Tissue, Blood and Biomarkers to Predict Future Atrial Fibrillation

Patients undergoing cardiac surgery are at risk of developing post-operative
and recurrent atrial fibrillation (AF), which is related to an increased
morbidity and mortality, but adequate risk prediction is currently impossible.
Generally, patient follow-up in this population is insufficiently focussed on
the development of AF. The mechanisms leading to the development of AF are
multifactorial and remain incompletely understood. MicroRNAs and circulating
plasma biomarkers may elucidate the pathophysiological process underlying AF
and are useful and promising tools for risk stratification, prognosis and
future targets of therapy of AF. These biomarkers may identify those patients
at risk for the development of AF.

The primary objective of this study is to identify atrial tissue miRNAs that
are associated with the incidence of AF and histological alterations in a
population of patients without documented AF. Secondarily, this study will
validate AF associated tissue miRNAs in plasma and will simultaneously
correlate blood protein biomarkers with the incidence of AF. This will allow
future risk stratification using circulating blood biomarkers.

This study will be an explorative study of a cohort of 150 cardiac surgery
patients. Left atrial appendages will be removed and epicardial mapping will be
performed during cardiac surgery at the beginning of the follow-up period.
Atrial tissue and blood samples will be collected at baseline. MiRNA sequencing
of atrial tissue will be performed a selection of patients. Potential disease
related miRNAs will be correlated with histopathological alterations of atrial
tissue and the expression of miRNAs will be validated in the patient*s plasma
samples that were collected at baseline. The blood samples collected at
baseline will in addition be used for determining plasma protein biomarkers.
All data and biomaterial collected at baseline will be correlated to the
incidence of AF. Patients will be followed for 24 months to detect
post-operative and newly developed AF. In case of detection of new onset AF,
patients will receive contemporary treatment conforming to the guidelines. The
study period will be extended to a total follow-up of 5 years with one
additional visit per year. The aim of the extended follow-up is to improve the
sensitivity of the time-to follow-up analysis in order to discover more and
different biomarkers.

Participants are estimated to have a 20% absolute risk of developing
post-operative AF and a 10% risk of developing new AF within 2 years after
surgery. These patients may therefore develop an indication for oral
anticoagulation therapy and are likely to benefit from LAA excision for stroke
prevention. LAA removal can be performed without additional risk. No adverse
events have been reported in our thoracic surgery center (>313 procedures) over
the past 5 years.
Follow-up of patients will be performed in our center at 1 month, 6 months, 12
months and 24 months with holter registration in order to detect atrial
fibrillation.
The study will be extended to five years follow-up in total with 1 visit per
year on 3, 4 and 5 years. Patients will be asked informed consent for the
extended follow-up separately. The impact of the extended follow-up is limited
as it includes only one visit per year and the preceding holter investigation
may take place in the local referring hospital. If patients are capable to come
to the AMC, they will be invited for a blood withdrawal. If patients are unable
to attend to the AMC, patients will receive a telephone call.
Patients are asked to comply to additional physician attendance, but have
potential benefit through the early detection of atrial fibrillation and start
of oral anticoagulation therapy.

Atrial biopsy has been suggested as an alternative to LAA resection. However,
when comparing LAA resection with LAA biopsy, it may be discussed whether the
risk of atrial biopsy would not exceed the risk of atrial appendage resection
due to the slender and fragile atrial wall. Lastly, participants may benefit
from LAA resection, because that procedure will reduce the risk of AF related
thromboembolic complications, whereas atrial biopsy does not carry any
anticipated benefit for the study population.