Epidemiology and Pathophysiology
With the ageing of society, the prevalence of Heyde’s syndrome in patients with severe AS is increasing annually and has reached 1.87%-3.2%, resulting in increasing disease mortality(1). The corresponding dominating mechanism is the excessive proteolysis of HMWM-vWFs by ADAMTS-13 in the context of the high shear stress related to stenotic valves, which not only predisposes patients to bleeding but also induces submucosal arteriovenous malformations in the digestive tract(4, 5).
It is generally believed that the diagnosis of Heyde's syndrome should be based on a triad of AS, refractory GIB, and associated angiodysplasia or AVWS. Additionally, other primary diseases that can cause GIB should be excluded, such as tumours; primary digestive, haematological or autoimmune diseases; and the side effects of drugs.
For AS, the risk of complicating haematochezia in patients with severe AS is known to be 100 times that in non-AS patients(6). As our patient had suffered from continuous dyspnoea, chest pain, palpitations, and even syncope during mild to moderate exercise, her diagnosis of AS should have been recognized earlier after excluding severe coronary heart disease, and combined with her symptoms of GIB, it should be further differentiated from Heyde's syndrome in a timely manner.
For angiodysplasia, locating the culprit lesion can be challenging. Despite the rapid development of endoscopic diagnostic technologies, including double balloon enteroscopy, in the past decade, 35% of angiodysplasia cases have gone undiagnosed(3). Although the gold standard diagnostic method is mesenteric arteriography, the average localization rate of the bleeding site is 40% since many cases of bleeding angiodysplasia only intermittently bleed, which decreases its sensitivity for detection(7). The angiodysplasia in our patient was confirmed by histological examination through local enterectomy, but angiodysplasia was not observed via mesentericography several years later. This might be primarily attributed to the fact that the observable suspicious lesions in the gut had been surgically removed or were restricted by thalidomide, and the patient was stable when she underwent mesentericography.
For AVWS, the necessity of gel electrophoresis to confirm the loss of large multimers also makes the biological diagnosis of Heyde's syndrome challenging. Coagulopathy may be absent in patients with aortic gradients below 50 mmHg, and the related testing process is costly and time-consuming(2). The vWFs were not examined in our patient due to the limited capabilities of our laboratory department. Research has shown that the prevalence of abnormal HMWM-vWFs in patients with native AS is estimated to be 65% to 92%, and the incidence of bleeding angiodysplasia in patients with AVWS is approximately 11.5%. Furthermore, 55.6% to 87.5% of patients with documented angiodysplasia have a deficiency in HMWM-vWFs(8). However, the results of other studies have indicated no increase in the prevalence of AVWS in patients with bleeding angiodysplasia(9). In the context of AS, other mechanisms, such as low perfusion, submucosal ischaemia and hypoxia, or cholesterol embolism, have also been considered to be the cause of the relationship between angiodysplasia, GIB and AS(10).
We searched for case reports of Heyde's syndrome that were published since 2000 in PubMed, and we obtained 91 articles. We excluded 13 articles (1) without available relevant information (n=10), (2) inconsistent with the disease (n=1), (3) that described a patient with epistaxis (n=1), and (4) that described an infant case (n=1). The remaining 78 articles involving a total of 83 cases were summarized (5 articles were double-case reports) with special references to the treatment methods, angiodysplasia and HMWM-vWFs (Supplement table 1). Among these case reports, the primary diseases were severe LVOTO in 6 patients, severe aortic regurgitation in 1 patient, and AS in the remaining 76 patients; 17 of the patients (20.5%) were not diagnosed with angiodysplasia, of which 11 (84.6%) of the 13 patients who were undergoing cardiac surgery (including aortic valve replacement and alcohol septal ablation) were cured of GIB. Additionally, 9 patients (10.8%) had no deficiencies in HMWM-vWFs; 46 patients (55.4%) did not get tested for HMWM-vWFs, of which 31 (91.2%) of the 34 patients who had cardiac surgery had GIB remission; and 10 patients were not diagnosed with either angiodysplasia or AVWS, of which 6 (85.7%) of the 7 patients who underwent heart surgery were cured of GIB.
Given the complicated mechanisms, imperfect accuracy, and lack of available relevant diagnostic methods, we should not simply exclude Heyde's syndrome in practice merely due to a lack of evidence for the presence of bleeding angiodysplasia or AVWS. Notably, we should consider both Heyde's syndrome as an exclusionary diagnosis and the feasibility of aortic valve replacement as a diagnostic therapy.
Endoscopic therapies are often ineffective, whereas local enterectomy could be a bridging therapy for aortic valve replacement in patients with continuous enterorrhagia or major or life-threatening haemorrhage; nevertheless, the bleeding recurrence rate after intestinal resection is approximately 30%, which is mainly due to angiodysplasia that cannot be cured locally(11). Our patient underwent segmental enterectomy for severe bleeding, which was temporarily alleviated with regular administration of the angiogenesis inhibitor thalidomide.
SAVR or TAVI has been demonstrated to be a radical therapy for Heyde's syndrome. In comparison, TAVI may be an optimal modality for stable patients who are at high risk, such as patients who are elderly, have multiple comorbidities, or have a haemorrhagic predisposition. Desai et al.(1) found no significant differences in all-cause mortality or total expenses during hospitalization between TAVI and SAVR. Moreover, TAVI is superior to SAVR in lessening the duration of hospitalization and the incidence of periprocedural complications such as stroke, myocardial infarction, or major or life-threatening bleeding. Nevertheless, patients who had TAVI have been shown to be prone to complications with paravalvular regurgitation (26.6% vs. 4.2%, P<0.001), and TAVI has been shown to be associated with a higher incidence of advanced GIB (3.3% vs. 1.5%, P<0.001) than SAVR(12, 13). Our patient, who had an extremely high risk of bleeding during the operation, consequently received TAVI to avoid surgical complications and to increase the benefit of valve replacement.
Although some cases of Heyde's syndrome are caused primarily by LVOTO, we are not aware of any prognostic reports concerning the complication of LVOTO after TAVI in patients with Heyde's syndrome. One study indicated that 89% of patients with baseline or latent obstructive HCM suffered abnormalities in HMWM-vWFs when the peak gradient of the obstructive LVOT was >15 mmHg (at rest) or >35 mmHg (during exercise). Additionally, approximately 30% of those patients developed GIB(14, 15). Our patient, who was verified as having no myocardial hypertrophy or LVOTO by preoperative echocardiography, was found to be complicated with an asymptomatic and simple LVOTO (maximum peak gradient in LVOT of 55 mmHg) at the 1-year follow-up. It is worth further investigating whether and how the complication of LVOTO following TAVI in patients with Heyde's syndrome impacts their prognosis regarding GIB.