**2. Causes of recurrent heart failure**

#### **2.1 Right heart failure**

#### *2.1.1 Defining right heart failure*

Failure of the RV is the commonest cause of recurrent HF after LVAD surgery. The reported prevalence of RV failure is extremely variable, ranging from 4 to 40% for continuous flow devices [11]. This variance is driven by a lack of standardization in post-operative management, differences in patient characteristics between implanting centers, and the wide range in follow-up time across studies.

The evolution of LVAD technology and usage have impacted the prevalence of RV failure. Though the pulsatile HeartMate XVE was approved for use as destination therapy (DT) in 2003, 2-year survival was low (23% in the REMATCH trial [12], 33% in a post-REMATCH registry [13], and 24% in the HeartMate II (HMII) *Recurrent Heart Failure after Left Ventricular Assist Device Placement DOI: http://dx.doi.org/10.5772/intechopen.107022*

#### **Figure 2.**

*Causes of recurrent heart failure (HF) after LVAD implant. HF can be caused by intrinsic cardiac disease that is pre-existing or that develops after LVAD implant, or may be secondary to severe anemia in the setting of GI bleeding. Alternately, HF may result from LVAD-specific issues, including outflow or inflow cannula obstruction, pump failure, or simply an inappropriate LVAD set speed.*

DT trial [14]) owing at least in part to mechanical failure of this pump. Further, the size of the HeartMate XVE restricted its use to larger patients. These factors limited long-term use, and bridge-to-transplantation (BTT) remained the dominant implant strategy in the first decade of the 2000s [15]. Consequently, analyses of HF in LVAD patients from >10 years ago largely focused on early post-operative RV failure. However, since approval of the HMII for DT in January 2010, DT has become the dominant implant strategy in the U.S. (**Figure 3**) [16]. This has led to substantially longer time on LVAD support with a concomitant shift in patient characteristics and outcomes. Finally, changes to the United Network for Organ Sharing OHT listing criteria in 2018 and advances in the use of temporary mechanical circulatory support (MCS), have resulted in an even more significant reduction in BTT LVAD usage in the last 3 years [17].

Analysis of recurrent HF has also been hampered by the variable definitions used for RV failure. Nearly all studies define RV failure when a right ventricular assist device (RVAD) is required, but inotrope use as a criterion has been variable as has the requirement for clinical signs of HF. In 2008, the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) defined RV failure by a central venous pressure (CVP) >18 mmHg, cardiac index <2.0 L/min/m2 and either the need for an RVAD, or any use of vasoactive medications >7 days after LVAD implant. The limitations of this definition were quickly recognized, and it was revised in 2014 (**Table 1**). This refined definition required (1) elevated right sided filling pressures and (2) physical or laboratory evidence for congestion. If these criteria were met, then the severity of RV failure was further qualified.

Though the 2014 definition was more inclusive, some patients with RV failure were still not captured, and hybrid definitions remained commonplace. In 2020, the Academic Research Consortium convened a multidisciplinary working group to

#### **Figure 3.**

*Evolution of continuous flow LVAD implant strategies in the U.S. (2010–2019). The total number of implants per year is listed below each year. From: STS-INTERMACS database [16].*

define adverse events related to MCS use (MCS-ARC) [18]. In this simplified definition, RV failure is divided into early or late based on the timing relative to LVAD surgery (**Table 2**). The need for an RVAD continues to define right HF, while vasoactive medication use without RVAD requires that additional clinical criteria be met including findings of elevated right atrial pressure, or evidence of end organ dysfunction/ hypoperfusion. In late 2021, the Society of Thoracic Surgeons (STS)-INTERMACS database adopted this MCS-ARC definition of right HF [19].

#### *2.1.2 Right heart function in the LVAD patient*

The RV is anatomically and physiologically distinct from the LV [20]. Under normal conditions, RV output is roughly equal to that of the LV. However, the mechanics of RV contraction are distinct. The RV is thin walled and shaped like a tetrahedron (**Figure 4**). It is highly compliant and pumps blood into the low impedance pulmonary vasculature. Consequently, the RV requires only one sixth the energy of the LV per contraction [20]. As the LV contracts, it twists around its longitudinal axis; this twisting motion (akin to wringing a wet towel) contributes significantly to septal contraction. Meanwhile the RV contracts along longitudinal and transverse axes, with longitudinal shortening being the major driver of RV stroke volume (**Figure 5**) [21]. Importantly, a significant portion of longitudinal RV contractility is derived from the septum.


#### **Table 1.**

*2014 INTERMACS definition of right heart failure.*

RV function is primarily governed by three physiologic parameters: (1) preload; (2) contractility; and (3) afterload. In chronic HF, primary RV dysfunction (i.e., independent of LV failure) is common, being identified in about half of patients with HF and reduced ejection fraction [22]. RV afterload is determined by pulmonary vascular resistance (PVR) and compliance. The RV displays a steep decline in cardiac output with increasing PVR [20]. In chronic HF, PVR rises and compliance declines secondary to (1) elevated left heart pressures and (2) pulmonary arterial remodeling, thus substantially increasing RV afterload.

Right HF after LVAD implant is multifactorial. The abrupt increase in venous return to the right heart can cause HF in a myopathic RV that fails to adequately compensate for the increased preload. RV contractility can be compromised by LVAD support in multiple ways (**Figure 5**): (1) reduced LV preload leads to a leftward shift of the septum, limiting the contribution of septal contraction to RV force generation; (2) apical LVAD insertion coupled with the loss of pericardial constraint reduces LV contractility (especially twisting), which also limits septal contraction; and (3) the leftward shift of the septum can lead to stretching of the tricuspid valve (TV)


*\* Clinical findings of RV failure: (1) ascites; (2) functional/limiting peripheral edema; (3) elevated JVP halfway up the neck in an upright patient; (4) measured CVP >16 mmHg.*

*† Manifestations of RV failure: (1) serum creatinine >2 times baseline; (2) ALT/AST* ≥*2 times the upper limit of normal or total serum bilirubin >2.0 mg/dL; (3) reduction in LVAD pump flow >30% below baseline in the absence of cardiac tamponade; (4) central or mixed venous blood oxygen <50%; (5) cardiac index <2.2 L/min/m2; (6) serum lactate >3.0 mmol/L.*

#### **Table 2.**

*2020 MCS-ARC & 2021 STS-INTERMACS definition of right heart failure.*

#### **Figure 4.**

*Anatomy and geometry of the right ventricle. Transverse (A), coronal (B) and sagittal (C) views of the heart showing the unique tetrahedral or half-ellipsoid shape of the RV. The sagittal view (C) is from the perspective of the interventricular (IV) septum in the foreground and looking "into" the RV towards the RV free wall. Lines correspond to the following: WX = junction of the interatrial and IV septa; WY = anterior atrioventricular sulcus; XZ = posterior atrioventricular sulcus; WZ = anterior IV sulcus; XZ = posterior IV sulcus; YZ = margo acutus. RV regions correspond to the following: WXY = approximate valvualr plane; WYZ = anterior RV free wall; XYZ = posterior RV free wall; WXZ = IV septum.*

*Recurrent Heart Failure after Left Ventricular Assist Device Placement DOI: http://dx.doi.org/10.5772/intechopen.107022*

#### **Figure 5.**

*Vectors of ventricular contraction. (A) In the normal heart, the LV contracts in a wringing, or spiral, motion around its long axis while the normal RV contracts in perpendicular planes along its longitudinal and transverse axes. This LV twisting motion augments septal contractility and RV stroke volume. (B) An LVAD limits LV twisting and triggers a leftward shift of the interventricular septum by decreasing LV preload, in turn reducing septal contraction and overall RV longitudinal contractility. If RV free wall contractility cannot increase to compensate, then total RV cardiac output may decline.*

annulus with a concomitant increase in tricuspid regurgitation (TR). Finally, the abrupt reduction in left heart filling pressures after LVAD typically improves PVR, reducing RV afterload and improving contractility [23]. However, PVR (and therefore RV afterload) may remain elevated due to vascular remodeling, thus further contributing to post-LVAD RV failure.

#### *2.1.3 Early right heart failure*

Early right HF increases the risk of death and end-organ dysfunction, prolongs hospital length-of-stay (LOS), delays recovery, and reduces functional capacity [24–26]. The most consistent defining feature of early right HF is the need for RVAD support. In clinical trials, early RVAD support has been steady: HMII BTT trial, 6%; [27] ADVANCE trial of the HeartWare LVAD (HVAD), 2.1%; [28] MOMENTUM 3 trial of the HM3, 4.1% [9]. Registry data have shown a similar prevalence of RVAD use in patients with continuous flow LVADs: INTERMACS, 4.1%; [8] EUROMACS 2017–2020 cohort (European Registry for Patients with Mechanical Circulatory Support), 5.4%; [29] IMACS (ISHLT Mechanically Assisted Circulatory Support registry), 6.1%; [30] and MOMENTUM 3 continued access protocol (CAP) registry, 7.6% [9].

However, the reported prevalence of all early right HF events has been plagued by variable definitions. In the HMII BTT trial, early right HF was defined as the need for RVAD or inotrope support for at least 14 days following LVAD implant [27]. Using this definition, 13% had early right HF. In the HMII DT trial, early right HF was identified in 17.5%, with 43% of those with early right HF dying within 30 days of LVAD surgery [31]. In the ADVANCE trial, 14.3% were diagnosed with early right HF [28]. The prevalence of early right HF was 25% in a meta-analysis of 36 studies (4428 LVADs), however differences were noted in study design, right HF definition, and proportion of continuous flow devices [32]. In the INTERMACS database, the prevalence of right HF 1 month after LVAD implant was 24% [33]. Notably, right HF resolved in 96.5% of these individuals by 12 months. Similarly, in EUROMACS, the prevalence of early right HF was 21.7% [34].

Peri-operative factors contribute significantly to early right HF. Most LVADs are implanted with cardiopulmonary bypass (CPB) support. While CPB maintains adequate organ perfusion and gas exchange, blood contact with the circuit provokes an inflammatory response that leads to increased capillary permeability, vasoplegia, and acute organ dysfunction [35, 36]. The large volume of priming solution administered upon CPB initiation may cause volume overload and RV dysfunction [37]. Blood loss, platelet dysfunction and coagulopathy often mandate transfusion, which can also contribute to right HF [38]. Finally, myocardial stunning [39], pericardiotomy-associated changes in RV contraction [40, 41], pulmonary hypertension [42], and inadvertent air embolism to the right coronary artery [43] may all contribute to acute RV dysfunction.

#### *2.1.4 Late right heart failure*

Even more than early right HF, analysis of late right HF has been plagued by variable definitions, different clinical parameters (e.g., time from surgery, type of support, presence of HF symptoms) and study types (e.g., single-center, clinical trials) that may not be representative of the general LVAD population [44]. Study duration is also critical: 59% of right HF was diagnosed >1 year after LVAD implant in the HMII DT trial [31], and de novo late right HF in the STS-INTERMACS database developed at a relatively constant rate of 5–10% [33, 45].

In the HMII BTT trial, late right HF was defined as initiation of inotropes >14 days after implant. Using this simplistic definition, 7% had late RV failure [27]. However, the median duration on LVAD support was only 126 days [46]. In the HMII DT trial, RV failure occurred in 21% over a median follow-up of 1.7 years at a rate of 0.13 events per patient-year (EPPY) [47]. When divided into early and late right HF (causing hospitalization >30 days post-LVAD), late right HF was identified in 8% of DT patients at a median of 480 days after LVAD implant [31].

In the ADVANCE trial, inotropes were used beyond 30 days in 6% (0.12 EPPY) [28]. Longer follow-up from the HVAD registry found RV failure in 9% (0.10 EPPY), though events were not adjudicated as early or late [48]. Similarly, the MOMENTUM 3 trial did not split early from late right HF events, simply defining RV failure as "symptoms and signs" of RV dysfunction with either RVAD implant, or therapy with inhaled nitric oxide or inotropes for >1 week at any point after LVAD surgery [49]. In MOMENTUM 3-CAP, right HF (early and late) was identified in ~37% (0.27 EPPY) [9].

In the National Readmission Database, 4.2% of all patients discharged after the implant hospitalization were readmitted with recurrent HF within 30 days of discharge (13.4% of all readmissions) [50]. When using the 2014 INTERMACS definition (**Table 1**) in patients who survived 3 months after LVAD surgery, the incidence of new, mild RV failure was 5–6% at 12-months, with moderate HF in an additional 4–5%, and severe HF being very rare as a late presentation (≤0.2%). In a single center study of DT patients who survived 1-year post-LVAD surgery without right HF, 45% developed right HF at a steady rate over a mean of 3.5 years [51]. Importantly, this incidence of de novo right HF, while highest in the early post-op period, appears to stabilize at 5–10% by 3–6 months post-LVAD implant and remains steady for at least 4–5 years [33, 45, 51, 52].

The prevalence of right HF after LVAD implant is ~10% by 3 months and remains constant for ≥3 years [33]. After diagnosis of late right HF, 9–20% will die and an additional ~25–33% will have persistent HF within 3–6 months [33, 45]. Two factors

seem to predict persistence of RV failure. First is the time from LVAD implant to diagnosis of right HF, with HF that develops later associated with a higher rate of persistence [33]. Second is the severity of HF at diagnosis: of patients with no right HF 3 months post-LVAD, only 3.4% developed HF at 6- or 12-months after surgery. By contrast, of those with moderate right HF 3 months after implant, HF persisted in 32.5% and 11.5% at 6- and 12-months, respectively [45].

#### *2.1.5 Outcomes associated with right heart failure*

Right HF is a morbid complication in LVAD patients; this includes increased rehospitalizations, excess complications, poorer functional metrics and, critically, worse survival. Right HF has been adjudicated as the cause of death in 11–13% in the STS-INTERMACS [8] and IMACS registries [30]. Right HF as the cause of death in clinical trials has been more variable: 5% for continuous flow devices in the HMII DT trial [14], 12% in the ROADMAP trial (also HMII) [53], 17% in the ADVANCE trial (HVAD) [28], and 28% in the MOMENTUM 3 trial (HM3) [7].

In the HMII BTT trial, early RV failure was associated with a lower combined end point of (1) survival to OHT, (2) recovery, or (3) continuing support at 180 days (71% vs. 89% without right HF; p < 0.001); those requiring an RVAD had the poorest outcomes [27]. In a single high-volume center, 6-month mortality with early RVAD use was 41% [54]. This study also showed that (1) successful RVAD weaning was associated with ~3-fold better survival; and (2) planned biventricular support during the index surgery yielded better outcomes than later RVAD implant. A meta-analysis of retrospective studies found that RVAD use after LVAD was associated with significantly worse survival, and increased rates of bleeding and stroke [55]. Finally, data from INTERMACS [24] and EUROMACS [56] show that RVAD use is associated with lower 1-month, 6-month and 1-year survival.

Late right HF is also associated with reduced survival [31, 45, 57]. In the HMII DT trial, patients with late right HF had lower 1-year (78% vs. 84%), 2-year (58% vs. 81%) and 3-year survival (36% vs. 56%, p < 0.001) [31]. Notably, when analyzed from the time of diagnosis of de novo right HF, 1-year survival in this DT cohort was only 38%. BTT patients have reduced survival to OHT if right HF develops. In STS-INTERMACS, the presence and severity of late right HF predicted worse outcomes, including mortality (**Figure 6**) [45]. Perhaps not surprisingly, those with persistent right HF have the worst outcomes [33]. Finally, late right HF was associated with modest but significantly more strokes, arrhythmias and infections [45]. However, a causal link to right HF has not been established.

Post-LVAD right HF may also put patients at elevated risk after OHT. Patients requiring an RVAD with a BTT LVAD had a 22% increase risk of death post-OHT [58]. A retrospective, large, single-center study showed reduced post-OHT survival up to 5-years in BTT LVAD patients who developed right HF [57]. A study of 2 large European transplant centers found a post-OHT 1-year survival of 75% in BTT LVAD patients with right HF; [59] while not significant in their cohort, this is substantially lower than the ~93% 1-year post-OHT survival in the International Thoracic Organ Transplant Registry [60]. The mechanism for this risk is not clear. BTT LVAD use increases the risk for primary graft dysfunction (PGD) [61], and 2 single center analyses found an increased risk for PGD in BTT patients with pre-OHT right HF [57, 62].

Finally, right HF after LVAD has a negative impact on functional capacity and possibly QOL. Early RVAD use is associated with poorer QOL in some patients [63]. In the HMII DT trial, those with late right HF had lower QOL as assessed by the

#### **Figure 6.**

*Clinical outcome at 12-months in patients who survived to 3-months after LVAD implant. Patients are grouped by right heart failure (RHF) status 3-months post-LVAD. From: STS-INTERMACS database [45].*

Kansas City Cardiomyopathy Questionnaire [31]. This was not true of patients in STS-INTERMACS using a visual acuity scale; [45] these investigators noted ample missing data that could have biased the analysis, and a lack of agreement as to the optimal tool for assessing QOL in LVAD patients. Functionally, those with right HF have a reduced 6-minute walk distance, supporting a detrimental effect of recurrent HF in LVAD patients [31, 45, 64, 65].

#### *2.1.6 Predicting right heart failure after LVAD surgery*

Numerous attempts have been made to predict post-LVAD RV failure in order to better guide patient selection and improve post-operative outcomes. Close to 100 variables have been found to be associated with post-LVAD right HF across dozens of studies [11, 66]. A handful of these risk factors have been consistently identified in multiple studies (**Table 3**). Although some variables are not actionable, others can be mitigated. While these predictors generally have high specificity, their sensitivity and negative predictive value are low, limiting their utility in clinical practice. A meta-analysis found that no single parameter was sufficiently sensitive to predict post-LVAD right HF [32].

Scoring systems have been developed that use a combination of these risk factors to predict post-LVAD right HF. More than 20 such models exist, most from singlecenter cohorts [11]. Fewer than 40% have been validated in ≥2 external cohorts. The validation studies are fraught with bias and have consistently shown poor discriminatory power with C-statistics of only 0.53–0.65 [67]. Modeling has been hindered by the many variable definitions of right HF. Further, nearly all models were derived


*BUN – blood urea nitrogen; Cr – creatinine; ALT – alanine aminotransferase; AST – aspartate aminotransferase; INR – international normalized ratio; LV – left ventricle; RV – right ventricle; MCS – mechanical circulatory support; IABP – intraaortic balloon pump; ECMO – extracorporeal membrane oxygenation.*

**Table 3.** *Risk factors for post-LVAD right heart failure.* using data from pulsatile or early-generation continuous flow LVADs, limiting their applicability. Consequently, results have been disappointing, and have limited wider use of these predictive models in clinical practice.
