The association of aortic valve stenosis (AS) and gastrointestinal bleeding (GIB) from angiodysplasia is known as Heyde syndrome (HS) [1]. The prevalence of GIB related to HS has been described as 1 to 3 percent of patients with aortic stenosis [2‐5].

The prevalence, pathogenesis and treatment options of HS remain controversial. The development of angiodysplasia has been associated with mucosal ischemia leading to vessel dilatation and formation of coral-formed vessels throughout the GI tract with highest prevalence in the right colon and cecum [6]. The pathogenesis of HS involves hemostaseologic alterations leading to an acquired von Willebrand syndrome (aVWS). High shear stress caused by severe aortic stenosis leads to a decreased content of the high-molecular-weight multimers (HMWM) and decreased collagen-binding activity of VWF [7‐9]. The combination of both factors, vascular malformations, i.e. angiodysplasia, and hemostaseologic alterations due to AS, result in a higher bleeding risk in these patients [10].

Surgical or transcatheter implantation of an aortic valve prosthesis is commonly performed for the treatment of severe AS. A resolution of GIB from angiodysplasia in patients with HS by surgical aortic valve replacement (SAVR) in the majority of patients has been previously reported [11, 12]. Since transcatheter aortic valve implantation (TAVI) has become the preferred treatment in the majority of patients with severe AS, it remains to be determined whether TAVI would likewise resolve recurrent GIB in patients with HS. First reports suggested a resolution of bleeding but these assumptions were drawn from small analyses including only few Heyde patients or case reports and evidence overall remains scarce [3, 4, 8, 13‐16].

Thus, we aimed to evaluate the prevalence of HS in a real-life cohort of patients undergoing TAVI, to identify variables associated with bleeding events in HS and to analyze the incidence of recurrent GIB during post-TAVI follow-up in these patients.

In the present study we assessed the prevalence of HS in a real-life cohort of patients with severe AS undergoing TAVI and evaluated bleeding complications and GIB during follow-up.

Three key findings can be drawn from this retrospective single-center analysis: First, HS was prevalent in a relevant number of TAVI patients (1.8%) which was in line with previously published data from smaller observational analyses [2‐5]. To date, the present study is the largest cohort of TAVI patients evaluating the prevalence of HS. Second, during a follow-up period of 12 months after TAVI the recurrence of GIB in Heyde patients was significant (39.8%) and higher compared to patients with GIB unrelated to angiodysplasia. Third, patients with HS and recurrent GIB during follow-up had more residual paravalvular regurgitation compared to Heyde patients with an unremarkable course.

Previous studies reported a resolution of GIB from angiodysplasia after SAVR in the majority of Heyde patients, although systematic evidence was lacking [11, 12, 19‐22]. Hemostaseologic findings with a correction of the HMWM content after SAVR suggested a “surgical cure” of HS [9, 23]. Within the past decade, TAVI has become the preferred treatment option for AS in most patients [24, 25]. A normalization of hemostasis parameters including vWF was reported after TAVI, especially in those with pre-existing aVWS [4, 8]. Few small studies and case series reported no recurrence of GIB in patients with HS after TAVI, albeit limited due to short-term follow-up and small patient numbers [3, 4, 8, 13‐15]. In contrast to these earlier publications, we observed that a substantial number of Heyde patients suffered from recurrent GIB after TAVI already during 1-year follow-up despite adequate treatment of AS.

An association of paravalvular leakage (PVL), late bleeding complications and impaired survival was demonstrated before. An analysis from the PARTNER (Placement of Aortic Transcatheter Trial) trial found late bleeding events, mainly GIB, in a relevant number of patients (5.9%) after TAVI, which were associated with a fourfold increase in late mortality (26). Interestingly, PVL was the strongest predictor of these bleeding events between 30 days and 1 year after TAVI [26]. Moreover, mild to moderate PVL was discovered in patients without recovery of abnormal multimer levels, emphasizing the effect of persistent shear stress as cause of HMWM deficiency [8] Consistent with these findings, we discovered a significantly higher rate of ≥ mild PVL in Heyde patients with recurrent GIB after TAVI compared to those with an unremarkable course. As angiodysplasias persist after replacement of the aortic valve [2] this suggests that the association between PVL and recurrent GIB is caused by hemostaseologic rather than vascular alterations associated by PVL. Future studies should evaluate if individualized antithrombotic strategies, e.g. guided by post-TAVI HMWM levels or vWF activity can prevent GIB events in patients with HS (with PVL) after TAVI.

Furthermore, we found more periprocedural transfusion of packed red blood cells in Heyde patients, possibly related to lower baseline hemoglobin values and numerically higher rates of bleeding complications. The adverse impact of red blood cell transfusion after TAVI was previously described [27‐29], emphasizing the need for close monitoring of this vulnerable patient cohort.

Individualized antithrombotic treatment will be essential to minimize bleeding risk in these patients at risk. Recent evidence demonstrated superiority for restrictive antithrombotic strategies after TAVI [30, 31]. Additional analyses suggested that patients after TAVI may have hemostatic disorders apart from aVWS that may cause bleeding complications [32]. Whether bleeding complications can be reduced with tailored antithrombotic strategies in these vulnerable HS patients, needs further investigation.

Limitations of the current study relate to the retrospective single-center study design. Since TAVI patients from 2008 to 2017 were included, early data include the learning curve, high rates of non-transfemoral access, paravalvular regurgitation and notable rates of short- and mid-term mortality compared to current practice. Despite careful evaluation of clinical documentation and discharge letters, incomplete detection of bleeding episodes cannot entirely be ruled out. Our focus was on the evaluation of clinical bleeding events rather than hemostaseologic parameters. Hence, levels of vWF were not be included in this analysis. Additional prospective studies with larger patient samples may address these shortcomings in the future.

In this large cohort, we demonstrated that Heyde syndrome was prevalent in a relevant number of patients presenting for the treatment of AS. In contrast to earlier publications, a substantial number of recurrent GIB events was observed despite correction of AS by TAVI. Patients with residual paravalvular regurgitation after TAVI may be at higher risk of GIB and should be monitored more closely for bleeding events. In the meantime, optimal hemodynamic results and individualized antithrombotic strategies should be targeted to minimize bleeding risk and improve outcomes in these vulnerable patients with Heyde syndrome.