Pulmonary hypertension (PH) is a pathophysiological disorder characterized by an elevated pulmonary artery mean pressure (PAMP) ≥ 25 mmHg [1]. Hemodynamic parameters evaluated by a right heart catheterization defined the precapillary PH, isolated postcapillary or combined post- and precapillary PH [1, 2]. Despite advances in the management of patients with PH, most treatment strategies relieve symptoms and functional status while evidence of prognostic improvements and survival is limited [1].

Supraventricular tachycardias has been frequently (range of cumulative incidence 10–25%) observed in patients with idiopathic pulmonary arterial hypertension (PAH) [3], in all types of PH [4‐6], inoperable chronic thromboembolic pulmonary hypertension (CTEPH) [4, 6] or Eisenmenger syndrome [7]. Atrial tachyarrhythmias leads to clinical deterioration and may be associated with an increased risk of death [3, 4, 6, 8]. Out of all types of supraventricular tachycardias in the PH population, atrial fibrillation (AF) and related atrial tachyarrhythmias (AT), including type I atrial flutter (AFL) are the most frequently observed [3‐7].

It is known that there is a relationship between right atrium (RA) enlargement in patients with PH and the increased prevalence of supraventricular arrhythmia [9], however, limited data is available on the arrhythmogenic substrate for complex ATs including AF in patients with precapillary PH. Although some studies in patients with PH or respiratory disease suggested that substrate for AF / AT could be predominantly situated in the RA [10‐13], the role of the arrhythmogenic substrate in the left atrium (LA) and left atrial pressure in patients with precapillary PH is generally unknown.

In order to further evaluate the role of the left and right atrial substrate in the development of AF / AT in patients with precapillary PH, we conducted a retrospective analysis of records focused on left and right cardiac morphology and haemodynamics in patients with precapillary PH and AF / AT.

Consecutive unselected patients, who were diagnosed and treated for PH at a single centre between 2003 and 2017, were enrolled in the retrospective analysis. Patient data was retrieved from a dedicated registry. The study was performed according to good clinical practice and in compliance with the Helsinki declaration. An individual written consent was obtained from each patient. The study was approved by the local Ethics committee.

All patients have undergone a complete routine baseline in-hospital work-up according to contemporary standards [1, 10, 11] including a medical history assessment, concomitant diseases, clinical severity, functional capacity, complete laboratory tests, echocardiography, and other noninvasive and invasive methods. All included patients underwent a right heart catheterization demonstrating PH with a pulmonary artery mean pressure (PAMP) ≥ 25 mmHg. Only patients with precapillary PH with a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg were included in the current analysis. The classification of PH and patient management was done according to current European Society of Cardiology guidelines [2]. Patients with PAH, PH due to lung diseases and/or hypoxia, CTEPH and a group of PH with unclear and/or multifactorial mechanisms were enrolled in the study.

For patients with CTEPH, assessment of operability included perfusion scintigraphy and pulmonary angiography and when eligible, pulmonary endarterectomy (PEA) was indicated.

All patients were regularly seen at 1 to 6 monthly intervals, or whenever clinically indicated, in an outpatient clinic. Standard 12-lead ECG were obtained as part of a regular follow-up program.

Prevalent AF / AT (common, type I AFL included) was defined as the presence of arrhythmia on 12-lead surface ECGs, 24-h ECG monitors and / or during invasive electrophysiology testing and / or as indicated by a diagnosis found in the medical records, hospitalization or ambulatory databases. The diagnosis of AF / AT was confirmed by an experienced cardiologist.

Based on clinical experiences and referred guidelines, rhythm control, i.e. the restoration of the sinus rhythm was usually attempted in all patients with symptomatic or clinically significant tachycardia which was not previously classified as permanent, irrespective of the heart rate and underlying conditions. Patients with previously documented, known paroxysmal or persistent AF or other AT than type I AFL were treated with electrical cardioversion, if the sinus rhythm was not restored spontaneously or after initial antiarrhythmic therapy or in cases of heart failure symptoms. When symptomatic recurrent AF / AT was manifested, a catheter ablation (CA) was scheduled. In cases of type I AFL, the primary strategy was to restore the sinus rhythm with an early CA and whatever seemed appropriate in the given clinical context. Electro-anatomical mapping (CARTO 3, Biosense-Webster Inc., Diamond Bar, CA, USA) was used in several cases when a more complex arrhythmia or arrhythmogenic substrate was predicted. In that case, manual catheter navigation was used for reconstruction of the atrial endocardial surface. Uniformly distributed mapping points were acquired at sites with stable endocardial contact. Special attention was paid to make sure mapping points were not included behind the pulmonary vein ostia. The orifice and proximal part of LA / RA appendage was always mapped. Precise delineation of the mitral annulus was performed in all cases. Intracardiac echocardiography was used to visualize and tag critical structures. 3D dense bipolar voltage maps of the atria were built (> 100 points). Low-voltage regions were defined as bipolar voltage < 0.1 mV. The size of low-voltage areas was rated as a proportion of the surface area with reduced bipolar voltages from the whole atrial surface (mitral and tricuspidal annuli were excluded). Atrial volume was assessed using a built-in computation function of the Biosense system.

A total of 814 patients (aged 59 ± 14 years; 46% males) were analysed. Baseline characteristics of the total population and subgroups are shown in Table 1. Arrhythmia was documented in 225 (28%) of the subjects. Patients with a history of AF / AT were older, had more frequently arterial hypertension, diabetes mellitus and were treated with a specific therapy. Out of all patients with arrhythmia, AF was manifested in 149 (66%) and AT in 76 (34%) subjects, respectively. Type I AFL was diagnosed in 49 patients (64% of all subjects with AT). An excessive prevalence of AF / AT was noticed among patients with CTEPH (AF: 49 (55%), AFL: 28 (31%), other AT: 11 (12%)), and more specifically when patients were treated by PEA (AF: 25 (64%), AFL: 20 (40%), other AT: 6 (12%)).

Patients with a history of AF / AT had significantly larger LA diameters, end-diastolic left ventricular (LV) diameter and RA short diameter estimated with 2D echocardiography. In the same group, the PAWP and RA pressure (RAP) were also elevated as compared to patients without arrhythmias, Table 2 and Fig. 1. In contrast, there was no significant difference in right ventricular (RV) diameters, tricuspid annular plane systolic excursion (TAPSE) and LV ejection fraction when patients with and without AF / AT were compared. For more details see Table 2. When comparing patients who already had existing arrhythmia at the time of the PH diagnosis of PH with those with new-onset of AF / AT during a follow-up, no significant difference in the LA diameter was recognized (46 ± 8 vs. 44 ± 8 mm; p = 0.3). Patients with paroxysmal forms and persistent / permanent forms of arrhythmia had LA diameters without any variance (46 ± 7 vs. 48 ± 8 mm; p = 0.1).

In a multivariate model of the LA diameter in a parasternal long axis projection; age, arterial hypertension, diabetes and type of PH were associated with the occurrence of AF / AT (Table 3).

Out of all patients with arrhythmia, 49 (22%) subjects manifested type I AFL. When compared to patients with type I AFL, subjects with AF or other AT were more frequently female, had more prevalent diabetes, were older, manifested more reduced 6-min walking test distance, lower PAMP values, advanced LA dilatation, smaller RA and RV diameters and better TAPSE. More details are shown in Fig. 2. In addition, patients with AFL manifested higher values of RAP then patients with AF (12 ± 6 vs. 9 ± 5 mmHg; p = 0.01). After excluding AFL patients, the differences in RAP between AF patients and patients without arrhythmia are nonsignificant (9 ± 5 vs. 10 ± 5 mmHg; p = 0.1). The PAWP values were comparable between AFL and AF patients (11 ± 3 vs. 12 ± 3 mmHg, p = 0.15).

Out of 45 patients treated with CA, electro-anatomical mapping was used in 11 (24%) cases. Overall 9 patients (20%) manifested common AFL as a clinical diagnosis. One patient had both AFL and a non-specified AT. One patient manifested AF and a different AT. And 1 patient had AF. In all patients an electro-anatomical map of RA was performed. In three cases left atrial mapping was performed as well. More details are listed in Table 4 and Fig. 3.

The major finding of our study is that in addition to right atrial dilatation, the left atrial substrate is very likely to be involved in the pathogenesis of AF / AT in patients with invasively confirmed isolated precapillary PH. Our data indicates that a different arrhythmogenic mechanism is probably involved in typical right atrial arrhythmia such as type I AFL as compared to AF or other types of AT.

Our study supports the role of the LA substrate in arrhythmogenesis of complex atrial arrhythmias, especially AF, despite the evidence of pure precapillary PH as diagnosed by right heart catheterization at rest. Conversely, our data suggest that the mechanism of type I AFL is more likely dependent on right atrial remodeling. An existence of both left and right atrial substrate was incidentally detected in some cases ablated with use of electro-anatomical mapping.