Team Bruna Gigante
Overarching aim of our line of research is to define clinical and molecular profiles associated with the risk of cardiovascular diseases.
Major research lines
At present we have three main lines of research.
1. Novel approaches to target inflammation in atherosclerosis.
A chronic inflammation in the vascular wall is one of the forces driving the progression of atherosclerosis. Atherosclerosis is the biological lesions underlying the clinical manifestations of coronary heart diseases (myocardial infarction and angina pectoris) and some forms of ischemic stroke. It has been estimated that the modulation of the inflammatory response could prevent 1 cardiovascular event every 200 patients treated.
The figure below summarizes the different players of the so called central axis of inflammation in atherosclerosis, a cascade that starts with the activation of Interleukin 1b and proceeds through the activation of Interleukin 6 (IL6). IL6 is able to activate different pathways: through the modulation of the synthesis of CRP, IL6 participates to the regulation of the immune response; through the binding to a soluble receptor, sIL6R, IL6 modulates the inflammation in the vascular wall.
The main challenge in treating inflammation in atherosclerosis is to identify the right molecular target. We have recently shown that increasing levels of IL6:sIL6R associate with the risk of future myocardial infarction and ischemic stroke in a large Swedish population of healthy individuals. The pro-inflammatory effect of IL6:sIL6R can be buffered by a circulating protein sgp130 that binds and inactivates IL6:sIL6R. We have shown that elevated IL6:sIL6R:sgp130 levels are protective towards cardiovascular diseases. From this perspective treatment with sgp130 could represent a novel cardiovascular treatment moiety. We are currently trying to define if sgp130 is causally related to the progression of atherosclerosis through the discovery of genes associated with sgp130 levels in the circulation, the analysis of the pattern of expression in healthy and diseased vessels and finally through a functional analysis of this inflammatory/anti inflammatory pathway in simple experimental animal models such as Zebrafish.
2. Novel clinical and biological markers of risk for stroke and major bleeding in patients with atrial fibrillation.
Atrial fibrillation (AF) is a common cardiac arrhythmia whose prevalence increases with age from 4% at the age of 65 years to 14% in 85-years old. AF creates a milieu in the heart that facilitates the formation of thrombi (clots). With the blood flowing through the heart chambers small part of the clots may be released in the circulation and occlude peripheral vessels in the brain, causing an ischemic stroke, or in other organs. To reduce the risk of thrombi, AF patients need a life-long treatment with anticoagulants since they reduce the ability of the blood to coagulate and to form clots. Anticoagulants however increase the risk of bleeding, the most feared event being intracranial haemorrhage. Elderly patients with AF experience the highest risk of ischemic stroke and at the same time the highest risk of major bleeding during treatment with anticoagulants.
Both ischemic and hemorragic events are associated with long term disabilities, dramatic for the individual and expensive for the society. What we lack at the present are clinical and molecular markers to identify those patients who have the highest risk of bleeding while on anticoagulants and/or the highest risk of thrombotic events. With this in mind, we have established a large cohort of elderly patients (n=2943) the Atrial fibrillation: risk and benefits of anti-coagulation (Carebbean)-elderly [ClinicalTrials.gov Identifier: NCT03828162] to identify thrombosis/bleeding clinical risk profiles. We have collected clinical, biochemical and imaging data on all patients who have initiated an anticoagulant treatment and we follow them up for ischemic and bleeding complications. 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.
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.
Bruna Gigante MD, PhD, Team Leader
Louise Dencker Ziegler MD, PhD student
Hanne Ehrlinder MD, PhD student
Angela Silveira PhD, Senior researcher
Rona Strawbridge PhD, Associated
Anders Hamsten MD, PhD, Associated