Casper Zijderhand

Chapter 1 gives a general introduction to this thesis and describes the aims and brief outline of this thesis.

Chapter 2 aimed to assess the safety and efficacy of intermittent levosimendan infusions in ambulatory patients with end-stage heart failure in a systematic review. The review included 15 studies (8 randomized and 7 observational) encompassing 984 patients. Levosimendan infusions were linked to improved New York Heart Association (NYHA) functional class, increased left ventricular ejection fraction, and led to a decrease of the B-type natriuretic peptide (BNP) levels. All-cause death did not differ significantly, but cardiovascular death was lower in the group with levosimendan infusions. An improvement in the health-related quality of life was seen, and adverse events were similar between levosimendan and placebo groups.

Chapter 3 investigated the association between infections and thromboembolic events, particularly cerebrovascular accidents during LVAD support. This study included data from the European Registry for Patients Assisted with Mechanical Circulatory Support, with 3282 LVAD patients. During the study, 1262 patients experienced infections, and 457 experienced a cerebrovascular accident. The contemporary analysis showed that the occurrence of an infection increased the risk of cerebrovascular accidents, with a hazard ratio of 1.90. Multivariable analysis confirmed this association, with a hazard ratio of 1.99. Categorization of infections showed that VAD-specific and VAD-related infections were associated with cerebrovascular accidents. This study emphasizes the importance of rigorous anticoagulation management and appropriate antibiotic treatment during infections in LVAD-supported patients.

Chapter 4 describes the relationship between the angular position of the LVAD inflow cannula and relapsing low-flow alarms. The study included 48 LVAD patients. A standardized protocol was made to measure the inflow cannula position by using contrast-enhanced computed tomography scans. The study showed a significant increase in low flow alarms when the septal–lateral angulation was 28° or more. The low-flow alarms increased over time as the angulation expanded towards the septal–lateral plane, with a constant rate function indicating a 0.031 increase in low-flow alarms per month per degree of angulation (P = 0.048). In contrast, anterior–posterior and maximal inflow cannula angulation did not show significant differences. This emphasizes the importance of the LVAD inflow cannula angular position to prevent relapsing low-flow alarms with the risk of diminished quality of life and morbidity.

Chapter 5 investigated the incidence of mechanical device malfunction in HeartMate II and HeartMate 3 LVADs. The analysis included 163 patients, with 39% receiving HeartMate II and 61% receiving HeartMate 3, and median support times of 24.6 and 21.1 months. Major and potential major mechanical device malfunction occurred significantly less in HeartMate 3 patients, with a hazard ratio of 0.37. HeartMate 3 patients also had a significantly lower hazard of requiring pump or outflow graft exchange. Although system controller defects occurred less frequently in HeartMate 3, battery-clip defects were more common. The study concludes that HeartMate 3 exhibited fewer major device malfunctions and highlighted the importance of ongoing technical assessments during long-term LVAD support.

Chapter 6 explores the impact of pectus excavatum on early and late outcomes, particularly right ventricular failure, following LVAD implantation. The study included 80 patients and was categorized into two groups based on chest wall dimensions: 28 with a normal chest wall and 52 with pectus excavatum. Early RVF, acute kidney injury, and overall mortality did not differ between groups. However, late recurrent readmissions for RVF were more common in patients with pectus excavatum. The onset of late RVF occurred around 18 months post-implantation and increased thereafter in the overall cohort. The study suggests that pectus excavatum is frequently observed in LVAD patients and is associated with increased late RVF and readmissions.

Chapter 7 presents the potential impact of the angular position of the outflow graft on thromboembolic events and aortic valve regurgitation in patients with LVAD. The analysis involved contrast-computed tomography data from 59 patients. Three-dimensional reconstructions were used to calculate the horizontal and vertical angles, as well as the relative distance of the outflow graft between the aortic valve and the brachiocephalic artery. A vertical angle ≥ 107° was significantly associated with an increased risk of cerebrovascular accidents and gastrointestinal bleeding during a median 25-month follow-up. No significant associations were found between the vertical angle and aortic valve regurgitation or survival.

Chapter 8 investigated external compression of the outflow graft obstructing patients with a HeartMate 3 LVAD. This study is a multi-center analysis of 2108 patients between November 2014 and April 2021 and was conducted across 17 cardiac centers in 8 countries. External outflow graft obstruction was defined as obstruction >25% in the cross-sectional area in imaging. The prevalence of external outflow graft obstruction was 3.0%, and the incidence increased over time: 0.6%, 2.8%, 4.0%, 5.2%, and 9.1% at 1, 2, 3, 4, and 5 years of support. In total, 62 patients were diagnosed with external outflow graft obstruction and interventions included observation, surgical revision, percutaneous stent implantation, heart transplant, and death. Mortality with therapeutic intervention was 17.0%. While uncommon, external outflow graft obstruction may occur in LVAD-supported patients, highlighting the importance of early detection and remaining vigilant by clinicians.

Chapter 9 describes the association between anatomical variations of the aortic arch branching and adverse events, particularly the risk of cerebrovascular accidents, in patients with LVAD. The analysis involved 101 patients and computed tomography scans were used to categorize aortic arch branching variations into seven types. The study found no significant differences in the rate of early re-exploration due to bleeding after LVAD implantation, cerebrovascular accidents, and mortality during follow-up. The study suggests that while there were no differences in adverse events, knowledge of aortic arch variations could be meaningful during cardiac surgery.

Chapter 10 presents the clinical impact and long-term course of tricuspid regurgitation examined, considering its dynamic nature in 572 patients after heart transplantation. About 32% of patients had moderate-to-severe TR immediately after surgery, but this declined to 11% at 5 years and 9% at 10 years after transplantation. Preimplant mechanical support was associated with less tricuspid regurgitation during follow-up, while concurrent left ventricular dysfunction was linked to more tricuspid regurgitation. Survival rates at 1, 5, 10, and 20 years were 97%, 88%, 66%, and 23%, respectively. Moderate-to-severe TR during follow-up was associated with an increased mortality. The course of TR was positively correlated with the course of creatinine, indicating an association with worse renal function. The study suggests that tricuspid regurgitation is significantly associated with higher mortality and worse renal function, the probability of tricuspid regurgitation is highest immediately after heart transplantation and decreases over time.

Chapter 11 provides a systematic comparison of biatrial and bicaval heart transplantation in the early and late phases. In total, 36 publications (3555 biatrial and 3208 bicaval heart transplantations) were included. Early outcomes, including mortality, tricuspid regurgitation, mitral regurgitation, and permanent pacemaker implantation, favored the bicaval technique. Additionally, long-term survival and freedom of tricuspid regurgitation were superior in the bicaval technique.

Chapter 12 discusses the results of the studies, and clinical implications, answers the research questions, and proposes further research.