Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

In the past, we generated transgenic mice that overexpress the human histamine 2 (H2)-receptor (H2-TG) or that overexpress the human serotonin 4 (5-HT4)-receptor (5-HT4-TG) in the heart. Here, we crossbred these lines of mice to generate double transgenic mice that overexpress both receptors (DT). This was done to study a conceivable interaction between these receptors in the mouse heart as a model for the human heart. When in left atria, initially, force of contraction was elevated maximally with 1 µM serotonin, and subsequently, histamine was cumulatively applied; a biphasic effect of histamine was noted: the force of contraction initially decreased, maximally at 10 nM histamine, and thereafter, the force of contraction increased again at 1 µM histamine. Notably, functional interaction between 5-HT and histamine was also identified in isolated electrically stimulated trabeculae carneae from human right atrium (obtained during cardiac surgery). These functional and biochemical data together are consistent with a joint overexpression of inotropically active H2-receptors and 5-HT4-receptors in the same mouse heart. We also describe an antagonistic interaction on the force of contraction of both receptors in the mouse atrium (DT) and in the human atrial muscle strips. We speculate that via this interaction, histamine might act as a “brake” on the cardiac actions of 5-HT via inhibitory GTP-binding proteins acting on the activity of adenylyl cyclase.

Simultaneous Endo‐Epicardial Mapping of the Human Right Atrium: Unraveling Atrial Excitation

Background The significance of endo‐epicardial asynchrony (EEA) and atrial conduction block (CB), which play an important role in the pathophysiology of atrial fibrillation (AF) during sinus rhythm is poorly understood. The aim of our study was therefore to examine 3‐dimensional activation of the human right atrium (RA). Methods and Results Eighty patients (79% men, 39% history of AF) underwent simultaneous endo‐epicardial sinus rhythm mapping of the inferior, middle and superior RA. Areas of CB were defined as conduction delays of ≥12 ms, EEA as activation time differences of opposite electrodes of ≥15 ms and transmural CB as CB at similar endo‐epicardial sites. CB was more pronounced at the endocardium (all locations P <0.025). Amount, extensiveness and severity of CB was higher at the superior RA. Transmural CB at the inferior RA was associated with a higher incidence of post‐operative AF ( P =0.03). EEA occurred up to 84 ms and was more pronounced at the superior RA (superior: 27 ms [interquartile range, 18.3–39.3], versus mid‐RA: 20.3 ms [interquartile range, 0–29.9], and inferior RA: 0 ms [interquartile range, 0–21], P <0.001). Hypertension ( P =0.009), diabetes mellitus ( P =0.018), and hypercholesterolemia ( P =0.015) were associated with a higher degree of EEA. CB ( P =0.007) and EEA ( P =0.037) were more pronounced in patients with a history of persistent AF compared with patients without AF history. Conclusions This study provides important insights into complex atrial endo‐epicardial excitation. Significant differences in conduction disorders between the endo‐ and epicardium and a significant degree of EEA are already present during sinus rhythm and are more pronounced in patients with cardiovascular risk factors or a history of persistent AF.

P380Simultaneous endo-epicardial mapping of the human right atrium: unravelling 3-dimensional excitation

Funding Acknowledgements Prof. Dr. NMS de Groot is supported by funding grants from CVON-AFFIP (914728), NWO-Vidi (91717339), Biosense Webster USA (ICD 783454) and Medical Del Abstract Introduction & Purpose Mapping studies demonstrated that endo-epicardial asynchrony (EEA) and conduction disorders, mainly longitudinal dissociation, play an important role in the pathophysiology of atrial fibrillation (AF). The aim of our study was therefore to investigate the correlation between features of conduction disorders assessed in the endo- and epicardial plane and the degree of EEA. Methods In 80 patients (63 male (79%), age 66 ± 9 years, 31 history of AF (39%)) undergoing cardiac surgery, simultaneous endo-epicardial mapping (256 electrodes, interelectrode distance:2mm) of the inferior, middle and superior right atrium (RA) was performed during SR. Areas of conduction block (CB) were defined as conduction delays of ≥12ms, EEA as activation time differences of opposite electrodes of ≥15ms and transmural CB as CB at similar endo-epicardial sites. Results Amount of CB was highest at the endocardium (endo median:1.9% [0-21.6] vs. epi median:1.1% [0-19.2], all locations p &lt; 0.025) and was more pronounced at the superior RA. Amount of conduction block at both the endo-epicardium combined was higher at the superior RA in patients with hypertension (p = 0.046). Likewise, prevalence of transmural CB and EEA,-up to 84ms-, significantly increased from inferior to superior RA (all p &lt; 0.001). Transmural CB at the inferior RA appeared to be associated with a higher incidence of post-operative AF (p = 0.03). Degree of EEA was also highest at superior RA (superior: 17.5ms [16-21.75] vs mid: 17ms [0-20] and inferior: 0ms [0-17], p &lt; 0.001). Prevalence of CB was correlated with prevalence EEA (r= 0.74-0.87; all locations p &lt; 0.001). In patients with hypertension (p = 0.009), diabetes (p = 0.015) and hypercholesterolemia (p = 0.015), EEA degree was higher at inferior RA. Significantly more CB (p = 0.007) and EEA (p = 0.037) were observed in patients with a history of persistent AF compared to patients without AF history. Conclusions This study provides important insights into the complex 3-dimensional endo-epicardial excitation and arrhythmogenesis. Knowledge of 3-dimensional excitation during SR is essential to understand the substrate underlying AF in order to improve (ablative) AF therapy.

Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart

Prostacyclins are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostacyclins on right heart function are still not clarified. The aim of this study was to investigate the possible direct inotropic properties of clinical available prostacyclin mimetics in the normal and the pressure-overloaded human right atrium. Trabeculae from the right atrium were collected during surgery from chronic thromboembolic pulmonary hypertension (CTEPH) patients with pressure-overloaded right hearts, undergoing pulmonary thromboendarterectomy (n = 10) and from patients with normal right hearts operated by valve replacement or coronary bypass surgery (n = 9). The trabeculae were placed in an organ bath, continuously paced at 1 Hz. They were subjected to increasing concentrations of iloprost, treprostinil, epoprostenol, or MRE-269, followed by isoprenaline to elicit a reference inotropic response. The force of contraction was measured continuously. The expression of prostanoid receptors was explored through quantitative polymerase chain reaction (qPCR). Iloprost, treprostinil, epoprostenol, or MRE-269 did not alter force of contraction in any of the trabeculae. Isoprenaline showed a direct inotropic response in both trabeculae from the pressure-overloaded right atrium and from the normal right atrium. Control experiments on ventricular trabeculae from the pig failed to show an inotropic response to the prostacyclin mimetics. qPCR demonstrated varying expression of the different prostanoid receptors in the human atrium. In conclusion, prostacyclin mimetics did not increase the force of contraction of human atrial trabeculae from the normal or the pressure-overloaded right heart. These data suggest that prostacyclin mimetics have no direct inotropic effects in the human right atrium.