**2. History**

For decades since the inception of the first surgical aortic valve repair in 1962, the only treatment option available for surgically high-risk patients suffering from severe aortic stenosis (AS) was medical management. In 1985, Alain Cribier performed the first catheter-based balloon aortic valvuloplasty in a 77-year-old inoperable female [1]. Unfortunately, this still provided little to no long-term improvements in outcomes for patients. On May 1, 1989, Henning R. Andersen successfully developed and implanted the first percutaneous synthetic aortic valve in an 80-kg closed chest pig in Aarhus University Hospital of Denmark (**Figure 1**) [2, 3].

His inspiration stemmed from the works of Andreas Grüntzig and Charles Dotter who pioneered and performed the first-in-man percutaneous transluminal coronary angioplasty in 1977 in Zurich, Switzerland. Their works led to their nomination for the Nobel Prize in Medicine the following year. Augmenting what these two pioneers established, it was their student Julio Palmaz who then went on to invent and successfully implant the first balloon-expandable coronary stents. According to Andersen, it was in February 1989 during a conference lecture about balloon-expandable stents led by Palmaz in Scottsdale, Arizona when he suddenly thought of the idea of attempting such balloon-expandable stents but with larger diameters with collapsible valve tissue on the inside to mimic the structure and function of heart valves [2]. Andersen believed that if he utilized a very similar technique as Grüntzig and Palmaz, then he would be able to also perform percutaneous artificial heart valve implantations without the need for surgery. Upon returning to Denmark from the conference, Andersen spent several months creating his own valve prototypes utilizing iron and steel wires of various thickness and stiffness which he would buy from local hardware stores. These early valves were roughly 25 mm in diameter and consisted of 15–16 loops closed by soldering [2]. Over the next 3 years, Andersen continued to optimize durability and functionality of his device on pigs. Eventually he went on to add high loops for the commissure posts to be able to mount biological leaflets which he would harvest from pig hearts purchased from a local slaughterhouse (**Figure 2**).

Andersen credited J. Michael Hasenkam, a young cardiovascular surgeon intraining at the time, for this idea of mounting on biological leaflets to his new device.

#### **Figure 1.**

*Henning Rud Andersen preparing an 80 kg pig in 1989 in the animal lab of Aarhus University Hospital (image obtained from Ref. [2]).*

#### **Figure 2.**

*Early handmade prototype of an aortic valve with three high loops for mounting leaflets harvested from pig valves (image obtained from Ref. [2]).*

He also credited his medical student, Lars Lyhne Knudsen, for assisting him in developing various stents and mounting the leaflets and valves within. Andersen et al. went on to implant 35 more devices in-vitro in pigs. Their work was initially widely rejected and even ridiculed by journals, as well as many cardiothoracic surgeons around the world. In May 1992, their work was finally accepted and published by European Heart Journal [3]. In 1995, Andersen, Hasenkam, and Knudsen obtained a patent for their new invention. Over the next few years, their work rapidly began to gain recognition and other groups replicated their techniques utilizing both self-expandable and balloon-expandable valves on dogs, sheep, and pigs, all with positive outcomes.

On April 16, 2002, at the Charles Nicolle University Hospital in Rouen, France, Alain Cribier became the first to successfully perform aortic valve placement in an adult human patient [4]. Cribier went on to repeat his success utilizing both the traditional retrograde approach as well as the antegrade atrial trans-septal approach [5, 6]. All his implantations were performed under conscious sedation without the need for extracorporeal circulation and on high-risk inoperable patients, some of which were already in a state of cardiogenic shock. His trans-septal approach proved to be time-consuming, complex, and associated with more complications. Furthermore, interventionalists were becoming more comfortable with percutaneous techniques via various arterial access sites (more recently including the carotid artery). Thus, the anterograde methodology was abandoned. In 2003, Cribier's startup company, Percutaneous Valve Technologies, was acquired by Edwards Lifesciences for \$125 million. Thus, the Cribier-Edwards bioprosthetic valve became the firstgeneration of in-human transcatheter aortic valve replacement (TAVR) valves. In 2004, the first TAVR procedure was performed in the United States by Dr. William O'Neill at Henry Ford Hospital.

In the subsequent years, many clinical scientists, biotechnological companies, investors, and physicians joined this attractive and fiercely growing industry. Many augmented the devices and delivery systems while others continued to work on improving the technique itself. In 2007, the Edwards SAPIEN valve, made of bovine pericardium, was introduced as a life-saving option for prohibitive high surgical risk patients [7, 8]. Meanwhile that same year, Webb et al. demonstrated the feasibility and efficacy of the retrograde approach for TAVR [9].

The first clinical trials which successfully elucidated the feasibility and safety of TAVR were the Registry of Endovascular Critical Aortic Stenosis Treatment (RECAST) and the Initial Registry of EndoVascular Implantation of Valves in Europe (I-REVIVE) [5, 6].

By 2009, the two predominant valves in the industry were the self-expandable CoreValve ReValving system (CoreValve Inc., Irvine, California) and the balloonexpandable Edwards SAPIEN valve (Edwards Lifescience, Irvine, California). In 2009, CoreValve Inc. was acquired by Medtronic for over \$700 million, thus allowing rapid global marketing, larger clinical trials, and continuous device refinement to minimize procedural complications and optimize outcomes. At the time, two momentous clinical trials which enrolled nearly 10,000 patients—the CoreValve/ Evolut trial and the PARTNER (Placement of Aortic Transcatheter Valves) trial demonstrated significant superiority with TAVR compared to medical management in patients with severe AS with high surgical risk [10]. Thus, prompt approval for TAVR by the U.S. Food and Drug Administration followed in 2011. By 2014, TAVR was being performed in over 50 countries, in over 720 centers around the world [11].

In 2016, positive results from the PARTNER II and the Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) trials proved the balloon expandable Edwards SAPIEN XT and Medtronic's CoreValve self-expanding valve to be non-inferior to surgery with respect to stroke and mortality even in patients who were intermediate surgical risk [12]. In 2019, published results from the PARTNER 3 trial revealed that the newer-generation SAPIEN 3 Ultra TAVR valve demonstrated superiority to surgery in both primary and numerous secondary endpoints in even low surgical patients [13]. As of 2023, the three-year follow-up outcomes from the ongoing Evolut Low Risk trial paired with the PARTNER 3 outcomes, continue to demonstrate overall non-inferiority of TAVR to SAVR in low-risk patients [14]. These promising results continue to be sustained. By 2025, over a quarter million TAVRs are projected to be performed annually around the world [11]. As more other ongoing global clinical trials continue to suggest both feasibility and safety of TAVR regardless of surgical risk, the paradigm global shifts towards perfecting the solution to severe aortic stenosis are expected to continue.

#### **3. Indications**

Today, TAVR is an FDA-approved treatment option for patients with severe native calcific AS of all risk profiles and for patients with failed surgical bioprosthetic valves. Preliminary results from clinical trials investigating outcomes in patients with low surgical risks are ongoing. We determine this risk using the Society of Thoracic Surgeon (STS) scoring system. A score greater than or equal to 4% (predicted risk of surgical mortality at 30 days) is the cutoff in today's practice in determining eligibility for TAVR. The EuroSCORE II is an alternative scoring system that can be used for risk stratification. An STS score of ≥8% or a EuroSCORE II >15–20% indicates high risk.

According to the American Heart Association (AHA) guidelines and the European Society of Cardiology (ESC) guidelines, patients with severe low-flow low-gradient AS who have a left ventricular ejection fraction of less than 50% should also undergo TAVR regardless of the presence or absence of symptomatology [15]. If ejection fraction is preserved in these patients, the AHA issues a class 1 recommendation for intervention whereas Europe issues a class IIa recommendation. Asymptomatic patients with severe AS who have a preserved ejection fraction, should only undergo

intervention on a case-by-case basis such as in patients with rapid rates of stenosis, severely elevated serum levels of B-type natriuretic peptide (Pro-BNP), or exercise intolerance [15–19].

Both North American and European guidelines mutually share the same criteria to classify severity and type of AS. We define severe high gradient AS a maximum velocity greater than or equal to 4.0 m/s with a mean transaortic gradient greater than or equal to 40 mmHg typically associated with an aortic valve area of <1.0 cm<sup>2</sup> . We define low-flow low gradient severe AS having a valve area of less than 1.0 cm<sup>2</sup> with a concomitant maximum velocity less than 4.0 m/s and a mean transaortic gradient less than 40 mmHg. Although both North American and European societies agree on the indication of TAVR for older and high-risk patients. The European guidelines currently remain more conservative in their approach in younger patients requiring bioprosthetic valves. TAVR is generally considered in these patients only after the age of 75. The AHA however, recommends considerations of TAVR in patients above the age of 65 [15]. A schematic for diagnosis and treatment of AS adopted from the 2020 AHA guidelines is shown in **Figure 3** [16].

Factors that favor TAVR over SAVR include age, frailty, higher surgical risk, redo surgery, patients with prior radiation therapy to the chest, presence of a porcelain aorta, and the availability of a healthy percutaneous access sites. Factors that favor SAVR include younger age, bicuspid aortic valve, multivessel CAD, aortopathy requiring intervention, and concomitant significant valvulopathy necessitating cardiac surgery. As of now, there are no recommendations for early transcatheter intervention in patients with moderate AS. Clinical trials such as the TAVR UNLOAD trial in which we are assessing the safety and efficacy of TAVR in patients with moderate AS have been initiated and are currently ongoing. The indications for TAVR are anticipated to continuously evolve in years to come.

#### **4. Contraindications**

It is imperative for clinicians to be aware of both absolute and relative contraindications for TAVR. Absolute clinical contraindications include patient life expectancy of less than 12 months, myocardial infarction within the last 30 days, stroke within the last 6 months, patient intolerance to an anticoagulation/antiplatelet regimen, the absence of a Heart Team and cardiothoracic surgical team, and active bacteremia or endocarditis. Absolute anatomical contraindications include heavy aortic or left ventricular outflow tract disease and calcification, a short distance between the coronary ostia and the native aortic annulus, annulus size that is too small (less than 18 mm) or too large (greater than 29 mm), and the presence of mobile plaques and thrombi in the aorta and unsuitable access options [20].

Relative contraindications for TAVR include severe left ventricular dysfunction (EF <20%), inadequate heavily calcified femoral arteries, hemodynamic instability, severe pulmonary hypertension resulting in right ventricular dysfunction, hypertrophic cardiomyopathy, and severe mitral regurgitation.
