Psychological Spectrum Experienced by Heart Failure Patients After Left Ventricular Assist Device Implantation

Depression and anxiety disorders are prevalent in patients with heart failure. They are associated with adverse effects such as rapid disease progression, poor medication compliance, low quality of life and increased mortality rate. The current literature review aims to provide an overview of the overall rate of depression in patients who receive left ventricular assist device (LVAD) implantation and identify the psychological phases that these individuals experienced peri- and post-LVAD implantation. A PubMed search using regular and Medical Subject Headings (MeSH) keywords identified 239 articles. After applying inclusion/exclusion criteria, removal of duplicate studies, and careful review of articles, 40 studies provided relevant information on our primary end-point. These 40 studies selected include 13 paid articles with abstracts and 27 free full-text articles comprising eight prospective cohort studies, five retrospective cohort studies, six cross-sectional studies, one qualitative study, one randomized clinical trial, one systematic review, four literature reviews, and one practice guide. Our review shows that patients experienced different psychological phases after LVAD implantation. However, as the time from implantation progressed, these patients showed a significant improvement in depression, anxiety, and health-related quality of life.


Introduction And Background
Over the years, heart failure has garnered multiple definitions, most of which explicitly define it as a clinical syndrome characterized by a variety of symptoms (shortness of breath, lower limb swelling, weakness) and signs (elevated jugular venous pressure, pulmonary congestion, peripheral swelling) caused by structural and functional cardiac abnormality resulting in reduced cardiac output and elevated intra-cardiac pressures [1]. Heart failure cases are estimated to rise to eight million by 2020 in the United States [2]. The disabling nature of heart failure is commonly associated with depression. The prevalence rate of depression in patients with heart failure is about 20%-40%, which is 4%-5% higher for major depression in the general population [3]. Depression in patients with heart failure results in low quality of life, poor selfcare, increased use of medical resources, and high readmission rate and mortality rate [4]. To enhance the outcome in advanced heart failure patients, who are unresponsive to medical management, left ventricular assist device (LVAD) has become a therapeutic choice. LVADs may serve as a bridge to heart transplant or destination therapy for poor transplant candidates. The goal for implanting an LVAD is to improve the overall quality of life of patients with advanced heart failure; studies have consistently shown that patients' quality of life is significantly enhanced post-LVAD implantation [5,6].
The symptoms of advanced heart failure can mask the symptoms of depression as they both have certain similarities (i.e., sleep disturbances, fatigue, or low energy). This can represent a diagnostic challenge in differentiating the typical symptoms of heart failure against those of depressed patients [7]. Multiple symptoms caused by heart failure can create a burden on the psychological health of patients. The mental stress these patients experience can easily remain undiagnosed due to their reluctance to disclose emotional stress out of fear of being labeled mentally ill; also, health professionals focus more on the treatment of heart failure symptoms and may write off depressive symptoms as a normal response to heart failure [8][9][10][11][12]. Ultimately, depression manifests itself through physical symptoms such as loss of appetite, weight loss, and sleep disturbance. Thus, most patients consult with other specialists rather than psychiatrists [8][9][10][11][12]. It is of utmost importance to identify heart failure patients with concomitant depression. Only after identifying heart failure patients with comorbid depression will we truly understand the role of LVAD in alleviating or worsening depression in patients with heart failure peri-and post-LVAD implantation. Some recipients of LVAD also describe emotional and psychological stress due to difficulties encountered in the care of the device (e.g., adapting to dependence on a power source and handling of the device), reduced sleep, pain, reduced activities of daily living, and reduced adherence to complex medication regimens [13]. The symptoms experienced by patients after LVAD implantation need to be thoroughly studied to understand if the resultant symptoms are an initial response to major surgery or heart failure depression.
This literature review will compare data from various studies providing an insight into understanding the overall rate of depression in patients who received LVADs, identify the psychological phases experienced by patients post-LVAD implantation, and whether LVAD improves existent heart failure depression or brings about a new-onset depression.

Review
Using parallel strategies to identify original research and review articles from PubMed, data was collected using Medical Subject Headings (MeSH) and regular keywords. After carefully reviewing titles, abstracts, and free full-text articles, relevant publications and their reference lists were reviewed to identify additional publications. Table 1 presents MeSH and regular keywords used for the literature search. Studies were selected based on the following inclusion criteria: (1) English publications, (2) studies published within the past 10 years, (3) human subjects above 19 years old, (4) observational studies and clinical trials, including randomized controlled trials, cohort studies, case-control studies, or review articles. However, studies were exempted using the following exclusion criteria: (1) non-English language publications, (2) human subjects below 19 years old, (3) animal studies, (4) case series and meta-analyses. Table 2 presents the total number of studies selected after applying the inclusion/exclusion criteria.
After reviewing 27 free available full-text articles, the minimum number of subjects in a study was nine, and the maximum was 1887 [33,49]. In total, the number of subjects in all publications excluding the review article was 4721 38,39,[41][42][43][44][45]48,49]. Among all 40 studies, 23 studies focused on LVADs' psychological implications in heart failure patients. Two publications also included the psychological experience of secondary individuals, such as spouses and caregivers of LVAD implantation patients explicitly [29,31]. All 27 publications are available for review in the free full-text form on PubMed and citations on information borrowed from the literature are provided. Figure 1 represents a flowchart of the selection process of the current literature review.

Discussion
The analysis conducted was intended to demonstrate the overall rate of depression in patients who received LVAD and identify the post-LVAD psychological phases experienced by these individuals. Advanced heart failure patients may eventually evolve from medical management to requiring a heart transplant. Due to the limited availability of donor heart or weak candidacy, some patients may require a heart assist device either as a bridge to heart transplant or as destination therapy. Most patients with advanced heart failure already experience anxiety, depression, and other mood disturbances, which if diagnosed early can improve outcomes after LVAD implantation. The evaluation of the psychological response LVAD patients experience after implantation has led to the synopsis of four phases. In the pre-LVAD period, patients provide an insight into the limitation brought on by heart failure symptoms and how the desperate need to relieve these symptoms may have influenced their decision on LVAD implantation [35]. The next phase after LVAD implantation is the hospitalization phase [35]. During this phase, patients are highly dependent on the medical team and learn essential skills about the heart device, which can be overwhelming for them [35]. Studies show a high prevalence of adjustment disorder after LVAD implantation [14,22]. During this phase, the anxiety level is amplified, which can be explained by the presence, weight, and sound of the heart assist device. In this phase, patients can also experience disruption in their endocrine, metabolic, cerebral circulation, or adverse effect of medication [14]. The third phase is an early adaptation phase [35]. In the early adaptation phase, patients learn to apply skills learned from the hospital to their everyday routine and modify their home environment to accommodate the electrical necessity of the heart assist device [35]. In this phase, patients are usually anxious as they recognize the need to be attentive as the heart assist device is vital in sustaining their lives [14]. Due to the vulnerability of patients in this phase, caregivers play a huge role in their physical and psychological well-being. Lastly, in the final stage described as a late adaptation phase, the patient becomes accepting of the new normal and show appreciation of the device [35]. In this stage, patients express a sense of increased self-esteem as they understand the complexities of the heart device and how to manipulate it [35]. The duration of these phases can vary as every patient responds differently to stressors.
After an overall view of the selected studies, majority of them showed statistically significant improvement in anxiety, depression, and quality of life after LVAD implantation with some studies identifying changes as early as within 30 days to 12 months after implantation regardless of treatment strategy (bridge to therapy vs. destination therapy). The ability of humans to adapt to changes can explain the findings in the studies. In the past 10 years, multiple research on patients with LVAD implantation has provided more insight into understanding patients' psychological responses to the implantation of a heart device designed to keep them alive. Tables 3, 4 summarize retrospective cohort studies, prospective cohort studies, and systematic reviews on the evolution of ideas on patients' psychological well-being post-LVAD implantation. Retrospective study 33 LVAD patients showed a better quality of life at three months and six months than patients with stage D heart failure and extracorporeal LVAD (P<0.05).
Patients hospitalized for LVAD-related complications, female sex, and patients with higher levels of anxiety before the operation had lower quality of life.  Prospective cohort study 51 The most prevalent mood disturbance was adjustment disorders. Two-third of all patients (VAD dest , VAD htx , and HTX vad , or heart transplant for HTX prim ) suffered significantly from response to severe stress and adjustment disorders (F43.x) and 15% from mild or moderate depression (F32.0 and A randomized clinical trial compared the outcome between women and men using a continuous-flow LVAD as a bridge to transplantation. The study showed that the survival rate between men and women with LVAD was equivalent [32]. The percentage of patients with New York Heart Association (NYHA) functional class I or II symptoms improved from 0% at baseline to 83% for women and 85% for men at six months (P<0.001) [32].
Next are summaries of more prospective cohort studies that provided in-depth insight into the research analogy. Patient-Reported Outcomes Measurement Information System® (PROMIS®) Depression sleep disturbance short form (SF) 8a and Anxiety sleep disturbance SF8a showed patients had a mean t-score of 56 (±5) and 53 (±12), respectively, before LVAD implantation. In contrast, the t-score changed to 44 (±6) and 42 (±9), respectively, 48 weeks after implantation. When plotted on a generalized linear mixed (GLM) model, a decrease overtime signifying improvement with P=0.03 and P<0.001 for depression and anxiety, respectively, was observed [18]. Another study by Shah et al. showed improvement in health-related quality of life (HRQOL), depression, and heart failure symptoms seen in LVAD patients as compared to patients on medical management in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 4 group [19]. The two-year survival of LVAD patients, when compared with optimal medical management (OMM) patients in INTERMACS 4 group met allcomposite end-point with improvements in (1) New York Heart Association (NYHA ) functional class (≥1 class), (2) EuroQoL (EQ)-5D visual analog scale (VAS) (>20 points), and (3) Patient Health Questionnaire -9 (PHQ-9) score (≥5 points) (P<0.001) [19]. In a study by Lee et al., during the follow-up period of 6 months, LVAD patients in both patient groups (destination therapy and bridge to transplant) showed similar significant improvements in HRQOL, and significant improvement in shortness of breath, while moderate to significant improvements in wake disturbances [20]. A similar study, also conducted by Lee et al., showed significant improvement in shortness of breath (<0.001) and fatigue within 30 days after LVAD implantation, which was followed by subsequent improvement through 180 days [21]. During the study, it was found that heart failure causes the cardiac muscle to stretch, which led to the elevation of serum N-terminal pro-B-type natriuretic peptide (NTproBNP) [21]. The implantation of LVAD led to a reduction in myocardial stretching and improvement in cardiac output. Thus, changes in myocardial stretching, which was measured by NTproBNP, were associated with an enhancement in shortness of breath, fatigue, cough, early satiety, and depression [21]. The findings in each study are crucial in the management of patients with LVAD implantation. It is essential to know the psychological implications exerted by the heart assist device in an individual's life, as a drastic change in one's routine can impact his or her social, physical, sexual, and psychological experience. The most extensive and most current study in our database had a follow-up period of two years after LVAD implantation [26]. Findings in this study are consistent with evidence that LVAD is highly effective in enhancing hemodynamics and improving functional capacity, which resulted in a favorable effect on the aspect of anxiety and depression in the two-year follow-up period. However, due to a lack of improvement in pain, discomfort, and self-care, patients experience difficulties with LVAD management and care, including LVAD tasks and limitations, and device's effect on self-image [26].
Despite a decrease in depression and anxiety in the majority of studies, adjustment disorders were found in 43%, depression in 14%, and multiple diagnoses in 18% LVAD patients [22]. Symptoms of depression and anxiety can be debilitating, leading to an increase in medication non-compliance, hospital readmission, higher medication cost, higher mortality rate, and decline in physical health [33]. Thus, early identification is necessary as the incorporation of psychological support as a significant part of their treatment plan might be lifesaving. It is clinically and statistically significant to assume that improvement in LVAD patients' mental well-being reflects on their quality of life as studies show depression in these patients to be a powerful predictor of their quality of life [16,28,30]. Partners of patients who received LVAD implantation reported higher levels of psychological breakdown, anxiety, and depression than LVAD patients [29]. They, therefore, stand a chance to gain from psychological therapy. An exciting find was in a study that measured saliva cortisol as a physiological response to stress in patients post-LVAD implantation [28]. This study shows the correlation between psychological and physiological factors in these patients as normal morning saliva cortisol was associated with low levels of depression in the study sample [28].

Limitations
There are limitations to writing a literature review on the psychological effect of LVAD implantation in heart failure patients. The variabilities of heart failure as a subject and relatively limited information on an LVAD can explain these limitations. The target population of choice posed a challenge. Only limited studies were available on patients who received LVAD, and already available reviews had additional variables in their analyses, which affected the literature's homogeneity. Current research studies restricted their review in terms of gender (no gender-specific research) and length of follow-up (no study discussed long-term follow-up beyond two years). Studies used various modalities and criteria to diagnose depression, anxiety, and other mood disorders in LVAD patients. As such, the analysis and comparison of the results of multiple studies presented a challenge.

Conclusions
The current literature concludes that in the peri-implantation and immediate post-LVAD implantation periods, patients experienced depression, anxiety, and mood disorders. However, as time elapsed, these patients passed through psychological phases of various lengths where they learned to adapt to changes, and shortly after, the psychological burden brought on by the heart assist device improved exponentially. This review should prompt researchers to conduct lengthier studies that are gender specific and explore more on the psychological phases experienced after LVAD implantation. Researches should provide knowledge on how medical management can influence each psychological phase and if medical intervention can shorten the duration of these phases and optimize LVAD patients' quality of life.