Modulation of Cardiac Automaticity by IKACH in the Sinoatrial Node During Pregnancy

Obstetrics and Gynecology Cardiovascular System Medicine
pregnancy sinoatrial node acetylcholine-activated K+ current heart rate mouse model

Academic Background

Pregnant women undergo significant physiological changes in their cardiovascular system to meet the increased physiological demands during pregnancy. Among these changes, an increase in resting heart rate (HR) is common, typically rising by 10-20 beats per minute. However, this increase in HR can lead to the onset or exacerbation of arrhythmias, particularly supraventricular arrhythmias, posing a threat to maternal and fetal health. Although previous studies have shown that electrical remodeling of the sinoatrial node (SAN) is associated with increased HR during pregnancy, the underlying mechanisms remain incompletely understood. Specifically, the acetylcholine-activated potassium current (IKACh) plays a critical role in regulating SAN automaticity, but its precise role in HR modulation during pregnancy is still unclear.

To better understand the mechanisms underlying the increased HR during pregnancy, researchers hypothesized that, in addition to known electrical remodeling, functional changes in IKACh might also play a significant role in HR regulation during pregnancy. Therefore, this study aimed to explore the potential role of IKACh in the increased HR during pregnancy and provide new insights into the management of pregnancy-related arrhythmias.

Source of the Paper

This study was conducted by Valérie Long, Gracia El Gebeily, Élisabeth Leblanc, Marwa Senhadji, and Céline Fiset from the Montreal Heart Institute and the Faculty of Pharmacy at the Université de Montréal, Canada. The paper was published in 2024 in the journal Cardiovascular Research under the title “Cardiac automaticity is modulated by IKACh in sinoatrial node during pregnancy.”

Research Process and Results

1. Study Subjects and Experimental Design

The study used female CD-1 mice aged 2 to 4 months as subjects, divided into non-pregnant (NP) and pregnant (P; 17-18 days of gestation) groups. Researchers systematically investigated the functional and expression changes of IKACh in SAN cells of pregnant mice through electrophysiological experiments, surface electrocardiogram (ECG) recordings, real-time quantitative PCR (qPCR), and Western blot analysis.

2. Measurement of IKACh Current Density

First, researchers recorded the IKACh current density in SAN cells using the whole-cell voltage-clamp technique. The results showed that the IKACh current density was significantly reduced in pregnant mice and returned to non-pregnant levels shortly after delivery. Specifically, at -55 mV, the IKACh current density in pregnant mice was 46% lower than in non-pregnant mice (NP: 5.7 ± 0.6 pA/pF; P: 3.1 ± 0.4 pA/pF, p = 0.0026). This suggests that IKACh function is significantly suppressed during pregnancy.

3. Changes in IKACh-Related Gene and Protein Expression

To explain the reduction in IKACh current density, researchers measured the expression of genes and proteins related to IKACh function in the SAN using qPCR and Western blot. The results showed that the protein expression of the Kir3.1 channel subunit and the muscarinic type 2 receptor (M2R) was significantly reduced in the SAN of pregnant mice, while the expression of the Kir3.4 channel subunit remained unchanged. These changes in expression levels are consistent with the reduction in IKACh current density, further supporting the important role of IKACh in HR regulation during pregnancy.

4. Sensitivity of SAN Action Potentials to Acetylcholine

Next, researchers recorded spontaneous action potentials in SAN cells using the current-clamp technique and observed their response to the acetylcholine analog carbachol (CCh). The experiments revealed that SAN cells from non-pregnant mice exhibited significant hyperpolarization in response to CCh, while those from pregnant mice showed a weaker response. This further confirms the role of reduced IKACh function in the increased HR during pregnancy.

5. HR Response to Pharmacological Interventions

Researchers also recorded HR in mice using surface ECG and observed their response to atropine and the selective IKACh channel blocker tertiapin-Q (TPQ). The results showed that atropine and TPQ significantly increased HR in non-pregnant mice but had a weaker effect in pregnant mice. This finding further supports the reduced function of IKACh in HR regulation during pregnancy.

6. Changes in Heart Rate Variability (HRV)

Finally, researchers analyzed heart rate variability (HRV) and beating rate variability (BRV) in pregnant mice. The results showed that both HRV and BRV were significantly reduced in pregnant mice, indicating a decreased ability to regulate HR. This result is closely related to the reduced function of IKACh, further supporting its important role in HR regulation during pregnancy.

Conclusion and Significance

This study demonstrates that the function and expression of IKACh in the SAN are significantly reduced during pregnancy, which may be one of the key mechanisms underlying the increased HR during pregnancy. The findings not only reveal the critical role of IKACh in HR regulation during pregnancy but also provide a new theoretical basis for the management of pregnancy-related arrhythmias. Additionally, the study found that changes in IKACh function are rapidly reversed after delivery, suggesting that these changes are reversible and may be driven by hormonal changes during pregnancy.

Research Highlights

  1. Key Finding: This is the first systematic study of the role of IKACh in HR regulation during pregnancy, revealing changes in its function and expression.
  2. Scientific Value: Provides new insights into the mechanisms of increased HR during pregnancy, filling a gap in related research fields.
  3. Application Value: Offers potential therapeutic targets for managing pregnancy-related arrhythmias, with significant clinical implications.
  4. Innovative Methods: Combines electrophysiological, molecular biological, and pharmacological techniques to comprehensively elucidate the role of IKACh in HR regulation during pregnancy.

Other Valuable Information

This study also highlights the close relationship between reduced HRV and decreased IKACh function during pregnancy, suggesting that HRV monitoring may become an important indicator for assessing cardiac health during pregnancy. Furthermore, the findings provide a theoretical basis for future development of IKACh-targeted pharmacological treatments, potentially improving the management of pregnancy-related arrhythmias.

Through this research, we have gained a deeper understanding of the mechanisms underlying increased HR during pregnancy and provided new insights for the treatment of related conditions. Future studies on the regulatory mechanisms of IKACh and its interactions with other ion channels will help to further elucidate the complex network of cardiac electrophysiological changes during pregnancy.