**2. Clinical complications of aortic insufficiency during LVAD support**

Aortic insufficiency occurs when the AV does not close completely, thus inducing a backward flow from the aorta to the left ventricle (LV). As severe AI progresses, usually over many years, valve repair or replacement is needed to resolve the problem. Naturally occurring affects 0.5% of the general population and 2% of those over 75 years and is responsible for only 4% of all deaths from AV disease [8]. However, for LVAD patients, AI is a significant complication that occurs in more than 25% of recipients and has persisted despite improvements in design, surgical placement, and control.

The most recent INTERMACS report noted an average LVAD support duration of 1.7 years and a comparable survival rate in axial and centrifugal continuous-flow LVAD [9]. For axial and centrifugal LVAD designs, the leading causes of death are similar, including neurologic dysfunction, multisystem organ failure, infection, and stroke (ischemic or hemorrhagic) [9]. Moreover, the risk of readmission due to severe adverse events increases as patients stay longer in LVAD support [9]. Some recurrent adverse events with rates noted at 1 year post-implant are shown in **Figure 2** [9–12].

As LVADs are implanted for longer support durations, complications related to tissue remodeling or other adaptations to the altered physiology introduced by the LVAD arise. AI is one of those, appearing within a few months of LVAD support and worsening over time [6, 13, 14]. Reports of AI were not common for the early pulsatile LVADs but have risen with the implantation of rotary LVADs of axial and centrifugal designs. Many of these clinical studies are single-center with relatively few patients. Still, a consistent picture has emerged that ~15% of patients develop AI within three months of LVAD support, and the fraction increases to ~25% at 12 months and over 30% after 3 years (**Figure 3**) [1, 6, 12–16].

Rotary LVADs include axial designs, like the HeartMateII, which operate at high speeds and have a linear flow path through the housing. Centrifugal LVAD designs such as the HeartMate3 direct blood along a radial path, from the center towards the side, and operate at lower speeds which is gentler for the blood. Some LVADs have added speed modulation to introduce pulsatility to the flow, improving the washout to prevent thrombi from forming inside of the LVAD. These innovations have reduced hemolysis and thromboembolic complications but have not substantially reduced the occurrence of AI.

**Figure 2.** *Complications of left ventricular assist device (LVAD) support [9–12].*

#### **Figure 3.**

*Graphical illustration of AI progression in LVAD patients shows a progress worsening within the first-year post-implant. Adapted from Imamura 2020 [16].*

The progression of AI with LVAD support is well documented, but the underlying mechanisms remain unclear [17, 18]. Even mild AI that is unrepaired is associated with a higher incidence of AI progression to moderate/severe and worse NYHA functional class compared to trace or less AI patients in mid-term after LVAD implantation [19]. AI in LVAD recipients can occur de novo or progress from pre-existing AI conditions [1–3, 5–7]. De novo AI develops as early as three months post-implant, and freedom from significant AI decreases as LVAD support duration increases [12, 13, 15]. Long LVAD support duration and low ejection fraction have been identified as independent predictors of de novo AI development [2, 7].

When pre-existing AI is present, the severity tends to increase with time postimplant [1, 16]. LVAD support induced a larger regurgitant flow resulting in lower cardiac output, higher preload, and impacting HF status [18, 20, 21]. Worsening of

**Figure 4.**

*Three-chambered echo view of LVAD patients with mild AI (top) and moderate/severe AI (bottom). A. Early diastolic filling through the mitral valve (MV). B. Mid diastole shows a small regurgitant jet through the aortic valve (AV). C-D. a large regurgitant jet appears in early diastole and merges with mitral inflow.*

AI increases LVAD flow while systemic flow decreases, forming a regurgitant flow loop [21]. As shown in **Figure 4**, mild AI presents in mid-diastole but extends in magnitude and duration towards moderate/severe levels within a few months of LVAD support.

Moreover, LVAD patient with concurrent AI is associated with a higher readmission rate and adverse events, including mitral and tricuspid regurgitation, hemolysis, and worsening of right ventricle function [6, 20, 22]. Previous clinical studies have reported multiple factors associated with the worsening of pre-existing trivial AI in post-LVAD support. Patient-related factors included pre-existing valvular dysfunctions, old age, and abnormal cardiac function. Pre-existing valvular dysfunctions include uncorrected mild AI [23, 24], large aortic sinus diameters [6, 25], LVADrelated factors include reduction of AV opening area and duration, high LVAD speed, and types of LVAD [6, 25]. Previous studies have suggested that the higher rate of progressive AI with rotary LVAD support results from low pulsatility, which may induce a more significant regurgitant flow and a higher rate of valvular remodeling [22, 26–28].
