EFFECTS OF BLOOD THINNERS & BENZODIAZEPINES IN THE CARDIOVASCULAR SYSTEM

FOR PATIENTS WITH ARRHYTHMIA & ANXIETY

DISORDER

Shankha PaulProfessor Hui Meng

MAE 478 Research ProposalUniversity at Buffalo

05/03/2016

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TABLE OF CONTENTS

ABSTRACT 3

SPECIFIC AIMS 4

BACKGROUND 5

Arrhythmia 5

Anxiety Disorder 7

PREVIOUS RESEARCH 9

IMPORTANCE OF RESEARCH 10

PROBLEM STATEMENT 10

EXPERIMENTAL SETUP 11

Experiment 1 11

Experiment 2 12

Experiment 3 13

DATA COLLECTION & CONCLUSION DRAWING 15

HYPOTHESIS 15

IMPACTS OF WORK/ FUTURE RESEARCH 16

REFERENCES 17

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ABSTRACT

There have been many studies conducted on the cardiovascular system and effects of arrhythmia and its popular treatment of blood thinners. There are also a great deal of studies done based on anxiety and its treatment of benzodiazepines and their effects on the heart and the cardiac system. However, there aren’t much studies done for patients who might have both or could develop one of them while being diagnosed with the other.

From basic knowledge of the physiology and anatomy of the cardiovascular system, the effects of blood thinners can have a negative effect with patients with anxiety disorder and benzos can have a negative effect as well for those suffering with arrhythmia.

There are different types of arrhythmia and anxiety disorders but we will focus on specific type of each to make the studies clearer and help with drawing conclusions. We will focus on atrial fibrillation since it the most general type of arrhythmia in patients, and General Anxiety Disorder (GAD) will be the type of anxiety that will be tested because its long term, easy to measure and very common among patients.

This study is very important for a small percentage of patients who suffer from both AF and GAD or other forms of arrhythmia or anxiety. The available treatment limits their life and freedom since there are counteractive effects of the medicine or have to rely on very expensive surgical procedures to prevent one or the other illness. There aren’t any concrete studies conducted to observe effects of medications on patients with both AF and anxiety.

This study will look for correlations between blood thinners and anxiety disorders, benzos and arrhythmia. Then a final study will be conducted to see if a variation of both blood thinners and benzos can treat patients dealing with anxiety and arrhythmia. Since there is limited information on the subject of treating both, the tests will be conducted on mice.

SPECIFIC AIMS

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Aim 1: Find any correlation between blood thinner dosage and anxiety disorder symptoms and identify the strength and type (linear, exponential, etc.) of correlation. Also, check for increase in anxiety symptoms due to withdrawals from blood thinners.

In general blood thinners reduce clotting and let’s blood flow more smoothly. Internal anxiety symptoms include dilation of blood vessels to large muscles and constriction of blood vessels to organs and areas not necessary for quick movement. Any patient with anxiety symptoms taking blood thinners may experience unusual bleeding and excessive loss of blood during these occurrences. Severity and damage to heart muscles and blood vessels may increase as well. This focus will observe and conclude on scientific experiments based on this theoretical claim.

Note: There may or may not be any correlation since there are no prior studies based on these claims.

Aim 2: Find any correlation between benzodiazepine dosage and arrhythmia and identify the strength and type (linear, exponential, etc.) of correlation. Also, check for increase in arrhythmia due to withdrawal from benzodiazepines drugs.

Benzodiazepines are known to slow down the heart rate and relax the heart muscle and the blood vessels. There are many warning in benzo treatments not to prescribe to patients with tachycardia or fibrillation episode. After much research, there wasn’t any studies or data found to show exactly the consequences of taking benzo while dealing with arrhythmia. It can be only assumed the relaxation of the heart during fibrillation and increase blood clotting in the atria causing a heart attack.

Aim 3: Discover a balance of blood thinners and benzodiazepines and the dosage it takes of each medication for patients who suffer from both atrial fibrillation and anxiety.

There has to be a right amount of each drug (blood thinner and benzo) to patients suffering from arrhythmia and anxiety to help with both their conditions. Experiments need to be conducted to find the “sweet spot” dosage. If there doesn’t exist such dosage of each medication, then further research has to be conducted in the future testing other form of medications and treatments.

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BACKGROUND

Arrhythmia

Arrhythmia is a heart condition when there is an abnormal, fast or slow rhythm to the heartbeat. It can be brief or prolonged. Everyone experiences brief arrhythmia every now and then and is considered natural. This shouldn’t be consider a cause for concern. Prolonged arrhythmia, on the hand, can be a health risk and can be fatal.

Two basic kinds of arrhythmia are bradycardia and tachycardia. Bradycardia is when the heart rate is too slow and tachycardia is when the heart rate is too fast. The average human heart rate is about 80 beats per minutes, whereas, the heartrate during bradycardia is about 60 beats per minute and during tachycardia it’s about 100 beats per minute.

There are different symptoms of arrhythmia depending on the type the patient is experiencing. Brief arrhythmia has almost no symptoms at all. It feels like the heart is skipping a beat, a fluttering or a pause in the heartbeat. Bradycardia can cause fatigue, dizziness, lightheadedness, fainting or near-fainting spells, or, in extreme cases, cardiac arrest. Tachycardia can reduce the heart’s ability to pump, causing shortness of breath, chest pain, lightheadedness or loss of consciousness. If severe, it can also cause heart attack or death.

Arrhythmia can also be defined and separated by where it starts in the heart. This is done to diagnose the condition and for proper treatment to the area where the heart rate abnormality is located. Two major types of arrhythmia defined by location in the heart are atrial fibrillation and ventricular fibrillation.

Ventricular fibrillation occurs in the two lower chambers of the heart called left and right ventricles. This type of fibrillation is rare though it is more severe and fatal. The pumping chambers in the ventricles quiver uneasily which results in a massive pressure drop in the lower chambers. This pressure drop stops oxygen rich blood in the heart from reaching to the body organs. Patients experiencing ventricular fibrillation loses consciousness within seconds and their breathing and heartrate stop soon afterward. Some causes of this type of fibrillation have been linked to previous heart attacks, scarring of the heart muscles, stimulant drug abuse, congenital heart disease, etc.

Atrial Fibrillation

Atrial fibrillation, on the other hand, is less serious but more common. AF occurs in the upper chambers of the heart, the right and left atriums. This type of fibrillation occurs due to disruption or failure of the heart’s electrical system.

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Causes

With each heartbeat, an electrical signal spreads from the top of the heart to the bottom. As the signal travels, it causes the heart to contract and pump blood. Each electrical signal begins in the sinoatrial (SA) node. The SA node is located in the right atrium. In a healthy adult heart at rest, the SA node sends an electrical signal to begin a new heartbeat 60 to 100 times a minute. From the SA node, the electrical signal travels through the right and left atria. It causes the atria to contract and pump blood into the ventricles. The electrical signal then moves down to a group of cells called the atrioventricular (AV) node, located between the atria and the ventricles. Here, the signal slows down slightly, allowing the ventricles time to finish filling with blood. The electrical signal then leaves the AV node and travels to the ventricles. It causes the ventricles to contract and pump blood to the lungs and the rest of the body. The ventricles then relax, and the heartbeat process starts all over again in the SA node.

In atrial fibrillation, the electric signal doesn’t start in the SA node. Instead, it starts in another part of the atria or in the pulmonary veins. The signal travels abnormally in a rapid, disorganized fashion and leading to fibrillation in the atriums. The faulty signal floods the AV node with electrical impulses. As a result, the ventricles also begin to beat very fast. However, the AV node can't send the signals to the ventricles as fast as they arrive. So, even though the ventricles are beating faster than normal, they aren't beating as fast as the atria. Thus, the atria and ventricles no longer beat in a coordinated way. This creates a fast and irregular heart rhythm. When this happens, blood isn't pumped into the ventricles as well as it should be. Also, the amount of blood pumped out of the ventricles to the body is based on the random atrial beats. The body may get rapid, small amounts of blood and occasional larger amounts of blood. The amount will depend on how much blood has flowed from the atria to the ventricles with each beat.

Symptoms, Diagnosing & Common Treatments

Symptoms of atrial fibrillations can be unnoticed to very severe. Even when the patient can’t feel the atrial fibrillation, the risk of a stroke increases. Other symptoms of AF can cause chest pain or heart failure due to blood clotting in the heart from building up in the atria.

There are various ways to diagnose arrhythmia in patients. The most important factor the doctors look for when diagnosing arrhythmia is where it starts and the abnormality of the heartbeat. One of the common methods of diagnosing is an electrocardiogram (ECG). It creates a graphic record of the heart’s electrical impulses. Other methods to diagnose include but aren’t limited to Holter monitor, exercise stress tests, tilt table test and electrophysiological studies, etc.

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Treatments for arrhythmia depends on the type and the severity. Treatments can be as simple as lifestyle changes, medicine to prevent or control arrhythmia, blood thinners to prevent blood clotting to something more serious as pacemakers to control heartrate, ICDs, cardiac ablation and surgery.

Blood Thinners

Blood thinners are a common drug prescribed to reduce blood clotting during atrial fibrillation. Blood thinners can be anti-platelet or/and anti-coagulant. When blood clots form in the heart due to AF, they stop the flow of blood causing a heart attack. Blood thinners work by stopping platelets from adhering to one another and clotting proteins from binding together. Heparin and Coumadin (warfarin) are two common blood thinner medications for AF.

Anxiety Disorders

Anxiety is defined as a feeling of worrying, nervous, or unease typically about an event or a situation with uncertain outcome. Regardless of how it is defined, anxiety has significant physiological effects on the human body especially in the heart and blood vessels that make up the cardiovascular system.

There are many types of anxieties with different triggers such as panic attacks, Post-traumatic stress disorder (PTSD), Obsessive Compulsive Disorder (OCD), and General Anxiety Disorder (GAD). All anxiety types can be categories in two categories: short- term and chronic.

Short-term anxieties are often experiences by a person for a brief period of time from momentary situations such as meeting deadlines, traffic jams, or triggers specific to someone’s condition such as a social situation for someone with social anxiety disorder. Long term, or chronic, anxiety is experienced by a person over a long period of time with constant worrying and nervousness over any given situation. General Anxiety Disorder (GAD) is an example of this type of anxiety.

Symptoms

There are various physical, behavioral and emotional symptoms of stress that can be observed externally. Some examples of physical symptoms are sweating, muscle tension, dry mouth etc. Some examples of emotional symptoms include anger, paranoia, fear, and more. Some behavioral symptoms include teeth grinding, hair twisting and many more.

There are also physiological symptoms of anxiousness in the cardiovascular system. The heart rate increases when the patient is feeling anxiety, the heart muscles perform stronger

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contractions to pump more blood to the large muscles. The blood vessels constrict for this and increase blood pressure significantly. This is known as the “fight-or- flight response”.

Effects

Persistent chronic anxiety has negative effects to the circulatory system. Consistent and ongoing increase in heart rate can contribute to inflammation in the blood vessels, especially the coronary arteries. Studies have shown that anxious behaviors can increase cholesterol levels in a person. High levels of cholesterol can cause calcification in the blood vessels if cholesterol build up occurs. This can permanently damage the blood vessel tissues. Over time, ongoing anxiety increase the risk of hypertension, stroke or heart attack.

Cortisol & Cholesterol

The increase in heart rate and change in blood vessel diameter are responses that occur due to the stress hormones in the blood. The major stress hormones are cortisol, adrenaline and noradrenaline. Cortisol is a hormone produced by the adrenal glands. It is responsible for the “flight-or-fight” response in the body during danger and increases energy production by flooding the muscles with glucose. High level of cortisol have negative impacts on the body weight blood sugar levels, insulin production and especially on the blood vessels. Cortisol constricts blood vessels in inactive areas such as abdomen and kidneys to retain body heat and increase vascular resistance. Constriction in blood vessels causes shear stress and plaque buildup at the vessel walls.

Cholesterol is a fat-like substance the body uses to produce certain hormones required for the body. It travels through the cardiovascular system in the blood to target sites. Stress/ anxiety has been linked to an increased production of cholesterol. Excessive cholesterol can clog arteries especially if they are constricted. Cholesterol is also responsible for cortisol production.

Diagnosing & Common Treatments

There are a few ways to diagnose a person for anxiety and its type. Doctors use a combinations of physical exams, blood or urine test, detailed questions, family history related to anxiety, and psychological questionnaire. Doctors also use the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, to diagnose mental conditions, including types of anxiety disorders.

There are various types of treatments for anxiety depending on the type and its severity. Simple treatments include lifestyle changes such as diet, change in living conditions, exercise, etc.

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serious treatments include prescribed drugs such as benzodiazepines to rehabilitation programs.

A popular form of benzodiazepines prescribed by doctors to prevent panic attacks and subdue chronic anxiety is Xanax. This drug is a central nervous system depressant. This means it slows brain activity. It creates a calming effect as side effects including decrease in heart rate.

PREVIOUS RESEARCH

There hasn’t been much research done considering both arrhythmia and anxiety disorders, let alone their treatments and how they affect one another. Some of studies that looked at both showed vague observations between the two.

There was a study on yoga and its effects on arrhythmia, anxiety and depression. In the study, patients went through an hour session of yoga twice a week for 180 days. The results showed that patients suffering different levels of arrhythmia (symptomatic, asymptomatic, etc.) had improvements in the number of episodes they experienced post yoga session. Their anxiety and depression scores improved as well over the 180 days. Even though there was improvement, neither conditions were prevented or eliminated.

Another study conducted by the FDA and covered by FactMed analyzing blood thinners and their side effects had patients reporting signs of anxiety. The study was covered from January 2004 to October 2012 and 8 out of 89 patients reported showing signs of anxiousness.

Another study conducted very recently (2015) found that certain patients with anxiety disorder or depression are highly likely to mistake their panic attacks for fibrillation. From monitoring the heart rate of 458 patients over a week, researchers found that some of these patients also experience AF 10% of the time but claim to feel AF symptoms 90% of the time. This study also claimed that an anxiety attack could possibly trigger an AF episode. This study was the only study where subjects showed signs of both AF and anxiety.

There are articles that claim that blood thinners may cause anxiety in certain patients prescribed with the pharmaceutical drug, and other articles claim anxiety may be the cause of arrhythmia in patients. Doctors are advised not to administer benzos to patients with a history of tachycardia though there are no research found why this is so.

Lastly, a research in 2014 looked at 720 patients with AF going through catheter ablation. Researchers wanted to identify if baseline anxiety improve their quality of life. Overall, the results provided that there wasn’t any improvement in the patients’ conditions with baseline anxiety.

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IMPORTANCE OF RESEARCH

Some statistics on anxiety, atrial fibrillation, blood thinners and benzos are as follows:

40 million Americans suffer from a form of anxiety disorder and of those 6.8 million suffer from General Anxiety Disorder (GAD) every year, according to the Brain & Behavior Research Foundation.

About 33.5 million people worldwide and 3 million Americans have been diagnosed with atrial fibrillation and tachycardia in 2004 by the Cleveland Clinic.

In January 2010, Agency for Healthcare Research & Quality reported that 4.2 million Americans are prescribed a form of blood thinner.

In 2008, a study by the Department of Psychiatry in Colombia University found that about 12 million Americans between the ages of 18 to 80 are prescribed one form of benzo.

As of now, no research or study have been found that indicates that these numbers are decreasing. The exact number of patients diagnosed with both atrial fibrillation and GAD is unknown. There needs to be significant research in this area so that patients can receive better treatment and care.

If a balance between blood thinners and benzo can be found to prescribe to the patients, then they won’t have to seek out more drastic form of treatments such as surgery or rehab. These treatments can limit the lives of the patients and can be very expensive.

PROBLEM STATEMENT

Based on studies on AF, anxiety, blood thinners and benzos, there are a lot of suggestions and speculations of possibilities and effects among these conditions and treatments without concrete evidence. A study needs to be conducted to show evidence if

there are any effects of blood thinners on patients with anxiety,

any effects of benzos with patients with arrhythmia, and

effects of both treatments to patients with both conditions.

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EXPERIMENTAL SETUP

For these experiments, it would best advised to use mice as subjects rather than human since prior experiments were never committed and results could be fatal in certain test groups. Also, mice have a similar four chambered hearts as human beings. Every dosage for a mice is scaled down to the equivalent of a dosage for a human by weight.

Certain values to keep in mind are: a laboratory mouse average 0.68 oz, the resting heartrate of a lab mouse is 500-700 bpm, a daily human dose of Xanax is 1 mg (for this experiment), a daily human dose of Warfarin is 4mg, and the average weight of a human being is 80.7 kg.

A budget alternate experiment setup is provided if research doesn’t receive sufficient funding to conduct the initial experiment.

Electrocardiogram (ECG) will be used to measure heart rate of these mice by telemetric/remote means. CODA blood pressure system is a non-invasive method of measuring blood pressure of small animals such as mice and rats from their tail cuffs.

Experiment 1

This experiment will test and collect data on the effects of Warfarin (blood thinner) on mice with General Anxiety Disorder (GAD). There will be 4 test groups with 25 mice in every group.

All 100 mice will be given cortisol injected daily to the blood to induce anxiety symptoms. This will replicate the health issue in the mice. The severity of anxiety is controlled and should match the mice across all the groups. The following groups will receive a different dosage of Warfarin accordingly:

Group 1: 25 mice with anxiety receives no dosage of Warfarin daily (control group).

Group 2: 25 mice with anxiety receives half a dosage of Warfarin daily.

Group 3: 25 mice with anxiety receives one dosage of Warfarin daily.

Group 4: 25 mice with anxiety receives two dosage of Warfarin daily.

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Variables to document in every test groups are the age and weight of the mice. To acquire reputable data, all subjects should receive the same diet and environment. Make sure to take notes on the amount of sleep and physical activity of test subjects in all test groups. Blood pressure measurements and resting heart rate measurements should be taken daily as well.

The mice will receive the medication for 3 months, then they will be monitor till their death to observe their behaviors while off the drug and record their life expectancies in every group. Basic measurements of heart rate, blood pressure, weight, etc. should be recorded during this part of the experiment as well.

Budget Experiment 1

Repeat the above experiment but with the following changes to accommodate if funding and time isn’t available. This will allow data to be collected to make conclusion based on though they won’t be as reliable if we conduct the initial experiment itself. The changes are as follows:

Two groups of mice instead of four

1 month of receiving medication

Experiment ends after the first month and no observation of behavior off the drug and life expectancy will be recorded.

The two groups will receive medication as follows:

Group 1: 10 mice with anxiety disorder receives no dosage of Warfarin.

Group 2: 10 mice with anxiety disorder receives one dosage of Warfarin.

Experiment 2

This experiment will test and collect data on the effects of Xanax on mice with atrial fibrillation. There will be 4 test groups with 25 mice in every group.

All 100 mice will be given endocardial pacing after consuming cholinergic agonists to induce atrial tachycardia and fibrillation. This will replicate the health issue in the mice. The severity of AF is controlled and should match the mice across all the groups. The following groups will receive a different dosage of Xanax accordingly:

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Group 1: 25 mice with AF receives no dosage of Xanax daily (control group).

Group 2: 25 mice with AF receives half a dosage of Xanax daily.

Group 3: 25 mice with AF receives one dosage of Xanax daily.

Group 4: 25 mice with AF receives two dosages of Xanax daily.

Variables to document in every test groups are the age and weight of the mice. To acquire reputable data, all subjects should receive the same diet and environment. Make sure to take notes on the amount of sleep and physical activity of test subjects in all test groups. Blood pressure measurements and resting heart rate measurements should be taken daily as well.

The mice will receive the medication for 3 months, then they will be monitor till their death to observe their behaviors while off the drug and record their life expectancies in every group. Basic measurements of heart rate, blood pressure, weight, etc. should be recorded during this part of the experiment as well.

Budget Experiment 2

Repeat the above experiment but with the following changes to accommodate if funding and time isn’t available. This will allow data to be collected to make conclusion based on though they won’t be as reliable if we conduct the initial experiment itself. The changes are as follows:

Two groups of mice instead of four

1 month of receiving medication

Experiment ends after the first month and no observation of behavior off the drug and life expectancy will be recorded.

The two groups will receive medication as follows:

Group 1: 10 mice with AF receives no dosage of Xanax.

Group 2: 10 mice with AF receives one dosage of Xanax.

Experiment 3

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The purpose of this experiment is to find a balance between blood thinner and benzodiazepines for patients who suffer from BOTH atrial fibrillation and General Anxiety Disorder (GAD).

In this experiment, there will 100 mice who will be induced with both atrial fibrillation and anxiety symptoms through means discussed in the previous experiments. The severity of anxiety and AF is controlled and should match the mice across all the groups. The following groups will receive a different dosage of Warfarin and Xanax accordingly:

Group 1: 25 mice with anxiety & AF receives no dosage of Warfarin and Xanax daily (control group).

Group 2: 25 mice with anxiety & AF receives one dosage of Warfarin and one dosage of Xanax daily.

Group 3: 25 mice with anxiety & AF receives half a dosage of Warfarin and two dosage of Xanax daily.

Group 4: 25 mice with anxiety & AF receives two dosage of Warfarin and half a dosage of Xanax daily.

Variables to document in every test groups are the age and weight of the mice. To acquire reputable data, all subjects should receive the same diet and environment. Make sure to take notes on the amount of sleep and physical activity of test subjects in all test groups. Blood pressure measurements and resting heart rate measurements should be taken daily as well.

The mice will receive the medications for 3 months, then they will be monitor till their death to observe their behaviors while off the drug and record their life expectancies in every group. Basic measurements of heart rate, blood pressure, weight, etc. should be recorded during this part of the experiment as well.

Budget Experiment 3

Repeat the above experiment but with the following changes to accommodate if funding and time isn’t available. This will allow data to be collected to make conclusion based on though they won’t be as reliable if we conduct the initial experiment itself. The changes are as follows:

Two groups of mice instead of four

1 month of receiving medications

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Experiment ends after the first month and no observation of behavior off the drug and life expectancy will be recorded.

The two groups will receive medications as follows:

Group 1: 10 mice with anxiety & AF receives no dosage of Warfarin and Xanax daily (control group).

Group 2: 10 mice with anxiety & AF receives one dosage of Warfarin and one dosage of Xanax daily.

DATA COLLECTION & CONCLUSION DRAWING

The data collected for these experiments are daily measurements of:

Blood pressure

Heart rate

Weight

Of every mice in all test groups for the 3 months and then afterwards till their death. The life expectancy will be recorded.

Before the start of the experiment, the age and initial weight of every mice should also be recorded. Charts and graphs should be created to visualize the trend and effects of the drugs in all experiments.

Line graphs should be made of Blood pressure vs time, Heart rate vs. time, weight change vs. time for all test groups in all 3 experiments. Bar graphs should be created to visualize the life expectancy vs. the dosage of each medication for all test groups in all three experiments.

HYPOTHESIS

I predict that if the mice with AF receive Xanax, then their cardiac health (measured by abnormal heart rate and pressure) and life expectancy will worsen and the severity at which their health conditions and life expectancy decrease will be inversely proportional to the dosage of medication taken daily.

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Also, if the mice with anxiety disorder receive Warfarin, then their cardiac health (measured by abnormal heart rate and pressure) and life expectancy will worsen than if they weren’t taking any blood thinner (control group).

For the third experiment, I believe that if Group 3 and Group 4 will have extreme results in the data to be collected. Group 1 and Group 2 will have results that fall in between the previous groups. I’m unsure if Group 3 or 4 will display lower life expectancy and worse health conditions (measured by abnormal heart rate and pressure) among the mice.

IMPACTS OF WORK/ FUTURE RESEARCH

This research will be the stepping stone for further research in the future on anxiety and arrhythmia in patients suffering from both. If studies deem safe among mice and can be FDA approved, the next step would be to test on human subjects.

The research can also be expanded by testing with different levels of anxiety and arrhythmia among the subjects by administering the mice with different amounts of cortisol to create different severity of anxiety and then given different amounts of endocardial pacing and cholinergic agonists to mice for different severity of atrial fibrillation among different test groups.

The research can be more detailed as well. If more funding and time is available. The subjects can be cut open after their death to observe and record any blood clot formations (tests with blood thinners), damage to heart muscles or blood vessels, etc. This was avoided in these experiments due to impracticality of performing surgery on subjects that are very small in size.

The research can also test for other methods of treatments. This could include pacemakers, other forms of benzodiazepines, THC, lifestyle changes, etc. Many of these treatments were not looked into since blood thinners and benzos are the popular medications prescribed but there were no studies done prior to this in this manner.

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