Bicuspid Aortic Valve and Premature Ventricular Beats in Athletes

Background: The aim of this study was to identify a possible link between bicuspid aortic valve (BAV) and premature ventricular beats (PVBs), particularly from left and right ventricular outflow tracts, and to investigate possible associations between these arrhythmias and echocardiographic abnormalities. Methods: A comparison of sportspeople with and without BAV was performed to identify PVBs’ occurrence in these two series. Then, subdividing the BAV group on the presence of cardiovascular complications due to BAV, we compared arrhythmic features between these two subgroups and echocardiographic findings between athletes with and without left and right outflow tract PVBs. Results: PVBs in 343 athletes with BAV were compared with 309 athletes without BAV, showing an increased frequency (29% vs. 11.8%, p < 0.001; OR 3.1; CI 2.1–4.7) and origin from the left (18.4% vs. 3.2%, p < 0.001, OR 6.7; CI 3.4–13.4) and right (15.2% vs. 3.6%, p < 0.001, OR 4.8; CI 2.5–9.5) outflow tracts compared to other ventricular areas (fascicular PVBs p = 0.81, other morphologies p = 0.58). No difference in PVBs’ occurrence was found between near normal valve BAV and pathological BAV, nor was a difference in echocardiographic characteristics found between patients with and without outflow tract arrhythmias. Conclusions: A possible causal link between BAV and PVBs was highlighted, but no association between PVBs and complicated BAV was emphasized.

Even though the pathogenetical basis of BAV remains to be fully elucidated, most evidence supports the current interpretation of BAV as a multifactorial disease, in which both genetic and hemodynamic factors seem to play a key role in explaining the heterogeneity of phenotypes and natural history [12].
Some authors have hypothesized a role for neural crest (NC) cells in the pathogenesis of BAV. In fact, from an embryological point of view, the neural crest (NC) plays an important role in the development of cardiac structures, in particular the outflow tract and the aortic arch [13,14], and also the conduction system [15,16]: several studies have demonstrated the presence of smooth muscular cells (SMCs) in these structures that derive from the NC, whereas the SMCs in the descending aorta derive from the paraxial mesoderm [17].

BAV and Sports
Assessing the eligibility for competitive and/or professional sports of athletes with BAV can be challenging. In fact, all possible co-pathologies and complications must be researched and "weighed" in the overall assessment, also considering that the impact of regular training on the natural course of BAV is not fully established [18,19]. For this reason, current guidelines aim to highlight any structural and/or functional cardiac alterations in athletes with BAV, which may lead to disqualification from practising sport [19].
One of the less investigated aspects is the link between BAV, sport activity and the incidence of premature ventricular beats (PVBs), especially those originating from the left and right ventricular outflow tracts [20].
PVBs are a common ECG finding in the general population and are recorded in up to 75% of healthy individuals undergoing 24-h ambulatory ECG monitoring, with an age-related increase in prevalence [21,22] but no clear relationship with the degree of training [23,24].
Under the hypothesis that BAV is a malformation linked to an anomalous migration of the neural crest cells, which are involved in in the development of the outflow tracts, we sought to test the hypothesis that there is a correlation between this anomaly and arrhythmias originating from these cardiac areas, and that these arrhythmias are not related to a worsening of the patient's overall clinical profile. For this reason, we tried to assess whether BAV is linked to PVBs from the left and right outflow tracts, and that these arrhythmias are not related to the morphological and functional status of the aortic valve, aortic root and left ventricle.

Materials and Methods
We retrospectively analysed the database of Sport Medicine Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, between 1987 and 2020, in order to extract the records of sportspeople (competitive and non-competitive) with BAV (BAV), discovered incidentally during pre-participation screening or who came to our centre for counselling after diagnosis. We compared these subjects with a group of athletes without BAV, matched for age and sex (NOT-BAV). We defined competitive athletes according to the 16th Bethesda conference, which defines a "competitive athlete" as an individual who participates in an organized team or in a sport that requires regular competition against others, places a high premium on excellence and achievement and requires some form of systematic and intense training [25]. Furthermore, "non-competitive athletes" refers to individuals engaged in recreational or leisure-time sports activities, either on a regular basis or intermittently [26].
The inclusion criteria were: 1. Practicing sports on a non-competitive, competitive or professional level. 2. Having undergone a 12-lead resting electrocardiogram (ECG), stress-test ECG and 2-dimensional trans-thoracic echocardiography (ECHO). 3. No cardiovascular symptoms, known cardiovascular disease (other than BAV) and ECG abnormalities except for the possible presence of PVBs. 4. As for the control group, no ECHO evidence of cardiovascular anomalies, i.e., normal chamber size; normal volume and wall thickness; normal left ventricular systolic and diastolic function; absence of intracardiac shunts; normal valvular function and morphology; absence of pericardial effusion; normal size of ascending aorta and arch with normal flow velocities. 5. No history of cardiac surgery.
In both the BAV and the NOT-BAV group, we took into account any athlete who showed at least one PVB during ECG or stress-test ECG. We classified ventricular arrhythmias, based on current criteria [27], as follows: Stress-test ECG was performed using a cycle ergometer and incremental protocol of 30 watt/2 min until muscle exhaustion or the criteria defined by international guidelines for discontinuation were reached [28], with continuous monitoring of ECG during effort phase and for 10 min during recovery. Firstly, we compared the occurrence of PVBs, in particular PVBs with outflow tracts' pattern between sportsmen with and without BAV. Secondly, by subdividing the population with BAV into "near normal valve" (NNV) [29] (without any possible cardiovascular complications related to BAV, i.e., no significant aortic stenosis, no more than trivial regurgitation, normal aortic dimensions and no associated cardiovascular anomalies such as aortic coarctation or mitral valve prolapse) and "pathological BAV" (PBAV), which includes all other cases, we sought to highlight whether there were any differences in ventricular arrhythmias between these two series.
Finally, we tested the hypothesis that BAV athletes with PVBs from left and right outflow tracts had no worse echocardiographic status than athletes without this sort of ventricular arrhythmias.

Statistical Analysis
The normal distribution of all continuous variables was examined using the Shapiro-Wilk test, and data are presented as mean ± SD or median (IQR) accordingly. Categorical variables were reported as absolute numbers and percentages.
Comparisons were performed using chi-squared or Fisher exact tests in case of categorical variables, whereas Mann-Whitney U-test was used to check differences in case of continuous variables.
Differences were considered significant with a p < 0.05. Statistical analysis was carried out with SPSS 26.0.
Among the BAV, 24 subjects out of 343 (7.0%) had complex PVBs, whereas in the NOT-BAV they were present in 4 cases out of 309 (1.2%, p < 0.001; OR 5.7, CI 2.0-16.7); these complex PVBs in the BAV group were monomorphic in all cases, and they arose from outflow tracts in most of the cases (20 out of 24, 83%).
Within the group with BAV, the echocardiography allowed the participants to be classified into two groups (NNV and PBAV). According to this subdivision, the NNV group consisted of 99 people, while the PBAV numbered 244. When comparing the arrhythmias (morphology, complexity, number of morphologies, relationship with exertion) between these two series, no difference was noted; specifically, there was no different occurrence of PVBs from LVOT and/or RVOT between the two series (Table 3). To confirm the absence of a relationship between the occurrence of ventricular outflow tract arrhythmias and echocardiographic abnormalities, we finally tried to compare the echocardiographic parameters between people with and without these type of PVBs (Table 4): our analysis did not point out a worse echocardiographic status for athletes with PVBs from outflow tracts.

Discussion
Bicuspid aortic valve (BAV) is a congenital valvular heart disease with a natural history that sometimes evolves into complications (e.g., aortic dilatation, valvular stenosis or regurgitation and, rarely, aortic dissection); hence, the focus of follow-up is on echocardiography in order to identify cases that should be addressed by surgical correction [19,30]. As intense sport practice has a deep impact on both cardiovascular morphology and haemodynamics, its role in the development of BAV complications still needs to be fully elucidated [18,19]. Ventricular arrhythmias are often signs of haemodynamic deterioration and can be the cause of major events such as sudden cardiac death, the main concern of sport cardiologists [24]. At the same time, the occurrence of ventricular arrhythmias is very common in sportspeople, and represents one of the most important reasons to perform further investigations in order to properly stratify individual risk [31]. Whether BAV may have an impact on the occurrence of PVBs in athletes is an aspect that has been poorly studied: only one study to date has considered the possible clinical implications of the presence of ventricular arrhythmias in BAV, but a greater frequency of PVBs was not found in the population of athletes with BAV than in a healthy control group [20].
Our study, for the first time, showed an increased frequency of ventricular arrhythmias both at rest and during exercise in a group of sportspeople with BAV in comparison to a control group with normal hearts. As expected, the level of sports practice (competitive or non-competitive) does not seem to affect the occurrence of PVBs.
Moreover, these arrhythmias seem to originate mainly from the right and left outflow tracts, which embryologically derive from neural crest cells, the same cells that originate the cardiac conduction system: in fact, no difference in the occurrence of PVBs between the two groups was found for PVBs with fascicular morphology or with morphologies other than LVOT or RVOT. According to recent work by Corrado et al., PVBs from outflow tracts are defined as having a "common" morphology, as they are often found in athletes, typically in association with normal cardiac morphology and function and generally without an increased risk of sport-related sudden cardiac death [29]. Therefore, finding an association between BAV and ventricular arrhythmias and stratifying the risk of PVBs is extremely important when assessing athletes with this condition. From this point of view, we investigated the relationship between arrhythmias and echocardiographic characteristics of patients, firstly by subdividing the population on the basis of the development of typical complications of BAV. In doing so, we noticed that there is no difference in the frequency and morphology of and the relationship with exertion for PVBs between athletes with a NNV BAV and those with a PBAV. According to these data, it is reasonable to assume that, as a general rule, the detection of PVBs in athletes with a BAV is not typically associated with a worse echocardiographic status. A possible practical consequence of this finding is that the detection of ventricular arrhythmias in an athlete with BAV is unlikely to suggest a worse valve condition in the first instance. Moreover, as most PVBs in athletes with BAV appear to arise from both outflow tracts, the absence of a difference in echocardiographic parameters in athletes with BAV between people with and without outflow tract arrhythmias reinforces the idea that PVBs from outflow tracts are a typical feature of BAV, not having a relationship with the individual's cardiovascular status and, generally speaking, not increasing the risk of adverse events. Following this interpretation, we are prone to consider an increased presence of automatic foci in the outflow tract, linked to abnormal migration of the neural crest cells in the BAV [14], as more likely than the possible development of re-entry circuits due to disease-related haemodynamic factors [12] as an explanation for the increased presence of outflow tract PVB in athletes with BAV.
In light of our results, we believe that the identification of outflow tract arrhythmias should also be considered a "common" finding in BAV, which should prompt careful evaluation, but which could be considered "favourable", until proven otherwise, as in apparently "healthy" athletes.
In this regard, we would like to recall that, nowadays, the Italian guidelines on competitive sport eligibility recommend an ECHO, a stress-test ECG and a 24-h Holter ECG, possibly including a training session to evaluate competitive athletes with BAV [32], while other international guidelines on the same topic (European Society of Cardiology [19], American Heart Association [33]) suggest additional examinations beyond the ECHO only in the presence of aortic dilatation.

Study Limitations
Firstly, as our population consisted exclusively of athletes with BAV, our considerations are limited to them and cannot be generalised (in particular to people with advanced clinical status and potential indication for surgical correction).
Our series does not allow us to provide indications on the role of PVBs on the natural history of bicuspid aortic valve, as we have not carried out follow-up analysis (which are in progress): thus, we limited ourselves to highlighting the possible clinical implications of the observed relationship between BAV and PVBs.
Furthermore, we do not have any further data on 24-h ambulatory ECG monitoring, which could add different information about PVBs (i.e., frequency over 24 h) and on other diagnostic examinations, in particular imaging studies (i.e., Cardiac Magnetic Resonance and Contrast-enhanced Coronary Computed Tomography Angiography), electrophysio-logical studies and/or genetic screening, which could allow us to evaluate the presence of any kind of pathological issue.
Lastly, we are also aware of the possibility of the misinterpretation of PVBs' morphology, commonly due to the variable spread of excitation through the ventricle (in particular in patients with coronary artery disease), the presence of different degrees of fusion with the subsequent sinus complex and additional aberrant conduction secondary to the short RR interval in the second beat of a couplet [34].

Conclusions
BAV is very common in the general population, with a possible risk of serious complications. To date, there is no certainty that intensive sports practice does not increase the risk of these complications in the long term. Therefore, competitive sports practice for athletes with BAV requires extensive evaluation and proper follow-up over time. The relationship between PVBs and BAV has been scarcely explored in recent years. Our series demonstrated that PVBs are more frequent in athletes with BAV than in the general population and that they mainly originate from the left ventricular and right ventricular outflow tracts. Moreover, no difference was found in the occurrence of PVBs between people with near normal and pathological BAV. Lastly, echocardiographic findings were similar by dividing the BAV group into people with and without outflow tract arrhythmias. Our study, for the first time, highlights a possible causal link between BAV and PVBs from the outflow tracts and points out no association between the presence of PVBs and complicated BAV.