Epidemiology and Pathophysiology
The prevalence of Heyde's syndrome in patients with severe AS increased annually along with the aggravation of aging society and reached 1.87% to 3.2% currently, resulting in escalating mortality of the disorder.(1) The corresponding dominating mechanism is the excessive proteolysis of HMWM-vWFs by ADAMTS-13 around the context of high shear stress related to stenotic valves, which not only predisposes to bleed but also induces submucosal arteriovenous malformation in the digestive tract(4, 5).
It is generally believed that diagnosing Heyde's syndrome should be based on a triad of AS, refractory GIB, and associated angiodysplasia or AVWS. Meanwhile, other diseases that can cause GIB such as tumors, primary digestive, hematological or autoimmune diseases, and drug-induced effects should be ruled out.
As for AS, it is known that patients with severe AS have a 100 times risk of complicating hematochezia than those without(6). Our patient's symptoms of continuous dyspnea, chest pain, palpitations, and even syncope during mild to moderate exercise should be aware of a triad of AS earlier after excluding severe coronary artery disease, so as to differentiate from Heyde's syndrome timely.
As for angiodysplasia, locating the culprit lesion can be challenging. Despite the rapid development of endoscopic diagnostic technologies including capsule endoscopy for a decade, 35% of cases of angiodysplasia were undiagnosed(3). Although the gold standard diagnostic method is mesenteric arteriography, the mean rate of localization of the bleeding site is 40% since many cases of bleeding angiodysplasia are intermittent which will decrease its sensitivity on detection(7). Our patient's angiodysplasia was confirmed by histological examination through exploratory laparotomy. Nevertheless, it was not able to be observed via mesentericography several years later. It might be primarily attributed to both the primary suspicious lesion in the gut had been surgically removed or restricted by thalidomide, and the patient was non-bleeding when receiving inspection.
As for AVWS, the necessity of gel electrophoresis to confirm the loss of large multimers makes biologic diagnosis of Heyde's syndrome challenging. The coagulopathy may be absent in patients with aortic gradients below 50 mmHg besides its high cost and time-consuming(2). The vWFs were not examined in our patient due to the limited conditions of our laboratory department. Research shows that the prevalence of abnormality of HMWM-vWFs in patients with native AS is estimated from 65% to 92%, and bleeding angiodysplasia in patients with AVWS is 11.5% approximately. Meanwhile, 55.6% to 87.5% of patients with documented angiodysplasia have a deficiency of HMWM-vWFs(8). However, other studies showed that patients with bleeding angiodysplasia did not have an increased prevalence of AVWS(9). In the context of AS, other mechanisms such as low perfusion, submucosal ischemia and hypoxia, or cholesterol embolism have been advocated to explain the relationship among angiodysplasia, GIB and AS(10).
We searched for case reports of Heyde's syndrome published since 2000 in PubMed, revealing 91 articles. We excluded 13 articles (1) without obtaining relevant information (n=10), (2) not consistent with the disease (n=1), (3) the case of epistaxis (n=1), and (4) the patient is an infant (n=1). We summarized the remaining 78 articles that a total of 83 cases (5 articles were double-case reports) with special references to treatment methods, angiodysplasia and HMWM-vWFs (Supplement table 1). Among them, the primary diseases were severe LVOTO in 6 cases, severe aortic regurgitation in 1cases, AS in the remaining 76 cases; 17 cases (20.5%) were not diagnosed with angiodysplasia, of which, 11 (84.6%) of 13 patients undergoing cardiac surgery (including aortic valve replacement and alcohol septal ablation) were cured of GIB; 9 cases (10.8%) had not HMWM-vWFs deficiency, 46 cases (55.4%) were not examined for HMWM-vWFs, of which, 31 (91.2%) of 34 cases receiving cardiac surgery had remission of GIB; 10 patients were not diagnosed with both angiodysplasia and AVWS, of which, 6(85.7%) of 7 patients performed heart surgery were cured of GIB.
Given the complicated mechanisms and imperfect accuracy or availability of relevant diagnostic methods, we should not simply exclude Heyde's syndrome in practice merely due to lack of evidence of bleeding angiodysplasia or AVWS. It is worth paying attention to considering Heyde's syndrome as an exclusionary diagnosis and the feasibility of aortic valve replacement as a diagnostic therapy. （Fig. 2）
Endoscopic therapies are often ineffective, whereas exploratory laparotomy could be a bridging therapy to aortic valve replacement for patients with continuous enterorrhagia or major or life-threatening hemorrhage. Even though it remains about 30% of bleeding recrudescence due to angiodysplasia diffusing throughout the digestive tract(11). Our patient underwent segmental enterectomy as severe bleeding and temporarily alleviated after regular administration of thalidomide that the angiogenesis inhibitor.
It is demonstrated that SAVR or TAVI is a radical therapy for Heyde's syndrome. In comparison, TAVI may be an optimal modality for stable patients at high risks such as agedness, multiple comorbidities, or hemorrhagic predisposition. Desai et al.(1) found no significant differences between TAVI and SAVR in all-cause mortality or total expenses during hospitalization. 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, TAVI is pointed out to be prone to complicate paravalvular regurgitation（26.6% vs. 4.2%, P<0.001）and associated with a higher incidence of advanced GIB（3.3% vs. 1.5%, P<0.001）compared to SAVR(12, 13). Our patient, categorized as the population of extremely high bleeding risk in operation, consequently received TAVI to treat to avoid surgical complications and increase the benefit of valve replacement.
Although there are some case reports of Heyde's syndrome toward severe LVOTO, we have not seen any prognostic reports concerning the complication of LVOTO after TAVI in patients with Heyde's syndrome. A study indicated that 89% of patients with baseline or latent obstructive HCM suffered abnormality of HMWM-vWFs which were enough to be impaired when the peak gradient of the obstructive LVOT is >15mmHg(at rest) or >35mmHg(during exercise). At the same time, about 30% of those patients developed GIB(14, 15). Our patient, verified as having no myocardial hypertrophy or LVOTO by echocardiography preprocedurally, was found to complicate with asymptomatic and simple LVOTO(maximum peak gradient in LVOT of 55 mmHg) at 1-year's follow up. It is worth further investigating whether or how the complication of LVOTO following TAVI in patients with Heyde's syndrome impacts their prognosis on GIB.