The Assessment of Oxidative Stress Markers and the Development of Atrial Fibrillation After Cardiac Surgery
The Assessment of Oxidative Stress Markers and the Development of Atrial Fibrillation After Cardiac Surgery
The purpose of the investigators study is to investigate the correlation between naturally
 occurring chemicals, called reactive oxygen species (ROS), in the blood of human patients and
 the development of an abnormal heart rhythm, known as atrial fibrillation (AF). The
 development of atrial fibrillation is associated with increased medical problems like stroke.
 Many factors seem to cause the development of AF, and this rhythm occurs frequently after
 open heart surgery. When patients develop AF after cardiac surgery they are at increased risk
 for cognitive changes, infections, the development of kidney failure, and increased length of
 hospitalization. ROS are chemicals in blood and tissues that tend to cause microscopic blood
 vessel and heart damage. These chemicals occur naturally as the result of chemical reactions
 that occur in states of stress and inflammation, like tissue trauma and as the result of
 smoking. Patients who undergo cardiac surgery may have higher levels of ROS because of their
 underlying medical conditions. In addition, the organized tissue trauma that occurs in the
 setting of surgery may serve to increase ROS levels further. In turn, the higher ROS levels
 may put patients at even higher risk for the development of AF. The investigators believe
 that increased levels of ROS may help potentiate a patient's development of AF. Accordingly
 the investigators aim to measure ROS levels before and after surgery to see if there are
 particular levels that predict the development of this abnormal heart rhythm. By developing a
 better knowledge of the relationship between ROS and AF, the investigators hope to better
 understand another possible method of detecting patients who are at the highest risk of
 developing AF before it occurs after surgery. If these patients are better identified, this
 may eventually lead to medical treatment to prevent AF; and hopefully this will result in a
 decrease of the malicious effects that result from developing this abnormal heart rhythm.
Atrial Fibrillation (AF) is a common occurrence after cardiac surgery. This arrhythmia is
 reported to occur in up to 40% of patients following coronary bypass graft (CABG) surgery.
 The incidence of AF is even higher in patients who have undergone both CABG and valvular
 surgery during the same operation. In cardiac surgery patients, the occurrence of atrial
 fibrillation post-operatively lengthens hospitalization and adds to postoperative
 complications like renal dysfunction, infection, and cognitive defects. Postoperative AF is a
 known major risk factor for the development of stroke after cardiac surgery. Additionally,
 there is data to suggest that the development of AF after cardiac surgery is related to both
 reduced survival after CABG, and this dysrhythmia may also serve as an independent predictor
 of long-term mortality. Many studies have investigated the role of prophylactic
 pharmacological therapy to prevent post-operative AF after cardiac surgery. Despite this, the
 complete pathogenesis of AF in the post-cardiac surgery population remains unknown, is likely
 to be multifactorial, and includes clinical, structural, and biochemical risk factors.

 Biochemical risk factors such as inflammation and elevated markers of oxidative stress seem
 to be related to the development of AF. Also, It has been shown that AF is associated with
 decreased activity of nitric oxide synthases. Elevated C-reactive protein (CRP), a common
 marker of inflammation, has been shown to be associated with chronic AF at one year follow
 up. Additionally, elevated CRP levels drawn just prior to electrical cardioversion have been
 found to predict the development of recurrent AF after cardioversion. This relationship
 between this elevated marker of inflammation - CRP - and AF has been found to be independent
 of clinical risk factors for the development of AF, such as age, diabetes, and left
 ventricular function. Inflammation is a known source of oxidative stress at the cellular
 level; and it has been proposed that both inflammation and oxidative stress play a role in
 electrical remodeling of the atria, which promotes perpetuation of AF. Moreover, it has been
 proposed that CRP levels may directly reflect the condition of increased oxidative stress.

 Oxidative Stress and Arrhythmia:

 The association between AF and arrhythmias has been suggested by an array of evidence.
 Moreover, the pathogenesis likely involves both changes in the atrial architecture, such as
 dilation and fibrosis, and alterations in the electrophysiological substrate of atrial
 tissue. Oxidative stress markers are believed to be involved in remodeling of the atrial
 electrophysiological substrate.

 Recently, a correlation between AF and oxidative stress markers has been established. In one
 study, a correlation between the oxidative stress markers reduced glutathione, cysteine, and
 derivatives of reduced oxidative metabolites has been found. Although the relationship
 between AF and oxidative stress remains unclear, it is known from this human population study
 that oxidative stress markers are elevated in those with persistent AF. This relationship
 holds true even after controlling for conditions that promote oxidative stress: hypertension,
 smoking, and congestive heart failure. It has also been shown that atrial tachycardias are
 associated with increased hydroxyl radicals and peroxynitrite. These species are believed to
 cause myofibril damage and reduced myofibrillar creatine kinase activity in those with
 chronic AF. Similarly, superoxide free radicals were shown to be elevated in the porcine
 heart left atrial appendage when subjected to rapid atrial pacing and AF. Of further interest
 in this study by Dudley et al., was the role of an NADPH oxidase inhibitor, apocynin, in its
 ability to reduce superoxide production. This suggests that the NADPH oxidase plays a
 prominent role in the development of reactive oxidative species. In turn, such reactive
 oxidative species are thought to be related to inflammation and atrial electrical remodeling.

 It is believed that electrical remodeling leads to changes such as shortening of the
 effective refractory period (ERP), loss of rate adaptation of the refractory period, and
 prolonged atrial conduction. Rapid atrial conduction likely results in increased calcium
 (Ca2+) accumulation. This causes decreased inward L-type Ca2+ current (ICa), resulting in a
 shorter action potential duration (APD). Additional cellular mechanisms may include
 inactivation of the fast sodium current (INa) at more positive membrane potentials, and
 increased inward potassium rectifier (IK1) and acetylcholine dependent potassium currents
 (IKAch). Though these currents logically oppose one another, the net effect is that of
 increased repolarization heterogenicity and shortened APD. Moreover, experimental models have
 shown that rapid atrial pacing leads to decreased ERP and reduced of L-type Ca2+ channel and
 transient outward K+ ion currents. Shortening of the ERP leads to decreased conduction
 wavelengths, and shortened wavelengths have been proposed to increase the propensity for the
 development of AF because they reduce the mass of atrial tissue required to sustain reentry
 circuits.

 Given the changes above, it has been postulated that intracellular calcium overload as a
 result of AF is a trigger for electrical remodeling in AF. Nevertheless, further studies have
 demonstrated that blockade of L-type calcium channels alone with verapamil in canine hearts
 is not sufficient to prevent atrial electrical remodeling. Additional triggering mechanisms
 may include oxidative stress and inflammation. Simvastatin, a drug that has both anti-oxidant
 and anti-inflammatory properties has been shown to attenuate the development of AF from
 tachycardia induced atrial remodeling in dogs. More specific evidence of ion channel
 remodeling from free radicals was proved by Caouette et al. who showed that addition of
 hydrogen peroxide directly delayed ultra-rapid rectifier potassium currents in the Chinese
 Hamster Ovary cell line. These changes are mediated by Kv1.5 gene expression, which accounts
 for voltage-gated potassium repolarization currents that are similarly expressed in human
 atrial and ventricular myocytes. Further ion channel studies have demonstrated that lipid
 peroxidation causes Na+ channel dysfunction in cultured atrial myocytes when exposed to the
 oxidizing agent tert-butyl-hydroperoxide . Additionally, it is believed that reactive
 oxidative species may promote respiratory chain dysfunction in atrial myocytes by way of
 mitochondrial DNA damage.

 In summary, the relationship between oxidative stress and atrial fibrillation is complex and
 incompletely understood on the molecular level. Nevertheless, it is clear that this
 relationship does exist, and therefore serves as a potential focus for medical therapy. In
 fact, Carnes et al. clearly demonstrated that using ascorbate perioperatively to blunt the
 effects of oxidative stress results in both decreased peroxynitrite formation and a lower
 incidence of AF after CABG. Therefore, investigators propose to do more work in this arena to
 better elucidate the relationship of oxidative stress and AF.

 Oxidative Stress Markers in the Research Setting:

 Cardiac surgery leads to high oxidative stress and inflammation and is associated with
 postoperative AF. This is the ideal situation in which to better define oxidative stress
 markers and their correlation with AF. There are several ways to measure oxidative stress in
 humans. A minimally invasive method is the measurement of lipid peroxides (derivatives of
 reactive oxygen metabolites, dROMs) and oxidized and reduced thiol ratios. Glutathione is an
 important water-phase antioxidant and essential cofactor for antioxidant enzymes. It provides
 protection endogenous oxygen radicals. Since glutathione can exist in oxidized and reduced
 forms, it can serve as a buffer for increased oxidative stress. Moreover, the relative
 amounts of these two forms are a reflection of the oxidative state of humans. This balance
 can be measured out of blood. Measurement of this ratio has been validated by Neuman et al.
 and is known to be associated with AF. Additionally, these measurements have been validated
 in states that are thought to increase oxidative stress, such as diabetes, older age, and
 cigarette smoking.
Inclusion Criteria:

 -  Age ≥18 years

 -  Sinus rhythm at the time of enrollment as documented by ECG, telemetry, or Holter
 monitoring

 -  Scheduled for an open heart surgery

 -  Able to provide informed consent

 Exclusion Criteria:

 -  Systemic inflammatory diseases (e.g., collagen vascular diseases, infections)

 -  Malignant neoplasms

 -  Hyperthyroidism

 -  Uncontrolled hypertension (blood pressure > 180/100 at rest) on medications

 -  An illness that might result in death within 1 year

 -  Implanted devices for designed for active management of atrial arrhythmias by pacing
 or defibrillation

 -  Current illicit drug use

 -  Current ethanol abuse

 -  Presence of paroxysmal, persistent, or permanent atrial fibrillation at the time of
 enrollment