therapeutic targeting of this triad in primary and secondary prevention of cardiovascular events.

Cardiovasc Res 2021 Apr 1. Epub 2021 Apr 1.

Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1093/cvr/cvab121DOI Listing
April 2021

Rescue PCI in the management of STEMI: Contemporary results from the Melbourne Interventional Group registry.

Int J Cardiol Heart Vasc 2021 Apr 15;33:100745. Epub 2021 Mar 15.

Department of Cardiology, Ballarat Health Services, Ballarat, Victoria, Australia.

Background: Fibrinolysis is an important reperfusion strategy in the management of ST-elevation myocardial infarction (STEMI) when timely access to primary percutaneous coronary intervention (PPCI) is unavailable. Rescue PCI is generally thought to have worse outcomes than PPCI in STEMI. We aimed to determine short- and long-term outcomes of patients with rescue PCI versus PPCI for treatment of STEMI.

Methods And Results: Patients admitted with STEMI (excluding out-of-hospital cardiac arrest) within the Melbourne Interventional Group (MIG) registry between 2005 and 2018 treated with either rescue PCI or PPCI were included in this retrospective cohort analysis. Comparison of 30-day major adverse cardiac events (MACE) and long-term mortality between the two groups was performed. There were 558 patients (7.1%) with rescue PCI and 7271 with PPCI. 30-day all-cause mortality (rescue PCI 6% vs. PPCI 5%, p = 0.47) and MACE (rescue PCI 10.3% vs. PPCI 8.9%, p = 0.26) rates were similar between the two groups. Rates of in-hospital major bleeding (rescue PCI 6% vs. PPCI 3.4%, p = 0.002) and 30-day stroke (rescue PCI 2.2% vs. PPCI 0.8%, p < 0.001) were higher following rescue PCI. The odds ratio for haemorrhagic stroke in the rescue PCI group was 10.3. Long-term mortality was not significantly different between the groups (rescue PCI 20% vs. PPCI 19%, p = 0.33).

Conclusions: With contemporary interventional techniques and medical therapy, rescue PCI remains a valuable strategy for treating patients with failed fibrinolysis where PPCI is unavailable and it has been suggested in extenuating circumstances where alternative revascularisation strategies are considered.
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http://dx.doi.org/10.1016/j.ijcha.2021.100745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988313PMC
April 2021

A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction.

Basic Res Cardiol 2021 Mar 15;116(1):17. Epub 2021 Mar 15.

Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The monocyte β-integrin Mac-1 is crucial for leukocyte-endothelium interaction, rendering it an attractive therapeutic target for acute and chronic inflammation. Using phage display, a Designed-Ankyrin-Repeat-Protein (DARPin) was selected as a novel binding protein targeting and blocking the α I-domain, an activation-specific epitope of Mac-1. This DARPin, named F7, specifically binds to activated Mac-1 on mouse and human monocytes as determined by flow cytometry. Homology modelling and docking studies defined distinct interaction sites which were verified by mutagenesis. Intravital microscopy showed reduced leukocyte-endothelium adhesion in mice treated with this DARPin. Using mouse models of sepsis, myocarditis and ischaemia/reperfusion injury, we demonstrate therapeutic anti-inflammatory effects. Finally, the activated Mac-1-specific DARPin is established as a tool to detect monocyte activation in patients receiving extra-corporeal membrane oxygenation, as well as suffering from sepsis and ST-elevation myocardial infarction. The activated Mac-1-specific DARPin F7 binds preferentially to activated monocytes, detects inflammation in critically ill patients, and inhibits monocyte and neutrophil function as an efficient new anti-inflammatory agent.
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http://dx.doi.org/10.1007/s00395-021-00849-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960600PMC
March 2021

Platelets in Multiple Sclerosis: Early and Central Mediators of Inflammation and Neurodegeneration and Attractive Targets for Molecular Imaging and Site-Directed Therapy.

Front Immunol 2021 19;12:620963. Epub 2021 Feb 19.

Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

Platelets are clearly central to thrombosis and hemostasis. In addition, more recently, evidence has emerged for non-hemostatic roles of platelets including inflammatory and immune reactions/responses. Platelets express immunologically relevant ligands and receptors, demonstrate adhesive interactions with endothelial cells, monocytes and neutrophils, and toll-like receptor (TLR) mediated responses. These properties make platelets central to innate and adaptive immunity and potential candidate key mediators of autoimmune disorders. Multiple sclerosis (MS) is the most common chronic autoimmune central nervous system (CNS) disease. An association between platelets and MS was first indicated by the increased adhesion of platelets to endothelial cells. This was followed by reports identifying structural and functional changes of platelets, their chronic activation in the peripheral blood of MS patients, platelet presence in MS lesions and the more recent revelation that these structural and functional abnormalities are associated with all MS forms and stages. Investigations based on the murine experimental autoimmune encephalomyelitis (EAE) MS model first revealed a contribution to EAE pathogenesis by exacerbation of CNS inflammation and an early role for platelets in EAE development via platelet-neuron and platelet-astrocyte associations, through sialated gangliosides in lipid rafts. Our own studies refined and extended these findings by identifying the critical timing of platelet accumulation in pre-clinical EAE and establishing an initiating and central rather than merely exacerbating role for platelets in disease development. Furthermore, we demonstrated platelet-neuron associations in EAE, coincident with behavioral changes, but preceding the earliest detectable autoreactive T cell accumulation. In combination, these findings establish a new paradigm by asserting that platelets play a neurodegenerative as well as a neuroinflammatory role in MS and therefore, that these two pathological processes are causally linked. This review will discuss the implications of these findings for our understanding of MS, for future applications for imaging toward early detection of MS, and for novel strategies for platelet-targeted treatment of MS.
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http://dx.doi.org/10.3389/fimmu.2021.620963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933211PMC
February 2021

The tandem stenosis mouse model: Towards understanding, imaging, and preventing atherosclerotic plaque instability and rupture.

Br J Pharmacol 2020 Dec 23. Epub 2020 Dec 23.

Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

The rupture of unstable atherosclerotic plaques is the major cause of cardiovascular mortality and morbidity. Despite significant limitations in our understanding and ability to identify unstable plaque pathology and prevent plaque rupture, most atherosclerosis research utilises preclinical animal models exhibiting stable atherosclerosis. Here, we introduce the tandem stenosis (TS) mouse model that reflects plaque instability and rupture, as seen in patients. The TS model involves dual ligation of the right carotid artery, leading to locally predefined unstable atherosclerosis in hypercholesterolaemic mice. It exhibits key characteristics of human unstable plaques, including plaque rupture, luminal thrombosis, intraplaque haemorrhage, large necrotic cores, thin or ruptured fibrous caps and extensive immune cell accumulation. Altogether, the TS model represents an ideal preclinical tool for improving our understanding of human plaque instability and rupture, for the development of imaging technologies to identify unstable plaques, and for the development and testing of plaque-stabilising treatments for the prevention of atherosclerotic plaque rupture.
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http://dx.doi.org/10.1111/bph.15356DOI Listing
December 2020

Platelet CXCL14: introducing a new player and potential therapeutic target in thromboinflammation.

Cardiovasc Res 2021 Feb;117(3):645-647

Atherothrombosis & Vascular Biology Program, Baker Heart & Diabetes Institute, 75 Commercial Rd, Melbourne, VIC 3004, Australia.

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http://dx.doi.org/10.1093/cvr/cvaa351DOI Listing
February 2021

Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms.

Eur Heart J 2021 Mar;42(9):938-947

Vascular Biology and Atherosclerosis, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.

Aims : Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI.

Methods And Results : We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis.

Conclusion : Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.
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http://dx.doi.org/10.1093/eurheartj/ehaa995DOI Listing
March 2021

Transcatheter Aortic Valve Implantation, Atrial Fibrillation, and Bleeding: A Surprisingly Fatal Attraction.

Thromb Haemost 2020 Nov 18;120(11):1479-1482. Epub 2020 Oct 18.

Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1055/s-0040-1718533DOI Listing
November 2020

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities.

Cardiovasc Res 2020 12;116(14):2197-2206

Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC 3004, Australia.

The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is a critical concern of the coronavirus disease 2019 (COVID-19) pandemic. Strikingly, men account for the majority of COVID-19 deaths, with current figures ranging from 59% to 75% of total mortality. However, despite clear implications in relation to COVID-19 mortality, most research has not considered sex as a critical factor in data analysis. Here, we highlight fundamental biological differences that exist between males and females, and how these may make significant contributions to the male-biased COVID-19 mortality. We present preclinical evidence identifying the influence of biological sex on the expression and regulation of angiotensin-converting enzyme 2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However, we note that there is a lack of reports showing that sexual dimorphism of ACE2 expression exists and is of functional relevance in humans. In contrast, there is strong evidence, especially in the context of viral infections, that sexual dimorphism plays a central role in the genetic and hormonal regulation of immune responses, both of the innate and the adaptive immune system. We review evidence supporting that ineffective anti-SARS-CoV-2 responses, coupled with a predisposition for inappropriate hyperinflammatory responses, could provide a biological explanation for the male bias in COVID-19 mortality. A prominent finding in COVID-19 is the increased risk of death with pre-existing cardiovascular comorbidities, such as hypertension, obesity, and age. We contextualize how important features of sexual dimorphism and inflammation in COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain their increased mortality risk. Ultimately, we demonstrate that biological sex is a fundamental variable of critical relevance to our mechanistic understanding of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and therapeutic strategies.
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http://dx.doi.org/10.1093/cvr/cvaa284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665363PMC
December 2020

Tunable Harmonic Flow Patterns in Microfluidic Systems through Simple Tube Oscillation.

Small 2020 10 1;16(43):e2003612. Epub 2020 Oct 1.

School of Engineering, RMIT University, Melbourne, VIC, 3000, Australia.

Generation of tunable harmonic flows at low cost in microfluidic systems is a persistent and significant obstacle to this field, substantially limiting its potential to address major scientific questions and applications. This work introduces a simple and elegant way to overcome this obstacle. Harmonic flow patterns can be generated in microfluidic structures by simply oscillating the inlet tubes. Complex rib and vortex patterns can be dynamically modulated by changing the frequency and magnitude of tube oscillation and the viscosity of liquid. Highly complex rib patterns and synchronous vortices can be generated in serially connected microfluidic chambers. Similar dynamic patterns can be generated using whole or diluted blood samples without damaging the sample. This method offers unique opportunities for studying complex fluids and soft materials, chemical synthesis of various compounds, and mimicking harmonic flows in biological systems using compact, tunable, and low-cost devices.
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http://dx.doi.org/10.1002/smll.202003612DOI Listing
October 2020

Cardiovascular and Metabolic Protection by Vitamin E: A Matter of Treatment Strategy?

Antioxidants (Basel) 2020 Sep 29;9(10). Epub 2020 Sep 29.

Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.

Cardiovascular diseases (CVD) cause about 1/3 of global deaths. Therefore, new strategies for the prevention and treatment of cardiovascular events are highly sought-after. Vitamin E is known for significant antioxidative and anti-inflammatory properties, and has been studied in the prevention of CVD, supported by findings that vitamin E deficiency is associated with increased risk of cardiovascular events. However, randomized controlled trials in humans reveal conflicting and ultimately disappointing results regarding the reduction of cardiovascular events with vitamin E supplementation. As we discuss in detail, this outcome is strongly affected by study design, cohort selection, co-morbidities, genetic variations, age, and gender. For effective chronic primary and secondary prevention by vitamin E, oxidative and inflammatory status might not have been sufficiently antagonized. In contrast, acute administration of vitamin E may be more translatable into positive clinical outcomes. In patients with myocardial infarction (MI), which is associated with severe oxidative and inflammatory reactions, decreased plasma levels of vitamin E have been found. The offsetting of this acute vitamin E deficiency via short-term treatment in MI has shown promising results, and, thus, acute medication, rather than chronic supplementation, with vitamin E might revitalize vitamin E therapy and even provide positive clinical outcomes.
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http://dx.doi.org/10.3390/antiox9100935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600583PMC
September 2020

Analyzing the shear-induced sensitization of mechanosensitive ion channel Piezo-1 in human aortic endothelial cells.

J Cell Physiol 2021 Apr 22;236(4):2976-2987. Epub 2020 Sep 22.

School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia.

Mechanosensitive ion channels mediate endothelial responses to blood flow and orchestrate their physiological function in response to hemodynamic forces. In this study, we utilized microfluidic technologies to study the shear-induced sensitization of endothelial Piezo-1 to its selective agonist, Yoda-1. We demonstrated that shear stress-induced sensitization is brief and can be impaired when exposing aortic endothelial cells to low and proatherogenic levels of shear stress. Our results suggest that shear stress-induced sensitization of Piezo-1 to Yoda-1 is independent of cell-cell adhesion and is mediated by the PI3K-AKT signaling pathway. We also found that shear stress increases the membrane density of Piezo-1 channels in endothelial cells. To further confirm our findings, we performed experiments using a carotid artery ligation mouse model and demonstrated that transient changes in blood-flow pattern, resulting from a high-degree ligation of the mouse carotid artery alters the distribution of Piezo-1 channels across the endothelial layer. These results suggest that shear stress influences the function of Piezo-1 channels via changes in membrane density, providing a new model of shear-stress sensitivity for Piezo-1 ion channel.
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http://dx.doi.org/10.1002/jcp.30056DOI Listing
April 2021

The opioid-P2Y inhibitor interaction: Potential strategies to mitigate the interaction and consideration of alternative analgesic agents in myocardial infarction.

Pharmacol Ther 2021 01 21;217:107665. Epub 2020 Aug 21.

Department of Cardiology, Alfred Hospital, Melbourne, Australia; Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Australia. Electronic address:

Despite advances in medical and interventional management of acute myocardial infarction, treatment of the associated chest pain has remained relatively unchanged since opioids were first utilized in the 1930's. This dominance can be partially attributed to initial studies suggesting hemodynamic benefits with opioid treatment. However, delayed gastrointestinal absorption of P2Y inhibitors due to opioids and the consequent impairment in antiplatelet activity of this established therapy is cause for concern. Coupled with the lack of randomized clinical trial evidence to support widespread opioid use, there is now an opportunity to re-evaluate our approach to analgesia in myocardial infarction. This review characterizes the mechanism of the opioid-P2Y inhibitor interaction, strategies aimed at mitigating the interaction and appraises promising alternative agents to opioid therapy in patients with myocardial infarction.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107665DOI Listing
January 2021

Combined Antiplatelet/Anticoagulant Drug for Cardiac Ischemia/Reperfusion Injury.

Circ Res 2020 Oct 17;127(9):1211-1213. Epub 2020 Aug 17.

Molecular Imaging and Theranostics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia (L.A.B., A.M., A.K.S., E.Y., X.W.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317450DOI Listing
October 2020

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice.

Sci Rep 2020 08 6;10(1):13211. Epub 2020 Aug 6.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes.
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http://dx.doi.org/10.1038/s41598-020-70043-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413393PMC
August 2020

Prehospital opioid dose and myocardial injury in patients with ST elevation myocardial infarction.

Open Heart 2020 07;7(2)

Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia

Objective: To characterise the relationship between opioid dose and myocardial infarct size in patients with ST elevation myocardial infarction (STEMI).

Methods: Patients given opioid treatment by emergency medical services with confirmed STEMI were included in this secondary, retrospective cohort analysis of the Air versus Oxygen in Myocardial Infarction (AVOID) study. Patients with cardiogenic shock were excluded. The primary endpoint was comparison of cardiac biomarkers as a measure of infarct size based on opioid dose (low ≤8.75 mg, intermediate 8.76-15 mg and high >15 mg of intravenous morphine equivalent dose).

Results: 422 patients were included in the analysis. There was a significantly higher proportion of patients with Thrombolysis in Myocardial Infarction (TIMI) 0 or 1 flow pre-percutaneous coronary intervention (PCI) (94% vs 81%, p=0.005) and greater use of thrombus aspiration catheters (59% vs 30%, p<0.001) in the high compared with low-dose opioid group. After adjustment for potential confounders, every 1 mg of intravenous morphine equivalent dose was associated with a 1.4% (95% CI 0.2%, 2.7%, p=0.028) increase in peak creatine kinase; however, this was no longer significant after adjustment for TIMI flow pre-PCI.

Conclusions: Our study suggests no benefit of higher opioid dose and a dose-dependent signal between opioid dose and increased myocardial infarct size. Prospective randomised controlled trials are required to establish causality given that this may also be explained by patients with a greater ischaemic burden requiring higher opioid doses due to more severe pain. Future research also needs to focus on strategies to mitigate the opioid-P2Y12 inhibitor interaction and non-opioid analgesia to treat ischaemic chest pain.
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http://dx.doi.org/10.1136/openhrt-2020-001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380835PMC
July 2020

Antithrombotic Therapy in Myocardial Infarction: Historic Perils and Current Challenges-A 70-Year Journey.

Thromb Haemost 2020 Oct 24;120(10):1352-1356. Epub 2020 Jul 24.

Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

There have been numerous and intriguing advancements in antithrombotic therapy for myocardial infarction since it was described in the earliest issues of . In this article, we revisit historical breakthroughs and describe the four most challenging contemporary themes relating to antithrombotic therapy in myocardial infarction. In all four, the challenge is to find the best balance of reducing specific levels of ischaemic risks without increasing bleeding risk. The first is the question of the optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). This includes discussion of monotherapy after a period of DAPT. The second relates to the role of genotype and phenotype-guided individualisation of antiplatelet therapy. There is emerging evidence for a role of pheno/genotyping in identifying individuals at high risk for recurrent ischaemic events or in guiding the timing of cardiac surgery for patients on DAPT. The third addresses the increasing evidence for dual pathway inhibition, for example, with rivaroxaban in addition to aspirin in patients where high ischaemic and low bleeding risk is demonstrated. Finally the fourth highlights the challenge of the most appropriate combination of antiplatelet and anticoagulation therapy for patients with known atrial fibrillation after PCI. In most individuals, oral PY inhibitor therapy combined with a direct acting oral anticoagulant appears to be the best strategy based on the available evidence. Overall, the progress in antithrombotic therapy achieved over the last seven decades is remarkable, however, there are important issues to address and progress still to be made.
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http://dx.doi.org/10.1055/s-0040-1714212DOI Listing
October 2020

Transcatheter Aortic Valve Implantation Represents an Anti-Inflammatory Therapy Via Reduction of Shear Stress-Induced, Piezo-1-Mediated Monocyte Activation.

Circulation 2020 Sep 8;142(11):1092-1105. Epub 2020 Jul 8.

School of Health and Biomedical Sciences (S.B., S.A.-A., P.V., A.J., K.P.), RMIT University, Melbourne, Victoria, Australia.

Background: Aortic valve stenosis is an increasingly prevalent degenerative and inflammatory disease. Transcatheter aortic valve implantation (TAVI) has revolutionized its treatment, thereby avoiding its life-threatening/disabling consequences. Whether aortic valve stenosis is accelerated by inflammation and whether it is itself a cause of inflammation are unclear. We hypothesized that the large shear forces exerted on circulating cells, particularly on the largest circulating cells, monocytes, while passing through stenotic aortic valves result in proinflammatory effects that are resolved with TAVI.

Methods: TAVI provides a unique opportunity to compare the activation status of monocytes under high shear stress (before TAVI) and under low shear stress (after TAVI). The activation status of monocytes was determined with a single-chain antibody, MAN-1, which is specific for the activated β-integrin Mac-1. Monocyte function was further characterized by the adhesion of myocytes to stimulated endothelial cells, phagocytic activity, uptake of oxidized low-density lipoprotein, and cytokine expression. In addition, we designed a microfluidic system to recapitulate the shear rate conditions before and after TAVI. We used this tool in combination with functional assays, Ca imaging, siRNA gene silencing, and pharmacological agonists and antagonists to identify the key mechanoreceptor mediating the shear stress sensitivity of monocytes. Last, we stained for monocytes in explanted stenotic aortic human valves.

Results: The resolution of high shear stress through TAVI reduces Mac-1 activation, cellular adhesion, phagocytosis, oxidized low-density lipoprotein uptake, and expression of inflammatory markers in monocytes and plasma. Using microfluidics and pharmacological and genetic studies, we could recapitulate high shear stress effects on isolated human monocytes under highly controlled conditions, showing that shear stress-dependent calcium influx and monocyte adhesion are mediated by the mechanosensitive ion channel Piezo-1. We also demonstrate that the expression of this receptor is shear stress dependent and downregulated in patients receiving TAVI. Last, we show monocyte accumulation at the aortic side of leaflets of explanted aortic valves.

Conclusions: We demonstrate that high shear stress, as present in patients with aortic valve stenosis, activates multiple monocyte functions, and we identify Piezo-1 as the mainly responsible mechanoreceptor, representing a potentially druggable target. We demonstrate an anti-inflammatory effect and therefore a novel therapeutic benefit of TAVI.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045536DOI Listing
September 2020

The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications.

Circ Res 2020 07 26;127(4):571-587. Epub 2020 Jun 26.

Department of Cardiology (K.P.), Alfred Hospital, Melbourne, Victoria, Australia.

The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing global pandemic has presented a health emergency of unprecedented magnitude. Recent clinical data has highlighted that coronavirus disease 2019 (COVID-19) is associated with a significant risk of thrombotic complications ranging from microvascular thrombosis, venous thromboembolic disease, and stroke. Importantly, thrombotic complications are markers of severe COVID-19 and are associated with multiorgan failure and increased mortality. The evidence to date supports the concept that the thrombotic manifestations of severe COVID-19 are due to the ability of SARS-CoV-2 to invade endothelial cells via ACE-2 (angiotensin-converting enzyme 2), which is expressed on the endothelial cell surface. However, in patients with COVID-19 the subsequent endothelial inflammation, complement activation, thrombin generation, platelet, and leukocyte recruitment, and the initiation of innate and adaptive immune responses culminate in immunothrombosis, ultimately causing (micro)thrombotic complications, such as deep vein thrombosis, pulmonary embolism, and stroke. Accordingly, the activation of coagulation (eg, as measured with plasma D-dimer) and thrombocytopenia have emerged as prognostic markers in COVID-19. Given thrombotic complications are central determinants of the high mortality rate in COVID-19, strategies to prevent thrombosis are of critical importance. Several antithrombotic drugs have been proposed as potential therapies to prevent COVID-19-associated thrombosis, including heparin, FXII inhibitors, fibrinolytic drugs, nafamostat, and dipyridamole, many of which also possess pleiotropic anti-inflammatory or antiviral effects. The growing awareness and mechanistic understanding of the prothrombotic state of COVID-19 patients are driving efforts to more stringent diagnostic screening for thrombotic complications and to the early institution of antithrombotic drugs, for both the prevention and therapy of thrombotic complications. The shifting paradigm of diagnostic and treatment strategies holds significant promise to reduce the burden of thrombotic complications and ultimately improve the prognosis for patients with COVID-19.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386875PMC
July 2020

Cardiomyocyte microvesicles: proinflammatory mediators after myocardial ischemia?

J Thromb Thrombolysis 2020 Oct;50(3):533-542

Cardiology and Angiology I, Heart Center Freiburg University, Medical Faculty, University of Freiburg, 79106, Freiburg im Breisgau, Germany.

Myocardial infarction is a frequent complication of cardiovascular disease leading to high morbidity and mortality worldwide. Elevated C-reactive protein (CRP) levels after myocardial infarction are associated with heart failure and poor prognosis. Cardiomyocyte microvesicles (CMV) are released during hypoxic conditions and can act as mediators of intercellular communication. MicroRNA (miRNA) are short non-coding RNA which can alter cellular mRNA-translation. Microvesicles (MV) have been shown to contain distinct patterns of miRNA from their parent cells which can affect protein expression in target cells. We hypothesized that miRNA containing CMV mediate hepatic CRP expression after cardiomyocyte hypoxia. H9c2-cells were cultured and murine cardiomyocytes were isolated from whole murine hearts. H9c2- and murine cardiomyocytes were exposed to hypoxic conditions using a hypoxia chamber. Microvesicles were isolated by differential centrifugation and analysed by flow cytometry. Next-generation-sequencing was performed to determine the miRNA-expression profile in H9c2 CMV compared to their parent cells. Microvesicles were incubated with a co-culture model of the liver consisting of THP-1 macrophages and HepG2 cells. IL-6 and CRP expression in the co-culture was assessed by qPCR and ELISA. CMV contain a distinct pattern of miRNA compared to their parent cells including many inflammation-related miRNA. CMV induced IL-6 expression in THP-1 macrophages alone and CRP expression in the hepatic co-culture model. MV from hypoxic cardiomyocytes can mediate CRP expression in a hepatic co-culture model. Further studies will have to show whether these effects are reproducible in-vivo.
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http://dx.doi.org/10.1007/s11239-020-02156-xDOI Listing
October 2020

Predicting the Risk of Recurrent Venous Thromboembolism: Current Challenges and Future Opportunities.

J Clin Med 2020 May 22;9(5). Epub 2020 May 22.

Clinical Haematology Department, Alfred Hospital, Melbourne, VIC 3004, Australia.

Acute venous thromboembolism (VTE) is a commonly diagnosed condition and requires treatment with anticoagulation to reduce the risk of embolisation as well as recurrent venous thrombotic events. In many cases, cessation of anticoagulation is associated with an unacceptably high risk of recurrent VTE, precipitating the use of indefinite anticoagulation. In contrast, however, continuing anticoagulation is associated with increased major bleeding events. As a consequence, it is essential to accurately predict the subgroup of patients who have the highest probability of experiencing recurrent VTE, so that treatment can be appropriately tailored to each individual. To this end, the development of clinical prediction models has aided in calculating the risk of recurrent thrombotic events; however, there are several limitations with regards to routine use for all patients with acute VTE. More recently, focus has shifted towards the utility of novel biomarkers in the understanding of disease pathogenesis as well as their application in predicting recurrent VTE. Below, we review the current strategies used to predict the development of recurrent VTE, with emphasis on the application of several promising novel biomarkers in this field.
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http://dx.doi.org/10.3390/jcm9051582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290951PMC
May 2020

Plasma levels of trimethylamine-N-oxide can be increased with 'healthy' and 'unhealthy' diets and do not correlate with the extent of atherosclerosis but with plaque instability.

Cardiovasc Res 2021 Jan;117(2):435-449

Heart Research Institute, The University of Sydney, Sydney, NSW, Australia.

Aims: The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis.

Methods And Results: Plasma TMAO increased in mice on 'unhealthy' high-choline diets and notably also on 'healthy' high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE-/- and Ldlr-/- mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage.

Conclusions: Dietary-induced changes in the microbiome, of both 'healthy' and 'unhealthy' diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk.
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http://dx.doi.org/10.1093/cvr/cvaa094DOI Listing
January 2021

Helical flow: A means to identify unstable plaques and a new direction for the design of vascular grafts and stents.

Atherosclerosis 2020 05 12;300:34-36. Epub 2020 Mar 12.

Baker Heart and Diabetes Institute, Melbourne, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.03.002DOI Listing
May 2020

Dynamic Solid-State Ultrasound Contrast Agent for Monitoring pH Fluctuations .

ACS Sens 2020 04 14;5(4):1190-1197. Epub 2020 Apr 14.

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Chemical Engineering, Monash University, 20 Research Way, Clayton, VIC 3800, Australia.

The key challenge for biosensing is to design biomarker-responsive contrast agents that can be readily detected and monitored by broadly available biomedical imaging modalities. While a range of biosensors have been designed for optical, photoacoustic, and magnetic resonance imaging (MRI) modalities, technical challenges have hindered the development of ultrasound biosensors, even though ultrasound is widely available, portable, safe, and capable of both surface and deep tissue imaging. Typically, contrast-enhanced ultrasound imaging is generated by gas-filled microbubbles. However, they suffer from short imaging times because of the diffusion of the gas into the surrounding media. This demands an alternate approach to generate nanosensors that reveal pH-specific changes in ultrasound contrast in biological environments. Silica cores were coated with pH-responsive poly(methacrylic acid) (PMA) in a layer-by-layer (LbL) approach and subsequently covered in a porous organosilica shell. Transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) were employed to monitor the successful fabrication of multilayered particles and prove the pH-dependent shrinkage/swelling of the PMA layer. This demonstrates that reduction in pH below healthy physiological levels resulted in significant increases in ultrasound contrast, in gel phantoms, mouse cadaver tissue, and live mice. The future of such materials could be developed into a platform of biomarker-responsive ultrasound contrast agents for clinical applications.
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http://dx.doi.org/10.1021/acssensors.0c00245DOI Listing
April 2020

C-Reactive Protein and Its Structural Isoforms: An Evolutionary Conserved Marker and Central Player in Inflammatory Diseases and Beyond.

Subcell Biochem 2020 ;94:499-520

Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

C-reactive protein (CRP) is an evolutionary highly conserved member of the pentraxin superfamily of proteins. CRP is widely used as a marker of inflammation, infection and for risk stratification of cardiovascular events. However, there is now a large body of evidence, that continues to evolve, detailing that CRP directly mediates inflammatory reactions and the innate immune response in the context of localised tissue injury. These data support the concept that the pentameric conformation of CRP dissociates into pro-inflammatory CRP isoforms termed pCRP* and monomeric CRP. These pro-inflammatory CRP isoforms undergo conformational changes that facilitate complement binding and immune cell activation and therefore demonstrate the ability to trigger complement activation, activate platelets, monocytes and endothelial cells. The dissociation of pCRP occurs on the surface of necrotic, apoptotic, and ischaemic cells, regular β-sheet structures such as β-amyloid, the membranes of activated cells (e.g., platelets, monocytes, and endothelial cells), and/or the surface of microparticles, the latter by binding to phosphocholine. Therefore, the deposition and localisation of these pro-inflammatory isoforms of CRP have been demonstrated to amplify inflammation and tissue damage in a broad range of clinical conditions including ischaemia/reperfusion injury, Alzheimer's disease, age-related macular degeneration and immune thrombocytopaenia. Given the potentially broad relevance of CRP to disease pathology, the development of inhibitors of CRP remains an area of active investigation, which may pave the way for novel therapeutics for a diverse range of inflammatory diseases.
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http://dx.doi.org/10.1007/978-3-030-41769-7_20DOI Listing
April 2020

The choice of targets and ligands for site-specific delivery of nanomedicine to atherosclerosis.

Cardiovasc Res 2020 Nov;116(13):2055-2068

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.

As nanotechnologies advance into clinical medicine, novel methods for applying nanomedicine to cardiovascular diseases are emerging. Extensive research has been undertaken to unlock the complex pathogenesis of atherosclerosis. However, this complexity presents challenges to develop effective imaging and therapeutic modalities for early diagnosis and acute intervention. The choice of ligand-receptor system vastly influences the effectiveness of nanomedicine. This review collates current ligand-receptor systems used in targeting functionalized nanoparticles for diagnosis and treatment of atherosclerosis. Our focus is on the binding affinity and selectivity of ligand-receptor systems, as well as the relative abundance of targets throughout the development and progression of atherosclerosis. Antibody-based targeting systems are currently the most commonly researched due to their high binding affinities when compared with other ligands, such as antibody fragments, peptides, and other small molecules. However, antibodies tend to be immunogenic due to their size. Engineering antibody fragments can address this issue but will compromise their binding affinity. Peptides are promising ligands due to their synthetic flexibility and low production costs. Alongside the aforementioned binding affinity of ligands, the choice of target and its abundance throughout distinct stages of atherosclerosis and thrombosis is relevant to the intended purpose of the nanomedicine. Further studies to investigate the components of atherosclerotic plaques are required as their cellular and molecular profile shifts over time.
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http://dx.doi.org/10.1093/cvr/cvaa047DOI Listing
November 2020

Extracellular HtrA2 Induces Apoptosis in Human Umbilical Vein Endothelial Cells.

Int J Mol Sci 2019 Oct 31;20(21). Epub 2019 Oct 31.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.

The serine protease high-temperature-required protein A2 (HtrA2) has been identified as a key intracellular molecule promoting apoptosis in cells during ischemia reperfusion (IR) injury. IR injury in ST-segment elevation myocardial infarction (STEMI) contributes to overall myocardial damage. HtrA2 has further been shown to be significantly increased in the serum of patients with STEMI. In the present pilot study, we use human umbilical vein endothelial cells (HUVECs) to investigate whether extracellular HtrA2 induces apoptosis using Annexin V staining. Furthermore, we examine whether HtrA2 is released extracellularly after staurosporine-induced apoptosis using ELISA. We find that HtrA2 is released upon induction of apoptosis by staurosporine into the cell culture medium. Furthermore, treatment of HUVECs with extracellular HtrA2-induces apoptosis, while the addition of anti-HtrA2 antibodies reduces both HtrA2- and staurosporine-induced endothelial cell apoptosis. In conclusion, we show here that extracellular HtrA2 induces apoptosis in human endothelial cells, although the exact molecular mechanisms have to be investigated in future.
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http://dx.doi.org/10.3390/ijms20215446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862081PMC
October 2019

Inflammation in acute coronary syndrome: Expression of TLR2 mRNA is increased in platelets of patients with ACS.

PLoS One 2019 23;14(10):e0224181. Epub 2019 Oct 23.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Platelets are key components in atherogenesis and determine the course of its clinical sequelae acute coronary syndrome (ACS). Components of the innate immune system-the superfamily of TLR receptors-are present in platelets and represent a link between atherothrombosis and inflammation. We hypothesize that alteration in platelet TLR mRNA expression is a result of inflammation driving coronary atherosclerosis and may represent an alternative platelet activation pathway in ACS. TLR2-, TLR4- and TLR9- mRNA-expression was determined in ACS patients and compared to patients with invasive exclusion of atherosclerotic lesions of coronary arteries.

Methods: A total of fifty-four patients were enrolled in this clinical retrospective cohort single centre study. Total RNA from sepharose-filtered highly purified platelets was isolated using acid guanidinium thiocyanate-phenol-chloroform extraction and transcribed to cDNA using a first strand cDNA synthesis kit. To determine absolute copy numbers of TLR2, TLR4 and TLR9 we used plasmid based quantitative PCR with normalisation to an internal control.

Results: We found that mRNA expression levels of TLR2 but not TLR 4 and 9 are up-regulated in platelets of patients with ACS when compared to patients without coronary atherosclerosis.

Conclusion: Our results suggest elevated TLR2 mRNA expression in platelets as a biomarker reflecting the underlying inflammation in ACS and possibly severity of coronary atherosclerosis. Platelet TLR2 may represent a link between inflammation and atherothrombosis in ACS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224181PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808418PMC
March 2020