Disclaimer- The posts in this series are intended to improve awareness of this important and potentially deadly disease. I am not an Allergist or Immunologist and I am not offering any medical advice. Please consult with your own physician or health care provider for that. An educated patient and their family are the best advocates for their health care.

There are several studies that have suggested a possible connection between Alpha-gal syndrome (AGS) and two types of heart disease. The first is the potential for premature deterioration of porcine or bovine prosthetic heart valves used in the treatment of valvular heart disease. This is a form of xenotransplantation where the patient’s diseased heart valve is replaced with one from either a pig or cow. The second is an association with coronary artery disease.

Bovine or porcine prosthetic heart valves

The first study suggesting that porcine heart valves could represent a problem for patients with AGS was carried out in 2005 by Konakci in Vienna, Austria. The authors were able to detect the α-Gal antigen on the surface of fibroblasts in commercially-prepared porcine heart valves by using confocal laser scanning microscopy. In addition, patients with surgically implanted bioprosthetic valves developed a statistically significant increase in cytotoxic IgM anti-α-gal antibodies compared to controls within 10 days of surgery. These were in patients without AGS but it did suggest that the increase in cytotoxic antibodies could play a role in the degeneration of bioprosthetic valves over time.

Subsequently, Mozzicato at the University of Virginia in 2014 reported three patients with AGS two of which developed allergic symptoms shortly after surgery. The first received a porcine valve in the mitral position. On the first postoperative day he developed extensive urticaria on the chest and lower extremities, which resolved with benadryl and famotidine. The second patient also had a known history of AGS and underwent aortic valve replacement with a bovine valve. At the end of the procedure he developed anaphylaxis that was treated with epinephrine, dexamethasone, famotidine and fluids. The implantation of the valves triggered symptoms in both patients but it did not extend beyond the immediate postoperative period. In both cases the valves were pretreated with glutaraldehyde to reduce antigenicity. The authors postulated that the implantation triggered a rapid release of antigen that was short lived.

In 2016 at the University of Virginia Hawkins reported two patients with bioprosthetic aortic valves who developed AGS after surgery followed by rapid degeneration of their bioprostheses. In the first case the patient received a porcine aortic valve in 2004. Eight years later in 2012 he was diagnosed with AGS. Severe aortic insufficiency requiring replacement of the bioprosthesis with a mechanical valve occurred two years later. After removal the valve leaflets were noted to be severely damaged. The second patient underwent aortic valve replacement in 2009 with a bovine pericardial aortic valve. In April 2014, he developed symptoms compatible with AGS requiring several emergency department visits but serum IgE levels to α-gal were never measured. He was subsequently referred to an allergist that same year and the diagnosis established. Early in 2015 he developed chest pain and shortness of breath with a high transvalvular gradient indicating worsening aortic stenosis. His bioprosthesis was replaced with a mechanical valve. The bioprosthetic valve showed severe calcific degeneration, shown below. In both cases the patients required repeat surgery within 1-2 years after developing AGS.

Bloch in Germany reported data on the decellularization of bioprosthetic valves in order to attempt to reduce their antigenicity. He writes “Conventional biological heart valves treated with glutaraldehyde (GA) reveal a limited lifespan due to calcification. This is assumed to be an immune response initiated process, which is not seen with decellularized valves. However, their immunological potential is still a matter of debate. Therefore, serum samples from patients undergoing heart valve surgery were obtained before (Pre), after (Post), and 9-12 months after operation (Follow Up). Immunoglobulin G (IgG) and M (IgM) antibodies against porcine collagen I and α-Gal were determined for decellularized and GA treated valves. Antibody titers for collagen type I revealed no significant alteration for both types of valves. However, a considerable anti-α-Gal antibody response was observed in patients with GA-treated porcine valves. In detail, IgM antibodies were increased during follow up (p<0.05), whereas decellularized valves revealed a minor decrease in the IgM response (p<0.001). IgG antibodies were considerably increased with GA-treated porcine (p <0.05) and bovine (p <0.01) xenografts, whereas there was lack of response with decellularized valves. This indicates that GA treatment is not sufficient to eliminate immune response to the α-Gal epitope completely. Future investigations will have to verify whether immune response to α-Gal can be linked to the limited durability of conventional valves.”

Porcine and bovine bioprosthetic valves have traditionally been used instead of mechanical valves in younger patients because they do not require anticoagulation. The reports above involve very small numbers of patients but raise concerns about their durability in patients with AGS. Newer decellularization methods outlined in the Bloch paper if replicated could reduced the antigenicity of the allograft and may be able to address these issues.

IgE to α-Gal and Cardiovascular (CV) Disease

The hypothesis that AGS might be associated with CV disease began with the observation that patients with the disease seen in the University of Virginia allergy clinics seemed to suffer a higher incidence of heart attacks than expected. This could have resulted from the fact that AGS patients are more likely to be male and older. In 2018 Wilson and McNamara at the University of Virginia measured total IgE and α-Gal specific IgE in 118 patients that presented for cardiac catheterization and also underwent intravascular ultrasound. Twenty six percent of patients had measurable levels of IgE antibodies to α-Gal and this subgroup had an increased atheroma burden and volume compared to unsensitized patients. Data was not available regarding whether the patients were symptomatic. The strength of the association with atheroma burden was stronger in those individuals age 65 and younger and they were more likely to have plaques with less stable characteristics on intravascular ultrasound. The association remained significant even after adjusting for diabetes mellitus, sex, hypertension, total IgE and statin use. This was the first published study to suggest a link between anti-α-Gal antibodies and CV disease. In a subsequent review Wilson, McNamara and Platts-Mills postulated that the continued ingestion of α-gal containing foods in those with anti-α-Gal IgE antibodies could induce chronic inflammation in the coronary artery vessel wall.

This was followed by a report from Vernon in Australia in 2022. They performed a cross-sectional analysis of 1056 patients referred for coronary angiography for suspected coronary artery disease and 100 selected patients with ST-segment elevation myocardial infarction (STEMI) enriched for patients without standard modifiable risk factors enrolled from the BioHEART-CT and Bio-HEART-MI cohorts. CT coronary angiograms were assessed by coronary artery calcium scores and segmental plaque scores. The presence of α-Gal specific IgE was associated with the presence of noncalcified plaque (Odds ratio- 1.62, 95% confidence interval 1.04-2.53), and obstructive coronary artery disease (Odds ratio- 2.05, 95% confidence interval 1.29-3.25) independent of age, sex and traditional cardiovascular risk factors. The association was even stronger in patients with STEMI (12.8-fold higher compared to healthy matched controls- 17% vs. 1.3% and 2.2-fold higher compared to matched patients with stable CAD- 20% vs 9%. Data was not collected on whether or not the patients were symptomatic.

A third study that we will not discuss in detail examined subjects with a wide variety of IgE-related food allergies and their possible link to CV disease. These included cow’s milk, α-Gal, peanuts, eggs, and shrimp. Not enough α-Gal patients were included to analyze this subgroup. Food sensitization was associated with increased CV mortality.

Considering only the first two studies it is important to realize that the study population consisted of patients with elevated α-Gal-specific IgE levels not symptomatic patients with AGS. Patients with AGS are a small subset of those with elevated α-Gal-specific IgE levels (16.2% in one study in central Virginia). The study population includes but is much larger than those affected by AGS. The first study showed an association with increased atheroma burden and volume compared to unsensitized patients, which was stronger in study subjects age 65 and younger. In the second study the presence of α-Gal specific IgE was associated with: the presence of noncalcified plaque (Odds ratio- 1.62); obstructive coronary artery disease (Odds ratio- 2.05) independent of age, sex and traditional risk factors; and with ST-segment elevation myocadial infarction (12.8-fold higher compared to healthy matched controls- 17% vs. 1.3%, and 2.2-fold higher compared to matched patients with stable CAD- 20% vs 9%. In a recent review in 2024 Wilson, Commins and Platts-Mills wrote (link) “A causal relationship with atherosclerosis remains to be established but our working hypothesis is that sub-clinical inflammation in the vessel wall results from an interaction between a specific immune response to alpha-gal and routine ingestion of the allergen as part of the Western diet. Further studies are needed to clarify the magnitude of risk, determine whether dietary avoidance mitigates the risk and also to investigate whether sensitization could confer the risk of other subclinical chronic inflammatory diseases.”

Next- Medications and Other Medical Products that May Contain Alpha-gal