Abstract
Background
Alpha-gal syndrome (AGS) is an IgE-mediated hypersensitivity response to galactose-alpha-1,3-galactose (alpha-gal), an oligosaccharide present in beef and pork. This complicates bioprosthetic heart valve selection, as both bovine and porcine valves contain alpha-gal, posing risks of allergic reaction and potentially accelerated structural valve degeneration.
Case Summary
A 78-year-old man with AGS and severe symptomatic aortic stenosis underwent transcatheter aortic valve replacement with a porcine-derived Evolut FX 29-mm valve following multidisciplinary evaluation. Preoperative allergist-guided prophylaxis, including IgE risk stratification, antihistamines, and corticosteroids, enabled successful implantation without complications.
Discussion
Bioprosthetic valves may pose unique risks for individuals sensitized to alpha-gal, where an alpha-gal IgE to total IgE ratio ≤5% is a proposed threshold in which patients can be rechallenged with animal products. This case highlights the successful management of a slightly higher ratio.
Take-Home Message
The interplay between AGS, bioprosthetic valve selection, and structural valve durability necessitates an individualized approach to mitigate the hypersensitivity risks.
Key words: aortic valve, cardiac risk, Doppler ultrasound, echocardiography, stenosis, valve replacement
Visual Summary
History of Presentation
A 74-year-old man with alpha-gal syndrome (AGS), severe aortic stenosis (AS), and recurrent gastrointestinal bleeding without a source presented with progressive exertional dyspnea and declining exercise tolerance over several months. He was evaluated for aortic valve replacement, which was complicated by his history of AGS with prior allergic reactions manifesting as urticaria and gastrointestinal discomfort following red meat consumption. His first hypersensitivity reaction to beef was reported in 2020 with diffuse pruritus, chest urticaria, and mild shortness of breath. Subsequent episodes followed meat ingestion, including one emergency department visit requiring epinephrine for severe shortness of breath. Notably, the patient reported tolerating pork on multiple occasions without symptoms.
Take-Home Messages
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Alpha-gal syndrome complicates valve selection in aortic stenosis due to the presence of alpha-gal epitopes in bovine and porcine bioprosthetic valves, which may trigger allergic or inflammatory responses.
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An IgE:total IgE ratio ≤5% may serve as a practical threshold for rechallenge with animal-derived products, where individualized allergist-guided prophylaxis and valve selection may enable safe porcine valve implantation.
Past Medical History
The patient's past medical history was significant for AGS, severe AS, coronary artery disease with 2 percutaneous coronary interventions (2008 and 2019), type 2 diabetes mellitus, and recurrent gastrointestinal bleeding without an identified source. He was functionally NYHA class II and Canadian Cardiovascular Society class I at presentation.
Differential Diagnosis
The differential diagnosis of progressive exertional dyspnea in this patient included coronary artery disease, heart failure with preserved ejection fraction, and anemia due to recurrent gastrointestinal bleeding.
Investigations
Transthoracic echocardiogram (TTE) demonstrated a mean pressure gradient of 41.1 mm Hg, a peak aortic valve velocity of 4.0 m/s, and a calculated valve area of 0.989 cm2, all consistent with severe AS (Figure 1A). Moderate aortic valve calcification is present (Figure 1B). He had a preserved left ventricular ejection fraction of 55%.
Figure 1.
Transthoracic Echocardiogram With Spectral Doppler
(A) Spectral Doppler echocardiography demonstrating severe aortic stenosis. Red arrows show a mean pressure gradient of 41.1 mm Hg, peak aortic velocity of 4 m/s, and aortic valve area of 0.989 cm2. (B) Parasternal short-axis view showing an incompletely closed aortic valve during diastole with thickened cusps from moderate valve calcification.
An expert alpha-gal allergy consultation was obtained to guide perioperative planning for transcatheter aortic valve replacement (TAVR) in the context of the patient's known AGS. The patient's alpha-gal IgE measurement was 1.4 kU/L, constituting 7% of his total IgE, which reflected a low reactivity, near the 5% threshold proposed by our expert, for safe rechallenge. Consultation also noted a dose-dependent incidence of anaphylaxis with heparin use in alpha-gal patients and that bovine valves are typically a more provocative trigger than porcine valves.
Management (Medical/Interventions)
Given the patient's progressive symptoms and echocardiographic findings, aortic valve replacement was indicated. With ongoing gastrointestinal bleeding events and the potential risk of heparin-induced hypersensitivity, a mechanical valve was deemed suboptimal, and a bioprosthetic option was preferred. To minimize heparin exposure, a transfemoral approach was recommended by an alpha-gal allergy specialist along with a prophylactic pretreatment regimen. Two days prior to the procedure, the patient's hemoglobin was 14.3 g/dL, hematocrit 40.3%, platelet count 204 × 109/L, and white blood cell count 13.05 × 109/L without clinical signs of infection. These values reflected a stable baseline prior to intervention. Intravenous diphenhydramine would be administered 1 hour prior to valve implantation, and antihistamines would be continued for 48 hours postoperatively to reduce the risk of allergic complications.
In addition to these safeguards, given the patient's history of reactions solely to beef and having tolerated eating pork chops on occasion, he opted for a porcine-derived Evolut Fx 29-mm valve (Figure 2). The patient was pretreated for 4 days, receiving prednisone 30 mg twice daily, montelukast 10 mg daily, and cetirizine 10 mg nightly. Diphenhydramine 50 mg intravenously was administered 1 hour before the procedure. Systemic heparin was administered with a target activated clotting time of 250 seconds utilized with protamine readily available intraoperatively in the event of an adverse reaction. The procedure was successful without complications, and postoperatively, aspirin 81 mg was given daily. No clopidogrel was ordered due to a history of clopidogrel-induced bleeding.
Figure 2.
Left Coronary Angiography Evolut Fx 29-mm Porcine Valve in the Aortic Position During Left Coronary Angiography
Outcome and Follow-Up
Following his procedure, the patient experienced no allergic reactions and reported significant symptomatic improvement at both 1- and 2-year interval follow-up. Four days after implantation, TTE demonstrated a mean pressure gradient of 10 mm Hg and a peak aortic valve velocity of 2.2 m/s. At 2 years, TTE showed a mean pressure gradient of 9.2 mm Hg, a peak aortic valve velocity of 2.2 m/s, and an aortic valve area of 2.3 cm2, indicating preserved valve function without structural degeneration. The patient's Kansas City Cardiomyopathy Questionnaire score improved from a baseline of 57 (moderate health status) to 86 (excellent health status) at 1-year follow-up.
Discussion
AS is the most prevalent valvular heart disease encountered in clinical practice and a leading cause of morbidity among older adults. Current guidelines recommend aortic valve replacement as a Class I indication for severe symptomatic AS.1 With TAVR now extended to intermediate- and low-risk populations as supported by the PARTNER 3 and Evolut Low Risk trials, valve selection has become a critical aspect of preprocedural planning, particularly in patients with atypical risk factors.2,3 AGS presents one such challenge, particularly with the growing use of bioprosthetic valves. Both bovine and porcine valves contain alpha-gal, posing risks of allergic reactions or anaphylaxis, and may contribute to premature valve degeneration mediated by eosinophilic infiltration of valve tissue.4,5 Early bioprosthetic valve failure is associated with increased morbidity and worse long-term survival. Despite these risks, screening for alpha-gal sensitization is not currently a part of standard preoperative evaluation for valve-replacement candidates, and no formal guidelines exist for managing AGS.1 Preclinical studies have shown that glutaraldehyde-treated bioprosthetic valves may retain residual xenoantigens inherent to their tissue origin, including alpha-gal epitopes, which can provoke immune responses.6 Therefore, final risk assessment and valve selection remain at the discretion of the implanting heart team, guided by patient-specific factors.
Currently, no validated cutoff for alpha-gal reactivity exists. Fischer et al7 identified 0.59 kU/L as the optimal threshold for clinically meaningful sensitization, based on receiver operating characteristic analysis demonstrating 83% sensitivity and 81% specificity. Mabelane et al8 reported a 95% probability of reactivity when alpha-gal–specific IgE exceeds 5.5 kU/L or the IgE:total IgE ratio surpasses 2.12%. Our consulting allergist suggested a threshold ratio of ≤5% as a reasonable cutoff to permit animal product rechallenge. This 5% threshold is not formally validated in published studies but was applied here based on clinical judgment. Prior reports, including those by Mabelane et al8 and Fischer et al7, have proposed lower ratio-based or absolute IgE thresholds associated with clinical reactivity. Our patient's alpha-gal–specific IgE of 1.4 kU/L exceeded the sensitization threshold, and his IgE:total IgE ratio of 7% surpassed the reactivity threshold, indicating clinical sensitivity. However, his absolute alpha-gal IgE remained below the high-risk value of 5.5 kU/L, highlighting the importance of contextual interpretation.
Notably, reactivity thresholds may be source-specific, with some patients exhibiting selective reactivity to beef but not pork, such as our patient. This phenomenon may relate to differences in alpha-gal antigenicity based on tissue source and processing methods. Prior studies have suggested that higher cooking temperatures reduce antigenicity in pork.9 In addition, bioprosthetic valves undergo glutaraldehyde fixation, which may diminish residual alpha-gal epitopes, although the extent of this effect remains unclear.7 Furthermore, our patient's blood type was O positive. The alpha-gal epitope shares structural similarity with the blood group B antigen, and individuals with blood group B or AB may exhibit partial immune tolerance to alpha-gal due to this resemblance.10 However, such tolerance is absent in individuals with blood group O, suggesting other factors such as source-specific antigenicity or processing effects likely accounted for our patient's lack of hypersensitivity.
A tailored prophylactic strategy including prednisone, montelukast, cetirizine, and perioperative diphenhydramine was implemented based on expert allergist input. This regimen successfully mitigated hypersensitivity risk and enabled the safe transfemoral implantation of a porcine-derived bioprosthetic valve, chosen based on the patient's selective tolerance of pork products. He was counseled to avoid Lone Star tick bites which can trigger increases in alpha-gal IgE levels.9 The success of this approach likely reflects the suppression of allergic pathways via antihistamines, leukotriene inhibition, and corticosteroids.9 This case demonstrates that with careful allergen risk stratification and targeted pretreatment, TAVR can be safely performed in alpha-gal–sensitized patients, even when IgE ratios exceed suggested thresholds.
Looking forward, the development of alpha-gal–negative biomaterials may offer safer and more durable alternative for patients requiring tissue-based implants. Ultimately, this case demonstrates the value of anticipatory, individualized pretreatment protocols to reduce allergic risk in sensitized patients.
Conclusions
This case reinforces the importance of individualized, multidisciplinary care in the management of patients with AGS undergoing aortic valve replacement. Careful preoperative assessment, including allergist-guided prophylaxis and tailored procedural planning, is essential to anticipate and mitigate the risk of hypersensitivity reactions. We also present practical perioperative strategies, such as targeted pharmacologic pretreatment and procedural safeguards, that appear effective in mitigating allergic risk in this context. In select patients with AGS, transfemoral TAVR with a porcine-derived bioprosthetic valve can be safely performed when appropriate precautions are in place. As clinical recognition of AGS increases, further research is needed to establish standardized screening protocols, refine perioperative management strategies, and optimize long-term valve performance.
Visual Summary.
Brief Timeline of Clinical Events and Interventions
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
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