Degenerative aortic stenosis is the most common valvular disease in the elderly and one of the leading causes of morbidity and mortality in that population. The prevalence increases with age and reaches 2-7% in those above 65 years of age (1). The classic triad of aortic stenosis symptoms – angina pectoris, heart failure, and syncope (2), is well-known to clinicians, but manifestations of aortic stenosis on other systems (e.g. gastroenterological or hematological) often remain unrecognized. Angiodysplasia is the most common vascular disorder of the gastrointestinal tract (2). It is a degenerative disease of the blood vessels, and 70% of angiodysplasias are localized in the cecum and ascending colon. After diverticulosis, it is the second most common cause of bleeding from the lower digestive tract in persons older than 60 (3).

The link between aortic stenosis and angiodysplasia of the colon is difficult to explain, given that they are both degenerative diseases and thus more common in the older population. It was first noticed and described in 1958 by Edward Heyde, who published 10 cases of calcified aortic stenosis and severe gastrointestinal bleeding. Today, Heyde syndrome refers to the triad of aortic stenosis, acquired coagulopathy (von Willebrand syndrome type 2A), and sideropenic anemia due to bleeding from gastrointestinal angiodysplasia or from an idiopathic site (4).

Pate et al. conducted a retrospective study that found a statistically significant association between aortic stenosis and gastrointestinal bleeding which was assumed to be the result of angiodysplasia (5). Another retrospective study by Greenstein et al. that included 3623 patients with aortic or mitral stenosis showed that bleeding from the gastrointestinal tract was statistically significantly more likely to be associated with aortic stenosis (6). Aortic stenosis has a long asymptomatic period, and intestinal angiodysplasia does not always result in significant anemia, so the exact prevalence of Heyde syndrome remains unknown (4). There are multiple pathophysiological mechanisms that could explain how aortic stenosis causes or exacerbates bleeding from angiodysplasia. Some of these include: sympathetic vasodilatation of intestinal blood vessels as a response to chronic hypoxia or cholesterol embolisms from a degenerative aortic valve and degradation of von Willebrand factor (vWF) high molecular weight multimers, the latter being the most convincing explanation (7). Acquired von Willebrand syndrome type 2A (vWS-2A) is caused by vWF multimer degradation due to shear stress across the stenotic aortic valve. Non-physiological degradation of large vWF multimers that are normally most active during thrombus formation is responsible for coagulopathy in Heyde syndrome (8), all of which is also exacerbated by the common concomitant antithrombotic or anticoagulation therapy in this patient group. It is likely that a pressure gradient of at least 50 mmHg over the aortic valve is necessary to develop this coagulopathy (9). Aortic stenosis is not the only “cardiogenic” cause of vWF deficiency, and other cardiovascular causes of acquired von Willebrand syndrome are: hypertrophic cardiomyopathy (with left ventricular outflow tract obstruction), dysfunctional prosthetic valves, ventricular septal defect, persistent ductus arteriosus, and left ventricular support systems (10).

The gold standard for vWS-2A diagnosis is vWF gel electrophoresis (5). The absence of large vWF multimers in SDS-agarose gel electrophoresis is pathognomonic (11).

Treatment of Heyde syndrome requires a multidisciplinary approach and includes the following treatment modalities: medication therapy, endoscopic and surgical treatment for changes within the gastrointestinal tract, and prosthetic replacement of the aortic valve (7). The classic treatment of von Willebrand disease with desmopressin, octreotide, or substitution of vWF and factor VIII is usually ineffective in treatment of vWF syndrome type 2A, although substitution of these coagulation factors immediately prior to surgical treatment can be considered in patients with transitory recovery in vW factor activity after a test dose (5).

Patients treated by resection of the colon with angiodysplastic changes usually had recurring bleeding from other parts of the colon or on other mucosa, whereas prosthetic aortic valve replacement addresses the disorder at the level of the coagulation cascade and leads to resolution of the anemia (4). Yoshida et al. used electrophoresis to demonstrate a deficit in large vWF multimers in patients with aortic stenosis and the post-surgical recovery in the concertation of these multimers. Therefore, replacement of the aortic valve leads to recovery of vWF factor multimer concentrations and the consequent resolution of gastrointestinal bleeding (12). A retrospective study that included 91 patients with aortic stenosis and unexplained gastrointestinal bleeding showed that the bleeding stopped in as many as 93% of patients after surgical implantation of an artificial aortic valve, as opposed to only bleeding cessation in only 5% of patients treated with other methods (with or without colon resection) (5, 13). Some authors even recommend that bleeding from gastrointestinal angiodysplasias and established acquired vWS in patients with aortic stenosis should be included as one of the indications for cardiac surgery, while vWS-2A severity assessment should be included as one of the factors determining the right time to perform the procedure (5). Oral anticoagulant therapy carries the risk of bleeding recurrence after surgical replacement of the stenotic aortic valve. Biological prosthetic valves generally do not require long-term anticoagulation therapy, as opposed to mechanical prostheses. In principle, implantation of a bioprosthetic valve to an aortic location should be the treatment of choice in patients older than 65, but also in patients in whom long-term anticoagulation therapy is contraindicated due to a high risk of bleeding (e.g. previous bleeding, comorbidities, etc.) (1). Transcatheter aortic valve implantation is an option in patients with severe aortic stenosis and a high risk of surgical valve replacement, however, the recommended dual antiplatelet therapy 1-3 months after the procedure, and aspirin especially, increases the risk of gastrointestinal bleeding (10).

Iron supplements and transfusion treatment are recommended in patients who refuse or are unsuited for surgical or transcatheter treatment of aortic valve stenosis, depending on the level of anemia. Endoscopic treatment and octreotide are recommended in recurrent and resistant bleeding (10).

Failure to recognize Heyde syndrome can lead to an undesirable vicious circle. Patients with indications for a surgical procedure on parts of the digestive tract with angiodysplasia (in which endoscopic treatment is unsuccessful or unsuitable) often do not undergo surgery due to aortic stenosis which increases perioperative mortality and morbidity. On the other hand, patients with indications for aortic valve replacement for severe stenosis have difficulties receiving approval for the surgery from the “heart team” if there is unexplained or recurrent bleeding from the gastrointestinal tract with consequent anemia, especially if the anemia is symptomatic and requires transfusion treatment.

In the population of patients with aortic stenosis, development of sideropenic anemia should raise suspicion of Heyde syndrome, especially if the required endoscopic examination does not reveal a clear cause for gastrointestinal bleeding other than angiodysplasia, or conversely, if endoscopic examination verifies presence of angiodysplasia in patients with sideropenic anemia as a consequence of gastrointestinal bleeding an echocardiogram should be performed to screen for aortic stenosis (4).