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.
Pathophysiological mechanism of AF / AT in precapillary PH
Apart from the clear mechanisms of supraventricular tachycardias (i.e. atrio-ventricular nodal reentry tachycardia or atrio-ventricular reentry tachycardia), an arrhythmogenic substrate for complex atrial arrhythmias including AF or AT in PH patients remains unclear. However, there is emerging evidence indicating a right sided substrate for complex atrial arrhythmia: PH leads to an increased afterload of the RV, resulting in RV hypertrophy and dilatation as well as upstream enlargement of the RA . Long-standing PH is frequently associated with decreased conduction and tissue voltage in some cases with regions of “electrical silence” in both the RA and RV . In addition, modulations of the autonomic system may trigger and perpetuate related arrhythmia [16, 17].
The mechanisms of arrhythmia have been suggested as most likely different and more similar to proarrhythmogenic substrate in left heart disease when a post-capillary component is present . In cases of left heart disease, elevated end-diastolic left ventricular pressure is a well-known mechanism leading to LA structural remodeling with proarrhythmogenic effect. Left atrial remodeling, particularly LA dilatation is a well-documented risk factor for the development of AF [18, 19].
Despite the inclusion of only precapillary PH patients, increased LA diameters, LV end-diastolic diameter and higher PAWP in combination with increased RA size and elevated RAP were detected in patients with arrhythmia in our study. In addition the only change in the LA diameter in PLAX was associated with an occurrence of AF / AT in a multivariate analysis, and not with right atrial parameters. We, therefore, speculate that the left atrial substrate plays a role in arrhythmogenesis of more complex atrial tachycardias even in the presence of purely precapillary PH.
One factor possibly explaining the involvement of the left heart in the pathogenesis of AF / AT in PAH patients may be due to the definition of precapillary PH itself. PAH diagnosis is based uniquely on resting invasive pulmonary pressure measurements. In addition, the PAWP limit is set relatively high, above the limits of presumed true physiological values. This may lead to a diagnosis of purely precapillary PAH in a group of patients, in whom pulmonary hypertension is actually a combined one (combined post-capillary and precapillary PH). It has been repeatedly shown [20, 21] that a fluid challenge or exercise can unmask a postcapillary component in a large number of patients. This hypothesis would be supported by the fact, that in our study diabetes and arterial hypertension – frequent risk factors for left heart involvement with diastolic dysfunction - predicted the development of arrhythmias. As suggested by Opitz , these cases represent a borderline category of patients with “atypical idiopathic PAH” in whom left heart involvement remains silent under resting conditions. Finally, in borderline PAWP cases, the measurement method of PAWP may lead to an underestimation (using a digitized mean value) or overestimation (using end-expiratory values) of PAWP . Our data supports the hypothesis of the participation of the truly elevated LA pressure on the development of LA substrate and its arrhythmogenity. The distribution of PAWP had negative skewness and a significant proportion of AT / AF patients contained values close to the threshold limit.
On the other hand, the high burden paroxysmal, persistent or permanent arrhythmia may be a cause of LA remodeling itself [18, 19]. Decreased atrial contraction, atrio-ventricular asynchrony, and a rapid heart rate with a reduction of diastolic filling are potential factors of left atrial remodeling. Moreover, it has been found that AF itself causes electrophysiological changes of the atrial myocardium which explains the progressive character of arrhythmia . Since the LA diameter has not been significantly different according to the type of arrhythmia and is not dependent on time of onset of AT / AF, the impact of pure arrhythmia’s burden to atrial remodeling is not a simple explanation of LA enlargement in our study population. However, aging and external stressors such as arterial hypertension or diabetes, associated in our study with the presence of AF / AT were identified in our data. All those conditions are also well known factors influencing atrial electrophysiological and structural remodeling of the LA, which can be associated with the initiation of AF in the general population [25, 26] and also in the PH population . These facts are well in line with our data and warrant a hypothesis of the existence of some left sided proarrhythmogenic substrate among patients with arrhythmia and precapillary PH.
Incidental findings of reduced bipolar voltages on some electro-anatomical maps of the LA support the hypothesis of the cooperation of both the left and right atrium in the pathogenesis of AF / AT in a given population. LA scarring can be detected by late enhancement magnetic resonance imaging and can be correlated well with reduced electrogram amplitudes as recorded by endocardial voltage maps [27, 28]. Atrial structural remodeling involving atrial fibrosis and scarring is a well-recognized factor in AF pathogenesis.
Comparison of patients with AF and AFL
Our data shows substantial differences between patients with typical right sided arrhythmia i.e. type I AFL and AF in clinical, echocardiographic and hemodynamic variables. Patients with AFL were more likely to be male, demonstrated an enlarged RA and RV, reduced RV systolic function and higher PAMP and RAP values. These cases are probably representing the consequence of true typical IPAH. Structural remodeling of the RA relating to long-standing PH with right ventricular overload and increased RV filling pressures would be prone to provoke reentry arrhythmia in the dilated RA [13, 14, 29]. Our data is in line with this observation, higher levels of RAP in patients with arrhythmia is given by higher RAP values in patient with AFL. After the exclusion of those patient with AFL, RAP is comparable between the rest of the arrhythmia group and patients without any rhythm disorder. We speculate, that the reduction of the 6-min walking test distance in the AFL subgroup is more likely a result from more advanced RA and RV dysfunction.
Prevalence of arrhythmia in precapillary PH
The prevalence of AF / AT in our PH population was higher than in a majority of published reports. Most retrospective and prospective studies have reported a cumulative incidence of supraventricular arrhythmia ranging from 10 to 25% in patients with PAH or inoperable CTEPH [5, 6, 8]. Only one retrospective study showed a similar (29%) cumulative incidence of arrhythmias comparable to our data in a subgroup of patients with PAH . The higher prevalence of arrhythmia in the overall PH groups in our cohort is more likely given to the inclusion criteria and systematic long-lasting follow-ups for patients. According to our protocol, all patients with a detected AF / AT in their entire personal history were taken into account. Thus, our data refers to a cumulative prevalence of cases as a baseline and new case incidences together.
We detected an excessive proportion of CTEPH patients in the arrhythmia group. This prevalence is most likely given, by the high prevalence of type I AFL. An excessive proportion of AFL was detected in the CTEPH subgroup treated with PEA. Two more explanations for the increased prevalence of AFL in that group may be offered. Both advanced RA scarring resulting from RA cannulation or incision and spontaneous RA remodeling might be a plausible explanation for right sided macro-reentrant tachycardia such as AFL.
We must admit several limitations of our study of which the most limiting is its retrospective design. Despite a meticulous and systematic follow-up, some arrhythmias may have been missed. Our data was based on standard electrocardiograms and carefully gathered patient histories. However, due to a lack of other means of rhythm monitoring, it is likely that some self-terminating, clinically silent AF episodes might have been missed. Moreover, our hemodynamic investigation was based on a standard resting right heart catheterization which is unable to detect cases of atypical forms of PAH in whom PCWP may steeply rise during the exertion of a fluid challenge, unmasking the postcapillary component.