Burden of Purkinje ectopies associated with sex hormone levels

Key Teaching Points.

• •The influence of sex hormones on susceptibility to arrhythmias is well established.
• •Idiopathic ventricular fibrillation is defined by ventricular fibrillation occurring in young adults with no discernible structural or electrocardiographic abnormalities and is mainly induced by Purkinje ectopies.
• •It may be reasonable to perform patient monitoring, during the pregnancy and the postpartum phase, in case of palpitations.

Introduction

Idiopathic ventricular fibrillation (IVF) is a significant cause of sudden cardiac death in young patients without structural heart disease,^1,2 with most arrhythmia triggers originating from the Purkinje system.^3,4 Differences in the right or left Purkinje triggers have recently been reported between men and women.⁵ The effect of sex hormones on cardiac channelopathies is well known and pregnancy has been associated with IVF in 4 case reports.⁶ Here, we report a case of arrhythmic events exacerbated during the luteal phase of the menstrual cycle and at the beginning of pregnancy.

Case report

A 31-year-old woman was hospitalized in 2019 for 3 episodes of syncope occurring at rest within 24 hours. Her electrocardiogram (ECG) showed sinus rhythm with frequent polymorphic premature ventricular complexes (PVCs) with a short coupling interval of 260 ms. The PVCs exhibited a sharp and rapid initial deflection, with right and left bundle branch block morphologies, suggestive of biventricular left and right Purkinje ectopics, respectively (Figure 1). No structural abnormalities were identified with transthoracic echocardiogram or cardiac magnetic resonance imaging. In the evening after admission, the patient presented 1 sustained ventricular fibrillation episode requiring an external electrical shock at 200 J. Amiodarone (900 mg/24 h) and metoprolol were initially administered, and a subcutaneous implantable cardiac defibrillator was implanted. The patient was discharged on verapamil (80 mg 3 times daily).

Figure 1.

A: Short run of polymorphic ventricular tachycardia initiated by a short-coupled left Purkinje ectopy (coupling interval = 260 ms). B: Short-coupled left Purkinje ectopy with different morphology.

Three years later, she was hospitalized following an appropriate implantable cardiac defibrillator shock for ventricular fibrillation. Ablation of Purkinje ectopics was not considered owing to their multiple (>7) different morphologies and the antiarrhythmic treatment was changed to hydroquinidine (300 mg twice daily). The patient was then observed with continuous ECG monitoring for 2 days, during which short-coupled PVCs (SCPVCs) did not recur. She was followed up for 31 months after discharge and reported that every month, palpitations increased consistently during the 10 days before her menstrual cycle. Because of the potential link between sex hormones and arrhythmia burden, we performed continuous Holter ECG for 28 days and dosed sex hormones (estradiol and progesterone) on day 2, day 13, day 24, and day 28 of the menstrual cycle. Coincidentally, the patient became pregnant during this single menstrual cycle, confirmed by an increase in progesterone and estradiol levels starting on day 13. Prior to day 13, in the initial days of the menstrual cycle, the arrhythmic burden was low, with around 6 SCPVCs over 24 hours (Figure 2). From day 13 onward, the beginning of pregnancy was associated with an increasing burden of SCPVCs and the occurrence of daytime short runs of polymorphic ventricular tachycardia (Figure 2). The patient is currently treated with hydroquinidine (300 mg twice daily).

Figure 2.

Illustration of progesterone (in red, pg/mL) and estradiol (in blue, ng/mL) levels during the menstrual cycle and the beginning of pregnancy. Number of premature ventricular complexes (PVCs)/24 h is indicated by a green triangle (except for the last value, which is over 14 hours because of a bad electrode contact).

Discussion

Here we describe a case of IVF in a woman with a history of consistent occurrence of ectopic activity symptoms during each menstrual cycle, which were exacerbated at the time of pregnancy, coincidentally occurring during serial Holter and hormone monitoring.

Sex-related differences in the clinical phenotype of inherited arrhythmia syndromes have been well established.^5,6 Several hypotheses have been proposed to explain such differences, including sex-related intrinsic differences in ionic currents, calcium handling, and hormonal influences.

Purkinje ectopics are the predominant origin of IVF related to a distinctive trigger, accounting for 87%–93%³ of IVF cases. The main mechanism of these Purkinje ectopics is triggered activity, and we have recently shown that their origin was different between males and females.⁷ Several studies have demonstrated that sex hormones could influence the expression and function of calcium-handling proteins and contribute to sex differences in the susceptibility to triggered activity.⁶ Calcium-handling proteins are differentially expressed between males and females. Disparities have also been described regarding I_Ca,L density,⁸ and RyR2⁹ expression between sexes, but discrepancies exist in the literature probably owing to the species studied and the experimental protocols used. Estradiol increases triggered activity formation by increasing I_Ca,L current density,¹⁰ NCX expression,¹¹ and the activity and leakiness of RYR2.¹² In contrast, progesterone has an antiarrhythmic effect by increasing SERCA expression^10,13 and decreasing I_Ca,L current density.¹⁰ However, some of these results have not been validated in human cell models or in Purkinje cells and the specific role of sex hormones on Purkinje arrhythmogenicity has not been investigated.

In the present case report, the link between Purkinje arrhythmogenicity and hormone levels was demonstrated by the consistently reported clinical burden of SCPVCs only during the luteal phase of the menstrual cycle and by the coincidental occurrence of pregnancy during concomitant Holter and hormone evaluation. However, the reproducibility of hormonal data during menstrual cycles could not be confirmed owing to pregnancy. These observations cannot be simply explained by the progesterone-to-estradiol ratio and likely involve other mechanisms, notably the role of catecholamines. To our knowledge, only 4 cases of IVF related to SCPVCs have been reported during pregnancy.¹⁴ In addition, a case of new-onset left ventricular fascicular ventricular tachycardia was described in a young female patient during pregnancy.¹⁵ After childbirth, ventricular tachycardia was not inducible despite pacing maneuvers and catecholamine infusion but could be induced by progesterone therapy. The above studies indicate a likely role of sex hormones in ventricular or Purkinje arrhythmogenicity, which may be more frequent clinically but undocumented. Further investigation is needed to elucidate the exact mechanisms involved in sex hormone–associated Purkinje arrhythmogenicity and to clarify the influence of catecholamine levels on arrhythmogenicity.

Conclusion

We reported 1 female patient with increased burden of SCPVC having a Purkinje-phenotype during pregnancy.