CCCardiol CroatCardiologia CroaticaCardiol. Croat.1848-543X1848-5448Croatian Cardiac SocietyCC 2020 15_9-10_262-510.15836/ccar2020.262Professional ArticleHeyde Syndrome – An Often-Neglected Pathophysiological Course in Daily Clinical PracticeHeydeov sindrom – nerijetko zapostavljeni patofiziološki slijed zbivanja u svakodnevnoj kliničkoj praksihttps://orcid.org/0000-0001-8848-0472LučingerDaren1*https://orcid.org/0000-0002-2329-2582LakušićNenad123https://orcid.org/0000-0002-5675-4202CerovecDuško123https://orcid.org/0000-0002-2723-8356FučkarKrunoslav13https://orcid.org/0000-0003-2432-802XVincelj ŠalkovićLjubica1Specijalna bolnica za medicinsku rehabilitaciju Krapinske Toplice, Krapinske Toplice, HrvatskaFakultet za dentalnu medicinu i zdravstvo Osijek, Sveučilište J. J. Strossmayer Osijek, Osijek, HrvatskaMedicinski fakultet Osijek, Sveučilište J. J. Strossmayer Osijek, Osijek, HrvatskaSpecial Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice, CroatiaFaculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek, CroatiaFaculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek, CroatiaADDRESS FOR CORRESPONDENCE: Daren Lučinger, Specijalna bolnica za medicinsku rehabilitaciju Krapinske Toplice, Gajeva 2, HR-49217 Krapinske Toplice, Croatia. / Phone: + 385-49-383-100 / E-mail: darenlucinger@gmail.com082020159-1026226502052020200520202020Croatian Cardiac SocietySUMMARY
The classic triad of aortic stenosis symptoms – angina pectoris, heart failure, and syncope - is well-known among clinicians, but manifestations of aortic stenosis on other systems often remain unrecognized. Gastrointestinal (GI) angiodysplasia, like aortic stenosis, is degenerative disease and both entities are more common in older patients. Heyde syndrome refers to a 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. Acquired coagulopathy arises from degradation of vWF multimers by the shear stress across the stenotic aortic valve. Aortic valve replacement leads to rise in vW factor multimers and ultimate resolution of gastrointestinal bleeding and sideropenic anemia. In patients with established aortic stenosis, development of iron deficiency anemia should raise the possibility of Heyde syndrome, but patients with GI bleeding with presence of angiodysplasia or failure of endoscopy to find the site of GI bleeding should also be evaluated for aortic stenosis.
SAŽETAK
Klasični trijas simptoma aortalne stenoze – angina pektoris, zatajivanje srca te sinkopa, kliničarima je dobro poznat, no manifestacije aortalne stenoze na druge organske sustave često ostaju neprepoznate. Angiodisplazije probavnog trakta, kao i aortalna stenoza, degenerativna su bolest, a samim time češće u starijoj populaciji. Heydeov sindrom obuhvaća trijadu aortalne stenoze, stečene koagulopatije (von Willebrandov sindrom tipa 2A) i sideropenične anemije koja nastaje kao posljedica krvarenja iz gastrointestinalnih (GI) angiodisplazija ili iz nepoznatog sijela. Stečena koagulopatija nastaje zbog degradacije multimera von Willebrandova faktora (vWf) i uzrokovana je stresom smicanja na stenotičnoj aortalnoj valvuli. Zamjena aortalne valvule dovodi do oporavka koncentracije multimera vW faktora i posljedične rezolucije gastrointestinalnoga krvarenja i sideropenične anemije. U populaciji bolesnika s aortalnom stenozom razvoj sideropenične anemije treba pobuditi sumnju na Heydeov sindrom, ali i kod bolesnika s dokazanim krvarenjem iz angiodisplazija GI trakta ili nerazjašnjenim GI krvarenjem nakon endoskopske obrade potrebno je obaviti ehokardiogram s obzirom na mogućnost postojanja aortalne stenoze.
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).
Conclusion
Heyde syndrome is often neglected in everyday clinical practice. It is important to keep in mind the “atypical” manifestations of common diseases such as aortic stenosis. Timely recognition of this syndrome can lead to breaking the undesirable vicious circle and choosing the right treatment modality, which is aortic valve replacement.
LITERATUREJoint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC)European Association for Cardio-Thoracic Surgery (EACTS)VahanianAAlfieriOAndreottiFAntunesMJBarón-EsquiviasGBaumgartnerH. Guidelines on the management of valvular heart disease (version 2012). . 2012 October;33(19):2451–96. 10.1093/eurheartj/ehs10922922415Tintinalli JE, Kelen GD, Stapczynski JS, Ma OJ, Cline DM, editors. Emergency Medicine: A Comprehensive Study Guide. 6th ed. New York, NY: McGrawHill, 2004; p.54.RegulaJWronskaEPachlewskiJ. Vascular lesions of the gastrointestinal tract. . 2008;22(2):313–28. 10.1016/j.bpg.2007.10.02618346686MassynMWKhanSA. Heyde syndrome: a common diagnosis in older patients with severe aortic stenosis. . 2009 May;38(3):267–70, discussion 251. 10.1093/ageing/afp01919276092PateGEChandavimolMNaimanSCWebbJG. Heyde’s syndrome: a review. . 2004 September;13(5):701–12.15473466GreensteinRJMcElhinneyAJReubenDGreensteinAJ. Colonic vascular ectasias and aortic stenosis: coincidence or causal relationship? . 1986 March;151(3):347–51. 10.1016/0002-9610(86)90465-43485386IslamSCevikCIslamEAttayaHNugentK. Heyde’s syndrome: a critical review of the literature. . 2011 July;20(4):366–75.21863647VincentelliASusenSLe TourneauTSixIFabreOJuthierFAcquired von Willebrand syndrome in aortic stenosis. . 2003 July 24;349(4):343–9. 10.1056/NEJMoa02283112878741TsujiATanabeMOnishiKKitamuraTOkinakaTItoMIntravascular hemolysis in aortic stenosis. . 2004 October;43(10):935–8. 10.2169/internalmedicine.43.93515575243HudzikBWilczekKGasiorM. Heyde syndrome: gastrointestinal bleeding and aortic stenosis. . 2016 February 2;188(2):135–8. 10.1503/cmaj.15019426124230GillJCWilsonADEndres-BrooksJMontgomeryRR. Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. . 1986 March;67(3):758–61. 10.1182/blood.V67.3.758.7583484979YoshidaKTobeSKawataMYamaguchiM. Acquired and reversible von Willebrand disease with high shear stress aortic valve stenosis. . 2006 February;81(2):490–4. 10.1016/j.athoracsur.2005.07.07416427837KingRMPluthJRGiulianiER. The association of unexplained gastrointestinal bleeding with calcific aortic stenosis.1987 November;44(5):514–6. 10.1016/S0003-4975(10)62112-13499881