Congenital long QT syndrome: Should citric fruits be avoided? A case report of a cLQTS type 1 with unusual QTc prolongation with citric juices

Abstract

Congenital long QT syndromes (cLQTS) are relatively rare diseases in which QT interval is prolonged due to several mutations on ion channels involved in cardiac cell repolarization. This condition confers higher risk of malignant arrhythmias and sudden cardiac death, and it is widely accepted that substances that prolong QT interval should be avoided by these patients. Most of these substances are antibiotics and non-antibiotics drugs, but almost nothing is known about frequently consumed fruits and juices. We report the case of a patient with a previously asymptomatic cLQTS type 1 (cLQTS1) with unusual QT prolongation of 167 milliseconds (ms) related to the consumption of large amounts of citric juices (oranges and lemons). A literature review was done for better understanding of its influence on QT interval duration and to know the concentration of flavonoids on citric fruits.

<Learning objective: The objective is to emphasize the relatively new concept of “proarrhythmic food”. A short number of clinical trials have demonstrated a modest QT interval prolongation with grapefruit juice, but nothing has been previously described of other citric fruits. We present a case of a patient with cLQTS1 that suffered severe QT interval prolongation related to orange and lemon juice consumption. Substances on these fruits involved in QT prolongation and pathophysiological mechanism are discussed.>

Introduction

The QT interval is the part of the electrocardiogram (ECG) in which ventricular repolarization occurs. The length of the QT interval may change between healthy individuals and even in the same person, but it is widely accepted that the corrected QT interval (QTc) should be shorter than 450 ms in males and 460 ms in females [1]. Congenital long QT syndromes (cLQTS) are a broad spectrum of genetically determined cardiac diseases characterized by QT interval prolongation, and its prevalence is estimated to be approximately 1/2500 newborns [1].

More than 11 different cLQTS have been described, with the cLQTS1, cLQTS2, and cLQTS3 being the most prevalent ones [2]. cLQTS1 accounts for more than 50% of all cLQTS described cases and it is caused by mutations on the KCNQ1 gene, which encodes the alpha subunit of the potassium channel responsible for the slow delayed rectifier potassium current (I_Ks), which is a major determinant of the phase 3 of the cardiac action potential [3]. More than 600 KCNQ1 gene mutations have been described, and the loss of function of this channel has been associated with predisposition to life-threatening arrythmias [4], mainly torsade de pointes.

An important number of drugs has been associated with prolongation of the QTc interval, including antiarrhythmic drugs, fluoroquinolones, and macrolide antibiotics being the most widely studied [5]. Also, flavonoids found on grapefruit have been associated with QTc interval prolongation in vitro and in vivo [6], but the proarrhythmic role of other citric juices that also contain these substances have not been studied. Patients with genetically determined QT interval prolongation could be at excessive risk of developing ventricular arrhythmias with the consumption of these citric fruits. In this case report we present a patient with a cLQTS1 who suffered a symptomatic QTc prolongation of 160 milliseconds (ms) associated with large amounts of lemon and orange juice consumption, something not described before.

Case report

A 52-year-old male patient with previously asymptomatic cLQTS1 came for his routine visit with the cardiologist and was admitted to cardiology hospitalization ward due to unusual QTc prolongation. Ten years prior to this admission, on a routine medical visit, a prolonged QTc was found and the patient was referred to the cardiologist. A 12-lead ECG and a genetical evaluation were performed. A heterozygous missense mutation (Gly325→Arg) at the chromosome 11, exon 7 of the KCNQ1 gene, which encodes the alpha subunit of the potassium channel responsible for the (I_Ks), was found. The cLQTS1 was confirmed and the same mutation was also found as heterozygosis in the patient's daughter and son.

The patient had no family history of sudden cardiac death, denied any kind of toxic habits, and his only comorbidities, besides the cLQT1, are asymptomatic hyperuricemia and stage 2 chronic renal failure (CRF). Allopurinol 300 mg once daily and bisoprolol 2.5 mg twice daily are the only chronic medications used by the patient. In 9 years of annual medical revisions following the diagnosis he has remained asymptomatic with a QTc between 470 ms and 500 ms, and his last ECG before admission is shown in Fig. 1A.

Fig. 1.

(A) Patient electrocardiogram (ECG) 1 year before the admission. Sinus rhythm at 58 bpm and a QTc of 471 ms is measured. (B) ECG the day of his 10th medical review and day of admission. An unusual prolongation of the QTc (638 ms) can be appreciated, along with a notched T wave on precordial leads, mainly on V4–V5. (C) ECG on the 6th day of admission (discharge day). A QTc of 524 ms can be shown and notched T waves on V4–V5 have disappeared.

Two days before the visit to the cardiologist he experienced for the first time a 30-minute long dizziness episode on a normal workday at his office, without associated chest pain, nausea, or diaphoresis. His smartwatch alerted him to an unusual resting heart rate (HR) of 140 bpm, which minutes later came back to usual 60 bpm. The patient remained asymptomatic since that day. The control ECG performed on his 10th routine visit (Fig. 1B) showed a sinus rhythm with QTc of 638 ms and a notched T wave on V4 and V5.

No changes to chronic medication were made and his last antibiotic therapy was more than 3 years previously. No signs or symptoms of current infectious disease were identified. Laboratory work-up on the day of admission showed a normal complete blood count. Biochemical analysis showed the following results: urea 43 mg/dL, creatinine 1.32 mg/dL, estimated glomerular filtration rate (CKD-EPI) of 63 mL/min/1.73 m². Blood electrolytes were within normal limits with ionic sodium of 143 mmol/L, ionic potassium of 4.5 mmol/L, ionic calcium 1.22 mmol/L, and magnesium of 0.83 mmol/L. Chest X-ray was normal.

The patient was asked if he had consumed grapefruit on previous days, but he clearly denied it. He stated that he had been consuming large amounts of lemon and orange juices since approximately one year (1–2 L daily), because he does not like the lack of flavor of mineral water. His last ingestion was two glasses of orange juice at breakfast, about 90 min before admission. The patient was admitted, maintaining beta-blocker and allopurinol, but banned from citric fruits consumption (juice or any other form). The patient was on continuous ECG monitoring and daily 12-lead ECG was performed for 6 days until discharge (QT interval progression is shown in Table 1). The last ECG during admission is shown in Fig. 1C.

Table 1.

Evolution of the QT interval, heart rate on electrocardiogram (ECG) and QTc (Bazett formula) before admission, during admission on daily ECG, and six months follow-up visit after discharge.

Day	QT interval	Heart rate on ECG	QTc (ms)
Last ECG registered before visit (Image 1, A)	479	58	471
Day1 – admission day (Image 1, B)	582	80	638
Day2	568	74	631
Day 3	565	70	610
Day 4	504	63	517
Day 5	535	65	557
Day 6 – discharge day (Image 1, C)	524	60	524
6 month visit	468	62	476

ms, miliseconds.

To assess the arrhythmic risk of the patient an exercise ECG was performed on day 4, being electrically and clinical negative for ischemia, and no arrythmias were registered during exercise (7.1 METS and reached 71% of predicted HR) or recovery. Since QT interval was improving toward patient's usual values and without arrhythmias (nor on continue ECG monitoring or exercise ECG), a subcutaneous Holter (SH) was placed on day 5 and the patient was discharged on day 6. QTc at six months follow-up visit without consumption of citric juices was of 476 ms and the patient remained asymptomatic (Table 1).

Discussion

A clinical case of a 52-year-old patient with a heterozygous cLQTS1 that was asymptomatic and with a stable but prolonged QTc (470 ms to 500 ms) for 9 years since diagnosis is presented. On his 10th annual medical review he stated that for the first time he felt dizziness while at his office, and on the 12-lead ECG an unusual QTc prolongation was found, with an associated notched T wave (Fig. 1A). The patient denied modifications in his chronic medications, recent ingestion of QT prolonging drugs, or grapefruit juice consumption.

When he was asked about grapefruit juice ingestion, he stated that for almost one year he consumed large amounts (1L to 2L daily) of lemon and orange juices, being the only remarkable change since his last medical review. Based on this statement, citric fruits were suspended during admission. In this patient it was preferred to implant an subcutaneous Holter over an implantable cardioverter defibrillator (ICD) because no arrhythmia was identified either on stress test or telemetry monitoring during hospitalization.

Different trials have confirmed that grapefruit juice prolongs the QTc in healthy individuals [6], [7] and in patients with cLQTS [7]. The molecular basis of this QTc prolongation is due to the inhibition of HERG (also known as KCNH2, which is a potassium channel responsible for the rapid delayed rectifier current I_Kr [2] of the phase 3 of the cardiac cells action potential) by flavonoids present on grapefruit, being the naringenin, morin, and hesperetin the three most potent inhibitors [6]. Naringenin and hesperetin are aglycones that result from the hydrolysis of glycosides present on citric fruits (naringin and hesperidin, respectively) [8], [9]. This hydrolysis seems to occur in the gut by human microbiota, facilitating its absorption [10], that reach its maximum concentration in blood at 4–5 h after ingestion [6]. Flavonoid concentration in the glycoside form in different citric fruits is shown in Table 2.

Table 2.

Relative content of aglycone flavanones in citric fruits (fresh fruit or fresh juice).

Fruit	Concentration of aglycone (mg/100 g of fruit or fresh juice)
	Naringin	Hesperidin
Pink grapefruit	16.6a	2.78a
Lemons	0.18a	15.78a
Limes	0.00a	15.64a
Sweet Orange	0.17b	15.25b
Sour Orange	18.83b	0.00b
Tangerine (Mandarin)	0.00b	19.26b

^aData based on Peterson et al. [8].

^bData based on Peterson et al. [9].

mg, miligrams; g, grams.

Maximum QTc prolongation occurs at 4–5 h after the ingestion of grapefruit juice by normal individuals, being the mean QTc of 12.5 ms [6] to 14.0 ms [7]. In patients with cLQTS, mean QTc prolongation was 21.8 ms and a maximum of 48.5 ms was registered [7].

In this patient, maximal QTc prolongation registered was of approximately 167 ms, almost 350% of the maximum prolongation registered in trials, which in our opinion could be explained by two situations. First, the patient had a cLQTS type 1 which affects the I_Ks current and naringenin and hesperetin affect the I_Kr current; this combination confers a double inhibition to potassium currents during phase 3 of the myocardiocyte action potential. The second situation that may explain this important QTc prolongation is that the patient had almost one year of drinking large amounts of citric juices, which in addition to his stage 2 chronic renal failure (glomerular filtration rate 63 mL/min/1.73 m²) could confer an important accumulation of these flavonoids in his body which results in an important inhibition of these potassium currents. This last situation may also explain why it took 6 days for him to partially recover the usual QTc values.

Although there has been growing evidence in the past 15 years about flavonoid content in fruits and its effects in humans, to date no studies have addressed other citric fruits that have similar components to grapefruit and that might prolong QTc as well. A trial may be necessary to establish the relationship between QTc prolongation and citric fruit consumption, because a simple recommendation of avoiding these fruits could prevent sudden cardiac death in patients with a relatively common (1/2500 newborns) disease, as the cLQTS.

Conflict of interest

The authors declare no competing conflict of interest with this manuscript.