The Impact of Clinical, Biochemical, and Echocardiographic Parameters on the Quality of Life in Patients with Heart Failure with Reduced Ejection Fraction

Despite significant advances in HF diagnosis and treatment over the recent decades, patients still characterize poor long-term prognosis with many recurrent hospitalizations and reduced health-related quality of life (HRQoL). We aimed to check the potential relationship between clinical, biochemical, or echocardiographic parameters and HRQoL in patients with HF with reduced ejection fraction (HFrEF). We included 152 adult patients hospitalized due to chronic HFrEF. We used the WHOQoL-BREF questionnaire to assess HRQoL and GNRI to evaluate nutritional status. We also analyzed several biochemical parameters and left ventricle ejection fraction. Forty (26.3%) patients were hospitalized due to HF exacerbation and 112 (73.7%) due to planned HF evaluation. The median age was 57 (48–62) years. Patients with low somatic HRQoL score had lower transferrin saturation (23.7 ± 11.1 vs. 29.7 ± 12.5%; p = 0.01), LDL (2.40 (1.80–2.92) vs. 2.99 (2.38–3.60) mmol/L; p = 0.001), triglycerides (1.18 (0.91–1.57) vs. 1.48 (1.27–2.13) mmol/L; p = 0.006) and LVEF (20 (15–25) vs. 25 (20–30)%; p = 0.003). TIBC (64.9 (58.5–68.2) vs. 57.7 (52.7–68.6); p = 0.02) was significantly higher in this group. We observed no associations between HRQoL and age or gender. The somatic domain of WHOQoL-BREF in patients with HFrEF correlated with the clinical status as well as biochemical and echocardiographic parameters. Assessment of HRQoL in HFrEF seems important in everyday practice and can identify patients requiring a special intervention


Introduction
The prevalence of heart failure (HF) is still increasing [1] and is estimated to be approximately 1-2% in adults in developed countries. Moreover, in patients above 70 years of age, HF incidence rises to ≥10%, making it a growing healthcare burden [2][3][4][5]. The population of patients with HF is enormous. Over 5 million Americans and 15 million Europeans suffer from HF [6][7][8][9], and in total, an estimated 26 million people suffer from HF worldwide [1]. Despite significant advances in HF diagnosis and treatment over the recent decades, HF patients still characterize poor long-term prognosis [1,10] with high rates of recurrent HF hospitalizations accompanied, however, by slightly lower mortality rates [1]. Although the prevalence of HF with reduced ejection fraction (HFrEF) has decreased in recent years, the mortality rate is still high in this group of HF patients [11]. The number of hospitalizations due to HF is still rising, and it has tripled over the last

Clinical Assessment
The medical history with a particular interest in comorbidities, HF etiology, and prescribed medicines was taken on admission. We assessed patients according to the New York Heart Association (NYHA) functional classification as indicated in the European Society of Cardiology (ESC) guidelines [10]. Blood pressure (BP), heart rate (HR), height, and body mass were measured during physical examination. The following formula was used to calculate body mass index (BMI): BMI = weight (kg)/(height (m)) 2 [33]. In fasting blood samples, the following parameters were analyzed: complete blood count, B-type natriuretic peptide (BNP), lipid profile, creatinine, fasting glucose, serum protein and albumin, thyroid hormones, electrolytes (sodium, potassium), and iron metabolism parameters, i.e., iron level, transferrin saturation, total iron-binding capacity (TIBC) and ferritin. LVEF was measured using the Simpson method [34]. The Geriatric Nutritional Risk Index (GNRI) is a tool used to define the level of nutritional risk based on only two variables: serum albumin level and BMI. GNRI for each patient was calculated using the formula (1.489 × serum albumin [g/L]) + (41.7 × body weight/ideal body weight (IBW) [kg]). IBW was calculated as follows: IBW = height 2 [m] × 22 [35].

Quality of Life Assessment
The use of validated instruments to assess HRQoL remains unclear and limited to clinical trials, with minimal guidance on the practical assessment of HRQoL outside this setting [36]. Therefore, in this study, the authors used the World Health Organization's Quality of Life Instrument-Short Version (WHOQoL-BREF) to evaluate the HRQoL of patients with HFrEF. It was designed and developed to allow easier and faster assessment of HRQoLmore applicable in common practice than the WHOQoL instrument based on 100 questions divided into six domains and 24 sub-domains [17]. WHOQoL-BREF consists of 26 questions; 24 questions are divided into four domains: physical (somatic), psychological, social, and environmental. There are two additional questions about the selfrated QoL and satisfaction from health status [37]. The score of every domain is transformed into the number ranging between 0 (worst possible QoL) and 100 (best possible QoL) [37]. It was validated and showed acceptable reliability to substitute the original form [38]. The authors used the Polish version of WHOQoL-BREF. The acceptable internal consistency was demonstrated with Cronbach's alpha coefficients greater than 0.70 for all domains except for the social domain [39].

Statistical Analysis
To assess the relation of the somatic domain score with the parameters studied, patients were divided according to their somatic HRQoL into three subgroups: subjects with the best somatic HRQoL (group 1), with intermediate results (group 2), and with the worst somatic HRQoL (group 3). Then, we compared analyzed parameters between the first and third groups using Student t-and U-Mann tests (depending on the presence of normality and variance compliance) for continuous variables and the Pearson Chi2 test for categorical ones. Continuous data values are presented as mean ± standard deviation (SD) or median (interquartile range) according to presence of normal distribution and categorical ones as number (%). p-value <0.05 was considered significant. All statistics were performed using Statistica version 13.3 software (StatSoft, now Tibco, Palo Alto, CA, USA).
We also evaluated the nutritional status using the GNRI assessment tool. Patients with low somatic HRQoL also presented lower GNRI (112.3 ± 11.4 vs. 117.8 ± 12.4; p = 0.045), although most patients were qualified to the no-risk group with the GNRI higher than 98 (Table 2).

Discussion
Increasing HF incidence poses a substantial social problem, and patients with HFrEF are a specific group characterized by poor prognosis. HF is a chronic disease; therefore, HRQoL is very important since patients must live with the disease for many years. Some studies showed that for certain patients, HRQoL is more important than the life span [16].
This was proved in a study with HFrEF patients and the mean LVEF of 33 ± 12% [16], i.e., in a group which we also analyzed in our research (median LVEF 22 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)). Several factors impact HRQoL, including both somatic as well as psychological factors [40][41][42]. The primary treatment goal in HFrEF patients is complex and should optimize their health status (i.e., symptoms, functions, and QoL) [9]. The Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Kansas City Cardiomyopathy Questionnaire (KCCQ), the two most widely used tools to measure HRQoL in HF, were developed in patients with HFrEF [43][44][45]. However, there is no single tool assessing HRQoL in HFrEF patients that would be recommended as a reference tool in this population. In our study, we have chosen the WHOQoL-BREF questionnaire as a simple in use but simultaneously a comprehensive tool.
There are multiple factors in HF which impact HRQoL. Patients with higher NYHA class had lower HRQoL [15,46,47] than patients in NYHA class I or II. We also reported this in our study. In the general population, older women reported worse QoL and a higher level of disability than men [23]. In some studies, women with HFrEF or with HF with preserved ejection fraction (HFpEF) reported worse QoL and a higher level of disability in a self-assessment tool compared to male patients [13,48]. At the same time, in the other, there was no correlation [46] or it was observed only in general HRQoL and not in HF-specific (not related just to HF but also to other comorbidities) [47]. In our study, the lower somatic domain score in the WHOQoL-BREF questionnaire was observed in patients with higher NYHA class, but we observed no difference according to age and gender.

Natriuretic Peptides
High BNP or NT-proBNP are well documented as connected with a worse prognosis in HF. They are predictors of more frequent hospitalizations [49], rehospitalizations [50], deaths [51], and more severe symptoms [52]. Higher BNP or NT-proBNP levels are associated independently with the worse overall and physical domain of QoL [47,53,54]. However, Faxén et al. used other QoL questionnaires, the generic EQ-5D3Land MLHFQ, based on differently determined domains [47]. Moreover, Faxén et al. also enrolled patients with stable HFpEF, and this was contrary to our study that comprised solely of patients with HFrEF. Interestingly, Allen et al. used the KCCQ to assess QoL [53]. Moreover, the group included in that study was similar to our group, i.e., all patients had LVEF ≤ 40% [53]. Furthermore, Hoekstra et al. applied three questionnaires to assess QoL [54]. Authors evaluated QoL in three different ways: global well-being (by using the Cantril' s Ladder of Life), general QoL (by using the Medical Outcome Study 36-item General Health Survey-RAND-36), and disease-specific QoL (measured by MLHFQ).The detail of the questions in the WHOQoL-BREF questionnaire and three questionnaires used by Hoekstra et al. seems to be similar. However, contrary to our study, Hoekstra et al. enrolled both HFpEF and HFrEF patients.
Decrease in BNP level is associated with improved QoL [55], nonetheless premises from many studies suggest that therapy guided on current BNP concentration is economically unreasonable and does not improve the QoL [50,[55][56][57][58].

Left Ventricular Ejection Fraction
The correlation between LVEF and the HRQoL in HF patients is not evident, and there are many contrary results. HFpEF patients are reported to have worse HRQoL than those with HFrEF; borderline LVEF patients generally had intermediate parameters [59]. Also, higher LVEF was associated with worse HRQoL when adjusted by sex, BMI, comorbidities, and non-white race [59]. Nevertheless, these studies were heterogeneous and enrolled both HFrEF and HFpEF patients. Other studies suggest no differences between HFpEF and HFrEF and no correlation between HRQoL and LVEF [46,60]. In another study, patients with lower LVEF showed a higher risk of death or severely decreased QoL after 1 and 24 weeks [53]. By contrast, NYHA III class patients with higher LVEF and less severe diastolic dysfunction were associated with better self-reported QoL. That association remained statistically significant after adjustment for age, gender, hypertension, angina pectoris class, nitrate, ACE inhibitors, and diuretics use [61]. In NYHA I and II, the correlation was not statistically significant [61]. In our study, patients with lower LVEF had the lower somatic domain score, as well as those with a higher NYHA class.
In previous papers, decreased systolic pressure, higher heart rate, and hyponatremia were associated independently with the risk of death or decreased QoL [53]. We did not observesuch associations in our study.

Iron Metabolism
In patients with HF, iron metabolism is one of the key issues. Iron is a microelement involved in the biochemical pathways of tissue metabolism [62]. The essential role of iron can be considered as taking part in transport, storage and usage of oxygen [63]. The deficiency of iron could be one of the most common comorbidities of HF, being a consequence of impaired erythropoiesis [64,65]. Cardiac myocytes have high energy requirements and are, therefore, particularly sensitive to iron restriction [66]. Moreover, iron deficiency (ID) also affects the functioning of skeletal muscle by impairing energetic metabolism [67]. Thus, the 2016 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic HF recommended that all patients with HF should be tested for ID [10].

Other Biochemical Parameters
Literature data have suggested the relationship between lipid profile and HRQoL. In our study, a higher total cholesterol, triglycerides and LDL levels were associated with better HRQoL. Previously, researchers have suggested that in hypertensive patients a decrease in LDL-C or an increase in HDL-C were independently associated with an increase in the HRQoL among middle-aged or older adults [89]. By contrast, other studies have shown that higher HRQoL in the EQ-5D questionnaire in centenarians was associated with higher levels of total cholesterol, triglycerides as well as LDL-C and HDL-C.A similar relationship was found between the total cholesterol level or LDL-C and HRQoL assessed in the EQ-VAS questionnaire [90]. However, that study [90] comprised much older subjects without HF.

Limitations
This study was conducted in a relatively small sample at a single medical center. This has potential limitations on being able to generalize the results. Further studies performed within a larger group of patients using different HRQoL instruments would be beneficial. The study reveals differences between patients with low and high HRQoL; however, it does not allow the determination of a casual relationship between QoL and the analyzed parameters.

Conclusions
The somatic domain of WHOQoL-BREF in patients with HFrEF is related to the patient's clinical status (NYHA class, LVEF, and iron status). HRQoL was not associated with age and gender, or comorbidities. The routine evaluation of clinical, biochemical, and echocardiographic parameters may disclose lower HRQoL in HFrEF patients. HRQoL assessment in HFrEF patients is important in everyday practice and can identify patients needing a special intervention. More studies are required to develop a comprehensive program for assessing HFrEF patients.