Cardiology

Faculty of Medicine | Lund University

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David Erlinge

Predicting, preventing and treating myocardial infarction

General aims

The aim is to find biomarkers or imaging modalities that can predict and localize the coronary segment that will cause myocardial infarction. Once identified we try methods to prevent the infarction. In patients who suffer an infarction the aim is to mitigate the reperfusion injury with cardioprotective therapies. The focus has in a very productive way been on how P2-receptors are involved in platelet aggregation, regulates endothelial function and dysfunction regulate blood flow and inflammation. However, the project is now broader looking also for other targets.

Specific aims

Endothelium and vascular flow: To understand how P2-receptors regulates endothelial function and dysfunction, regulates blood flow, inflammation, platelets, and cholesterol accumulation. A target for cardiovascular drug treatment has been identified. Perform large patient studies of coronary flow reserve to predict, identify new biomarkers and to test new treatments.

Understanding Platelets to prevent myocardial infarction: To understand the importance of the endothelial release of the endogenous P2Y12-antagonist FPP using a new LC-MS quantitative assay we developed. To understand the microparticle miRNA based crosstalk between platelets and endothelial cells.

Improving coronary microcirculation to reduce myocardial infarction size: To develop treatment strategies to improve coronary microcirculation to reduce infarct size and perform clinical trials to establish them in the clinic.

Nanoassays for biomarkers in plasma and microparticles: To use our register-based biobanks and large population studies to find biomarkers for cardiovascular disease. To use ultrasound-based capturing methods to enrich microparticles that can be used for specific analysis of intracellular endothelial markers of endothelial dysfunction and cardiovascular disease.

Register-based randomised clinical trials (RRCT): To develop and perform cost-effective clinical medication trials based on our excellent registers by performing the first pharmaceutical RRCT and to validate the RRCT-method.

Imaging studies to predict the coronary segment to cause a future myocardial infarction: Perform the first prospective study using intracoronary detection of cholesterol-accumulation to identify the coronary segment causing myocardial infarction before the event. To test if biodegradable stents can be used to stabilize the vulnerable plaque.

Project description and preliminary results

Endothelium and vascular flow

To understand how P2-receptors regulates endothelial function and dysfunction in regulating blood flow, inflammation, platelets, and cholesterol accumulation. We have established a shear stress model and we can see that endothelial release of ATP acting on P2X4-receptors are highly important for shear induced endothelial function, eNOS and KLF2 expression. A loss-of-function SNP in P2X4 coupled to increased pulse pressure is expressed in EC results in reduction in eNOS and KLF2. P2X4 receptors will be overexpressed to test if this could mimic the positive shear stress effects. In the shear stress model we examine how glucolipotoxicity of EC is mediated. It turns out that release of ATP acting on the P2X7 receptor mediates the main part of the effect. These mechanisms are extensively explored. P2X7 mediated glucotoxicity may explain the protective effect of a loss of function variant against stroke and AMI which makes it an excellent target for drug development. The importance of P2 receptor stimulation for miRNA release and regulation is examined with deep sequencing. Furthermore long-non-coding RNA regulation is studied with similar methods. The transfer of regulatory miRNA between cells is further studied.  Endothelial function is studied clinically with non-invasive coronary flow reserve and peripheral endothelial function (Endopat) in collaboration with Gothenburg (the PROFLOW study). 600 patients with previous ACS perform CFR, Endopat, IMT and biobanking, and are followed for clinical events. Novel biomarkers for endothelial function are correlated to the results. We have found that ticagrelor improves peripheral endothelial function in patients with a previous ACS. The CFR will be used to evaluate new drug candidates against cardiovascular disease.

Understanding Platelets to prevent myocardial infarction

We have discovered an endogenous P2Y12-receptor inhibitor, farnesyl pyrophosphate (FPP). The substance blocks the ADP mediated platelet aggregation with micromolar potency and it is therefore likely that it has physiological importance in modulating the platelet stimulating effects of ADP. We have found indications that EC release FPP to inhibit platelet aggregation. We will measure the levels of FPP with a quantitative LC-MS assay we recently developed. FPP will be measured both in in vitro models (endothelial shear stress) and in clinical studies (AMI, diabetes etc). The hypothesis is that individuals with low levels have a higher risk of thrombotic complications. We will continue our studies of the crosstalk via miRNA that occurs from platelets to EC, especially the microparticle mediated transfer of miRNA.

Improving coronary microcirculation to reduce myocardial infarction size

After a long series of pig studies to optimize hypothermia therapy we did the RAPID MI-ICE pilot study where awake STEMI patients where cooled to 33°C in before PCI. This reduced infarct size by 30%. The larger follow up study CHILL-MI showed reduction of infarct size but did not reach significance in the whole population. However, anterior STEMI had reduced infarct size by 31%, and in the whole group heart failure development was significantly reduced. The international interest was great and a larger study is now planned.

We have received an EU-grant to develop cardioprotective treatments based on cyclosporin analogues without the anti-inflammatory side effects but with the mitochondrie protective effects. I am responsible for the translational part, i.e. to examine which animal models are prognostic for outcome in man, by examining similar protocols, biomarkers and treatments in a pig model (Lund), rabbit (Paris), mouse (Sophia Antipolis) and rat (London). We have done a deep sequencing of long non-coding RNA and epigenic regulatory proteins in preconditioned rat hearts and found several long ncRNA associated with preconditioning that might be cardioprotective and involved in improved microcirculation. Their regulatory role are now extensively evaluated.

Nanoassays for cells, biomarkers in plasma and microparticles

We have several large biobanks: Lund, Uppsala and Karolinska are leading TOTAL-AMI, a SSF sponsored effort to establish a national biobank coupled to our excellent SWEDEHEART register based on our LUNDHEARTGENE strategy. I am responsible for cardiology in the BIG3-project were 10 000 MI-COPD-lungcancer-risk-individuals will be screened with CT-angio, endothelial function (Endopat) and biobank. We are especially interested in the combined predictive value of knowing endothelial function, coronary calcification (Agatston score), lumen stenosis and presence of soft vulnerable plaque. Patients with significant stenosis will perform an coronary angiogram where I also will image lipid content with NIRS and collect “Liquid Biopsies” from the vulnerable segment.

Acoustophoresis: The next generation cell handling in medical diagnostics and therapeutics. Together with Thomas Laurell at Lunds Tekniska högskola, we are developing nano-based ultrasound acoustic particle trapping methods to be able to enrich intact cells and microparticles for analysis. Most biomarker analysed are soluble molecules in plasma or serum and these will be examined with LC-MS, OLINK and conventional technologies. However, we believe that biomarkers contained in microparticles could give us better information about intracellular processes. Together with Thomas Laurell at Lunds Tekniska högskola, we are developing nano-based ultrasound acoustic particle trapping methods to be able to enrich intact microparticles for analysis. These projects are sponsored by KAW and SSF.

figure 2 ny

There are three main drivers of cardiovascular disease development: Endothelial dysfunction, Inflammation and Platelet activation. We now know that all three release microparticles to communicate and regulate cardiovascular physiology. Previous methodology have not been able to separate large numbers of undisturbed microparticles. Furthermore, studying the physiological effect of endothelial, inflammatory and platlet microparticles separately has not been possible. Based on the nanochip-based improved microparticle separation, we will develop diagnostic tools to improve prognostication and personalised therapy for cardiovascular disease. Use endothelial microparticles as markers for endothelial dysfunction by correlating to both non-invasive and invasive methods (echocardiography coronary flow reserve (CFR), invasive CFR during angiography and peripheral arterial function (Endopat). Use platelet microparticles as markers for platelet activation by correlating to platelet function tests (LTA, VASP, FACS).

Register-based randomised clinical trials (RRCT)

The first study using this concept was the TASTE study where thrombectomy was evaluated in 7200 patients and published in NEJM. DE is now the leader of the first medication RRCT, the VALIDATE trial, comparing heparin with bivalirudin in 6000 patients. It also includes an important substudy validating the RRCT concept and follow up. The study started Q3 2014.

Imaging studies to predict the coronary segment to cause a future myocardial infarction

NIRS is a novel technology able to identify lipid rich plaque, presumed to be vulnerable. We have found that close to all AMI patients have rings of lipid accumulation at the culprit site (Erlinge, late breaking trial at Eur Atheroscl. Soc, 2013). Now we want to study this prospectively in the multicentre-study PROPECTII where I am PI. 900 patients will be prospectively enrolled during angiography to perform 3 vessel IVUS and NIRS, examined by core lab and followed for 2 years. When a coronary event happens the segment causing the event is identified. The hypothesis is that we can detect a signature of lipid-rich plaque, which predicts coronary events. If they are identified early and then treated the AMI can be avoided. In the PROSPECT ABSORB substudy we build on the evidence from the PROSPECT trial that an IVUS identified plaque burden of >70% causes 10% event rate at 2-3 years. To avoid this we randomize to a biodegradable scaffold (stent that disappears) and do re-angio after 2 years. We hypothesize that treatment will result in improved mean lumen area.

nirs

10 Selected Scientific publications

h-index = 40

62. Wang L, Olivecrona G, Götberg M, Olsson ML, Sörhede Winzell M, Erlinge D. ADP acting on P2Y13 receptors is a negative feedback pathway for ATP release from human red blood cells. Circulation Research 96 189-196, 2005. Impact Factor 11.9

65. Wihlborg AK, Balogh J, Wang L, Borna C, Dou Y, Bhalchandra J, Lazarowski E, Jacobson KA, Arner A, Erlinge D. Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y2 and P2Y6 receptors on cardiomyocytes and release of UTP in man during myocardial infarction. Circulation Research 98, 970-976, 2006. Impact Factor 11.9

7. Amisten S, Melander O, Wihlborg A-K, Berglund G and Erlinge D. Increased risk of acute myocardial infarction and elevated levels of C-reactive protein in carriers of the Thr-87 variant of the ATP receptor P2Y11. Eur Heart J 28, 13-18, 2007. Impact Factor 14.1
78. Erlinge D, Siegbahn A, Varenhorst C, James S, Braun ÖB, Brandt JT, Jacubowski JA, Sugidachi A, Winthers KJ, Wallentin L. Patients with poor responsiveness to Thienopyridine treatment and those with diabetes have lower levels of circulating active metabolites but their platelets respond normally to the active metabolite added ex-vivo. JACC, 2008, 52, 1968-77. Impact Factor 14.0

96. Götberg M, Olivecrona GK, Koul S, Carlsson M, Engblom H, Ugander M, van der Pals J, Algotsson L, Arheden H, Erlinge D. A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction Circulation (Cardiovascular Intervention) 2010, 5, 400-7. Impact Factor 6.1

105. Koul S, Smith JG, Scherstén F, James S, Lagerqvist B, Erlinge D. Effect of upstream clopidogrel treatment in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J 2011;32:2989-2997. Impact Factor 14.1

123. Gidlöf O, van der Brug M, Ohman J, Gilje P, Olde B, Wahlestedt C, Erlinge D. Platelets activated during myocardial infarction release functional miRNA which can be taken up by endothelial cells and regulate ICAM1 expression. Blood. 2013; 121, 3908-3917. Impact Factor 9.0

126. Erlinge D, Gurbel P, James S, Lindahl T, Svensson P, Ten Berg J, Foley D, Wagner H, Brown PB, Luo J, Zhou C, Moser B, Jakubowski JA, Small DS, Winters KJ Angiolillo DJ. Prasugrel 5-mg in the very elderly is non-inferior to prasugrel 10-mg in non-elderly patients:  The GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J Am Coll Cardiol 2013, 62, 577-583. Impact Factor 14.0

138. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Åneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Køber L, Langørgen J, Lilja G, Møller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013; 369(23):2,197-206. Impact Factor 51.7

146. Erlinge D, Götberg M, Lang I, Holzer M, Noc M, Clemmensen P, Jensen U, Metzler B, James S, Bötker HE, Omerovic E, Engblom H, Carlsson M, Arheden H, Ostlund O, Wallentin L, Harnek J, Olivecrona GK. Rapid Endovascular Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction: The CHILL-MI Trial: A Randomized Controlled Study of the Use of Central Venous Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction. J Am Coll Cardiol. 2014;63(18):1857-65. Impact Factor 14.0

David Erlinge

david erlinge

 

MD, PhD, Professor

David.Erlinge@med.lu.se 
Phone: +46 46 17 25 97

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