**5. Discussion**

Recent works have shown that the beat-to-beat analysis of the P-wave can reveal clinically relevant information about the altered atrial conduction preceding the onset of PAF as any signal-averaging approach. Furthermore, the main advantage of the individualized single Pwave analysis is the possibility of being easily used in a routine clinical environment, because it can be developed from daily recordings such as short surface ECGs or long-term Holter signals. Hence, this kind of P-wave analysis could be considered as the most practical way to perform exploratory investigations about the onset of PAF.

It is highly relevant to highlight that in recent years, the analysis of PAC has been improved to reach a clinically significant result. Thus, it has been able to identify the imminent onset of PAF with an accuracy very near to 100%. However, it has also been noticed that the frequency of these ectopics is considerably decreased as the distance to the episode onset increases [53, 52]. Therefore, it could be elucidated that this approach is only feasible just before the ar‐ rhythmia starts [31], which is too late for the application of an efficient prophylactic therapy [72, 73]. In contrast, the analysis of the P-wave variability over time has proven to be able to operate with notably more anticipation in the prediction of PAF onset. Indeed, the time evolution of all the studied P-wave features has revealed an interesting ability to predict successfully the onset of PAF with, at least, one hour in advance.

Moreover, it is worth noting that all the analyzed P-wave features show a time course variation as a function of how far is the onset of PAF. Indeed, all the analyzed features provided an increased variability trend as the PAF onset approximates. This outcome is in strong agreement with the atrial electrophysiological alterations noticed in clinical studies before the onset of spontaneous or induced AF. To this respect, a common atrial alteration in patients prone to PAF is the presence of decreased and different cell refractory periods in various atrial regions. Sometimes, these site-specific conduction delays can be increased by intracellular or intercel‐ lular factors, such as connections, ion channels, or regulatory proteins [9, 74]. This heteroge‐ neity may provoke irregular atrial conduction which could result in overlapped atrial depolarizations or even premature atrial repolarizations [42, 2]. Thus, the way through which the sinus beat travels across the atria may be notably altered by the presence of these delays as well as structural abnormalities in atrial walls (e.g., fibrosis) [9]. Hence, the highly variable and fragmented atrial activation morphology over time could be a result from this sitedependent inhomogeneous and intermittent atrial conduction [39]. Overall, the beat-to-beat analysis to quantify P-wave progression over time seems to be a promising new way to identify the onset of PAF. Furthermore, the study about how this method's performance is maintained in more anticipated predictions has to be validated in future prospective studies. In this way, earlier predictions of the onset of PAF could be reached and patients could benefit from preventive therapies.

Finally, although the single P-wave analysis from short ECGs cannot provide information about the time progression of the atrial electrophysiological alterations preceding the onset of PAF, it can reveal interesting information about the regional differences in atrial activation and conduction [39]. To this respect, previous works have shown that the electrical activity in the surface ECG closely correlates with the conduction in specific parts of the atria [75]. Hence, inhomogeneous atrial conduction can be identified by variations in the P-wave duration between differently oriented surface ECG leads [39]. This information has proven to be widely useful to discern between PAF patients and healthy subjects from the sinus rhythm ECG. This is also an interesting clinical challenge [32] because PAF can sometimes be asymptomatic and not only a single episode may appear during long-time Holter monitoring. Thus, this infor‐ mation could allow the identification of patients with PAF without the need of long-term recordings and they may be early treated, thus minimizing the atrial remodeling and reducing the probability of arrhythmia perpetuation.
