Atrial fibrillation and hemostatic changes: is it a hypercoagulable state?
PhD project by Morten Mørk, MD, PhD Student (January 2012-September 2015)
Background: Atrial fibrillation (AF) is the most common treatment-requiring cardiac arrhythmia. Patients with AF are at an increased risk of having a stroke. Most AF-related thrombi causing stroke are formed in a specific area of the heart called the left atrial appendage, and there are indications that changes in blood flow and composition as well as the cardiac wall in this anatomical region are responsible for this complication. In recent years, cell-derived microvesicles carrying procoagulant molecules in their membrane have attracted attention as possible contributors to the thrombogenic process in AF.
Aim: In this project, we aim to study the coagulation state and the atrial appendage tissue in patients with AF in order to potentially predict which patients may be at an increased risk of having a thromboembolic event and thus be able to optimise the prophylactic treatment.
Hypotheses: We hypothesise that
- blood collected from the left atrial appendage in patients with AF is measurably hypercoagulable
- mRNA’s coding for procoagulant and apoptosis-related proteins are upregulated in left atrial appendage tissue in patients with AF
Methods: Blood samples from the left atrial appendage and a peripheral vein and tissue samples from the atrial appendages will be collected from patients with nonvalvular AF and a control group, all patients undergoing thoracic surgery. The blood will be analysed with novel methods for detection of procoagulant extracelleular vesicles, tissue factor and procoagulant phospholipids and also well-established methods for measurement of coagulability indices.
The transcriptome of the atrial appendages will be quantified with a focus on mRNAs coding for procoagulant and apoptosis-related proteins.
Also, the actual amount of procoagulant proteins – including tissue factor and von Willebrand Factor – in the atrial appendages will be studied by use of immunohistochemical staining.
Perspectives: Further knowledge on the pathophysiologic mechanisms leading to thrombus formation in the left atrial appendage in patients with AF may contribute to the continued development of methods for risk stratification and individualised treatment.
Project status: The establishment of new coagulation analyses and analysis of extracellular vesicles has presented some interesting challenges that have led to additional substudies. We have collected data that we expect to publish in a paper on microparticle reference values in fasting and non-fasting individuals on fresh as well as stored plasma samples and a paper on observed changed concentrations of tissue factor-bearing extracellular vesicles in the postprandial as compared to the fasting state.
Furthermore, we have established a safe and efficient method for sample collection from the left atrial appendage during bypass surgery. We have obtained ethical approval and have proved viability of the method in practice.
Thromboembolism and Death in Patients with Atrial Flutter
PhD project by Henrik Vadmann (September 2010-summer 2015)
Atrial fibrillation (AF) and atrial flutter (AFL) are often described jointly, and there is no clear discrimination between these two common and, presumably, independent cardiac arrhythmias. AFL usually is characterised by a rapid and organised atrial rhythm rate, whereas AF is a disorganised rhythm. There are, however, clinical and perhaps also physiological similarities between these two cardiac arrhythmias.
Numerous internationally published studies and international guidelines do not discriminate between the two arrhythmias. Despite increasing focus on the association between AF and the risk of stroke in recent years, little is known about the risk associated with AFL.
This PhD project investigates the association between AFL and the risk of thromboemblic events, death and adverse outcomes, using data from the Danish national registries and historical data.
The project consists of three separate studies: Study 1 is a systematic review of current literature on the issue, Study 2 will follow patients for up to 12 years after an ablation procedure for AFL, and Study 3 aims a mapping what other diseases, age and/or gender may affect outcome following ablation for AFL. Data from study 2 and 3 will be compared with data from patients who have been treated with ablation for AF.
This PhD project is expected to contribute to further knowledge and a deeper understanding of the consequences of AFL and the thromboembolic risk associated with this arrhythmia.
Atrial Fibrillation, from Self-Rated Health Status to Patients’ Perceptions of Living with the Disease
PhD project by Vibeke Høgh, RN, MCN, PhD Student (May 2011-May 2015, including maternity leave from September 2011 to December 2012)
The overall purpose of this PhD project is to elucidate the patient perspective of living with atrial fibrillation (AF).
AF is the most common cardiac arrhythmia. Despite this, very little is known about the patient perspective of living with this disease.
The results from this project is expected to contribute to the development of a person-oriented rehabilitation programme and a better and more convenient pathway structure for patients diagnosed with AF. The study is thus expected to have a preventive effect on the number of readmissions due to recurrent AF and to reduce the growing socio-economic health burden while at the same sustaining the patients’ perception of a process taking the entirety of their life situation into account. Furthermore, the results of the project are expected to contribute to the validation of disease-specific health questionnaires for use in Denmark.
The PhD project has a mixed-method framework and consists of three studies that include both quantitative data such as self-rated health status and qualitative data such as field data and interviews.
Study 1. A literature study examining the validity of the concept of quality of life on patients living with AF in 53 scientific studies. Results from this study can be downloaded here: http://omicsgroup.org/journals/quality-of-life-exemplified-through-patients-living-with-atrial-fibrillation-2167-1168-3-150.pdf.
Study 2. An epidemiological cross sectional study on the association between being diagnosed with AF and self-reported health status, using the generic questionnaire Short Form 36 (SF-36), in 873 persons from the Danish cohort Diet, Cancer & Health diagnosed with AF compared with the rest of the cohort (41.725 persons).
Study 3. A case study following the pathway of a patient newly diagnosed with symptomatic paroxysmal AF with special focus on lived experience and perception of health, quality of life, everyday life, family life and work life. Peter is a 55-year-old employed man who is living with his wife and has two grown-up children and a grandchild. The complexity and context of his life will be will be followed for one year after he received the diagnosis of symptomatic paroxysmal AF, using participant observations, interviews, letters, medical journal and questionnaires (SF-36, AFEQT and AF-QOL-18).
From 15 November 2014 to 14 May 21015 (6 months) at the university of Tasmania, Australia
Effects of Marine Fatty Acids on Heart Rate Variability, Atrial Fibrillation and other Arrhythmias in Patients Receiving Chronic Dialysis (Renal Rhythm Study)
PhD project by Jesper Moesgaard Rantanen, MD, PhD Student (June 2013-May 2016)
N-3 and n-6 PUFA; interactions, genetic pathways, and risk of atrial fibrillation
PhD project by Lotte Maxild Mortensen, MSc, PhD Student (January 2011-February 2016)
Purpose and hypothesis:
Atrial fibrillation (AF) is a complex disorder with multiple partly unknown causes and risk factors. Much research has been carried out to elucidate the association between dietary fatty acids and the risk of AF. So far, results have been inconclusive which may be due to the fact that the genotype variation affecting the processing of different types of fatty acids in the body has not been taken into account.
The main purpose of this study is to investigate the relation between dietary intake of polyunsaturated fatty acids (PUFA), the genotype of selected genes and the development of AF.
The hypothesis is that polymorphisms in the genes encoding the enzymes of the PUFA pathway and the eicosanoid pathway: D6 desaturase, D5 desaturase, elongase 5, prostaglandin synthases, prostacyclin synthases, thromboxane synthases, and lipoxygenases affect the risk of AF through differential processing of n-3, n-6 fatty acids, and their derived metabolites resulting in genetic predisposition towards light or strong inflammatory phenotypes.
The overall plan is to analyse the intake of n-3 and n-6 fatty acids, and SNP-polymorphisms in the selected candidate genes measured as single SNP and haplotypes and correlate this with diagnosis of AF. The project will use data from the Diet, Cancer, and Health Cohort where we have information on diet and genetic material from 57,000 Danish participants.
The studies in this PhD project include exposure information from a simple, traditional epidemiological point of view into advanced modelling using bioinformatics aiming at analysing the interaction of the multiple factors involved.
Fig. 1: PUFA pathway (C18-C20) and the synthesis of eicosanoids
Postoperative new-onset atrial fibrillation following cardiac surgery with special reference to potential new predictors
PhD project by Jiwei Gu, MD, PhD Student (March 2014-March 2017)
Background: Postoperative new onset atrial fibrillation(POAF)develops in 20-60% of patients undergoing cardiac surgery depending on definition, type of surgeries and method of identifying the diagnosis. Because POAF is associated with an increased risk of early and late stroke as well as mortality, there is a continuous awareness regarding possibilities to prevent and treat POAF. The cause of POAF is multifactorial and therefore multidirectional efforts are needed in order to predict and prevent development of POAF.
Aim: The overall aim of this thesis is to serve as an example of a multidirectional search for potential new predictors of POAF by performing the individual studies outlined below.
- Detect potential predictors in pre – and perioperative ECGs for the development of POAF using a new electhronic algorithm capable of semi-automatic reading of minor ECG changes.
Hypothesis: Minor perioperative ECG changes can be detected as predictors for development of POAF in cardiac surgery.
Study design: Retrospective observation.
Data sources: ECGs from the patient records, clinical databases.
- Evaluate if age of transfused allogeneic blood is associated with development of POAF
Hypothesis: Increased storage time of transfused blood in the blood bank is associated with an increased risk of POAF.
Study design: Retrospective observation.
Datasources: Clinical and laboratory databases.
- Evaluate if the composition fatty acids in epicardial fatty tissue is associated with development of POAF and if the fatty acid composition in subcutaneous reflects the composition in subcutaneous tissue.
Hypothesis: Specific compositions of PUFA in epicardial tissue are predictors of POAF and reflect the fatty acid composition in subcutaneous tissue.
Study design: Clinical and laboratory study.
Datasources: Patient’s tissue samples
Methods: : For study 1,ECGs will be obtained from the patient records of patients who underwent cardiac surgery (either coronary artery bypass grafting (CABG), valve surgery or combinations) during 2010-2014 at Aalborg University Hospital (100 patients). For study 2,data on blood transfusions will be obtained from local databases in the local blood banks. Data on possible confounding will be retrieved in the same way. For study 3,epicardial adipose tissue biopsy samples from 50 patients undergoing cardiac surgery at Aalborg University hospital.
These studies will have the potential to increase the possibility to identify more patients at risk for the development of POAF in whom a focused prophylaxis and treatment can be initiated.
Project status: Approval from the Danish data protection agency and the Ethical Committee of Nord Denmark Region have been obtained. Now we have already scanned all of the ECGs and converted them to digital versions.(POAF and NO POAF,50 patients in each group) and analysed part of the data for study 1. Now we have already obtained tissue biopsy samples from 45 patients undergoing cardiac surgery including subcutaneous adipose, epicardial adipose, pericardial adipose, right atrium and a blood sample for study 3.