Degenerative aortic stenosis represents the leading native valve pathology in developed countries [1, 2]. Aortic valve degeneration is independently associated with same cardiovascular risk factors as coronary artery disease [3], showing us it is not only influenced by aging but also by an atherosclerotic-like processes including dynamic inflammation, lipid accumulation and calcification [4]. In the vasculature, all these structural alterations are preceded by endothelial dysfunction, a process of impaired vessel nitric oxide (NO) mediated regulation, present also in early stages of aortic stenosis [5]. Furthermore, it has recently been shown that atherosclerosis is associated with autonomic dysfunction [6], an imbalance between sympathetic and parasympathetic activity resulting in sympathetic predominance modulating heart rate response, cardiac contractility and vascular function [7]. It is influenced by intrinsic or extrinsic factors. Intrinsic factors are diseases that directly affect the autonomic nerves, such as diabetes mellitus and other neurological syndromes of primary autonomic failure. Extrinsic factors reflect changes that result as a consequence of cardiac diseases (e.g., myocardial infarction, heart failure, structural heart disease) [8]. The resulting sympathetic predominance generates a rise in catecholamines and inflammation cytokines that in turn, lead to worsening of heart failure, atherosclerosis, left ventricular hyperthrophy and increased risk of malignant arrhythmias [6, 8, 9]. Such sympathetic activity alterations have already been described in patients with degenerative aortic stenosis and connected with cardiovascular events and mortality [10, 11, 12, 13, 14].

In the last decade transcatheter aortic valve implantation (TAVI) became the treatment of choice for elderly patients at high surgical risk presenting with severe symptomatic aortic stenosis [15]. Previous studies have already demonstrated a significant improvement of endothelial function measured by flow mediated dilatation (FMD) at early and late follow-up after TAVI [16, 17, 18]. Conversely, studies on surgical valve treatment have yielded conflicting results suggesting a possible negative effect on endothelial function and subsequent early in-hospital recovery [18, 19, 20]. TAVI has also shown to have a lesser impact on autonomic function parameters measured by heart rate variability (HRV) in comparison to patients after surgical aortic valve replacement [21, 22]. Interestingly, its effects on long-term follow-up are still unknown. We hypothesized that improvement in hemodynamic proprieties after TAVI will have a positive effect on endothelial function which will be paralleled by improved autonomic parameters.

This prospective, single-center study carried out at the national TAVI referral University Medical Centre (UMC) Ljubljana, Slovenia, screened 50 consecutive patients eligible for TAVI between July 2019 and January 2020. Exclusion criteria were as follows: unstable cardiovascular disease or recent (3 months prior to inclusion) cardiovascular events, acute illness or recent (3 months prior to inclusion) non-cardiovascular disease requiring hospitalization, hemodynamic instability, stage 5 chronic kidney disease and active malignancy. The study was approved by the National Ethics Committee (reference number: 0120-215//2019/4) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants sign an informed consent form prior to their inclusion. The study is registered in ClinicalTrial.gov (NCT04286893).

After including 50 consecutive patients in the study, one was excluded due to acute illness, one had an unsuccessful TAVI procedure, one patient died and 4 (8%) were lost to follow-up due to COVID-19 restrictions accounting for a totaled drop-out rate of 15%. Mean age of 43 participants who completed the study was 81 (75–85), 26 (60%) were women (Table 1). All patients included in the study analysis had a successful TAVI implantation with CoreValve Evolut R or PRO (Medtronic, Minneapolis, USA) being the mostly implanted valves in 23 (53%) patients. One patient had a transaortic and one a valve-in-valve implantation. 6 (14%) patients received a pace-maker after TAVI. Aortic valve maximal velocity and mean gradient decreased from 4.3 $\pm$ 0.7 to 1.9 $\pm$ 0.4 m/s and from 45 $\pm$ 14 to 8 $\pm$ 4 mmHg respectively (p 0.001). We also observed a significant reduction in non-invasively measured systolic pulmonary arterial pressure from 51 $\pm$ 14 to 43 $\pm$ 14 mmHg (p = 0.002).

FMD measurements improved significantly from 2.8 $\pm$ 1.5% before TAVI to 4.7 $\pm$ 2.7% early after TAVI (p 0.001) and were later maintained on late 3–6 months follow-up with a FMD of 4.8 $\pm$ 2.7% (p = 0.936 when comparing with early follow-up results) (Table 2, Fig. 1). FMD differed significantly between time points (F (1.626, 63.418) = 9.063, p 0.001). Measurements increased from baseline to early follow-up (–1.88 (95% CI, –3.01 to –0.75) %, p 0.001), and from baseline to late follow-up (–2.0 (95% CI, –3.18 to –0.83) %, p 0.001), but not from early to late follow-up (–0.12 (95% CI, –1.73 to 1.48) %, p = 1.0).

Fig. 1.

Changes of mean FMD (%) on different follow-up times after TAVI. FMD, flow mediated dilatation; TAVI, transcatheter aortic valve implantation.

When looking for predictors of change in FMD we found significant correlation with echocardiographic parameters comprising baseline maximal aortic valve velocity (R = 0.415; p = 0.011), mean aortic gradient (R = 0.373; p = 0.018), indexed stroke volume (R = 0.503; p = 0.006), change in aortic valve maximal velocity (R = 0.365; p = 0.031) and change in mean aortic gradient (R = 0.394; p = 0.019). Furthermore, NT-proBNP levels before TAVI were also a significant predictor of change in FMD (R = 0.491; p = 0.001). Multiple linear regression modelling identified that younger age (B = –0.101, 95% CI: –0.198 to –0,004; p = 0.043) and lower baseline mean aortic gradient (B = –0.07, 95% CI: –0.135 to –0.005; p = 0.035) were associated with higher change in FMD.

Autonomic cardiac functions measured by high-resolution ECG remained preserved at early and improved at late follow-up (3–6 months after TAVI). Significant improvement was detected in a high frequency-domain parameter-HF-representing parasympathetic activity (from 5231 $\pm$ 1783 to 6507 $\pm$ 1789 ms${}^2$; p = 0.029) and in two Poincare plot parameters: SD1/SD2 (from 0.682 to 0.884 ms${}^2$; p = 0.003) and SDRR (from 9.6 to 23.9 ms; p = 0.001). Two time-domain HRV parameters reached borderline significance: Mean RR increased from 860 to 1002 ms (p = 0.064) and rMSSD from 50.8 to 114.8 ms (p = 0.087) (Table 2, Fig. 2).

Fig. 2.

Changes of HRV parameters on different follow-up times after TAVI (p values comparing baseline and late follow-up are shown). (A) Mean RR = mean of all normal R-R intervals. (B) rMSSD = root mean square of successive R-R interval differences. (C) HF = high frequency power (parasympathetic activity). (D) SD1/SD2 = ratio of the short- and long-term R-R variability in the Poincare plot. (E) SDRR = short-term R-R variability in the Poincare plot. HRV, heart rate variability; TAVI, transcatheter aortic valve implantation.

TAVI was also associated with significant decrease in hemoglobin levels after implantation from 126 $\pm$ 18 to 115 $\pm$ 18 mg/L (p 0.001) with two reported serious bleeding events (one tamponade and one femoral access site bleeding). Changes in other laboratory results–including NT-proBNP, cholesterol levels, and liver and kidney function–were not statistically significant.

Our study showed that endothelial function (measured with FMD) and autonomic function (obtained with high-resolution ECG-derived HRV parameters) significantly improved after TAVI. Improvement in vascular function was evident early after TAVI and remained relatively unchanged at late follow-up; conversely, selected indicators of autonomic function did not change immediately after TAVI, but increased only later on.

To the best of our knowledge, this is the first study investigating both endothelial and autonomic function after TAVI, at different time-points in the course of disease management. In patients undergoing TAVI, significant concomitant coronary artery disease can be found in up to 75% of cases [26]. Additionally, patients with degenerative aortic stenosis exhibit an atherosclerosis-like process paralleled by increased wall shear stress due to turbulent blood flow [5, 27, 28]. Laminar wall shear stress promotes endothelial cells survival and acts as a major determinant of endothelial apoptosis [29]. This activates a systemic adaptive mechanism with increased NO production and subsequent vasodilatation. The resulting basal hyperemic state impedes further vascular upregulation to stimuli, resulting in depleted NO reserves and impaired FMD [30]. This suggests that, after the resolution of aortic valve stenosis by non-invasive means of TAVI, wall shear stress rapidly decreases leading to reduced resting NO release and greater brachial vasodilatory response during FMD testing. Both FMD and cardiac autonomic function have been validated as predictors of prognosis in diverse populations, such as apparently healthy individuals, individuals with cardiovascular risk factors, patients with coronary artery disease and heart failure [31, 32, 33, 34, 35]. Our findings have shown these surrogate prognostic parameters improve in patients after TAVI, suggesting a systemic improvement in cardiovascular health not limited to the aortic valve intervention.

The early detected improvement in endothelial function could be explained by amelioration of hemodynamic proprieties immediately after TAVI. Post-TAVI hemodynamic recovery is characterized by an increase in ejection fraction and decrease in blood turbulence and wall shear stress [17, 36]. In our study, echocardiography-derived parameters of aortic stenosis hemodynamic severity (maximal aortic valve velocity, mean aortic gradient, change in aortic valve velocity and change in mean aortic gradient) emerged as significant predictors of FMD recovery immediately after TAVI. In addition, NT-proBNP levels before TAVI—i.e., a marker of increased ventricular wall stress from volume and pressure overload [37]—were also identified as an important predictor of FMD change. Interestingly, conventional cardiovascular risk factors (i.e., arterial hypertension, diabetes and hyperlipidemia) and coronary artery disease, otherwise associated with impaired endothelial function [38, 39, 40, 41], did not emerge as significant predictors of change in our patient population. Multiple regression modelling additionally identified that younger age and lower baseline mean aortic gradient result in higher change in FMD, suggesting treatment of severe aortic stenosis should be performed as early as possible when indications are fulfilled.

Previous studies have shown that different types of aortic valve interventions influence FMD differently. FMD seems to improve early after TAVI but transiently decrease after cardiac surgery [19, 20, 42], a characteristic most probably attributed to use of cardio-pulmonary bypass and its impact on systemic inflammation [42]. The latter translates into a vascular injury process caused by decreased NO bioavailability and hemolysis [43]. In contrast, transcatheter intervention seems to provide a quick and non-invasive approach to aortic valve physiological restitution and subsequent rapid patient recovery without affecting endothelial function.

HRV is a widely-used, non-invasive, indirect method for measuring cardiovascular autonomic regulation. Decreased HRV is linked to increased cardiovascular risk and mortality [44, 45]. Patients with degenerative aortic stenosis have a known sympatho-vagal imbalance with reduced HRV, potentially resulting in fatal arrhythmic complications [10, 12]. While surgery has been shown to further depress HRV on early follow-up, it remains stable after TAVI [21, 22]. The underlying mechanism has been mostly attributed to its non-invasive approach that avoids surgical heart manipulation, general anaesthesia and cardioplegia, direct surgical nerve damage during aortic clamping and incision, pain and potential surgical complications [21]. Our results support this finding with no significant change detected in both time and frequency-domain HRV parameters on early follow-up. However, in our study a potential early improvement in autonomic functions might have been counterbalanced by a significant 9% post-procedure reduction in hemoglobin levels. In fact, previous reports have demonstrated an association between anemia and decreased HRV in patients with coronary artery disease [46]. Importantly, we also observed a significant improvement in selected HRV parameters at late (3–6 months) follow-up. As cardiac hypertrophy of various etiologies including aortic stenosis has a known negative effect on HRV parameters [47], this delayed change might be attributable to gradual regression of left ventricular mass and left ventricular reversed remodeling after TAVI [48, 49]. The letter has already been described in a pilot study where morphological and functional changes where followed with advanced ECG-derived parameters [50].

In our study, both FMD and autonomic function parameters improved, albeit at different time points. On the one hand, vascular function seems to be more influenced by immediate (hemodynamic) effects of TAVI, while autonomic function may be more related to long-term effects, such as myocardial reverse remodeling. On the other hand, vascular and autonomic function can both be affected by a common underlying pathophysiology, such as chronic low-level inflammation [6, 51]. As such, the demonstrated paralleled improvement in FMD and HRV parameters might indicate that patients after TAVI experience a significant reduction in underlying patophysiologies, such as systemic inflammation and atherosclerosis progression. This gives us some more understanding into the demonstrated effectiveness of TAVI in elderly patients at high surgical risk [52, 53]. With the forthcoming advancement of TAVI indications to intermediate and low surgical risk groups more studies are needed to demonstrate its potential benefits in this study populations.

We have found some limitations in our study. First, this is a single-center observational pilot study and is therefore subject to its inherent methodological design, including unforeseen co-founders. Although UMC Ljubljana is the national reference center for TAVI patients and this population might be regarded as representative, larger multi-center international trials are needed to confirm our findings. Second, sample size is relatively small but powered enough to detect significant changes and comparable with previous studies observing FMD and HRV changes in patients with degenerative aortic stenosis [16, 17, 21, 22]. Third, FMD is an operator dependent ultrasound measurement technique with a great possibility of deviation in case of unexperienced personnel. Fourth, as the majority of this otherwise representative TAVI patient’s population were women and were treated with antihypertensive drugs this could have prevented a correct, independent analysis of autonomic functions in this study population. All data were collected by the same experienced operator in a center with extensive experience in performing FMD measurements [54, 55, 56].

Our data shows that endothelial and autonomic functions improve after TAVI. While endothelial function improves early and is maintained later after TAVI, autonomic function remains stable and improves on late follow-up. This is most likely caused by hemodynamic changes after resolution of aortic valve obstruction and gradual left ventricular remodeling. The overall improvement suggests a potential decrease in cardiovascular risk after TAVI in this study population. Our data needs to be interpreted with caution as it has been done on a relatively small sample.

The data presented in this study are available on request from the corresponding author.

All authors have read and agreed to the published version of the manuscript. LV contributed to drafting the work, acquisition, analysis, and interpretation of the data for the work, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. VS substantially contributed to the conception, critical revision and analysis of the work. MB performed all TAVI implantations. BJ and MB substentialy contributed to the study conception and design, drafting the manuscript, revising it critically for important intellectual content, and provided approval for the final manuscript.

The study was approved by the National Ethics Committee (reference number: 0120-215//2019/4) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants sign an informed consent form prior to their inclusion. The study is registered in ClinicalTrial.gov (NCT04286893).

We would like to thank all the participants in the study. We specially thank all nurses and administrators from the Centre of Preventive Cardiology, Department of Vascular Diseases for generously helping us in this research.

This research received no external funding.

The authors declare no conflict of interest.