DISCUSSION
The main finding of this study is that NLR, a marker of inflammation, is significantly associated with PPI in patients undergoing TAVR procedure, but only in those without previous CAs. Multivariable analysis showed that only NLR at TAVR day analysis (within two hours after the procedure) was significant, avoiding than any predictive strength to this variable.
TAVR is an established alternative to surgical valve replacement for high and low surgical risk patients with severe AS but is associated to an increased risk of high-grade AVB requiring PPI (4). The incidence of PPI has been reported as 6.6% to 34.8% depending on the use of balloon expandable or self-expandable valves (5) (6) (7).
Several aspects affecting the occurrence of PPI have been identified, some of which depend on the procedure itself and can be prevented, such as depth of valve implantation (13) and use of self-expandable bioprosthetic valves. Other risk factors for post-TAVR PPI, such as age, systemic arterial hypertension, type 2 diabetes mellitus, history of myocardial infarction, are non-preventable. Pre-existing CAs, including RBBB and LBBB, have been reported as the most powerful predictors for PPI. Our study confirmed this finding.
There is an established relationship between inflammation and calcific aortic valve disease (14). Nevertheless, the identification of a biochemical marker of disease progression has not been achieved, so far. CRP is considered a reliable marker of systemic inflammation and while it has been significantly associated with progression of atherosclerosis (15), its role in the progression of calcific AS is still debated. Indeed, data from the Cardiovascular Health Study (16) showed a poor predictive value of CRP on progression of subclinical calcific aortic valve disease. On the other hand, in 135 patients with asymptomatic AS, CRP levels were found to be significantly associated with disease severity, progression, and prognosis (17). More recently, in TAVR candidates with severe AS, high sensitivity CRP at baseline predicted post-TAVR mortality and its variation at 3 months follow-up was associated to increased mortality, thus confirming its predictive power (18).
In our population CRP levels were not associated with severity of aortic disease (data not shown). Furthermore, in between groups analysis no significant differences in CRP between subjects receiving and not receiving PPI.
NLR has been proposed as inflammatory marker in several cardiovascular diseases (9). In AS it showed significant correlation with calcific AS severity, LV disfunction (10), and MACE (11). In our population, neutrophil and lymphocyte count and their ratio (NLR) were assessed at different timepoints across the TAVR procedure. NLR at TAVR day was significantly higher in patients underwent PPI and, at multivariate analysis, was predictive of PPI together with implantation depth, first degree AVB and first degree AVB plus RBBB/LBBB. However, this finding was driven only by patients without previous CAs, where we observed significantly higher NLR values at implantation day in patients receiving PPI.
While the role of inflammation in the progression of AS is well established (8), we found that the behavior of components of the innate immune response may represent a readout of TAVR-related CAs. The analysis at different timepoints across the TAVR procedure of neutrophils and lymphocytes count and their ratio provided a hint on the innate immune state both in the setting of chronic inflammation before the intervention and following an acute injury represented by the TAVR procedure. It has been reported that early after acute ischemic injury, neutrophils are the first recruited inflammatory cell population (19). Our report highlights a possible relationship between the acute-over-chronic inflammatory response to the TAVR-induced injury and the need of PPI. During TAVR procedure, anatomic factors such as membranous septum length (13) and the severity or distribution of left coronary cusp leaflet calcification can play an important role in prediction of PPI which can be enhanced by an increased inflammatory status, the extent of which might affect the need of PPI.
NLR at TAVR day is related to higher PPI, but after the procedure. ROC curve analysis provided a cut point where the possibility of PPI is more likely to happen. As we observe the variable, but cannot prevent it, the association of no pre-procedural CAs and post-procedural NLR>7.25 advices to prolong the observation of such patients, who can need PPI even after many days from the procedure, for at least 21 days.