Alpha-gal xenoantigens in bioprosthetic valve recipients: clinical implications for bioprosthesis longevity

Abstract

Background

Structural valve degeneration (SVD) is a key limitation of bioprosthetic heart valves (BHVs). The underlying mechanisms for this degeneration and pathophysiology remains only partially defined. Emerging evidence implicates a xenogeneic carbohydrate epitope, galactose-α-1,3-galactose (Alpha-gal), as a potential driver of immune-mediated valve deterioration. This review explores the current knowledge on alpha-gal (AG) sensitization and evidence linking it to SVD and the potential clinical implications.

Methods

A literature search was conducted using Embase, PubMed and Scopus, using variants of the following keywords, such as “alpha-gal”, “bioprosthetic valve”, and “degeneration”. Studies included reported human subject findings and focused on BHVs. Only original works were permitted, published between January 2014 and December 2025.

Results

Six studies met the inclusion criteria. Case reports demonstrated heterogenous clinical outcomes with, rapid SVD observed in some alpha-gal sensitized patients, while other patients showed tolerance to bioprosthetic implantation in the perioperative and short-term period. The only study with longitudinal follow-up demonstrated that anti-AG IgG responses were associated with increased SVD and calcification. Another study found no perioperative adverse valvular outcomes, although follow-up was limited to in-hospital assessment. Overall, his manuscript identifies that AG sensitization may contribute to SVD in certain patients, however, its broader significance remains uncertain.

Conclusions

Immune recognition of AG may contribute to SVD based on the limited available evidence. Larger prospective investigations are required to clarify a causal relationship and to assist in guiding potential preventative strategies. Recognition of this mechanism may ultimately inform management of valve replacement and bioprosthesis selection plans.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13019-026-04270-y.

Introduction

Alpha-gal (AG), also known as galactose-α−1,3-galactose, is a carbohydrate epitope widely expressed in all non-primate mammals and some invertebrates [1]. In humans, apes, and Old-World monkeys, the gene encoding α−1,3-galactosyltransferase (GGTA1) is inactive, resulting in a lack of AG production [2]. As a result, humans develop natural antibodies (IgG, IgM and sometimes IgE) against AG through continuous stimulation by intestinal flora bacteria (which constitutively express antigens) or following the exposure to such antigen by tick bites [3, 4].

In particular, AG Syndrome (AGS) is a form of food allergy due to sensitivity to AG [5]. Sensitization in the United States (US) is considered primarily to result from tick bites, particularly from the Lone Star Tick (Amblyomma Americanum), a species mainly found in southeastern/eastern regions of the US. However, studies have demonstrated that other tick species are also capable of inducing AGS, for instance, Ixodes scapularis/the blacklegged tick) [6, 7]. In fact, AGS cases have been documented worldwide, in regions where entirely different tick species are present. In Europe (Ixodes ricinus), Australia (I. holocyclus), Brazil (Amblyomma sculptum), Japan (Haemaphysalis longicornis), and in parts of Africa and South America, where bites from local hard-bodied ticks are implicated in AG sensitization [8]. Therefore, while initial awareness of AGS was closely linked to the Lone Star tick in the US, it is now well-established that multiple tick species around the world can carry or transmit AG, thereby triggering this serious allergic condition globally.

Where a human subject suffers a bite from a species of tick that carries AG, subsequent consumption of mammalian meat may trigger the onset of AGS symptoms (within two to eight hours in a typical patient). Presentation can range from allergic responses such as rashes and nausea to life-threatening anaphylaxis [9, 10]. While the exact number of cases is unknown (due to lack of mandatory reporting), the Centers for Disease Control and Prevention (CDC) estimates nearly 450,000 people may have AGS in the US [11]. This represents a marked increase in prevalence over the past decade, with the number of cases expected to rise. Reasons for increasing incidence include expanding tick populations and range, greater awareness, and changes to human behaviors, as well as land use [12]. The increasing prevalence of AGS has significant implications for public health, clinical practice, and food safety.

Over time, the range of drugs and medical products derived from mammalian cells or tissues that may pose a risk for individuals sensitized to AG has steadily expanded. To date, cetuximab remains the only therapeutic antibody associated with a high risk of reaction in these patients. Nonetheless, the AG epitope is also present in several other biologically sourced products, including gelatin, antivenoms, heparin, plasma expanders such as Gelofusine, conjugated estrogens and vaccines. Notably, cases of allergic reactions to systemic heparinization during cardiac surgery have been reported in patients with pre-existing AGS [13].

An analysis conducted by Tatham and Patel on the 100 most commonly prescribed medications in primary care in the UK (NHS Business Services Authority) sheds light on this issue [14]. Excipients of animal origin are frequently employed in drug formulation: lactose from cow’s milk is often used as a filler or processing aid, gelatin of bovine or porcine origin is common in capsules, and heparin continues to be manufactured from bovine lung or porcine intestinal tissue. Their findings revealed that 74% of these products contained at least one of three potentially problematic excipients: lactose, gelatin, or magnesium stearate. Lactose was identified in 59 drugs, 48 of which had corresponding public assessment reports; in approximately one-fifth of these, the presence of animal-derived material was not explicitly declared. Even when animal origin was acknowledged, details on the production method were usually omitted. Magnesium stearate appeared in 49 formulations, with its animal origin confirmed in only four cases, a vegetarian source verified in 31, and no provenance information provided for the remaining 14. Gelatin was present in 20 drugs, yet labeling inconsistencies were frequent: in some cases, products were incorrectly reported as free of animal components, while others acknowledged animal-derived ingredients but failed to specify their source. Among those that did, porcine, bovine, or mixed bovine/porcine origins were identified.

Bioprosthetic heart valves (BHVs) are typically derived from bovine or porcine tissue, which inherently express the AG epitopes, even in decellularized tissues [15, 16]. The implantation of BHVs into humans thus results in recognition of the AG epitopes as xenoantigens, with the potential to elicit an immune response [17]. Immune recognition may contribute to chronic inflammation, accelerated calcification and tissue degeneration- hallmarks of structural valve degeneration (SVD) [18]. Heightened anti-AG activity, particularly in those patients who have been sensitized, could accelerate bioprosthesis failure. This raises concerns regarding the role of AG in the long-term durability of BHVs, and may help explain observed variability in valve longevity, especially among younger recipients [19].

Understanding this immunological interaction and host response is becoming of increasing importance, with implications for valve design, patient selection and postoperative monitoring[20]. This review synthesizes current evidence linking alpha-gal–mediated immunity to BHV performance and explores its potential role in guiding future clinical practice. The proposed mechanism of AG sensitization and the resultant implications are illustrated in Fig. 1.

Fig. 1.

Proposed pathways linking AG sensitization to SVD in BHVs

Clinical patterns and unresolved mechanisms

BHVs have become a preferred option for many patients due to the lack of requirement for lifelong anticoagulation (in contrast to mechanical valves), along with their expanding use in transcatheter procedures [21, 22]. It is reported that from 1996 to 2013, BHV use in aortic-valve replacement (AVR) increased from 11.5% to 51.6%, and for mitral-valve replacement (MVR) from 16.8% to 53.7%, particularly in the under 60-year-old population [23]. Despite the aforementioned advantages, SVD remains the most common reason for reintervention [24]. Goldstone et al., 2017 reported an association with mechanical valves and a longer-term survival in younger patients, with a seen benefit persisting up to ~ 55 years for AVR and up to ~ 70 years for MVR [25]. Additionally, one sub-analysis of the AUTHEARTVISIT study (near 14,000 sample size in this group), found that use of BHVs had significantly higher mortality than mechanical valves for AVR in patients aged 50–65 years [26]. Mechanical degeneration and dystrophic calcification have long been recognized as causes of SVD [27]; however, increasing attention has turned towards foreign body rejection and host immune responses as potential contributors to SVD, offering a partial explanation as to why some BHVs may exhibit earlier signs of degeneration and consequent higher rates of mortality [28, 29].

SVD is an inevitable process often characterized by thickening, stiffening and calcification that can lead to stenosis, regurgitation or even both [30]. Typical signs and symptoms include dyspnea, fatigue, angina and syncope, often accompanied by new or changing cardiac murmurs present due to worsening stenosis or regurgitation. In advanced stages, features of heart failure may be present [31, 32]. Histopathologic studies of explanted BHVs such as the findings reported by Lepidi et al., 2006 and Sakaue et al., 2023, reveal features suggestive of chronic inflammation, macrophage infiltration and foreign-body type responses, often without mechanical wear [33, 34]. The interaction between circulating anti-alpha-gal antibodies and calcification of BHVs has been established, but how it contributes to long-term dysfunction is not yet fully understood [35]. Although there have been advances in anti-calcification treatments and tissue preservation techniques, early SVD remains an issue with all current valves, and the exact role of anti-alpha-gal antibodies warrants investigation. The purpose of the current study is to review the existing literature on AG and clinical research pertaining to bioprosthetic valve durability. Patient risk factors for SVD are outlined in Table 1.

Table 1.

Patient risk factors for SVD

Category	Risk factors
Patient-related	Younger age, female sex, hyperparathyroidism, metabolic syndrome, diabetes, hyperlipidemia, smoking status, AG sensitization [36, 37]
Valve-related	Porcine vs. bovine, lack of anti-calcification treatment, stented vs. stentless [38, 39]
Procedural	Patient–prosthesis mismatch, suboptimal implantation [40]
Hemodynamic	High cardiac output, hypertension [41]
Infective/inflammatory	Prosthetic valve endocarditis, chronic inflammation, autoimmune disease [42, 43]

Materials and methods

Review design and search strategy

We conducted a literature search between May 2025 and July 2025 using three databases, namely: Embase, PubMed and Scopus (via Elsevier). The aforementioned databases were searched using the variants of the following keywords, such as “alpha-gal”, “bioprosthetic valve”, and “degeneration” combined using Boolean operators. The full search strategy for the databases is provided within the Supplementary Index. The articles selected were published between January 2014 and December 2024 to reflect contemporary evidence, while earlier studies have been selectively referenced throughout the manuscript to provide relevant background and mechanistic context. All articles had to be in full, published in the English Language.

Selection criteria

For a study to be included in this review, the following inclusion and exclusion criteria had to be met: the study had to be an original work (case reports, case series, retrospective/prospective studies, cohort studies), reporting human subject findings. The studies had to focus on BHVs. Studies that involved animal subjects, mechanical valves, or non-original content such as editorials, letters to editors, conference abstracts without full text and reviews were also excluded. Study eligibility was initially assessed through reading of the titles and abstracts, and then following this, selected studies were read in full.

Data extraction

Data was extracted from the selected studies using a predefined template, including publication year, study design, population, valve type, AG assessment, clinical AG status, comparator (where applicable), follow-up duration and outcomes. Outcomes were categorized into perioperative outcomes, early post-implantation valve function and SVD. Follow-up duration was recorded as reported.

Results

The initial search identified 190 potentially relevant studies, with 170 remaining after duplicate removal. Upon reviewing titles and abstracts 42 potentially suitable studies remained, with these then reviewed in full, leaving just 5 that met the criteria. The key findings of the literature search are summarized in Table 2. The database search was further expanded to include publications in 2025. As a result, an additional study met the criteria, bringing the total to 6.

Table 2.

Results of the literature search

Study	Study type	Population/model	BHV type/tissue	Alpha-gal Assessment	Clinical AG status	Comparator	Follow-Up Duration	Outcome Category	Key AG-related findings
Hawkins et al., 2016 [44]	Case series	n = 2	Porcine (Case 1), Bovine pericardial (Case 2)	AG IgE specific > 100 kU/L in Case 1 and 1.48 kU/L alpha-gal titer in Case 2 ‡	Confirmed AGS (clinical + serology)	None	Valve degeneration occurred within 1–2 years after onset of AGS (implanted 6–10 years prior)	SVD + reoperation	Both patients developed AGS post tick exposure. Subsequently showed rapid increase in transvalvular gradients and SVD. Required mechanical valve replacement. Explants showed advanced calcific degeneration
Senage et al., 2022 [45]	Prospective multicenter cohort + translational/mechanistic analyses	n = 1668	Predominantly bovine pericardial BHVs (~ 80%), also porcine	Anti-AG IgG and anti-Neu5Gc IgG (serial measurements); IgG and complement detected in explanted human BHVs	Not AGS-specific (no clinical AGS stratification)	Yes (mechanical valve/coronary artery bypass grafting (CABG) controls)	Mean 34 ± 43 months (range 0.1–182 months; up to ~ 15 years)	SVD + explant pathology	Anti-AG IgG increased after BHV implantation (peaked ~ 1 month); early SVD detected in ~4.9% at ~ 21 months; calcified human BHV explants showed glycan (Neu5Gc), IgG deposition and complement activation
Taira et al., 2024 [46]	Case report	n = 1	Bovine pericardial patch (Atrial septal defect closure); valve repair (no prosthetic valve)	Serum α-gal IgE elevated (1.71 kU/L pre-op → 7.59 kU/L post-op)	Confirmed AGS (mild; no prior anaphylaxis)	None	~ 12–15 months	Perioperative tolerance + short-term implant outcome	No intraoperative or postoperative allergic reaction; at 1-year follow-up, no evidence of patch degeneration or dysfunction on echocardiography
Chen & Zeigler, 2024 [47]	Case report	n = 1	Bovine pericardial BHV (INSPIRIS RESILIA)	Serum AG IgE elevated (10.6 kU/L; class IV “very high”)	Confirmed AGS (severe; symptomatic)	None	~ 2–3 months (11-week echo follow-up)	Perioperative tolerance + early valve function	No intraoperative or postoperative allergic reaction; early follow-up showed normal valve function with no thrombosis, stenosis, or regurgitation
Aykut et al., 2024 [48]	Prospective cohort (single center)	n = 155; 48 with detectable α-gal IgE; 22 meeting AGS criteria	BHV (SAVR* + TAVR**; bovine/porcine-derived)	Preoperative serum AG IgE (ELISA†; sensitization ≥ 0 IU/mL, AGS > 0.1 IU/mL)	Mostly asymptomatic sensitization; AGS defined serologically (not clinically symptomatic cohort)	Yes (IgE-positive vs. IgE-negative patients)	In-hospital + discharge (short-term only)	Perioperative outcomes + early valve function	No serious allergic reactions or in-hospital mortality in AG sensitized patients; no difference in intensive care unit (ICU) stay, hospital stay, or transvalvular gradients at discharge; immediate valve function comparable between groups
Sami et al., 2025 [49]	Case report	N = 1	Porcine (TAVR)	AG IgE 1.4 kU/L (7% of total IgE)	Confirmed AGS (clinical + serology)	None	2 years	No SVD observed	No perioperative allergic complications. Preserved valve function at 2 year follow-up with no evidence of structural degeneration

‡ Reference valves for AG IgE level and titers are available in the supplementary index

*SAVR- surgical aortic valve replacement

**TAVR- transcatheter aortic valve replacement

The six reviewed studies comprised both individual case reports and larger prospective cohort studies. Reported follow-up duration across the studies ranges from in-hospital outcomes to longitudinal follow-up of up to 15 years, ultimately limiting direct comparability.

The case-based studies (Hawkins et al., Chen & Zeigler Taira et al., and Sami et al., [50–52]) reported that in those with prior mammalian meat allergy or diagnosed AGS, elevated AG specific IgE levels were present. In the series by Hawkins et al., this sensitization correlated with rapid SVD and consequent early mechanical valve re-replacement, whereas in contrast, the other reports demonstrated no early adverse outcomes with valve function preserved. It should be noted however that in these cases, follow-up durations was limited to short and mid-term periods. Similarly, the case reported by Taira et al. suggests that mild AG sensitization may not necessarily preclude the short-term use of bovine-derived BHVs, with no adverse outcomes observed at one-year follow-up.

A larger prospective multicenter study by Senage at al. provided broader insights, including a cohort of 1,668 patients with a mean follow-up of 34 ± 43 months (range up to 15 years). Senage at al. was the only study to provide longitudinal data capable of assessing SVD. This study demonstrated a strong post-implantation anti-glycan immune response, including that of anti-AG IgG, alongside evidence of immunoglobulin and complement deposition. Early SVD was observed in a small proportion of patients, however, this correlation between antibody levels and clinical outcomes was limited [53].

Aykut et al. reported no differences in perioperative outcomes or immediate post-procedural valve function among patients despite nearly one-third of the patients undergoing the SAVR or TAVR procedures being sensitized to AG. However, as the study follow-up period was limited to in-hospital, these findings do not inform the risk of SVD.

When taken together, perioperative and early post-implantation outcomes appear consistently favorable across studies. In contrast, limited evidence suggests a potential association between AG sensitization and delayed SVD, however, the overall clinical significance of the relationship is uncertain.

Discussion

Variable clinical impact of AG sensitization

Despite plausible biological mechanisms that could link AG sensitization to SVD, the clinical outcomes across the reviewed studies remain inconsistent. The heterogeneity seen may not only reflect differences in study design and follow-up duration, but also variabilities in patient susceptibility, specifics of valve choice, and immunological profiles. The discrepancies seen may suggest that AG sensitization acts as a modifying factor, as opposed to a primary driver of SVD. It could also be possible that only certain subsets of patient populations could progress to clinically meaningful SVD, such as those with higher-titer antibodies, concurrent chronic inflammation, or younger populations, for example. Such observations underscore the multifactorial nature of SVD and highlight a need for greater understanding of the exact biologic processes involved, patient-level risk factors, and improved risk stratification in valve type selection.

Immunological mechanisms

The reviewed evidence demonstrates both IgE-mediated (allergic) and IgG-mediated (non-allergic) responses to AG. IgE-mediated reactions are typically central to AGS, often manifesting as hypersensitivity Type I responses [54]. The variability in results between Hawkins et al. and Chen & Zeigler, suggests that IgE sensitization may not universally result in adverse outcomes, reflecting a need to assess other immune metrics [55]. Senage et al.’s focus on IgG-mediated responses highlights an alternative immune focus, providing us with an insight into a more chronic and degenerative inflammatory tissue picture [56]. The findings of higher anti-alpha-gal and anti-Neu5Gc IgG titers correlating with increased calcification and SVD over time suggest that AG may not, in fact, work alone, but also underscore a need to distinguish immune phenotypes to predict and mitigate potential immune acute and chronic reactions. Both bovine and porcine BHVs contain the AG epitopes, meaning differences in tissue origin and processing could influence antigenicity. However, at present there is currently insufficient human evidence to establish a clinically meaningful difference in immune response or SVD risk between the BHV types.

Consideration to the contextual nature of AG exposure should also be given with regards to the immunological consequences of different exposure sources. Mucosal exposure is typically associated with tolerogenic immune responses, which reflects a need to prevent chronic inflammation against food antigens. This includes exposure from dietary sources and the intestinal microbiota [57]. In contrast to this, exposure via tick bites may promote sensitization through pro-inflammatory adjuvant-like effects, leading to the development of clinically significant AG-specific IgE responses [58]. This distinction may be clinically relevant as only sensitized individuals are likely to mount a pathogenic response to BHVs with a potential to contribute to SVD.

Implications for screening and patient selection

AG sensitization in patients who are to undergo BHV implantation presents a relevant clinical consideration as to whether additional preoperative assessments should be introduced through the means of targeted questioning about meat allergy and consumption, prior anaphylaxis, or tick exposure, particularly in younger patients, where a more responsive immune system makes valve longevity even more critical. AG sensitization is typically diagnosed through a combination of clinical history and measurement of AG-specific IgE [59]. With a lack of formal guidelines, management remains individualized. As such, considerations in those patients with sensitization could be beneficial, such as prosthesis type selection and allergist guided perioperative prophylaxis; albeit there is currently limited evidence to support such specific strategies. Additionally, the impacts of postoperative sensitization or the development of concurrent immune-mediated conditions on BHV durability remains unclear, with no current evidence-based management strategies in place to guide clinical practice. Hawkins et al.’s two documented cases, where both patients went on to develop rapid rises in transvalvular gradients and consequent requirement for mechanical valve re-replacement, highlight a scenario whereby BHV implantation in those who may already be sensitized could be mitigated through a thorough preoperative assessment and resultant establishment of an alternative treatment plan [60]. Although routine alpha-gal IgE testing is not yet standard, in light of the findings of the adverse outcomes of the reviewed studies, there may be merit in screening individuals with previous unexplained allergic symptoms or in regions with high tick prevalence, to name just a few instances [61]. Such steps could help identify high risk patients for BHV implantation from population groups where BHV risk of implantation was previously overlooked.

Importantly, IgE-mediated allergic sensitization does not appear to have immediate post-implant implications. Therefore, attention should focus on potential long-term effects. Boer and colleagues demonstrated that anti-AG antibody levels rise following BHV implantation and do not return to baseline even after five years, indicating that the implanted BHV constitutes a persistent source of immune stimulation for anti-AG antibodies [62]. Preoperative quantification of circulating anti-AG antibody isotypes, including IgG, IgM, and IgA, could provide an estimate of the magnitude of the immune response likely to occur upon contact with the BHV in the patient’s blood. This assessment may be particularly informative for stratifying patients at risk of heightened immune reactivity. Evaluation of comorbid conditions, particularly autoimmune diseases, is also crucial. In some autoimmune disorders, aberrant anti-AG antibody production can activate complement via the lectin pathway without direct antigen engagement, as observed in Crohn’s disease [63], potentially exacerbating tissue damage or inflammation post-implantation.

Furthermore, determining the antigenic load of the BHV itself could allow the development of a ranking system, guiding the selection of the most suitable device for patients with heightened sensitivity. At present, due to limited sample sizes, heterogenous study design and insufficient longitudinal follow-up, the available human data does not support the definition of a clinically meaningful antibody titer threshold at which overt SVD develops.

Design limitations and future innovations

Current BHVs have marked limitations concerning immunogenicity, in particular, as mentioned, having the alpha-gal epitopes. Tissue derived from porcine and bovine materials, even after decellularization and glutaraldehyde fixation, still retains glycan antigens, capable of provoking host antibody responses [64, 65]. Additionally, conventional anti-calcification treatments such as ethanol and surfactant rinses are typically directed at reducing calcium binding and lipid retention, while their effect on immunogenic glycan residues appears limited and less clearly defined [66]. While the aforementioned methods can improve mid-term outcomes, they do not fully address the increasingly suspected immune-mediated SVD mechanisms in early BHV failure.

Current regulatory frameworks, such as those established by the U.S. Food and Drug Administration (FDA) and the European Medical Device Regulation (MDR), do not mandate evaluation of AG content in bioprosthetic devices, pharmaceuticals, or food products. Although there is no specific request, the FDA has recently approved genetically modified pigs lacking AG expression (GalSafe pigs), providing a safer source of bioprosthetic material [67]. The AG knockout animals prevent the sugar from being expressed on cell surfaces, reducing the risk of immune reactions in sensitized individuals. While this advancement is promising, it remains speculative whether long-term durability and broader immunological effects of devices derived from such genetically modified animals are fully understood, and whether elimination of AG may influence immune responses to other antigens.

Ongoing research should aim to address AG-mediated immunogenicity at its source, using promising approaches such as polyphenol-based treatments, which have shown potential to reduce immunogenicity and improve long-term BHV performance [68, 69]. Finally, it is possible to completely avoid the presence of such antigenic molecules using synthetic and polymeric materials for the manufacture of prosthetic valve. Challenges remain regarding the long-term thrombogenicity and hemodynamic performance of these [70].

Conclusion

Although current evidence is limited, the largest prospective study with longitudinal follow-up (Senage et al.) suggests that anti-glycan immune responses may contribute to SVD in BHVs. In contrast, the remaining evidence in this review consists primarily of case reports and short-term cohort data. As a result, meaningful assessment of long-term valve durability is not feasible. The heterogeneity across the studies is largely explained by differences in study design and follow-up duration as opposed to conflicting biological evidence. Routine screening for AG sensitization is not currently standard of care; however, patient-specific risk assessments could assist in optimizing short and long-term outcomes, especially in select instances such as those in high tick exposure regions or unexplained allergic symptoms. Emerging technologies may offer potential solutions, although remain in early stages at the time of writing.

Author contributions

Jack Gosden conceived and drafted the manuscript. Guido Ascione, Seth Wolf, Joseph W. Turek, Isaac George revised it critically. All authors approved the final version.

Funding

This research was not supported by any funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Disclosures

Jack Gosden reports no disclosures. Guido Ascione reports no disclosures. Seth Wolf reports no disclosures. Joseph W. Turek reports no disclosures. Isaac George reports the following disclosures: Grant Support: Medtronic, Boston Scientific, Edwards Lifesciences Consultant (honoraria) – Zimmer Biomet, Atricure, Neosurgery, Neptune Medical, Abbvie, Johnson & Johnson, Durvena, Boston Scientific, Edwards Lifesciences, Medtronic, Encompass Medical, Summus Medical, Abbott SJM, BCI, Xeltis, Innocardiac, KIS Medical Advisory Boards: Edwards Surgical, Medtronic Surgical, Medtronic Structural Mitral & Tricuspid, Trisol Medical, Valcare Medical, Durvena, Abbvie, Johnson & Johnson, Foldax Medical, Zimmer Biomet, Neosurgery, Abbvie, Boston Scientific, Summus Medical, BCI, Encompass Medical, HVT Medical, Innocardiac, KIS Medical, Retex Medical, Abbott Global TAVI Equity: Valcare Medical, Durvena, CardioMech, Vdyne, MitreMedical, BCI, Trisol Medical, HVT Medical, Foldax, KIS Medical Institutional funding to Columbia University: Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, JenaValve.Jack Gosden reports no disclosures.

Competing interests

Isaac George reports a relationship with Medtronic that includes: consulting or advisory and funding grants. Isaac George reports a relationship with Boston Scientific Corporation that includes: consulting or advisory and funding grants. Isaac George reports a relationship with Edwards Lifesciences Corporation that includes: consulting or advisory and funding grants. Isaac George reports a relationship with Zimmer Biomet that includes: consulting or advisory. Isaac George reports a relationship with AtriCure Inc that includes: consulting or advisory. Isaac George reports a relationship with Neosurgery that includes: consulting or advisory. Isaac George reports a relationship with Neptune Medical that includes: consulting or advisory. Isaac George reports a relationship with AbbVie Inc that includes: consulting or advisory. Isaac George reports a relationship with Johnson & Johnson that includes: consulting or advisory. Isaac George reports a relationship with Durvena that includes: consulting or advisory and equity or stocks. Isaac George reports a relationship with Encompass medical that includes: consulting or advisory. Isaac George reports a relationship with Foldax medical that includes: consulting or advisory and equity or stocks. Isaac George reports a relationship with Summus Medical that includes: consulting or advisory. Isaac George reports a relationship with Xeltis that includes: consulting or advisory. Isaac George reports a relationship with Innocardiac that includes: consulting or advisory. Isaac George reports a relationship with KIS medical that includes: consulting or advisory and equity or stocks. Isaac George reports a relationship with Trisol Medical that includes: consulting or advisory and equity or stocks. Isaac George reports a relationship with Valcare medical that includes: consulting or advisory and equity or stocks. Isaac George reports a relationship with HVT medical that includes: consulting or advisory. Isaac George reports a relationship with Retex medical that includes: consulting or advisory. Isaac George reports a relationship with Abbott that includes: consulting or advisory and funding grants. Isaac George reports a relationship with CardioMech that includes: equity or stocks. Isaac George reports a relationship with Vdyne that includes: equity or stocks. Isaac George reports a relationship with MitreMedical that includes: equity or stocks. Isaac George reports a relationship with BCI that includes: equity or stocks. Isaac George reports a relationship with HVT medical that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.