Postpartum QT Prolongation in a Long QT Syndrome Type 1 Patient

ABSTRACT

Background

Female LQTS patients are at high risk for arrhythmogenic events during the postpartum period due to hormonal influence on cardiac repolarization.

Methods

We observed an LQT1 patient with previous cardiac events during pregnancy and 3 weeks postpartum. We obtained ECG recordings and quantified sex hormone levels.

Results

Peak pregnancy: QTc: 420 ± 7 ms, Estradiol: 24.18 ng/mL, Progesterone: 218 ng/mL. Seven days postpartum: QTc prolongation to 455 ± 5 ms. 22 days postpartum: QTc: 452 ± 5, Estradiol: 0.013 ng/mL, Progesterone: 0.25 ng/mL.

Conclusions

Estradiol and Progesterone decline rapidly after birth, correlating to QTc prolongation and elevated risk for arrhythmogenic events. Therefore, modification of pharmacological or device therapy may be considered.

We present the case of an LQT1 patient with a previous cardiac event during the postpartum period. Performance of electrocardiograms and Estradiol as well as Progesterone levels revealed prolonged QT intervals postpartum correlating to declining sex hormone levels elevate the risk for arrhythmic events in this period.

1. Introduction

The hereditary long QT syndrome (LQTS) is a genetic cardiac disorder characterized by prolonged ventricular repolarization and associated with ventricular arrhythmia that may cause syncope and sudden cardiac death (Goldenberg and Moss 2008).

The two most common types of LQTS are LQT1 and LQT2. LQT1 is caused by mutations in the KCNQ1 gene that encodes Kv7.1—the pore‐forming α‐subunit of a voltage‐gated potassium channel. Kv7.1 gives rise to the slow component of the delayedrectifier potassium current (I_Ks), which is important for action potential repolarization. LQT2 is characterized by mutations in the α‐subunit of the Kv11.1 channel (KCNH2 gene) that conducts the rapid component of the delayedrectifier potassium current (I_Kr) in cardiac myocytes (Moss and Kass 2005; Kekenes‐Huskey et al. ²⁰²²).

Among LQTS patients, female sex is an important risk factor for life‐threatening cardiac events in adulthood (Sauer et al. 2007). In particular, pregnant women with LQTS are at a high risk for cardiac events during the postpartum period, compared to the pregnancy and pre‐pregnancy periods, indicating hormonal influence on cardiac repolarization during the postpartum (Seth et al. 2007).

Conflicting observations regarding the impact of sex hormones on the QT interval exist. An inverse correlation between progesterone levels and QTc interval was documented during the menstrual cycle of LQT2 patients (Bjelic et al. 2022). In line with these findings, estradiol increased the risk of cardiac events in LQT2 rabbits, while progesterone was protective (Odening et al. 2012). Accordingly, progestin‐only oral contraceptives were suggested as a therapeutic approach for female LQTS patients. However, LQTS women who used progestin‐only oral contraceptives had an increased risk of cardiac events (Goldenberg et al. 2022). On the other hand, higher estradiol levels induced through clomiphene were associated with shorter QTc intervals—potentially due to enhanced KCNH2 membrane trafficking—in female probands and LQT patients (Anneken et al. 2016). So a protective role of estradiol seems possible.

Unlike the menstrual cycle, pregnancy represents a state of exception for the female body with extreme hormonal changes. Both progesterone and estradiol rise during pregnancy and decrease quickly postpartum, potentially contributing to the higher risk of cardiac events during that period. Animal studies also suggest a pro‐arrhythmic effect of the postpartum hormones oxytocin and prolactin on LQT2 rabbits (Bodi et al. 2019).

The present case illustrates prominent changes in the QT interval during peak pregnancy and the early postpartum period of an LQT1 patient.

2. Case Report

We present the case of a 31‐year‐old LQT1 female (p.Leu273Phe, c.817C > T) who came to our attention during the third trimester of her third pregnancy. A series of electrocardiograms as well as sex hormone levels in blood samples were obtained at peak pregnancy, 1‐week, and 3‐weeks postpartum.

She had two prior births, after one of which she had to be resuscitated during her in‐hospital stay at 5 days postpartum. She then denied implantation of an implantable cardioverter‐defibrillator (ICD). Her family history (pedigree Figure 1C) is remarkable for the sudden death of an uncle at age 36 with no genetic status available. Her nephew (son to this uncle) was a carrier of the family mutation and had received an ICD at the age of 5 years due to resuscitated cardiac arrest. Her mother and brother were also carriers of this mutation. All asymptomatic family members and the index patient were treated with beta blockers.

FIGURE 1.

(A) ECG recordings (lead II and V5) obtained at the third trimester of pregnancy. QTc was 420 ± 7 ms. Hormone measurements were: Estradiol (E): 24.18 ng/mL, progesterone (P): 218 ng/mL, P/E ratio: 9.0. (B) ECG recordings (II and V5) at 22 days postpartum. QTc: 452 ± 5 ms. Hormones: E: 0.013 ng/mL, P: 0.25 ng/mL, P/E ratio: 19.2. (C) pedigree of the KCNQ1 L273F mutation kindred. Filled black forms indicate symptomatic genotype positives, dots show asymptomatic genotype positives, and hatched is the index patient (III.3). Family member II.2 experienced sudden death at age 36, and III.1 had an ICD implanted at the age of five.

The first ECG recording (Figure 1A) and blood sampling were performed in October 2009 during the third trimester of her pregnancy. The QT interval, corrected for the heart rate using Bazett's formula (QTc = QT/√RR), was 420 ± 7 ms. Estradiol (E) level was at 24.18 ng/mL and progesterone (P) was 218 ng/mL, making up for a 9.0 P/E ratio. Seven days postpartum, her QTc interval was prolonged to 455 ± 5 ms, ~35 ms longer than at peak pregnancy. We did not take blood samples at this visit. At 22 days postpartum, the patient had a QTc interval of 452 ± 5 ms (Figure 1B). Estradiol levels were 0.013 ng/mL and progesterone 0.25 ng/mL, resulting in a P/E ratio of 19.2.

In summary, in this patient with a history of previous postpartum cardiac arrest, sex hormone levels were high during the third trimester of pregnancy and dropped rapidly in early postpartum while the QTc intervals prolonged by a delta of 35 ms. This observation supports the inverse correlation of estradiol changes and QTc in women. Since the QTc measures are within normal range, including the increase postpartum, this case shows that even in LQTS women with a normal‐range QTc, a prolongation in the postpartum period may be a marker of increased risk of arrythmia and sudden cardiac death.

3. Discussion

3.1. Correlation of Hormonal Changes and Ventricular Repolarization

We noticed QTc prolongation in the first 3 weeks of the postpartum period correlating to decreasing levels of both progesterone and estradiol. This could be caused by the different effects of sex hormones on repolarization.

Endogenous progesterone shortens the QT interval (Bjelic et al. 2022; Nakagawa et al. ²⁰⁰⁶; Rodriguez et al. ²⁰⁰¹). In LQT2 patients (but not in LQT1 or healthy patients) an inverse correlation between the QT interval and progesterone levels during the menstrual cycle was found, with the longest QT intervals in the follicular phase when progesterone levels are low and progressive shortening as progesterone levels rise (Bjelic et al. 2022). The inverse correlation also applies to the progesterone to estradiol ratio in the menstrual cycle, but this was not the case in our observation. In patients with drug‐induced QT prolongation, a similar correlation was found with shorter ventricular repolarization during the luteal phase (high estradiol) compared to menstruation and the follicular phase (Rodriguez et al. 2001). Experimental animal studies have demonstrated the same effects on transgenic LQT2 rabbits (Odening et al. 2012).

The role of estradiol on repolarization dynamics remains unclear as studies yielded contrasting effects. While in animal models estradiol seemed to have a proarrhythmic effect (Odening et al. 2012), clinically QTc shortening effects of estradiol during pregnancy and clomiphene stimulation (potentially due to enhanced KCNH2 trafficking to the membrane increasing repolarizing current) was shown (Anneken et al. 2016).

So, the shorter QT interval during pregnancy in our patient followed by a prolongation in the postpartum may be due to the synergistic effects of progesterone and estradiol.

3.2. Risk of Cardiac Events in the Early Postpartum Period

Our patient had previously been resuscitated during the early postpartum phase of a previous pregnancy. This may have been due to ventricular arrhythmias (torsade‐de‐pointes tachycardia) resulting from prolonged ventricular repolarization. In accordance with this observation, recent studies found a higher risk of cardiac events for women with LQTS 9 months postpartum compared to the pregnancy or pre‐conception period (Seth et al. 2007). Notably, LQT2 patients have a higher risk of postpartum events than LQT1 patients (Seth et al. 2007; Khositseth et al. ²⁰⁰⁴). A more detailed look—regarding weeks or days—into the progression of cardiac events during the postpartum period would be interesting in order to potentially adapt optimal device and medical therapy.

Author Contributions

The author takes full responsibility for this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.