Alpha-Gal Syndrome—A Case Series of Successful Transcatheter Mammalian-Derived Aortic Valve Replacements

Case 1

A 74-year-old male with AGS and critical aortic stenosis underwent TAVR with a 29 mm Medtronic CoreValve ® (Minneapolis, MN) with no evidence of paravalvular leak on postoperative echocardiogram. The patient had a prior history of delayed allergic reactions following mammalian meat ingestion, which prompted formal allergy evaluation and confirmatory testing for AGS, and perioperative prophylactic premedication included prednisone, fexofenadine, solumedrol, and diphenhydramine. Intraoperative unfractionated heparin was tolerated without adverse reaction.

Postoperatively, the patient experienced a transient episode of ventricular tachycardia that was self-resolving. He was discharged on postoperative day 3 and followed regularly. Six years later, he developed severe aortic regurgitation likely related to structural valve degeneration and prosthetic fatigue. Although a contribution from chronic immune-mediated processes related to AGS cannot be completely excluded, there was no definitive evidence linking AGS to accelerated valve degeneration in this case. The patient was offered a replacement of his prosthetic valve, but the patient declined. No allergic or hypersensitivity reactions were reported throughout his course.

Case 2

A 68-year-old male with AGS, hypertension, hyperlipidemia, paroxysmal atrial fibrillation, atrioventricular block, mast cell syndrome, and aplastic anemia (receiving bi-weekly transfusions) underwent TAVR with a 26 mm Edwards SAPIEN ® valve (Irvine, CA) with no evidence of paravalvular leak on postoperative echocardiogram. Despite a history of mild cutaneous reactions to red meat, he had no history of anaphylaxis. No preoperative pharmacologic prophylaxis was administered.

The intraoperative course was unremarkable, and the patient tolerated intravenous heparin without reaction. The postoperative period was uncomplicated, and he remains symptom-free on cardiology follow-up roughly 4 months after the procedure, without allergic manifestations.

Case 3

A 72-year-old male with AGS (previous mild red-meat reaction), Type 2 diabetes mellitus, BMI 32, and hypertension underwent TAVR with a 26 mm Edwards SAPIEN ® valve (Irvine, CA) for severe aortic stenosis with no evidence of paravalvular leak on postoperative echocardiogram. No perioperative prophylaxis was given.

The intraoperative course was uncomplicated. Postoperatively, the patient developed complete heart block requiring permanent pacemaker implantation, attributed to the anatomical location of valve placement rather than hypersensitivity. At 4-years of follow-up, he remains asymptomatic with preserved valve function and no allergic sequelae.

Comparison With Prior Studies

There is little published work describing AGS in the context of cardiac surgery, with most data limited to isolated case reports and small series. Hawkins et al (2016) reported perioperative allergic reactions in AGS-positive patients undergoing surgical bioprosthetic aortic valve replacement, including immediate reactions intraoperatively and delayed cutaneous or systemic symptoms occurring within days to several weeks postoperatively. These reactions were presumed clinically, as confirmatory histopathology was not uniformly available. ⁹ Stone et al (2021) described AGS patients undergoing surgical AVR, with delayed hypersensitivity noted months after implantation, manifesting as recurrent urticaria and eosinophilia. ¹⁰ These cases were likewise clinically diagnosed, although one case demonstrated inflammatory changes on explant pathology consistent with immune activation. In both reports, the valves involved were surgical bioprostheses, not TAVR valves. ¹⁰ A multicenter study found that approximately 17% of patients screened before surgical bioprosthetic valve implantation had α-gal sensitization. In that cohort, no clinically significant allergic reactions were reported during a follow-up period of approximately 6-12 months, suggesting that currently used surgical valve materials are generally well tolerated despite sensitization. ¹¹ Our findings (summarized in Table 1) are consistent with those reports because all three patients in our case series underwent TAVR with mammalian-derived valves and heparin without any hypersensitivity reactions, even in the absence of prophylactic therapy. This describes successful transcatheter valve implantation in AGS patients, contrasting prior literature that primarily focuses on open surgical AVR.

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Table 1.

Summary of Cases: Alpha-Gal Syndrome Patients Undergoing Mammalian-Derived TAVR

Case	Age/sex	AGS history	Valve type	Heparin use	Premedication	Intraoperative course	Postoperative course	Follow-up
1	74/M	Severe, confirmed by testing	Medtronic CoreValve	Yes	Prednisone, fexofenadine, solumedrol, diphenhydramine	Unremarkable	Transient VT; discharged POD 3	6 years; asymptomatic until valve fatigue
2	68/M	Mild cutaneous reactions only	Edwards SAPIEN	Yes	None	Unremarkable	No complications	4 months; asymptomatic
3	72/M	Mild red meat reaction	Edwards SAPIEN	Yes	None	Unremarkable	Pacemaker for heart block	4 years; valve intact

Considerations

Several factors may explain the absence of allergic reactions in our patients. Modern TAVR valves undergo extensive decellularization and glutaraldehyde fixation, processes that markedly reduce α-gal antigenicity. Although glutaraldehyde fixation has been standard for surgical valves for decades, current-generation TAVR valves, which have been commercially available since 2011-2014, incorporate more aggressive decellularization and anticalcification treatments than earlier surgical bioprostheses. It is therefore possible that earlier reports of hypersensitivity reflected exposure to less-processed valve tissue, whereas contemporary transcatheter valves contain substantially lower levels of residual immunogenic epitopes. ¹² Experimental data have shown that α-gal-free or enzymatically treated xenografts provoke significantly less IgM- and IgE-mediated immune activation, correlating with improved bioprosthetic durability.^13,14 Moreover, delayed hypersensitivity may not be efficiently triggered by the limited antigen exposure that occurs during TAVR, as opposed to systemic exposure to heparin or parenterally administered bovine-derived agents. Variability in α-gal IgE titers among individuals also likely contributes to heterogeneous clinical responses. ¹⁵ Heparin presents a unique challenge because, although it is porcine in origin, its antigenic α-gal content may vary by manufacturer and lot. ¹⁶ Prior studies demonstrated that up to 50% of AGS patients with high IgE titers may develop hypersensitivity to high-dose heparin during cardiopulmonary bypass, particularly in those with recent tick sensitization. ¹⁷ In contrast, low-dose heparin used during TAVR may fall below the threshold for reaction.

Recent advances in xenogeneic tissue engineering have focused on the development of genetically modified pigs that lack expression of the α-gal epitope. Alpha-gal–deficient (“GalSafe”) pigs have received U.S. Food and Drug Administration approval for food and biomedical applications, and their tissues are being actively investigated for use in implantable medical devices, including bioprosthetic heart valves. Preclinical studies suggest that α-gal–negative porcine tissues provoke less IgM- and IgE-mediated immune activation and may exhibit reduced calcification compared with conventional porcine xenografts. At present, however, no commercially available transcatheter or surgical heart valve marketed by major manufacturers, including Edwards Lifesciences or Medtronic, is derived from genetically modified α-gal–deficient porcine tissue. As such, current clinical practice continues to rely on extensively processed conventional porcine bioprostheses. The emergence of α-gal–free valve technologies may ultimately alter recommendations for patients with AGS, but further clinical validation is required. ¹⁸

Clinical Implications

Our findings highlight the importance of a coordinated team approach in caring for AGS patients who require cardiac procedures. Taking a thorough allergy history and checking α-gal IgE levels ahead of time may help identify patients at higher risk and inform how we manage them perioperatively. ¹⁹ For patients who have had recent reactions or have positive α-gal titers, it is reasonable to give corticosteroids, H₁ and H₂ blockers, and a leukotriene inhibitor before the anticipated procedure. ²⁰ In higher-risk cases, or when cardiopulmonary bypass is needed, non-heparin anticoagulants like bivalirudin or argatroban can be used instead. However, they are more difficult to reverse and require close monitoring. ²¹ Clear multidisciplinary communication among anesthesia, cardiology, allergy, and surgical teams is also important to minimize perioperative risk and avoid unexpected intraoperative reactions. Additionally, heparin skin testing may help identify tolerance preoperatively when the clinical history is not clear. ²²

Study Limitations

This case series is limited by its small sample size, retrospective design, and absence of uniform α-gal IgE quantification. Given the rarity of AGS and the heterogeneity of clinical presentations, the lack of systematic allergy testing and follow-up precludes definitive conclusions regarding long-term valve durability or the protective effect of decellularization. ²³ We are also unable to rule out the possibility of subclinical hypersensitivity or delayed, immune-driven changes in the valve over an extensive period of time. Prospective studies that combine biochemical valve analysis with immunologic profiling will be crucial for better understanding these potential links.

Future Directions

Future investigations would ideally establish multicenter registries to capture procedural and immunologic outcomes of AGS patients undergoing cardiac surgery and TAVR. Laboratory studies assessing residual α-gal antigenicity in commercially available bioprostheses, as well as the efficacy of α-gal–negative xenografts, could further inform device selection. It would be helpful to have standardized perioperative guidelines that cover premedication, heparin testing, and postoperative monitoring to make these procedures safer for patients. Taken together, these steps could improve how we assess risk and might eventually allow for more personalized approaches to cardiac surgery for the increasing number of patients with α-gal sensitization.