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What Are ACE Inhibitors And How Do They Work? 

ACE inhibitors (Angiotensin-Converting Enzyme inhibitors) are drugs used to relax the veins and arteries in order to lower blood pressure. They also help reduce blood volume and the heart’s demand for oxygenated blood.

ACE inhibitors bring down the activity of the angiotensin-converting enzyme. This enzyme controls fluid volumes in the body. It converts a hormone called angiotensin I into a more active form called vasoconstrictor angiotensin II. 

This conversion causes constriction of blood vessels and increased blood flow. These lead to an increase in blood pressure.

ACE inhibitors reduce the conversion of angiotensin I into vasoconstrictor angiotensin II and hence relax blood vessels. 

Acetylcholine response

Image: Action of ACE Inhibitors

Studies have reported that ACE Inhibitors can reduce the chances of developing heart failure that occurs due to high blood pressure. 

Beta-blockers and diuretics are similar drugs used to treat high blood pressure and related health conditions. 

Beta-blockers work by reducing the effects of the adrenaline hormone. This causes the heart to beat slowly and relaxes veins and arteries. 

Diuretics reduce the amount of water in the blood, thereby reducing blood volume and blood pressure. 

Angiotensin II Receptor Blockers (ARBs) also work very similarly to ACE inhibitors. These drugs can offer better inhibition of angiotensin II and are becoming popular types of antihypertensive medications.  

Digoxin is another drug commonly prescribed for reducing heart rate. Digoxin is usually used along with other kinds of heart medicines to treat symptoms of heart failure. It is preferred when ACE inhibitors or beta-blockers cannot be used

Side Effects Of ACE Inhibitors

The common side effects of ACE inhibitors are:

Other extreme side effects of ACE inhibitors are:

Interactions With Other Drugs

ACE inhibitors can interact with many drugs and can lead to extreme side effects. Inform your doctor if you are on the following medications.

ng medications.

ACE Inhibitors: Gene-Drug Interactions

ACE Inhibitors-Related Angioedema - XPNPEP2 Gene 

Angioedema is a condition that causes rapid swelling beneath the skin. Studies report that up to one-third of all emergency visits for angioedema are by those who use ACE inhibitor drugs.

The XPNPEP2 gene contains instructions for the production of X-Prolyl Aminopeptidase 2 protein. The gene plays a role in the functioning of bradykinin, a molecule that helps relax the blood vessels. 

rs3788853 is a Single Nucleotide Polymorphism (SNP) in the XPNPEP2 gene. 

According to a  study, the A allele of this SNP is associated with low aminopeptidase P (APP) activity. 

Low APP activity leads to increased bradykinin production, which increases the risk of developing angioedema in black men. 

However, this relationship was not found in women or white men.

AlleleImplications
AIncreased risk of developing angioedema in black men
CNormal risk of developing angioedema 

ACE Inhibitors And ADRB2 Gene 

The ADRB2 gene (Adrenoceptor beta 2 gene) helps produce the beta-2 adrenergic receptor. This receptor is activated by adrenaline and is associated with mental health conditions like anxiety and phobias.

A study analyzed the association between ACE inhibitors and changes in the ADRB2 gene. 336 participants were treated with ACE inhibitor drugs. The time taken to reach a Mean Arterial Pressure (MAP) of 107 mmHg was noted. 

rs2053044 is an SNP in the ADRB2 gene. People with the GG genotype of this SNP reached the MAP about 12 days later than those with the AA or AG genotype. 

GenotypeImplications
GGLowered response to ACE inhibitors in reducing blood pressure
AGNormal response to ACE inhibitors in reducing blood pressure
AANormal response to ACE inhibitors in reducing blood pressure

ACE Inhibitors And NOS3 Gene

The NOS3 gene (Nitric Oxide Synthase 3 gene) helps produce the endothelial NOS (eNOS) or nitric oxide synthase 3 enzyme. This enzyme plays a role in Nitric Oxide (NO) synthesis. 

rs3918226 is an SNP in the NOS3 gene. According to a study, people with the T allele of this SNP responded better to enalapril, a type of ACE inhibitor. An opposite effect was observed in those with the A allele.

AlleleImplications
TBetter response to ACE inhibitors
ALowered response to ACE inhibitors

Recommendations To Safely Use ACE Inhibitors

ACE Inhibitors Efficacy Lowers With Age

ACE inhibitors are more effective for people younger than 55. This is because young individuals have higher levels of renin in the blood. 

Renin is a type of enzyme released by the kidney - higher levels of this enzyme are associated with higher blood pressure in younger adults. 

ACE inhibitors effectively bring down renin levels.

People older than 55 are less responsive to renin, and hence, ACE inhibitors don’t make an impressive difference to blood pressure levels. 

Cautious Use In People With Existing Health Conditions

ACE inhibitors lead to lowered blood flow, which can be problematic in those with existing circulatory problems

Low blood volume and hypotension can lead to ischemia (inadequate blood supply to organs), myocardial infarction, stroke, and even kidney failure. 

ACE inhibitors also cause kidney failure in those with existing renal artery stenosis (narrowed/blocked arteries that lead to the kidneys) or chronic kidney disease. 

People with diabetes (both type 1 and type 2) are at increased risk of developing hyperkalemia with ACE inhibitor intake. 

Opt For Genetic Testing

Genetic testing can help understand how a person is likely to respond to ACE inhibitor treatment.  It gives insights into how a person’s body reacts to the drug and identifies if dosage alterations are needed to improve the efficiency of the medicine and reduce its toxicity risk. 

Analyze Your Genetic Response to ACE Inhibitors

Summary

  1. ACE inhibitors are drugs used to treat high blood pressure.
  2. Beta-blockers, diuretics, and Angiotensin II Receptor Blockers are drugs similar to ACE-Inhibitors, used to manage hypertension and cardiovascular issues.
  3. Some of the side effects of ACE inhibitors are fatigue, nausea, headaches, high potassium levels, kidney impairment, angioedema, and liver damage and kidney failure in fetuses. 
  4. ACE inhibitors interact with other hypertensive medications, chronic kidney disease medications, NSAIDs, calcineurin inhibitors, and DPP-IV inhibitors.
  5. Changes in the XPNPEP2, ADRB2, and NOS3 genes can alter the body’s response to ACE inhibitors.
  6. People younger than 55 respond better to ACE inhibitors. People with certain existing diseases can develop extreme health conditions when they consume ACE inhibitors.
  7. Genetic testing can help understand how a person will respond to ACE inhibitor treatment.  

References

Abstract

The simplest of daily physical activity almost all people accomplish is walking. The advancement of technology has made it easier to track the number of daily steps with wearable devices. A study recently published in JAMA discovered that individuals taking 7000 steps or more per day lowered their risk of death.

Acetylcholine response

How Does Physical Activity Prevent Health Conditions & Mortality?

The health benefits reaped from regular physical activity, be it moderate- or vigorous-intensity, are many. From reducing the risk of heart diseases to promoting mental wellbeing, the list is long.

According to the CDC, almost a dozen of health conditions can be prevented or managed with routine physical activity:

According to some stats, about 6-10% of the health burden of chronic diseases worldwide and 9% of premature death can be attributed to physical inactivity. 

The 2019 Physical Activity Guidelines for Americans recommends adults to engage in weekly 150-300 minutes of moderate-intensity physical activity or 75-150 minutes of vigorous-intensity physical activity.

Image: Physical Activity Guidelines for Americans

Every individual has a different body type and consequently different bodily needs. Therefore, the realization of a personalized therapeutic approach has aided in the fitness world too. 

A strength-based approach uses healthcare professionals in close collaboration with clients - wherein the focus is put on clients’ abilities, objectives, and present situation.

Strength-based personal approaches to exercise regimes have been observed to bring about more excellent patient outcomes.

Xcode Life’s Gene Fitness Report analyzes your body’s genetic predisposition for fitness traits and gives personalized recommendations. Click here.

Physical Activity & Reduction in Mortality Risk: Previous Studies

A study in 2020 found a reduction in mortality risk by 40% when subjects followed the 2018 Physical Activity Guidelines for Americans and engaged in both aerobic and muscle-strengthening activities. Further, individuals who engaged in either aerobic or muscle-strengthening activities decreased their mortality risk by 29% and 11%, respectively.

According to data, between 1997-2014, only 15.9% of 479,856 Americans followed the recommended physical activity guidelines.

A 2015 study on European subjects showed a 14% reduction in mortality risk with only 15 minutes/day of exercise. 

Further, in a study done in 2020 on a group of 70-years olds, a higher step count was associated with a reduced incidence of diabetes.

The Study: Per Day 7000 Steps Or More Can Reduce Mortality Risk

The study led by Amanda Paluch was part of a Coronary Artery Risk Development in Young Adults (CARDIA) study which drafted subjects from four States - Alabama, Illinois, Minnesota, and California.

The study analyzed a subset of 2110 participants belonging to the age group of 38-50 years. Out of 2110, 1205 participants were women, and 888 were Black.

Study Conditions

The researchers grouped the participants into three categories:

  1. Low (<7000 steps per day)
  2. Moderate (7000 to <10,000 steps per day)
  3. High (>=10,000 steps per day)

Between 2005-2006 and a follow-up in 2015-2016, participants wore an accelerometer for seven days to measure average step count. The accelerometer was only allowed to be removed during sleep and any water-related activities.

At the end of the follow-up period of an average of 10.8 years, 72 participants had died. 

Additionally, the participants’ highest number of steps per minute in any 30 minutes was measured. The time duration each day in which the participants took 100 steps a minute was also tracked.

The researchers considered several other health-related factors like alcohol intake, weight & BMI (body mass index), smoking, cholesterol & fasting glucose levels, blood pressure, medication history & heart disease.

Findings of The Study

Compared to participants who took less than 7000 steps each day, participants who took at least 7000 steps each day reduced mortality risk by 50-70%.

Neither a step count exceeding 10,000 steps each day nor the step intensity had any additional impact on reducing mortality risk.

The study’s findings bear clinical significance as remote patient monitoring devices are gaining ground. Wearable devices to track daily step count is an easy way to track and promote routine physical activity. While many individuals may be reluctant to engage in planned-out exercise regimes, walking to accomplish step goals can be an acceptable form of daily activity.

Summary

  1. Routine physical activity has multiple health benefits, including reducing the risk of heart diseases and promoting mental wellbeing.
  2. A strength-based approach for physical activity depending on individual abilities and objectives has benefited more in the long run.
  3. Many studies have confirmed the reduction of mortality risk in light of routine physical activity.
  4. The study discovered that a minimum of 7000 steps each day could reduce mortality risk by 50-70%.

References

  1. https://doi.org/10.1001/jamanetworkopen.2021.24516
  2. https://www.cdc.gov/nccdphp/sgr/npai.htm
  3. https://www.cdc.gov/nccdphp/sgr/mm.htm
  4. https://www.bmj.com/content/370/bmj.m2031 
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947527/

What Are Analgesics?

Analgesics, also called painkillers or pain relievers, are a group of medications that relieve pain and inflammation without making you drowsy. They are available as over-the-counter and prescription drugs. 

There are different classes of analgesics, but the two most commonly used ones are Non-steroidal Anti-inflammatory Drugs (NSAIDs) and opioid analgesics (narcotics).

Analgesics are always prescribed based on how strong they are. The WHO recommends using the analgesic ladder, a step-wise approach to pain relief. 

According to this ladder, non-opioid analgesics (like acetaminophen and NSAIDs) are prescribed for mild-to-moderate pain, weak opioids (like codeine tramadol) for moderate-to-severe pain, and stronger opioids (oxycodone and morphine) for severe pain.

Genes and Analgesics

Image: WHO Analgesic Ladder

Analgesics are available in different forms:

Analgesics may be used to relieve pain and inflammation due to various reasons:

How Do Analgesics work?

Different analgesics have different mechanisms of action.

NSAIDs bring about pain relief by blocking the effect of cyclo-oxygenase enzymes

These enzymes play a role in producing prostaglandins, chemicals responsible for pain and inflammation at the injury site.

When there is a reduction in prostaglandin production, pain and inflammation are reduced. 

Other analgesics that have a similar mechanism of action to NSAIDs include acetaminophen, aspirin, and COX (cyclo-oxygenase) inhibitors.

Though paracetamol is known to work similarly to NSAIDs (blocking the cyclo-oxygenase enzymes), it does not reduce inflammation.

Opioids work by binding to opioid receptors in the central nervous system or CNS, gut, and other parts of the body and altering how your brain perceives pain. 

As a result, you feel less pain, and in a way, these drugs increase your pain tolerance

Some examples of opioids are codeine, fentanyl, methadone, naloxone, and oxycodone.

What Are The Side Effects Of Analgesics?

Though analgesics are widely used, they may cause side effects in some individuals when used too often or in large doses. 

Some side effects of analgesics are:

Opioid Addiction - What Are The Signs?

Opioid analgesics may also cause any of the above side effects in addition to causing physical dependence. 

Some signs that you may be addicted to an opioid analgesic are:

If you experience any of the side effects mentioned above, you must consult your doctor. If you notice any of the following side effects, stop taking the NSAIDs or analgesic drugs and report to your doctor immediately:

How Do Analgesics Interact With Other Drugs?

Some drugs that cause significant interactions with analgesics are:

Antacids and food are both known to delay the absorption of analgesics, which means the slow effect of the analgesic on pain.

Drugs bound to proteins such as phenytoin, warfarin, and phenylbutazone compete with the binding site of salicylates (a subclass of NSAIDs). This reduces the efficacy of the analgesic.

Consuming beta-blockers with salicylates can affect their metabolism (breaking down and processing the drug) and elimination from the liver.

Some NSAIDs interactions with other drugs that may cause adverse reactions are:

Taking NSAIDs with blood thinners like warfarin can increase the risk of bleeding.

When combined with ACE inhibitors (medicines used to treat high blood pressure and heart problems), analgesics may cause kidney failure. The same adverse effect may be seen when analgesics are consumed with diuretics (medicines that remove excess fluid from the body).

When two NSAIDs like a low-dose aspirin are combined with another NSAIDs drug, there may be a greater risk of ulcer formation or bleeding in the gastrointestinal tract.

Taking analgesics with antibiotic isoniazid may cause liver damage. So, it is best to avoid taking these drugs together.

Always inform your doctor about your current medications to avoid adverse effects due to analgesic interaction with other drugs you may be taking.

Genes- Drug Interaction: Analgesics

KCNJ6 and Analgesics

The KCNJ6 gene contains instructions for producing an enzyme called Potassium Inwardly Rectifying Channel Subfamily J Member 6. This enzyme allows a greater inflow of potassium ions into the cell

In doing so, this gene regulates body processes like heart rate and the activity of nerve cells.

Certain changes in the KCNJ6 gene have been associated with analgesic requirements in patients who have undergone surgery. 

Patients having a change (variation) called 1032A/A in the KCNJ6 gene required more analgesics than those with the other variations - 1032A/G and 1032G/G. 

This is because 1032A/A is associated with lower levels of the enzyme and insufficient analgesic effects.​​

COMT and Analgesics

Val/Met

The COMT gene provides instructions for making the enzyme catechol-O-methyltransferase. 

The COMT gene has 3 types named Val/Val, Val/Met, Met/Met. The three types each produce different levels of the COMT enzyme. 

The COMT gene has been associated with postoperative pain treatment using opioid analgesics. 

According to a study, individuals having the Val/Met type required less opioid analgesia in the first 24 hours after surgery.

This was not seen with individuals carrying the Va/Val and Met/Met types.

OPRM1 and Analgesics

The OPRM1 gene gives instructions for making a mu-opioid receptor protein. 

These receptors form a part of the body’s system that regulates pain, reward, and addictive behaviors.

A study found that individuals with the 118G or GG type of the OPRM1 gene require more postoperative analgesics than those with the AA or the AG types.

Recommendations For The Safe Use Of Analgesics

Analgesics like NSAIDs, opioid analgesics and acetaminophen are all metabolized in the liver. 

So, if you suffer from any liver disease or condition, you must inform your doctor. 

To avoid adverse reactions or severe side effects of analgesics, people with chronic liver diseases, especially hepatitis and cirrhosis, must avoid consuming analgesics.

Analgesics are known to interact with different drugs. Therefore, to avoid adverse reactions, you must inform your doctor about any medicines or supplements you are currently taking before taking analgesics.

Alcohol and analgesics are both known to irritate the stomach lining. 

Drinking alcohol while taking NSAIDs may increase your risk for gastrointestinal lining damage and bleeding. 

So, if you are taking analgesics, especially NSAIDs, you must avoid drinking alcohol.

Always take an analgesic when necessary and in the minimum dose possible that relieves your pain. 

It is also important to take the painkiller only as long as it is needed. 

Genetic testing can be beneficial in determining how your body may respond to analgesics and identify your risk for any side effects.

Analyze Your Genetic Response to Analgesics

Summary

  1. Analgesics, also called painkillers, are a group of drugs that relieve pain and inflammation. 
  2. There are different groups of analgesics, but the most commonly used are NSAIDs and opioid analgesics.
  3. Opioid analgesics carry a risk of substance abuse and physical dependency on the drugs.
  4. Different analgesics have different mechanisms of action to bring about pain relief and decreased inflammation.
  5. Though analgesics are largely safe, they may cause side effects in some individuals.
  6. Analgesics interact with other drugs, including NSAIDs, beta-blockers, antihypertensive, and blood thinners.
  7. Three genes that show modified analgesic requirements in post-operative patients are the KCNJ6, COMT, and OPRM1.
  8. To ensure safe consumption of analgesics, inform your doctor about your medical history and current medications, and avoid alcohol consumption.
  9. Genetic testing helps your doctor determine the right type and appropriate dosage of analgesics for you.

References

What Is Amprenavir?

Amprenavir is an antiviral drug used to treat the Human Immunodeficiency Virus (HIV) infection. 

This drug was approved by the Food and Drug Administration (FDA) in 1999 and is available as capsules or oral solutions. 

The drug is sold under the brand name Agenerase

Is Amprenavir Still Available?

Amprenavir was discontinued in 2007. 

However, a prodrug version of the same, called Fosamprenavir, is available now. 

A prodrug is a substance that is converted into an active drug form in the body after the person consumes it. Sometimes when the actual drug is poorly absorbed or leads to severe side effects, a prodrug form of the same is developed.

The prodrug is created to ensure maximal absorption by the target cells and bring down the risk of adverse effects. 

In this case, Fosamprenavir, on administration, is metabolized into amprenavir and directly targets the virus.

Is Amprenavir Available Over-The-Counter?

No. You will need a prescription to be able to buy the drug. 

How Does Amprenavir Work?

Amprenavir belongs to a class of drugs called protease inhibitors. Protease is a type of enzyme that the virus makes. 

This HIV-1 protease enzyme makes the virus infectious and, as a result, harmful.

Protease inhibitors attach themselves to the virus’s protease and prevent it from functioning. As a result, the virus remains infectious. 

An adult will need 1200 mg of the drug twice a day, and the drug is available in the form of 50 mg or 150 mg capsules. 

Side Effects Of Amprenavir

Some of the common side effects of amprenavir are:

About 27% of people may develop skin rashes and itchy skin when amprenavir is administered. 

In addition, a severe skin condition called Stevens-Johnson Syndrome (losing the outer layer of the skin) may occur in 1% of people using the drug. 

16% of people who use amprenavir may also experience psychiatric disorders, including mood swings and depression. 

Amprenavir oral solution can lead to the following side effects:

Like other protease inhibitors, Amprenavir may lead to increased cholesterol levels, insulin resistance, and worsening diabetes. 

In General, Are Protease Inhibitors Safe?

Yes, protease inhibitors are safe to use under the guidance of a healthcare provider. However, make sure to talk to your doctor about your existing health conditions and the drugs you use to prevent the risk of side effects. 

Interactions With Other Drugs

Amprenavir may interact with other drugs and lead to changes in drug efficacy or worsening of the adverse effects. Therefore, notify your doctor if you use amprenavir along with the following medications.

Amprenavir: Gene-Drug Interactions

SLCO1B1 Gene And Amprenavir

The SLCO1B1 gene (Solute Carrier Organic anion transporter family member 1B1 gene) provides instructions for producing the organic anion transporting polypeptide 1B1 (OATP1B1) protein. 

This protein transports drugs, toxins, hormones, and other substances from the blood to the liver for elimination. 

rs4149056 is a Single Nucleotide Polymorphism (SNP) in the SLCO1B1 gene. 

In people with HIV infection, the CC and CT types of this SNP may lead to reduced blood amprenavir levels.

In contrast, TT type may lead to increased blood amprenavir levels. 

However, this association was only found in people of European descent.

Low levels of amprenavir may not be sufficient to fight HIV effectively, while high drug levels may lead to an increased risk of developing adverse side effects. 

Knowing specific gene changes can help plan the right drug dosage to maintain optimal drug levels in the body. 

GenotypeImplications
CCDecreased blood amprenavir levels in people of European descent with HIV
CTDecreased blood amprenavir levels in people of European descent with HIV
TTIncreased blood amprenavir levels in people of European descent with HIV

Recommendations To Safely Use Amprenavir

Usage During Pregnancy And Breastfeeding

Studies in animals show that usage of amprenavir during pregnancy may be associated with an increased risk of abortion and low birth weight in babies. 

Talk to your doctor and weigh the benefits and risks of using amprenavir if you are pregnant. 

Animal studies also show that amprenavir is secreted in the milk of lactating animals. This is not confirmed in humans, though. 

Hence, talk to your doctor and understand the risks of the same. 

Doctors generally don’t recommend mothers with HIV to breastfeed because of the risk of postnatal transmission of the virus from the mother to the baby. 

Usage In People With Existing Liver Conditions

People with existing liver conditions must use amprenavir with caution. 

The Child-Pugh score is an assessment to determine the extent of liver damage. 

People with a Child-Pugh score of 5-8 should bring down amprenavir dosage to 450 mg/twice a day.

Those with a score of 9-12 should decrease the dosage to 300 mg/twice a day.

Using Amprenavir Oral Solution

The oral amprenavir solution contains high amounts of propylene glycol. This colorless liquid is harmful in large doses. 

Doctors recommend patients choose the capsules over the oral solution for this reason.

Also, the oral solution is not recommended for pediatric patients below four and the elderly. 

Amprenavir And A High-Fat Diet

Studies show that a high-fat diet may decrease the absorption of amprenavir. Therefore, patients are advised to monitor their fat intake while on the drug. 

Amprenavir And Birth Control Pills

Certain hormonal birth control pills can interfere with amprenavir and reduce its efficacy. Talk to your doctor if you are on birth control pills and are prescribed amprenavir. 

Amprenavir Overdose

If you think you have overdosed on Amprenavir, make sure you call 911 or visit the nearest Emergency Room right away. 

Genetic Testing

Genetic testing will help find out if you have SLCO1B1 gene changes. This can help plan the right dosage of amprenavir, preventing both lowered drug efficacy and drug overdose. 

Analyze Your Genetic Response to Amprenavir

Video

Summary

  1. Amprenavir is an antiviral medicine used to treat HIV infections.
  2. Amprenavir belongs to the category of protease inhibitors and prevents viruses from maturing and getting infectious.
  3. Some of the common side effects of amprenavir are headaches, nausea, dizziness, stomach cramps, and diarrhea.
  4. Amprenavir can cause skin rashes and psychiatric disorders in a few people.
  5. Amprenavir may interact with antibiotics, antifungal drugs, psychiatric drugs, opioid painkillers, and other protease inhibitors and lead to changes in drug efficacy or worsen the side effects. 
  6. SLCO1B1 gene changes can increase or decrease the levels of amprenavir found in the blood in HIV-infected people of European descent. 
  7. Pregnant and breastfeeding women and people with existing liver conditions should consume amprenavir with caution.
  8. Combining amprenavir with a high-fat diet may reduce the absorption of the drug.
  9. Genetic testing will help plan the correct dosages of amprenavir and avoid the risk of reduced drug efficacy and overdose. 

References

Abstract

Sleep is the best way to relax and rejuvenate your body. It curbs all physical and mental stressors and reduces the risk of various health conditions, including cardiovascular complications. Researchers have found an "ideal time" to fall asleep that is best for your heart health. According to this study by the British Academics, going to bed in the "golden hour" can reduce your risk of dying from a heart attack or stroke.

Introduction: Sleep and Heart Health

While there are many reasons to prioritize a good night's sleep, protecting your heart tops the list!

From sleep quality to sleep duration, many parameters of your sleep affect your heart health.

According to the American Heart Association, poor sleep is associated with increased calcium build-up in the arteries. This can result in plaque formation, increasing your risk for heart attacks.

In fact, just one hour more sleep each night is associated with a 33% decreased risk of calcium build-up in arteries.

Sleep and atherosclerosis

Image: Calcium plaque formation in the heart's artery

Not getting enough sleep (7-9 hours per night) can induce hormonal changes - especially those that regulate hunger. It increases the levels of the hunger hormone ghrelin and decreases the levels of the satiety hormone leptin. This can lead to overeating and obesity, which is again a risk factor for heart diseases.

Excessive sleeping (>9 hours) can also increase the risk of developing a range of heart conditions.

Check Out: Gene Sleep Report - Your Guide to a Good Night’s Sleep

Heart conditions associated with bad sleep include:

Sleep Onset Timing And Cardiovascular Disease Incidence: The Study

Study Participants and Data

This study from the United Kingdom used an accelerometer device to examine the sleep onset and waking time in the study participants. 

Accelerometers are devices that monitor sleep by sensing movements.

103,679 participants (in the UK Biobank recruited between 2006 and 2010) were made to wear the accelerometer for 7 days, and accelerometer data were studied.

After some filtering, a total of 15,653 participants were excluded from the study for reasons like:

The sleep-onset time (SOT) of the remaining 88,026 patients was recorded, and the relationship between SOT and heart diseases was investigated.

The study was done over a period of 6 years and reported that 3.6% of subjects later developed heart disease.

Study Results

There was a U-shaped relationship between increased risk of heart disease and SOT - this suggests that there is an optimal SOT for reducing heart disease risk.

Sleep onset time and heart disease risk

Image: Relationship between sleep-onset time and heart disease risk

Any deviations from this range - earlier SOT or later SOT can increase heart disease risk.

The findings

Sleep and heart disease risk

Image: Study Results

Lower Risk of Heart Diseases For SOT from 10 PM to 11 PM - Why?

The findings of this study do not show a causal relationship between SOT and heart disease risk - it just implies a correlation.

However, there is a mountain of evidence that sleep is related to other risk factors of heart disease, like diabetes, obesity, and hypertension.

Study Limitations

How To Sleep At The Right Time

Creating a consistent sleep pattern: Waking up and going to bed at the same time every day (even during weekends and holidays) can help your sleep cycle function well.

Planning your naps: Midday naps, if not done correctly, can interfere with a good night's sleep. A short nap during the afternoon can help you get through your midday lull and not disrupt the night's sleep!

Getting enough sunlight: Natural light, especially during the day, can help your body's clock to function well, thereby promoting good quality sleep.

Improving your bedtime routine: Instead of looking at devices like mobile phones and laptops that emit blue light, listening to music, reading, or taking a relaxing warm bath before bed can help with the quick onset of sleep.

Having an early dinner: The CDC recommends not eating or drinking anything within a few hours of bedtime to give your body enough time to wind down. 

Video

Summary

  1. Good quality sleep is very important for your heart health. Sleeping for less than 7 hours or more than 9 hours can increase your risk for various heart diseases.
  2. A recent study conducted in the UK found that sleep onset time before 10 PM and after 11 PM was associated with an increased risk of heart disease.
  3. The association between sleep onset time and heart disease risk was more profound in women.
  4. Creating a consistent sleep pattern, improving your sleep routine, and getting enough sunlight can help you fall asleep at the right time and improve your sleep quality.

References

Abstract

Cardiometabolic diseases include cardiovascular conditions such as heart attack, stroke, angina, and metabolic conditions like insulin resistance, type II diabetes, and non-alcoholic fatty liver disease. Over the years, low-fat diets have been embraced due to their health effects. But emerging evidence shows that low-carb diets may be just as effective. Recent research has suggested that low-carb diets have been shown to improve cardiometabolic risk profile.

Low-Fat vs. Low-Carb

In the last 50 years, the medical community has encouraged low-fat diets to avoid the effects of saturated fats on the heart. So low-fat and fat-free foods have been majorly circulating on the grocery shelves; however, many of these foods happen to be high in processed carbs.

However, recently many studies and healthcare professionals have been challenging this thought process. This has led to the emergence of the ketogenic diet.

A ketogenic diet is a very low carb, high-fat diet, restricting intake of sugar-sweetened beverages, baked goods, candies, and sweets. 

Some versions may also limit healthy carb sources, such as grains, starchy vegetables, high-carb fruits, pasta, and legumes.

The diet is high in protein, fat, and healthy vegetables. They may increase good cholesterol levels and decrease blood pressure and triglyceride levels.

Other than helping with weight loss, low-carb diets increase good cholesterol levels, reduce blood sugar levels, lower triglyceride levels, and keep your metabolism in control.

Please note: Some harmful effects like fatigue, kidney stones, headache, loss in muscle tissue have been reported with low-carb diets. Consult a qualified nutritionist before making any significant dietary changes. 

Low-Carb Diets May Lower Risk of Cardiometabolic Disease Risk: A New Study

The Boston Children's Hospital led a large clinical trial to examine the effects of a low-carb diet on cardiometabolic disease risk. 

The study included 164 adults who were overweight or obese. The participants had already lost 10-14 percent of their body weight by undergoing a reduced-calorie diet.

The participants were randomly assigned one of these three diets:

The participants received their customized meals, thus ensuring that all of them rigidly followed the protocol. 

In all the prepared meals, saturated fats comprised 35% of the total fat present. In the low-carb meal, saturated fat contributed to 21% of the calories, and in the high-carb meal, it contributed to 7% of the calories.

Study Findings

Compared to the lower-fat higher-carb diets, the low-carb diet had the following benefits:

Though this study was done on adults, the researchers say that low-carb diets may benefit children too. In fact, pediatric cardiologists are also starting to embrace low-carb diets.

 Tips To Follow Low-Carb Diet 

Summary

References

What Is Oxidative Stress?

Oxidative stress is an imbalance in the production of free radicals and antioxidants in the body.

Free Radicals

Free radicals are atoms or molecules that contain unpaired electrons. They are formed when oxygen reacts with certain molecules. 

The unpaired electrons stabilize themselves by attacking other molecules and poaching their electrons. 

They are called Reactive Oxygen Species (ROS). 

Some of the common types of free radicals are:

Free radicals cause cellular damage by altering cell structures like DNA, proteins, lipids, and lipoproteins. 

Antioxidants 

Antioxidants are molecules that neutralize free radicals by donating one of their electrons to the free radicals. Antioxidants are both produced in the body and obtained through food. 

Antioxidants can prevent or delay cellular damage.

Oxidative stress happens when the number of free radicals is more than the number of antioxidants. 

Effects Of Oxidative Stress

Oxidative stress can lead to cellular level damage and various chronic and degenerative conditions like:

Detoxification, Intermediate Metabolites Clearance, And Oxidative Stress

Detoxification is a natural process to help eliminate harmful toxins, chemicals, drugs, and other substances from the body. 

The Cytochrome P450 (CYP) enzymes play a significant role in phase I detoxification. These enzymes add a reactive group to endogenous (produced inside the body) and exogenous (originated outside the body) chemicals, toxins, drugs, and other substances in the body to metabolize them.

The common reactive groups added are hydroxyl, carboxyl, or amino. After adding these reactive groups, these endogenous and exogenous substances are converted into more active forms. These active forms are called intermediate metabolites. The conversion of each molecule of these endogenous and exogenous substances into their intermediate metabolite forms releases free radicals.  

The free radicals, in turn, cause cellular level damage and oxidative stress.  

CYP enzyme-induced oxidative damage leads to physical damage in the body, increasing the risk of cancer, diabetes, and cardiovascular problems. 

Genes Involved in Oxidative Stress Pathway

SOD2 gene

Superoxide dismutase 2, mitochondrial (SOD2) gene provides instructions for the production of the SOD2 enzyme. This enzyme is an antioxidant and helps in converting superoxide radicals (O2•−) into oxygen (O2) and hydrogen peroxide (H2O2). 

Superoxide is a compound that contains the superoxide ion.

rs4880 is a Single Nucleotide Polymorphism (SNP) in the SOD2 gene. 

People with the GG genotype of this SNP have a lower SOD2 enzyme activity compared to those with the AA and GA genotypes. 

This increases their risk of:

GenotypeImplications
GGLower SOD2 enzyme activity and increased risk of oxidative stress
GANormal SOD2 enzyme activity and regular risk of oxidative stress
AANormal SOD2 enzyme activity and regular risk of oxidative stress

CAT gene

The Catalase (CAT) gene provides instructions for the production of the catalase enzyme. This enzyme is also an antioxidant and converts hydrogen peroxide (H2O2) into oxygen (O2) and water (H2O).

rs1001179 is an SNP in the CAT gene. The T allele of this gene is associated with an increased risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.

AllelesImplications
TIncreased risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.
CNormal risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.

GPX1 gene

The glutathione peroxidase 1 (GPX1) gene provides instructions for the production of an enzyme belonging to the glutathione peroxidase family. This enzyme plays a role in converting hydrogen peroxide into water and oxygen, thereby protecting the body from hydrogen peroxide-induced oxidative stress.

rs1050450 is an SNP in the GPX1 gene. People with the TT genotype of this SNP have increased mortality rates due to aging compared to people with the CC and CT genotypes. Oxidative stress is one of the key reasons for aging and mortality related to aging. 

GenotypesImplications
TTIncreased mortality rate due to aging
CCDecreased mortality rate due to aging
CTDecreased mortality rate due to aging

NQO1 gene

The NAD(P)H quinone dehydrogenase 1 (NQO1) gene provides instructions for the production of the NQO1 enzyme. This is a vital antioxidant enzyme that plays a role in preventing oxidative stress and activating vitamin E and vitamin K. 

This enzyme also helps maintain the right CoQ10 levels. CoQ10 or Coenzyme Q10 is a nutrient with immense health benefits in the body and acts as an antioxidant to prevent oxidative damage. 

rs1800566 is an SNP in the NQO1 gene. People with the A allele of this SNP have a higher risk of oxidative stress than those with the G allele. 

AlleleImplications
AHigher risk of oxidative stress
GLower risk of oxidative stress

Recommendations To Reduce Oxidative Stress

N-Acetyl Cysteine (NAC) Supplementation

NAC is a Food and Drug Administration (FDA) approved antioxidant made from the L-cysteine amino acid. Studies show that glutathione is an important antioxidant needed to fight free radicals. Phase 1 detoxification depletes glutathione levels and increases the risk of free radical oxidative stress.

NACs can restore glutathione levels. Your healthcare provider should be able to prescribe NAC for you.

Calorie Restriction (CR)

Some studies show that planned calorie restriction (without the risk of malnutrition) can bring down the effect of oxidative stress in the body. 

Choosing Antioxidant-Rich Foods

Fruits and vegetables have high levels of antioxidants. Therefore, include 3-5 servings of the below fruits and vegetables every day in your diet. 

Exercise

Regular moderate exercise can bring down oxidation damage and increase antioxidant activity in the body. Ensure you get at least 150 hours of moderate exercise/week to reduce  the risk of oxidative stress. 

Avoid Toxic Exposure

When your body is exposed to excessive chemicals, drugs, and other toxins, the CYP enzymes have to work harder to eliminate them. As a result, more intermediate metabolites and free radicals are produced.

You can bring down the risk of oxidative stress by avoiding exposure to substances including:

Genetic Testing

Genetic testing can help understand a person’s risk of oxidative stress. This can help predict future chronic and degenerative diseases and take preventive actions in the present. 

Summary

  1. Oxidative stress is an imbalance between the body’s free radical levels and antioxidant levels.
  2. Excess free radicals may cause cellular level damage to the body, leading to various physical conditions and chronic diseases.
  3. The Phase I detoxification process eliminates different endogenous and exogenous substances by adding a reactive group to them, thereby converting them into more active intermediate metabolites.
  4. The phase I conversion releases free radicals that can lead to oxidative stress.
  5. Changes in the SOD2, CAT, GPX1, and NQO1 genes may increase or decrease a person’s risk of oxidative damage. 
  6. NAC Supplementation may help bring down the effects of oxidative stress due to phase I detoxification.
  7. Eating 3-5 portions of fruits and vegetables, exercising regularly, and following planned calorie restriction can all help bring down the risk of oxidative stress.
  8. Excess toxic exposure may increase the need for phase I detoxification and hence increase the levels of free radicals in the body. 
  9. Genetic testing can help understand a person’s risk for oxidative stress and help predict the risk of chronic and degenerative diseases in the future. 

References

CYP2J2 Gene - An Introduction

The CYP2J2 gene contains instructions for the production of the cytochrome P450 2J2 enzyme. This enzyme is found in the extrahepatic tissues (tissues located outside the liver), especially in the gastrointestinal tract, kidneys, lungs, pancreas, and brain. 

The CYP2J2 enzyme is called an oxygenase. This is because it breaks down xenobiotics (substances not usually expected to be found in the body), cholesterol, fatty acids, and numerous other chemicals by adding an oxygen molecule to them. 

CYP2J2 is especially important in arachidonic acid (AA) metabolism. AA is a polyunsaturated omega-6 fatty acid found in organ meat, poultry, eggs, seafood, and seaweed. 

The CYP2J2 enzyme converts AA into four epoxyeicosatrienoic acids (EETs). EETs are types of signaling molecules that have various positive effects on the body.

EETs may be able to:

Drugs That The CYP2J2 Gene Acts On

The CYP2J2 enzyme metabolizes many drugs.

Ebastine

Ebastine is an antihistamine drug used to treat signs of allergies, including sneezing, swelling, itching, and rashes. 

Astemizole

Astemizole is also an antihistamine drug that provides long-term relief to allergy symptoms.  

Terfenadine

Terfenadine is also an antihistamine drug used to treat allergic symptoms.

Diclofenac

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used to treat inflammatory conditions like gout and arthritis. 

Perphenazine

Perphenazine is an antipsychotic drug used in treating mood disorders, including schizophrenia, bipolar disorder, and symptoms like hallucinations and aggressive behavior. 

Bufuralol

Budurarol is a non-selective adrenoceptor blocking agent that has antiarrhythmic properties. It reduces heart rate, stabilizes blood pressure, and helps protect cardiac health. 

Doxorubicin 

Doxorubicin is an anti-cancer drug and is used in chemotherapy. Doxorubicin, in higher doses, may lead to cardiotoxicity and heart failure. Studies show that higher levels of CYP2J2 enzyme may prevent doxorubicin toxicity and protect the heart. 

CYP2J2 - Inducers And Inhibitors

Inducers are substances that increase the metabolic activity of the enzyme. Inhibitors are substances that bind to the enzyme to reduce its activity.

Drugs That Induce CYP2J2 Activity

Inducers speed up the activity of the CYP2J2 enzyme, leading to quicker metabolism of the xenobiotics and drugs that the enzyme acts on. As a result, the drugs don’t get enough time to work.

Here is a list of drugs that induce CYP2J2 activity.

Drugs That Inhibit CYP2J2 Activity

Inhibitors slow down the activity of the CYP2J2 enzyme, resulting in slower metabolism of xenobiotics and drugs that the enzyme acts on. As a result, the drug stays in circulation for a longer time, and there is an increased risk of a drug overdose.

Here is a list of drugs that inhibit CYp2J2 activity.

Types of CYP2J2 Gene

CYP2J2*7 haplotype

There are many types or variations of CYP2J2, the most well-studied being the CYP2J2*7 haplotype. 

A haplotype is a group of gene changes that are inherited together. *7 is called a star allele. Star alleles are used to name different haplotypes.

A study shows that in the Caucasian population, the CYP2J2*7 allele leads to a 40% reduction in the CYP2J2 enzyme levels. This can increase the risk of developing cardiovascular diseases like myocardial infarction, ischemic stroke, and atherosclerosis. 

rs10889160 and rs11572325 SNPs

Two Single Nucleotide Polymorphisms (SNPs) - rs10889160 and rs11572325 in this gene have been associated with an increased risk of myocardial infarction. 

People with the G and A alleles of the SNPs rs10889160 and rs11572325, respectively, have a 1.24 and 1.27-fold increased risk of developing myocardial infarction than those with the A and T alleles.

SNPAllelesImplications
rs10889160 G1.24-fold increased risk of developing myocardial infarction
rs11572325 A1.27-fold increased risk of developing myocardial infarction

rs1155002 and rs2280274 SNPs

A case-controlled study analyzed the relationship between variations in the CYP2J2 gene and the risk of developing Chronic Obstructive Pulmonary Disease (COPD).

People with the T allele of the SNP rs1155002 had an increased risk of developing COPD, while people with the T allele of the SNP rs2280274 had a decreased risk. 

In addition, being a female and smoking further increased the risk.

SNPAllelesImplications
rs1155002 TIncreased risk of developing COPD
rs2280274 TDecreased risk of developing COPD

Recommendations To Boost CYP2J2 Metabolism

Butylated Hydroxyanisole (BHA) Usage

BHA is a preservative added to many food products. It is a food-based antioxidant to prevent oxidative damage to oils and fats. It keeps oil and fat-based foods fresher for a longer time. BHA is found in foods like the below.

BHA can induce CYP2J2 activity. Therefore, if you are on drugs metabolized by CYP2J2, limit intake of the above foods to prevent faster metabolism of the drugs. 

Be Aware Of Drugs That Inhibit CYP2J2 Activity

If you are on specific drugs that inhibit CYP2J2 activity, consult your doctor and understand the effects on the body. Combining medications metabolized by the CYP2J2 enzyme and these CYP2J2 inhibitors may lead to a drug overdose.  

Genetic Testing

Genetic testing will help understand how protective the CYP2J2 gene variations are against cardiovascular diseases. This can play a role in predicting heart conditions in the future. 

Videos

Summary

  1. The CYP2J2 gene provides instruction for the production of the CYP2J2 enzyme. This enzyme plays a role in the metabolism of different xenobiotics, drugs, fatty acids, and lipids. 
  2. The CYP2J2 enzyme is essential for arachidonic acid (a type of omega-6 fatty acid) metabolism. It converts arachidonic acid into four epoxyeicosatrienoic acids (EETs).
  3. EETs are beneficial to the body and help protect heart and brain health, reduce inflammation, prevent insulin resistance, and reduce blood pressure.
  4. The CYP2J2 gene helps in the metabolism of drugs like ebastine, astemizole, terfenadine, diclofenac, and Bufuralol. 
  5. Drugs like Rosiglitazone and Carbamazepine can induce CYP2J2 activity and lead to faster metabolism of drugs that the enzyme acts on. 
  6. Drugs like Danazol, Ketoconazole, Astemizole, Cisapride, and Pimozide inhibit CYP2J2 activity and can lead to a drug overdose.
  7. Specific CYP2J2 gene changes can increase or decrease a person’s risk of developing cardiovascular conditions and Chronic Obstructive Pulmonary Diseases.
  8. If you are on drugs that inhibit CYP2J2 activity, talk to your doctor to understand how they may affect your body.
  9. Genetic testing will help predict cardiovascular problems in individuals and help take preventive action. 

References

CYP3A4 Gene - An Introduction

Cytochrome P450 Family 3 Subfamily A Member 4 or CYP3A4 gene belongs to the cluster of cytochrome P450 genes and is located on chromosome 7. 

The family of Cytochrome P450 gene gives instructions for the production of enzymes that are responsible for the metabolism (the process by which drugs are broken down or chemically altered by the body to bring about the effect) of drugs, hormones, and other xenobiotics (substances not produced by the body).

The CYP3A4 gene produces the CYP3A4 enzyme that belongs to a group of monooxygenases (enzymes that contain one oxygen atom). It is involved in the metabolism of nearly 50% to 60% of the currently prescribed drugs, including acetaminophen, codeine, cyclosporin A, diazepam, etc. 

The CYP3A4 gene is also involved in the production of cholesterol, steroids, and other lipids (fats). 

Along with the CYP3A5 gene, the CYP3A4 gene is found predominantly in the liver.

CYP3A4 Gene - The Different Metabolizer Types

There are over 20 variants (types) of the CYP3A4 gene that have been studied. Based on the presence of the CYP3A4 variant people carry, they can be classified as:

The *22, *1, *29, *15, etc., mentioned above are star alleles. Star alleles are used to name different haplotypes. A haplotype is a group of gene changes that are inherited together (CYP3A4*20, CYP3A4*1). 

Drugs That The CYP3A4 Acts On

CYP3A4 Inducers And Inhibitors

Drugs that Induce CYP3A4 Activity

Inducers speed up the activity of the CYP3A4 enzyme, leading to quicker metabolism of the substances that the enzyme acts on. 

Some drugs that increase or induce CYP3A4 activity are:

Apart from drugs, some insecticides and pesticides are also known to induce CYP3A4 genes. These include 

Drugs that Inhibit CYP3A4 Activity

Inhibitors slow down the activity of the CYP3A4 enzyme, resulting in the slower metabolism of substances that the enzyme acts on.

Some drugs inhibit or reduce CYP3A4 activity, and these include:

CYP3A4 gene inhibitor drugs can be classified based on their potency as – strong, moderate, or weak inhibitors.

Variations In The CYP3A4 Gene 

CYP3A4 has fewer variants (types) than other CYP genes, and only a few of them are known to affect enzyme function. There are around 20 variants of this gene that have no clinical significance. Few significant variants include CYP3A4 *22, *1B, and *18B.

CYP3A4*22

Also referred to as rs35599367, people with the T allele of this haplotype show decreased CYP3A4 enzyme activity. This haplotype is found in 4% to 8% of the population.

Studies show that people with T/T allele had two times lower enzyme activity than those with the C allele. This is important because people having the T/T genotype require a 40% lower dose of simvastatin (a cholesterol-lowering drug).

Children with the CYP3A4*22 variant show improved asthma control by taking fluticasone propionate (a drug used to treat asthma).

Research also states that CYP3A4*22 carriers were less likely to suffer from severe hot flashes on taking tamoxifen therapy (used for breast cancer).

CYP3A4*1B

rs2740574 is a single nucleotide polymorphism or SNP in the CYP3A4 gene. The presence of the G allele in this SNP in this gene is known as CYP3A4*1B.

The *1B haplotype may be associated with methadone overdose and fatal intoxication

The G allele of this haplotype also increases the risk for prostate, ovarian, and lung cancers.

CYP3A4*18B

Also denoted as rs2242480, this variant of the CYP3A4 gene affects fentanyl (an opioid pain medication) dosage. Research states that patients with *18B/*18B alleles required lesser fentanyl dosage to control pain than patients with *1/*1 genotype.

Recommendations To Boost CYP3A4 Metabolism

Food and Herbal Medications

Some interactions of the CYP3A4 gene with herbal medicines and food can reduce its metabolic effect. 

Therefore, most doctors take a thorough history of all medications, herbal supplements, or alternative medicines that you may be taking to avoid any adverse reactions and prevent reduced CYP3A4 metabolism. 

Genetic Testing

Genetic testing may be advised before prescribing drugs that are metabolized by the CYP3A4 gene. This is particularly true while prescribing simvastatin, fluticasone propionate (in children), tamoxifen, methadone, and fentanyl.

Summary

  1. The CYP3A4 gene is part of the Cytochrome P450 family of genes and is located on chromosome 7.
  2. The CYP3A4 enzyme is found predominantly in the liver and is participates in the metabolism of nearly 50%-60% of commonly used drugs.
  3. The CYP3A4 enzyme plays a role in the synthesis of cholesterol, steroid, and lipids.
  4. The CYP3A4 enzyme acts on a wide range of drugs and substrates, many of which are inducers of the gene, while the rest are inhibitors.
  5. The most significant variants of the CYP3A4 gene include *22, *18B, and *1B.
  6. Genetic testing for the CYP3A4 gene may be helpful for doctors to determine the appropriate dosage of some drugs based on the variant you may have.
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