Faculty Peer Reviewed
In 1958, EC Heyde published 10 cases of aortic stenosis (AS) and arteriovenous malformations (AVMs) of the gastrointestinal tract in the New England Journal of Medicine . Thus, the association between aortic stenosis and intestinal angiodysplasia became known as Heyde Syndrome. Yet the existence of this syndrome has been controversial.
Contrasting conclusions have been obtained by studies conducted to evaluate this association. In a prospective study, Bhutani and colleagues did not find an increased prevalence of AS in 40 patients who were previously diagnosed with AVMs . Further studies confirmed this finding. Mehta and colleagues found no cases of aortic AS among 29 patients with angiodysplasia, while Oneglia and colleagues found one case of AS among 59 patients with AVMs [3,4].
However, other studies found a significant association between the two conditions. In a retrospective chart review, Pate and colleagues found a significant association between AS and GI bleeding assumed to be due to angiodysplasia (P<0.0001) . In another retrospective review, Greenstein and colleagues found that gastrointestinal bleeding was more prevalent in patients with AS compared to mitral stenosis (P< 0.0001) .
The two studies in support of Heyde Sydrome mentioned above used indirect clinical criteria, such as a cardiac murmur consistent with AS and idiopathic gastrointestinal bleeding, to diagnose AS and AVMs, respectively. Batur and colleagues conducted the first study that used objective criteria to diagnose AS and AVMs . They determined an association between AS, diagnosed by echocardiography, and AVMs, diagnosed by GI endoscopy or angiography. This study compared the prevalence of aortic stenosis to mitral stenosis in 73 patients with AVMs who underwent echocardiography. In addition, the prevalence of AS and MS in patients with AVMs was compared to the prevalence of AS and MS in all patients who had echocardiograms. The results revealed that AS, but not MS was significantly correlated with AVMs. The prevalence of AS was 31.7% in patients with AVMs, which was significantly higher than the 14% of AS found among all patients who underwent echocardiography (P<0.001). The prevalence of MS in patients with AVMs was 1.6% and not significant compared to the 6.0% among all patients with echocardiograms (P=0.14). Further, the severity of AS showed a stronger correlation to the presence of AVMs. Moderate-to-severe AS was 2.6 times more common, and severe AS was 4.1 times more common among patients with AVMs.
Given that studies support the entity of Heyde Syndrome, multiple explanations have been speculated. One theory is that chronic hypoxia from AS leads to sympathetic-induced vasodilation and smooth muscle relaxation and subsequently bleeding from AVMs. However, Batur et al argued with this explanation given that only severe AS compromises cardiac output and causes hypoxia, since an association was seen with milder forms of AS . Other explanations include colonic hypoxia due to cholesterol embolization from stenotic aortic valves or altered pulse waveforms from aortic stenosis.
In a recent publication, Massyn and Khan advocate that the basis for this association is an acquired coagulopathy caused by aortic stenosis . Aortic stenosis has been shown to cause von Willebrand syndrome type 2A. von Willebrand factor circulates as large multimers after synthesis by endothelial cells. The shear stress across a stenotic aortic valve causes degradation of the largest vWF multimers that are most effective in mediating platelet adhesion. In support of this mechanism, Yoshida and colleagues found abnormal gel electrophoresis in patients with AS, that normalized following aortic valve replacement surgery . Similarly, studies have shown prolonged bleeding time in patients with AS that resolves upon AVR [10,11]. These studies lend strength to the mechanism that aortic stenosis causes acquired vWD-2A and the coagulopathy leads to bleeding from intestinal AVMs.
Recognition of an acquired coagulopathy or vWD-2A as the root of the association allows for effective management of bleeding. AVR corrects the coagulopathy and has been shown to provide resolution of GI bleeding, while patients who have undergone intestinal resection continue to bleed from other sites. In a retrospective study of patients with AS and idiopathic GI bleeding, King and colleagues found that GI bleeding resolved in 93% of patients with AVR compared to 5% of patients who underwent intestinal resection . Given these findings, it would be appropriate for physicians to evaluate for aortic stenosis in patients, who are surgical candidates, with GI bleeds secondary to known intestinal angiodysplasia or persistent idiopathic GI bleeds in order to guide management. Further, aortic stenosis should be dismissed in all patients with intestinal AVMs prior to management involving intestinal resection.
Heyde syndrome appears to be a true entity. However, as Massyn and Khan advocate, it is a triad of aortic stenosis, an acquired coagulopathy due to vWD-2A, and bleeding from intestinal angiodysplasia . Understanding the mechanism by which AS leads to GI bleeding from AVMs allows for proper treatment and long-term resolution.
Commentary by Rosemarie Gambetta, MD Division of Caridiology
While bleeding from AVM’s are generally seen with higher degrees of aortic stenosis (Vincentilli,Andre et al NEJM2003 349:343-349 )secondary to the generally accepted mechanisms of a decrease in the largest multimers of von Willebrand factor, the hemostatic consequences of severe aortic stenosis are not indications for valve replacement.
At the present time, recommendations for aortic valve replacement are based on symptoms of severe aortic stenosis such as angina, syncope or heart failure(JAAC 2008:52:1-142)
To answer the question Does Heyde syndrome exist?
The next time you have a patient with intestinal bleeding from angiodysplasias take out your stethoscope and take a closer listen to heart sounds and murmurs.
Dr. Dunn is a second year resident at NYU Langone Medical Center
Peer reviewed by Rosemarie Gambetta, MD, Attending Physician, Department of Medicine (cardiology), NYU Langone Medical Center
Image courtesy of Wikimedia Commons (animation showing a moving echocardiogram; a 3D-loop of a heart viewed from the apex, with the apical part of the ventricles removed and the mitral valve clearly visible).
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