Heyde-like syndrome occurring for the first time following aortic valve replacement with a bioprosthesis: a case report

The co-occurrence of gastrointestinal (GI) bleeding and aortic valve stenosis (AS) is known as Heyde’s syndrome [1]. In patients with Heyde’s syndrome, aortic valve replacement (AVR) often ceases GI bleeding [2‐4], and bioprosthetic valve is recommended to avoid prolonged anticoagulant therapy [2, 3]. Herein, we illustrate a woman on hemodialysis (HD) with GI bleeding and hemodynamic AS that developed 3 years after AVR with a bovine pericardial bioprosthetic valve.

An 80-year-old woman, who had a 13-year history of HD for end-stage kidney disease, had undergone AVR with a 21-mm Carpentier-Edwards Perimount Magna bioprosthesis (Edwards Lifesciences, Irvine, CA, USA) for severe aortic regurgitation 3 years earlier.

She recovered uneventfully. However, follow-up transthoracic echocardiography started to reveal hemodynamic AS due to structural deterioration (SVD) 20 months after the AVR. The severity of hemodynamic AS worsened, with a peak velocity of 5.5 m/s at the aortic valve position, a mean pressure gradient of 67 mmHg, and an effective aortic prosthetic valvular orifice area of 0.56 cm² 3 years after AVR (Fig. 1).

From 27 months after AVR, she received repetitive blood transfusions for refractory anemia. Esophagogastroduodenoscopy revealed gastric telangiectasia and oozing hemorrhage in the gastric antrum (Fig. 2A). Colonoscopy did not reveal any bleeding. Although repeated endoscopic laser coagulation for hemostasis of the stomach was temporarily effective, bowel bleeding recurred. Capsule endoscopy showed multiple active bleeding in the small intestine (Fig. 2B).

She then started complaining of increased dyspnea and easy fatigability. Hypotension and frequent premature ventricular contractions were also observed during HD.

Heyde’s syndrome was strongly suspected, although hemodynamic AS occurred not in the native aortic valve but in the implanted bovine pericardial bioprosthetic valve. Platelet counts, activated partial thromboplastin time, and prothrombin time-international normalized ratio were 5.7 × 10⁴ /μl, 34.7 s, and 1.06, respectively. The gel electrophoresis analysis of von Willebrand factor (vWF) multimers was not performed. She underwent a redo AVR with a 19-mm Edwards Inspiris Resilia bioprosthesis (Edwards Lifesciences, Irvine, CA, USA) under standard cardiopulmonary bypass. All leaflets of the explanted bioprosthetic valve were calcified on both the aortic and left ventricular sides, and the leaflet in the direction of the left coronary cusp had lost its mobility (Fig. 3).

After the second AVR, refractory anemia promptly improved. The disappearance of telangiectasia and oozing hemorrhage in the stomach were confirmed by esophagogastroduodenoscopy, which was performed 4 months after the second AVR. The hemoglobin level was stable without further episodes of GI bleeding even though small blood transfusions were required at 5, 6, and 7 months after the second AVR (Fig. 4). At that time, neither fecal occult blood nor findings of hemolytic anemia were seen; thus, the cause of the anemia was likely due to chronic kidney disease. The hemodynamic performance of the second implanted bioprosthetic valve in the aortic position has been satisfactory for 2 years since the redo AVR (Fig. 4).

In 1958, Heyde reported an association between AS and GI bleeding [1]. Since then, several similar cases with the combination of AS and GI bleeding have been reported, which is clinically known as “Heyde’s syndrome” [2‐4]. AS generates high blood flow through the stenotic aortic valve that leads to high shear stress and mechanical disruption of the high-molecular-weight (HMW) multimer of vWF.

The vWF is an essential factor in platelet aggregation. In particular, the HMW multimer of vWF is essential for its hemostatic function [5]. Type 2A von Willebrand disease occurs due to the lack of an HMW multimer. Therefore, AS can cause this coagulation disorder [6]. Heyde’s syndrome can be confirmed in cases of acquired type 2A von Willebrand disease. Vincentelli et al. reported a negative correlation between the percentage of HMW multimers and the mean transvalvular gradient through the aortic valve [7]. Therefore, the HMW multimer deficit is thought to be the cause of coagulopathy in Heyde’s syndrome. Meanwhile, Undas et al. reported a case of Heyde’s syndrome without a decrease in large vWF multimers and concluded that Heyde’s syndrome is not always associated with acquired von Willebrand syndrome [8]. Gel electrophoresis, the gold standard examination for definitive diagnosis of Heyde’s syndrome, was not performed in our patient because it is expensive, resource intensive [3], time-consuming, and is not covered by the public health insurance system in Japan.

A relationship with GI bleeding of unknown origin has been observed in 3% of severe AS cases [3]. Severe AS occurs in 15–25% of patients with repeated bleeding [9]. Cody et al. reported a greater than 100-fold increased incidence of idiopathic GI bleeding in AS cases compared to general hospital cases [10]. Typically, the GI bleeding source in AS is angiodysplasia in the small intestine or colon; therefore, a whole intestinal examination is necessary. Although repeated endoscopic cauterization was temporarily effective for gastric angiodysplasia in our patient, the GI bleeding recurred. Capsule endoscopy was useful for identifying bleeding lesions in the small intestine.

The effectiveness of AVR in stopping the GI bleeding has been reported in 80–93% of patients with Heyde’s syndrome [2, 11, 12]. The use of a bioprosthetic valve rather than a mechanical valve may be preferable to avoid the long-term anticoagulation requirement [3]. Thus, AVR with a bioprosthesis should be the first-line therapy for Heyde’s syndrome. Prosthetic valve selection for dialysis patients remains controversial. Since the life expectancy of these patients is poor, a bioprosthetic valve is generally recommended for elderly patients undergoing HD [13‐15]. There are some reports indicating superior durability of bovine pericardial bioprostheses than that of porcine bioprostheses [16, 17]. However, there are no studies comparing the durability between bovine pericardial valve and porcine valve in HD patients. Our patient underwent the first AVR with a bovine pericardial bioprosthetic valve. Only 3 years later, the second AVR was required for Heyde-like syndrome. Although prosthetic valve selection was difficult, a bovine pericardial bioprosthetic valve was chosen because of her age and the existence of GI bleeding.

Some studies have reported transcatheter aortic valve implantation (TAVI) for patients with Heyde’s syndrome [18, 19]. However, TAVI for HD patients was approved in January 2021 and became available in Japan from February 2021. TAVI was not available during the time of second surgery for the patient. Soran et al. reported a patient with Heyde’s syndrome whose bleeding stopped immediately after AVR with a bioprosthetic valve and recurred when the implanted bioprosthetic valve was re-stenosed [20]. Vincentelli et al. reported a recurrence of hemostatic abnormalities in a case of a patient-prosthesis mismatch, even after AVR [7]. When a bioprosthetic valve is used for AVR, tissue valve stenosis due to SVD leads to coagulopathy recurrence and resolves again after redo AVR [21]. In our patient, coagulopathy did not occur prior to the initial AVR. This is probably because the first AVR was performed for aortic regurgitation rather than for AS. To the best of our knowledge, this is the first report on initial occurrence of Heyde-like syndrome following AVR.

Our patient recovered expeditiously after the second AVR and has remained well for the following 2 years. Redo AVR resulted in an immediate and sustainable cessation of bleeding and rapid resolution of chronic anemia. However, circumspect follow-up is mandatory.

In conclusion, the association between GI bleeding and valve stenosis in the aortic valve position can occur even after AVR because of bioprosthetic valve stenosis secondary to SVD. When Heyde’s syndrome is suspected even after AVR, redo AVR is a promising treatment.