Could your genes put you at risk for drug-induced heart arrhythmia?

Have you experienced dizziness, fainting, or heart palpitations while taking medications? These symptoms may be related to an abnormal or altered heart rhythm, also known as an arrhythmia. There are several different types of arrhythmias. While some are benign, arrhythmias are often a sign of underlying conditions and should be assessed by a medical professional. In some cases, arrhythmia can be caused by adverse reactions to certain medications. Here, we explain how a pharmacogenetic test can help you avoid severe drug-induced complications.

What is the QT interval, and why is it important?

To maintain a healthy, consistent heartbeat, the heart needs a specific time between beats to recharge the electrical “batteries” that trigger heart muscle contractions. This recharge period is called the QT interval and typically lasts about 400 milliseconds (ms). During physical activity, the QT interval shortens to 280-320 ms. For some people, the recharge takes longer, a condition called QT (interval) prolongation. Typically, QT prolongation is asymptomatic but can increase the risk of heart arrhythmias during vigorous exercise, overheating, dehydration, and exposure to certain medications. This abnormal QT prolongation can lead to fainting and increase the risk of sudden cardiac death.

Some people are born with genetic variations that increase the QT interval, or cause QT prolongation as an adverse reaction to a drug or even to excess stress. If someone in your family died of a sudden heart attack or experienced heart palpitations or fainting while taking medication, an electrocardiogram and genetic testing can help assess your risk.

Types of QT interval prolongation

There are two types of genetic QT prolongation syndromes: Congenital (inherited) Long QT Syndrome (CLQTS) and drug-induced QT prolongation, known as “acquired” Long QT Syndrome (aLQTS).

Congenital (Inherited) long QT syndrome:

Congenital long QT syndrome is rare and characterized by a consistently prolonged QT interval (>480 ms) while at rest and an abnormal T-wave on an electrocardiogram. People with a QT interval over 500 ms typically experience fainting episodes and are at high risk of life-threatening arrhythmia (Torsades de pointes).

CLQTS occurs in about 1 in 2000 people who carry a mutation in one of the KCNQ1, KCNH2, or SCN5A genes. Additional genetic variations in “modifier” genes encoding calcium channels can affect the severity of the condition. Current therapies for Long QT Syndrome (LQTS) and related syndromes are effective and include mexiletine and beta-blockers (metoprolol, propranolol). The minor surgical procedure called Left Cardiac Sympathetic Denervation is also helpful for patients who do not respond to medications. In severe cases, an implantable defibrillator helps promptly restore the heart rhythm if an arrhythmia occurs.

Acquired or drug-induced QT prolongation: a special case

Drug-induced QT prolongation is defined as a change of >60 ms from baseline ‘corrected QT interval’ (QTc) and/or an absolute QTc value ≥500 ms. However, in terms of health risks, symptoms trump numbers: a person with a QTc of 470 ms and syncope (fainting or ‘passing out') is more concerning than someone with a QTc of 490 ms who's asymptomatic. Because many factors can affect heart rhythm, including electrolyte levels, medications, heart rate, and autonomic tone, risk is calculated for each person, accounting for multiple individual factors, including genetics. The Tisdale Risk Score for QT Prolongation helps clinicians assess a person’s risk, but it lacks the most crucial genetic factors because most people and their doctors do not know whether they have a high-risk genetic variant.

Genetic variant underlying aLTQS

People with specific genetic variations in the KCNE1 (D85N) and KCNE2 (T8A) have been strongly associated with the risk of drug-induced QT prolongation. Additionally, over 100 genetic variants are suspected to contribute to the risk of acquired LQTS, including D76N in KCNE1, I57T in KCNE2, G615E in SCN5A, and L1825P in SCN5A. These variants are more common, increasing the frequency of drug-induced QT prolongation by more than tenfold compared with the inherited form.

These genetic variations slow down the potassium channels and lead to “Reduced repolarization reserve,” which is akin to the heart's safety margin for electrical recovery after each heartbeat. It's like having multiple backup systems. Under normal conditions, the QT interval is almost normal or borderline and clinically irrelevant. But if the person is stressed (or dehydrated or has a high fever) and is taking a drug that affects potassium, sodium or calcium channels, the diminished “backup” can lead to heart arrhythmias, which can be fatal.

For example, a person with a mild KCNH2 variant (reducing function by 30%) and a borderline baseline QTc of 450 ms is given erythromycin (which blocks IKr) for a minor infection. Their QTc jumps to 520 ms, leading to life-threatening arrhythmia (torsades de pointes, a polymorphic ventricular tachycardia). Unfortunately, if such a person takes erythromycin, just one of the 360 high-risk medications, at home, they could die before the ambulance arrives.

Some commonly prescribed medications might be dangerous for you

Common medications, including antibiotics, antipsychotics, and antiarrhythmics, can prolong the QT interval. The CredibleMeds website is an excellent resource for learning which medications can increase the risk of cardiac events. The list is constantly growing, and today, about 43 medications have a definitive risk for people with certain genetic variations.

The matter is even more complicated because other genes that encode liver enzymes that clear drugs from your body can also increase the risk of QT prolongation. For example, people with absent or very low function of the CYP2C19 enzyme are advised against using specific antidepressants, namely citalopram (Celexa) and, to a lesser extent, escitalopram (Lexapro, Cipralex) and sertraline (Zoloft), due to these risks.

The good news is that knowing the results of a DNA test can save your life.

If a close relative died suddenly and unexpectedly at a young age, or if the cause was never explained, speak with your doctor about a cardiology referral and a baseline ECG. Some doctors may also recommend a 24-hour Holter monitor, an ambulatory ECG, or an exercise stress test (to assess QT behaviour during activity).

If your cardiogram shows a longer-than-normal QT interval, sequencing a panel of known genes can help determine whether you carry a rare genetic variant predisposing you to congenital LQTS.

Separately, if you are taking or may be prescribed medications that affect heart rhythm, pharmacogenetic testing can identify variants that increase your risk of a drug-induced reaction. A pharmacogenetic test assesses how your body metabolizes medications, including metoprolol and mexiletine, and whether these medications are appropriate for you. People with significantly altered CYP2D6 enzyme activity (poor or ultrarapid metabolizers) should avoid these drugs and may need more intensive or even surgical treatment to reduce the risk of life-threatening arrhythmias.

If your electrocardiogram shows a slightly elevated or borderline QT interval, you should undergo pharmacogenetic testing to determine whether you carry a more common variant that predisposes you to acquired drug-induced LQTS. Currently, the European Heart Rhythm Association (EHRA), as well as the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin American Heart Rhythm Society (LAHRS) state that:

“Variants which are unequivocally associated with drug-induced LQTS (e.g. D85N in KCNE1) should be reported as a relevant result. Active family screening for the presence of these variants should be considered when QT-prolonging drugs are or could be prescribed.”

Meaning:

1. You should get a test for the D85N variant in the KCNE1 gene.
   
2. If your DNA contains this variant, your immediate family members (parents and siblings) should also be genetically tested.
   
3. Your doctors should avoid prescribing any of the medications listed on the CredibleMeds website.
   

What to do next?

For the most part, you can go about your everyday life, but it would be wise to avoid strenuous exercise (especially in hot conditions), ensure that you drink enough water or drinks with balanced electrolytes, and to consult your doctor or pharmacist if you take (or plan to take) any medication or even a food supplement. For example, popular curcumin supplements can also be dangerous for you.

As a precaution, regular ECG monitoring every 6-12 months is recommended for stable patients. The frequency may need to increase if you are:

• Starting new medications
  
• Experiencing fainting (syncope), heart palpitations, or seizures
  
• Pregnant or in the postpartum period
  
• Experiencing significant life changes affecting treatment
  

However, if you feel dizzy or have heart palpitations, immediately call an ambulance or your doctor for help.

Summary:

• Some people may have an increased risk of cardiovascular events due to genetic variations that prolong the QT interval.
  
• Congenital forms are exceptionally rare and can be diagnosed by a cardiologist. Genetic analysis can help confirm the diagnosis for you and your family members and initiate preventative treatment.
  
• Certain medications can cause acquired QT prolongation. It is much more common than the congenital form, but it is mostly asymptomatic.
  
• Pharmacogenetic testing can help determine whether you might be at risk of drug-induced QT prolongation and help you avoid high-risk medications.
  
• People with specific genetic variants should always consult a pharmacist or doctor before starting certain antibiotics, antidepressants, heart medications, or supplements.

References:

Schwartz PJ and Crotti L Long QT Syndrome N Engl J Med 2025;393:2023-2034.

Lopez Medina AI, Chahal CAA, Luzum JA. The genetics of drug-induced QT prolongation: evaluating the evidence for pharmacodynamic variants. Pharmacogenomics. 2022 Jun;23(9):543-557.

Wilde AAM, et al. Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24(8):1307-1367. PMID: 35373836.