Abstract
BackgroundCardiac surgery is one of the most commonly performed surgical procedures worldwide with >700,000 surgeries in 2006 in the US alone. Cardiac surgery results in a considerable exposure to physical and emotional stress; stress-related disorders such as depression or post-traumatic stress disorder are the most common adverse outcomes of cardiac surgery, seen in up to 20% of patients. Using information from a genome-wide association study to characterize genetic effects on emotional memory, we recently identified a single nucleotide polymorphism of the glucocorticoid receptor gene (the Bcll single nucleotide polymorphism) as a significant genetic risk factor for traumatic memories from cardiac surgery and symptoms of post-traumaticstress disorder. The Bcll high-risk genotype (Bcll GG) has a prevalence of 16.6% in patients undergoing cardiac surgery and is associated with increased glucocorticoid receptor signaling under stress. Concomitant animal experiments have confirmed an essential role of glucocorticoid receptor activation for traumatic memory formation during stressful experiences. Early cognitive behavioral intervention has been shown to prevent stress-related disorders after heart surgery.Methods/DesignThe proposed study protocol is based on the above mentioned earlier findings from animal experiments and preclinical studies in volunteers. Patients (n = 872) will be genotyped for the Bcll single nucleotide polymorphism before surgery, which should result in 120 homozygous high-risk carriers of the Bcll GG allele and 240 randomly selected low-risk heterozygous or non-carriers of the single nucleotide polymorphism. All patients will then undergo randomization to either cognitive behavioral intervention or a control intervention consisting of non-specific general information about the role of stress in heart disease. The primary efficacy endpoint will be post-traumatic stress levels at one year after surgery as determined by a standardized questionnaire that has been specifically validated in patients after critical illness.DiscussionThe proposed randomized controlled trial intends to demonstrate that a preoperatively administered minimal cognitive behavioral intervention targeted to homozygous carriers of the Bcll *G high-risk allele reduces traumatic memories and post-traumatic stress disorder symptoms after heart surgery to a level seen in non-carriers of the mutation, and thus improves the neuroemotional outcome of cardiac surgery.Trial registration numberThe trial will be registered at http://www.clinicaltrials.gov/ before commencing with the study.
Highlights
Cardiac surgery is one of the most commonly performed surgical procedures worldwide with > 700,000 surgeries in 2006 in the US alone
The proposed randomized controlled trial intends to demonstrate that a preoperatively administered minimal cognitive behavioral intervention targeted to homozygous carriers of the Bcll *G high-risk allele reduces traumatic memories and post-traumatic stress disorder symptoms after heart surgery to a level seen in non-carriers of the mutation, and improves the neuroemotional outcome of cardiac surgery
Using information from a genome-wide association study to characterize genetic effects on emotional memory in volunteers (Figure 1), we have recently identified an intronic Single nucleotide polymorphism (SNP) of the glucocorticoid receptor (GR) gene in patients undergoing Cardiac surgery (CS) that is associated with increased cortisol sensitivity of the GR and, enhanced glucocorticoid signaling under stress
Summary
Progress in the field of ICU therapy and medical procedures such as CS has resulted in improvements in shortand long-term survival rates in critically ill patients. This progress is, met by an in increasingly older population with increased life expectancy and multiple comorbidities requiring extensive surgical procedures and treatment in ICUs. there are more than 10,000 critically ill patients treated in >1,500 ICUs on any given day in Europe [48] and CS is one of the most common surgical procedures performed worldwide.
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