Abstract
Heyde’s syndrome is the association between aortic valve stenosis and gastrointestinal bleeding due to intestinal angiodysplasia. The pathophysiological basis of this syndrome appears to be an acquired deficiency of von Willebrand factor, leading to bleeding from angiodysplastic arteriovenous malformations. Treatment options include localization and cauterization of the bleeding sites, although this therapeutic approach is associated with a high recurrence rate. Aortic valve replacement appears to offer the best long-term resolution of bleeding and should be considered in most cases.
Keywords
Gastrointestinal Bleeding, Severe Aortic Stenosis
DISCUSSION
Angiodysplasia is a chronic-degenerative condition of the intestinal mucosa related to the aging process and is one of the main causes of gastrointestinal bleeding in the elderly. Its association with aortic stenosis is well established.(1,2) Both conditions are linked to cardiovascular risk factors. Numerous studies suggest a higher occurrence of intestinal angiodysplasia in individuals with aortic stenosis, and vice versa.(3,4) The leading hypothesis behind this association is that both diseases are closely related to the physiological processes of aging.(5)
In 1992, Warkentin and colleagues (2) proposed an etiopathogenic mechanism whereby the acquired deficiency of high molecular weight multimers of von Willebrand factor (vWF)—specifically type IIA—due to qualitative class A defect resulting from fragmentation, impairs hemostasis under high shear stress conditions,(4) such as those found in angiodysplastic arteriovenous malformations. This mechanism appeared to be the link between the two components of the syndrome (figure 2). vWF is constitutively produced in endothelial cells—specifically within Weibel-Palade bodies—as well as in megakaryocytes and subendothelial connective tissue. It contributes to thrombus formation and mediates platelet adhesion at sites of vascular injury.(5)
The high shear stress caused by the stenotic aortic valve alters the structure of the vWF molecule, leading to proteolysis of its high molecular weight multimers by the enzyme ADAMTS13.(4) In summary, acquired von Willebrand disease type IIA due to aortic stenosis causes hemostatic defects that predispose to bleeding from previously subclinical intestinal angiodysplasia.(4) This was demonstrated in a prospective study by Veyradier et al.(6), who showed that the absence of large vWF multimers caused bleeding in angiodysplastic lesions of the gastrointestinal tract.
Further evidence came from Vincentelli et al.(7), who demonstrated that the severity of aortic stenosis is proportional to the extent of hemostatic alteration: the higher the transvalvular gradient, the lower the availability of high molecular weight multimers. In their study, aortic valve replacement stopped the depletion of these multimers, with reversal observed in some patients as early as the first postoperative day.(5,7)
In high surgical risk patients in whom no clear bleeding source can be identified, anemia management with periodic blood transfusions may offer some symptomatic relief.(4,6) Aortic valve replacement appears to reduce the risk of gastrointestinal bleeding in patients with Heyde’s syndrome, resolving bleeding in approximately 80 % of cases. Although bleeding recurrence rates do not differ significantly between biological and mechanical prostheses, the increased bleeding risk in patients on anticoagulation therapy favors the use of biological valves in most cases.(8)
Bleeding recurrence only occurs when the underlying pathophysiology is reestablished—either due to restenosis or patient-prosthesis mismatch (effective valve area/body surface area < 0,85 cm²/m² on echocardiography), which can lead to persistently high postoperative gradients despite a normally functioning prosthesis.(6) Godino et al.(9) reported an incidence of 1,7 % of Heyde’s syndrome among 400 patients who underwent transcatheter aortic valve implantation (TAVI) at their institution, with complete resolution of gastrointestinal bleeding in all successfully treated patients.
Management of acute bleeding includes blood transfusion and emergency intestinal resection. However, segmental resection does not provide long-term benefit, as these patients often rebleed from different locations. Bleeding ceases in nearly all patients who undergo aortic valve replacement (93 %), reinforcing the causal relationship between aortic stenosis and gastrointestinal bleeding.(10)
Heyde’s Syndrome: Its Clinical Characterization in 10 Points
It was originally formulated by Edward Heyde in 1958 as the association between severe aortic stenosis and major gastrointestinal bleeding.
Its clinical-etiopathogenic definition and consolidation as a syndromic entity was a gradual and collaborative construction, with contributions from various disciplines.
The bleeding lesions are usually submucosal angiodysplasias, commonly located in the right colon, though they can occur anywhere along the digestive tract—from the cardia to the anal sphincter. The small intestine is often involved, and multifocal lesions are frequent.
Its presentation increases with age, due to the higher prevalence of aortic stenosis and angiodysplasias in elderly individuals.
It can manifest as overt bleeding, with visible angiodysplasias or no identifiable lesion (dark stools), or as chronic anemia with no external signs of bleeding (occult bleeding). It may also be accompanied by cutaneous or mucosal bleeding signs.
The bleeding trigger is a platelet dysfunction caused by a deficiency of high-molecular-weight von Willebrand factor (vWF) multimers, processed by the ADAMTS13 protease. This is due to a conformational alteration in vWF when it is elongated into a fibrillar shape, which exposes the cleavage site. The high shear stress caused by the aortic stenosis increases the breakdown of these multimers. The largest multimers are particularly necessary for effective hemostasis at sites of angiodysplasias.
Once its pathophysiology is understood, the syndrome is configured as the triad of aortic stenosis, gastrointestinal bleeding, and an acquired type 2A von Willebrand disease—and should be treated as such, including its therapeutic consequences.
Aortic valve replacement surgery usually resolves both the aortic stenosis and the bleeding in most cases. However, recurrence may occur if there is prosthesis–patient mismatch or a high residual gradient, a more frequent and risky condition in older patients with small aortic roots.
In principle, TAVI is preferable to surgical valve replacement due to its lower invasiveness in elderly patients, those with comorbidities, or those with anemia. However, its durability and effective prosthetic valve area must be considered.
The diagnostic process must include ruling out malignancy, as well as acquired vWF disease and aortic stenosis. Management usually requires the involvement of multiple disciplines—clinical cardiology, hematology, gastroenterology, interventional radiology, and interventional cardiology/cardiac surgery.
CONCLUSIONS
Heyde’s syndrome is a cause of gastrointestinal bleeding due to angiodysplastic changes in the digestive tract as a result of severe aortic stenosis. The bleeding from these angiodysplastic lesions is closely related to alterations in von Willebrand factor caused by increased valvular flow. The definitive long-term treatment for this condition is aortic valve replacement.
References
- 1 Heyde EC. Gastrointestinal bleeding in aortic stenosis. N Engl J Med. 1958;259:196.
- 2 Warkentin TE, Moore JC, Morgan DG. Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand’s disease the link? Lancet. 1992;340(8810):35–7.
- 3 Morishima A, Marui A, Shimamoto T, Saji Y, Tambara K, Nishina T, et al. Successful aortic valve replacement for Heyde syndrome with confirmed hematologic recovery. Ann Thorac Surg. 2007;83(1):287–8.
- 4 Pate GE, Chandavimol M, Naiman SC, Webb JG. Heyde’s syndrome: a review. J Heart Valve Dis. 2004;13(5):701–12
- 5 Vaz A, Correia A, Martins B, Capelo J, Ferreira P, Henriques P, et al. Heyde syndrome: The link between aortic stenosis and gastrointestinal bleeding. Rev Port Cardiol. 2010;29(2):309–14.
- 6 Veyradier A, Balian A, Wolf M, Giraud V, Montembault S, Obert B, et al. Abnormal von Willebrand factor in bleeding angiodysplasias of the digestive tract. Gastroenterology. 2001;120:346–53.
- 7 Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med. 2003;349(4):343–9.
- 8 Thompson JL, Schaff HV, Dearani JA, Park SJ, Sundt TM, Suri RM, et al. Risk of recurrent gastrointestinal bleeding after aortic valve replacement in patients with Heyde syndrome. J Thorac Cardiovasc Surg. 2012;144(1):112–6.
- 9 Godino C, Lauretta L, Pavon AG, Mangieri A, Viani G, Chieffo A, et al. Heyde’s syndrome incidence and outcome in patients undergoing transcatheter aortic valve implantation. J Am Coll Cardiol. 2013;61(6):687–9.
- 10 Figuinha FCR, Spina GS, Tarasoutchi F. Heyde’s syndrome: case report and literature review. Arq Bras Cardiol. 2011;96(3):e42–5.
Declarations
Funding
None.
Conflict of interest
None. AUTHORSHIP CONTRIBUTION Conceptualization: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López. Research: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López. Methodology: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López. Project administration: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López. Resources: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López. Writing - original draft: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López. Writing - revision and editing: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López.
Authorship contributions
Drafting – original draft: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López.
Writing–review and editing: Alejandra González Esquerra, Alexis Pérez Pérez, Yendry Gattorno Aguila, Marlon Durán Cárdenas, Luis Alberto Rodríguez López.