Using next-generation imaging techniques to identify new biomarkers of atherosclerotic plaque burden and vulnerability

Sammendrag av oppnådde forskningsresultater i rapporteringsåretI dette prosjektet forsøker vi å finne biomarkører i blod som reflekterer grad av åreforkalkninger i hjertet, og tester ut om disse biomarkørene kan hjelpe oss til å forbedre risikoprediksjonsmodellene for hjerteinfarkt.Vi har siden oppstart gjennomført 2 studier hvor vi har analysert assosiasjon mellom nye typer biomarkører (microRNA, lipoprotein subfraksjoner og metabolitter) og grad av åreforkalkninger målt ved avansert bildediagnostikk. Flere nye biomarkører var knyttet til grad av åreforkalkninger med større eller mindre sikkerhet. Disse markørene ble deretter målt i en uavhengig kohort av tilsynelatende friske individer for å se om de nye biomakrørene kunne forbedre risikoprediksjon for fremtidig hjerteinfarkt (studie 3). Her er et sammendrag av studie 3: Bakgrunn: Nåværende metoder for å forutsi risikoen for hjerteinfarkt har flere begrensninger, og flere som i dag utvikler hjerteinfarkt ble på forhånd misklassifisert som lavrisikopasienter av de verktøyene vi har i dag. Men nye typer stoffer i blodet som knyttes til åreforkalkning kan muligens forbedre disse metodene. Mål: Vi ønsker å se om visse stoffer i blodet kan forutsi fremtidige hjerteinfarkt hos tilsynelatende friske personer med forventet lav risiko for hjerteinfarkt de neste 10 årene. Metoder: Vi samlet blodprøver fra 200 tilsynelatende friske personer (100 av disse fikk hjerteinfarkt innen 10 år og 100 holdt seg friske) fra Helseundersøkelsen i Trøndelag (HUNT). Nye tyyper biomarkører ble analysert i blodprøver fra disse deltakerne. Resultater: Vi fant ut at to stoffer, miR-424-5p og triglyserider i LDL-4, hadde sterkest sammenheng med fremtidige hjerteinfarkt. For menn var triglyserider i LDL-4 en spesielt viktig risikofaktor. Konklusjon: Disse to stoffene i blodet kan være viktige for å forutsi risiko for hjerteinfarkt i tillegg til de klassiske risikofaktorene som benyttes i dag. De kan bidra til å forbedre dagens metoder for å forutsi hjerteinfarkt, men mer forskning er nødvendig for å bekrefte dette. Vi ser også at ulike risikofaktorer kan ha forskjellig betydning for menn og kvinner, noe som også trenger mer utforskning. Vi fortsetter nå videre med å utforske proteiner som nye risikomarkører for hjerteinfarkt, og har ekstra fokus på å utvikle kvinnespesifikke risikoprediksjonsalgoritmer for hjerteinfarkt i årene som kommer. Årsaken til dette er at vi se i preliminære studier at dagens risikoberegningsverktøy presterer dårligere for kvinner enn for menn.

Using next-generation imaging techniques to identify new biomarkers of atherosclerotic plaque burden and vulnerabilityStatistics from EU shows that cardiovascular disease (CVD) kills more Europeans than all cancers together. To address this major health problem, primary prevention should be the key focus. It is therefore extremely important to provide healthcare personnel with accurate risk prediction models for CVD, to facilitate early prevention strategies.We will apply advanced coronary imaging techniques to determine whether circulating lipoprotein subfractions can reflect coronary atherosclerosis plaque burden and plaque vulnerability (WP1). We will also examine whether lipid core-containing coronary plaques releases metabolic end-products that can be detected in the circulating (WP2). Finally, we will determine whether incorporation of atherogenic lipoprotein subfractions and/or circulating metabolites can improve the precision of the NORRISK 2 score to predict 10-year risk of CVD (WP3). Progress so far: WP1: Three studies on the association between plaque burden and lipoprotein subfractions have been completed. Sæther JC, Klevjer M, Giskeødegård G, Bathen T, Gigante B, Gjære S, Myhra M, Vesterbekkmo E, Wiseth R, Madssen E, Bye A. Small LDL subfractions are associated with coronary atherosclerosis despite no differences in conventional lipids, Physiological Genomics. Sperstad S, Sæther J, Klevjer M, Giskeødegård G, Bathen T, Røsbjørgen R, Dalen H, Bye A Lipidomics profiling in the search for new myocardial infarction risk markers (submitted, Plos1) Sæther JC, Vesterbekkmo E, Gigante B, Giskeødegård GF, Bathen TF, Follestad T, Wiseth R Madssen E, Bye A The association between circulating lipoprotein subfractions and lipid content in coronary atheromatous plaques assessed by near-infrared spectroscopy (submitted, American Heart journal) Another study will be completed during spring 2023. WP2: Data was acquired analyses in a pilot study autumn 2022. In this study, we did not find any serum metabolites associated with future myocardial infarction. The same methodology will now be applied in a larger and well-defined study population, to test whether serum metabolites may represent potential biomarkers for myocardial infarction in gender-specific analyses. WP3: In previous studies exploring lipoprotein subfractions as early risk markers of myocardial infarction, there seems to be important gender specific associations. Furthermore, as expected, statins mask some potential risk factor. Therefore, only participants without statin treatment are explored in our next studies. The first results from WP3 are currently being analyzed, and will be published during summer 2023.

USING NEXT-GENERATION IMAGING TECHNIQUES TO IDENTIFY NEW BIOMARKERS OF ATHEROSCLEROTIC PLAQUE BURDEN AND VULNERABILITYStatistics from EU shows that cardiovascular disease (CVD) kills more Europeans than all cancers together. To address this major health problem, primary prevention should be the key focus. It is therefore extremely important to provide healthcare personnel with accurate risk prediction models for CVD, to facilitate early prevention strategies.In the clinical setting, several different risk prediction models are available for determining the 10-year risk of CVD. However, the currently available risk prediction models only explain a modest proportion of the incidence. For myocardial infarction (MI), it is estimated that 15-20% of the patients have none of the traditional risk factors and would be classified as “low risk”. Thus, there is a clinical need for new risk markers that could complement the assessment of traditional risk factors, to identify the individuals at risk with greater precision than today. Lipid core-containing coronary plaques are thought to be the cause of most acute coronary syndromes, hence, their early detection may identify high-risk patients. Near-infrared spectroscopy (NIRS) is a new imaging technique that determines the chemical composition of substances that can be used to identify lipid core-containing plaques. By combining NIRS with intravascular ultrasound (IVUS), we now have access to the next-generation diagnostic tool for the characterization of coronary plaque structure and composition. In the last years, the possibility to identify and quantify subfractions of lipid components has been largely improved by advances in lipidomics technology. Increasing evidence suggest that quantification of lipoprotein subfractions may provide additional information that is missing in today's evaluation of CVD risk, thus potentially leading to a better outcome. Pilot data from our research team indicate that some lipoprotein subfractions (e.g. LDL-5-ApoB) have a strong discriminating effect of the presence of significant coronary atherosclerosis compared to traditional low-density lipoprotein cholesterol (LDL-C). To further explore these findings, we will now use advanced coronary imaging techniques to determine whether circulating lipoprotein subfractions can reflect coronary atherosclerosis burden and plaque vulnerability (WP1). We will also examine whether lipid core-containing coronary plaques releases metabolic end-products that can be detected in the circulating (WP2). Finally, we will determine whether incorporation of atherogenic lipoprotein subfractions and/or circulating metabolites can improve the precision of the NORRISK 2 score to predict 10-year risk of CVD (WP3). Progress so far: WP1: Two studies on the association between plaque burden and lipoprotein subfractions are currently in the data analysis/discussion step. These will be submitted for publication spring 2022. WP2: Data has been acquired and will be analyses autumn 2022. WP3: One Master thesis has been delivered (Sigri Bakken Sperstad, SINTEF) exploring lipoprotein subfractions as early risk markers of myocardial infarction using data from HUNT (This provides pilot data for WP3). There seems to be important gender specific risk markers for myocardial infarction among lipoprotein subfractions. Furthermore, as expected, statins mask some potential risk factor. Only participants without statin treatment are therefore selected for WP3.