Team Bruna Gigante

ENDOTYPES IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASES

Research focus

Aim of our research is to identify clinical and molecular profiles, so called endotypes, able to identify individuals at risk for atherosclerosis related cardiovascular diseases (ASCVD).

The figure below gives an overview our research strategy. We analyse molecular data in large and well established cardiovascular cohorts and try to dissect the inflammatory component of ASCVD, with main focus on coronary heart disease and ischemic stroke.

Chronic inflammation
Chronic vascular inflammation Photo: Bruna Gigante

Overview of our research strategy. We analyse panels of inflammatory biomarkers in large and well established cardiovascular cohorts (left panel): the Iganga-Mayuge cardiopulmonary study (I-M-Cardio-Pulm) a cohort of young individuals with a high burden of chronic infections; the cohort of 60 years old men and women from Stockholm (60YO), a cohort of middle aged men and women followed up for incident ASCVD in 20 years; the IMPROVE an European study with a large collection of measure of subclinical atherosclerosis; the Carebbean-e study, a cohort of elderly patients at high risk of ASCVD. In addition (right panel), we have also access to clinical materials collected at Danderyds Hospital to study the effects of acute inflammation on the risk of ASCVD, such as the COMMUNITY-study a collection of patients hospitalized because of covid-19 and healthy individuals challenged with an acute inflammatory stimulus.

The ultimate goal of our research is to identify the right treatment for the right patient, in line with the aims of personalized medicine.

Research lines

Our research projects can be summarized in three major lines of research:

1. Novel endotypes characterizing the inflammatory response in atherosclerosis.

We have recently shown that the excess of a circulating biomarker formed by interleukin 6 (IL6) and its soluble receptor (sIL6R) increases the risk for ASCVD. In healthy individuals this complex (IL6:sIL6R) is bound to an anti inflammatory molecule called sgp130 to form a ternary complex. We have seen that when the IL6:sIL6R in the circulation exceeds IL6:sIL6R:sgp130, the risk of myocardial infarction and ischemic stroke increases (Ziegler L et al Cardiovascular Research 2019). In particular, among those at risk for ASCVD, an excess of the IL6:sIL6R complex identifies a specific endotype for risk of ischemic stroke: young men with normal/low cholesterol levels and low cardiovascular risk (Ziegler L et al European J Preventive Cardiology 2020). Our preliminary data also show that all these molecules are expressed in atherosclerotic plaques and their expression levels partly mirror the circulating levels, suggesting a cross-talk between local and circulating inflammatory response, as shown in the figure below.

Cross-talk between local and circulating inflammatory response.
Cross-talk between local and circulating inflammatory response. Photo: Bruna Gigante

We now aim to integrate clinical variables such as age, body mass index, blood pressure with circulating biomarkers mirroring vascular and systemic inflammation to define endotypes of cardiovascular risk.

2. Novel clinical and biological markers of risk for stroke and major bleeding in patients with atrial fibrillation.

We have established a large cohort of elderly patients with atrial fibrillation (AF) (n=2943) the Atrial fibrillation: risk and benefits of anti-coagulation (Carebbean)-elderly (Ehrlinder H et al International J Cardiology Heart and Vasculature 2020) to identify thrombosis/bleeding clinical risk profiles. AF patients represent a group at very high cardiovascular risk, because of AF and because age per se is a hallmark of cardiovascular risk. Aging is associated with a chronic inflammatory state that creates a milieu favourable to ASCVD.  We have collected clinical, biochemical and imaging data on all AF patients (aged 75-104) who have initiated an anticoagulant treatment. We follow them up for ischemic and bleeding complications before and after initiation of anticoagulant treatment. In the next future we are going to collect blood samples before and after the start of the treatment with anticoagulants to identify molecular biomarkers related to hemostasis, inflammation and angiogenesis that can help us to improve the clinical characterization of these patients.

At present, we are analysing how loss of muscular mass which represents a marker for chronic inflammation affects the risk of future ASCVD and bleeding, the two major causes of death in this group of patients.

3. Getting fit to fight cardiovascular diseases in rural Uganda: the Iganga-Mayuge cardio-pulmonary study.

Cardiovascular diseases are rapidly increasing in Uganda. Malnutrition during childhood, the globalization of junk food, the aging population with its burden of comorbidities and chronic infectious diseases create a unique setting for the development of cardiovascular diseases in Uganda. The figure below summarizes the epidemiological transition from infectious to cardiovascular diseases in Uganda: while infectious diseases are still prevalent and are a common cause of death, cardiovascular diseases rise and cause progressively more deaths in the population. Infections can affect the occurrence of cardiovascular diseases in multiple ways: HIV and other chronic infectious diseases as well as the treatment against them are associated with a chronic low grade inflammation  that increases the life time risk of cardiovascular diseases.

The pattern of cardiovascular risk factors in Uganda is largely unknown and most of the existing data rely on extrapolation from other sub-Saharan regions.

To this exent, we are establishing a longitudinal cohort in a rural area in eastern Uganda districts of Iganga and Mayuge, 120 kilometres east of Kampala, the capital city of Uganda. (please see the small red circle on the Ugandan map on the left). Karolinska Institutet  and Makerere University (Uganda) have established the Iganga-Mayuge population-based Health Demographic Surveillance Site (IMHDSS) in 2004. Interviews are conducted every year and the demographic characteristics of this population are constantly updated. In particular, care is taken to update inhabitants for each one of the 17000 household, number of births and deaths as well as possible causes of death.

We have planned and recently started to link the demographic surveillance with a health screening of the population with special focus on young adults (25-35 years of age). We collect demographic, clinical and anthropometric data. In addition a large and complete biobank has been established. This long term project has a local and a global perspective. In the local setting of Uganda, the project is designed to build capacity, charachterize the cardiovascular risk with clinical and molecular data and provide care where possible. On a global perspective, undermining the risk factors of cardiovascular disease in Uganda where chronic inflammation is highly prevalent and other more traditional risk factors (like smoking) less prevalent can provide us with new knowledge and new directives to improve prevention of cardiovascular disease in patients with chronic inflammatory and autoimmune diseases.

Study materials

The IMPROVE Study

The Carebbean-elderly Study

Team members

Bruna Gigante MD, PhD, Team Leader

Louise Dencker Ziegler MD, PhD, Postdoctoral fellow

Hanne Ehrlinder MD, PhD student

Qiao Sen Chen, Master Student

Angela Silveira PhD, Senior researcher

Rona Strawbridge PhD, Associated

Selected Publications

Risk of Ischemic Stroke and Major Bleeding in Patients With Atrial Fibrillation and Cancer.
Aspberg S, Yu L, Gigante B, Smedby KE, Singer DE
J Stroke Cerebrovasc Dis 2019 Dec;():104560

Weight gain and blood pressure.
Sundström J, Lind L, Lampa E, Angerås O, Bachus E, Bergström G, et al
J. Hypertens. 2019 Nov;():

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al
Eur. Heart J. 2020 Jan;41(1):111-188

The predictive role of interleukin 6 trans-signalling in middle-aged men and women at low-intermediate risk of cardiovascular events.
Ziegler L, Frumento P, Wallén H, de Faire U, Gigante B
Eur J Prev Cardiol 2020 Jan;27(2):122-129

Circulating microRNAs as predictive biomarkers of myocardial infarction: Evidence from the HUNT study.
Velle-Forbord T, Eidlaug M, Debik J, Sæther JC, Follestad T, Nauman J, Gigante B, Røsjø H, Omland T, Langaas M, Bye A
Atherosclerosis 2019 10;289():1-7
Velle-Forbord T, Eidlaug M, Debik J, Sæther JC, Follestad T, Nauman J, et al
Atherosclerosis 2019 Oct;289():1-7

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.
Sung YJ, de Las Fuentes L, Winkler TW, Chasman DI, Bentley AR, Kraja AT, et al
Hum. Mol. Genet. 2019 Apr;():

Genetic variation in CADM2 as a link between psychological traits and obesity.
Morris J, Bailey MES, Baldassarre D, Cullen B, de Faire U, Ferguson A, et al
Sci Rep 2019 May;9(1):7339

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.
Marklund M, Wu JHY, Imamura F, Del Gobbo LC, Fretts A, de Goede J, et al
Circulation 2019 May;139(21):2422-2436

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.
Bentley AR, Sung YJ, Brown MR, Winkler TW, Kraja AT, Ntalla I, et al
Nat. Genet. 2019 04;51(4):636-648

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events.
Patel RS, Schmidt AF, Tragante V, McCubrey RO, Holmes MV, Howe LJ, et al
Circ Genom Precis Med 2019 Apr;12(4):e002471

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.
Patel RS, Tragante V, Schmidt AF, McCubrey RO, Holmes MV, Howe LJ, et al
Circ Genom Precis Med 2019 Apr;12(4):e002470

Serum IL8 is not associated with cardiovascular events but with all-cause mortality.
Moreno Velásquez I, Gajulapuri A, Leander K, Berglund A, de Faire U, Gigante B
BMC Cardiovasc Disord 2019 02;19(1):34

Interleukin 6 trans-signalling and risk of future cardiovascular events.
Ziegler L, Gajulapuri A, Frumento P, Bonomi A, Wallén H, de Faire U, et al
Cardiovasc. Res. 2019 01;115(1):213-221

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.
Feitosa MF, Kraja AT, Chasman DI, Sung YJ, Winkler TW, Ntalla I, et al
PLoS ONE 2018 ;13(6):e0198166

Cardiac Structure Injury After Radiotherapy for Breast Cancer: Cross-Sectional Study With Individual Patient Data.
Taylor C, McGale P, Brønnum D, Correa C, Cutter D, Duane FK, et al
J. Clin. Oncol. 2018 08;36(22):2288-2296

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.
van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, et al
Diabetes 2018 07;67(7):1414-1427

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.
Sung YJ, Winkler TW, de Las Fuentes L, Bentley AR, Brown MR, Kraja AT, et al
Am. J. Hum. Genet. 2018 03;102(3):375-400

Effects of Angiotensin-Converting Enzyme Inhibition and Alpha 1-Adrenergic Receptor Blockade on Inflammation and Hemostasis in Human Hypertension.
Ekholm M, Jekell A, Wallén NH, Gigante B, Kahan T
J. Cardiovasc. Pharmacol. 2018 04;71(4):240-247

Comorbidities in relation to fatality of first myocardial infarction.
Quintana HK, Janszky I, Kanar A, Gigante B, Druid H, Ahlbom A, et al
Cardiovasc. Pathol. ;32():32-37

Exposure to Traffic-Related Air Pollution and Serum Inflammatory Cytokines in Children.
Gruzieva O, Merid SK, Gref A, Gajulapuri A, Lemonnier N, Ballereau S, et al
Environ. Health Perspect. 2017 06;125(6):067007

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.
Scott RA, Scott LJ, Mägi R, Marullo L, Gaulton KJ, Kaakinen M, et al
Diabetes 2017 11;66(11):2888-2902

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.
Justice AE, Winkler TW, Feitosa MF, Graff M, Fisher VA, Young K, et al
Nat Commun 2017 04;8():14977

IgM antibodies to oxidized phosphatidylserine as protection markers in cardiovascular disease among 60-year olds.
Frostegård J, Su J, Sing S, Hua X, Vikström M, Leander K, et al
PLoS ONE 2017 ;12(4):e0171195

Serum Fatty Acids, Desaturase Activities and Abdominal Obesity - A Population-Based Study of 60-Year Old Men and Women.
Alsharari ZD, Risérus U, Leander K, Sjögren P, Carlsson AC, Vikström M, et al
PLoS ONE 2017 ;12(1):e0170684

Human IgM Antibodies to Malondialdehyde Conjugated With Albumin Are Negatively Associated With Cardiovascular Disease Among 60-Year-Olds.
Thiagarajan D, Frostegård AG, Singh S, Rahman M, Liu A, Vikström M, et al
J Am Heart Assoc 2016 12;5(12):

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.
Ehret GB, Ferreira T, Chasman DI, Jackson AU, Schmidt EM, Johnson T, et al
Nat. Genet. 2016 10;48(10):1171-1184

Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, et al
PLoS Genet. 2016 06;12(6):e1006166

Healthy Lifestyle and Risk of Heart Failure: Results From 2 Prospective Cohort Studies.
Larsson SC, Tektonidis TG, Gigante B, Åkesson A, Wolk A
Circ Heart Fail 2016 Apr;9(4):e002855